Findings from this new artificial intelligence (AI)-based tool, published November 11 in Lancet’s eClinicalMedicine, could lead to a minimally invasive, scalable method for continuous neurologic monitoring in NICUs, providing critical real-time insights into infant health that have not been possible before.

Every year, more than 300,000 newborns are admitted to NICUs across the United States. Infant alertness is considered the most sensitive piece of the neurologic exam, reflecting integrity throughout the central nervous system. Neurologic deterioration in NICUs can happen unexpectedly and has devastating consequences. However, unlike cardiorespiratory telemetry, which continuously monitors the heart and lung function of babies in the NICU, neurotelemetry has remained elusive in most NICUs despite decades of work in electroencephalography (EEG) and specialized neuro-NICUs. Neurologic status is evaluated intermittently, using physical exams that are imprecise and may miss subacute changes.

The Mount Sinai team hypothesized that a computer vision method to track infant movement could predict neurologic changes in the NICU. “Pose AI” is a machine learning method that tracks anatomic landmarks from video data; it has revolutionized athletics and robotics.

The Mount Sinai team trained an AI algorithm on more than 16,938,000 seconds of video footage from a diverse group of 115 infants in the NICU at The Mount Sinai Hospital undergoing continuous video EEG monitoring. They demonstrated that Pose AI can accurately track infant landmarks from video data. They then used anatomic landmarks from the video data to predict two critical conditions — sedation and cerebral dysfunction — with high accuracy.

“Although many neonatal intensive care units contain video cameras, to date they do not apply deep learning to monitor patients,” said Felix Richter, MD, PhD, senior author of the paper and Instructor of Newborn Medicine in the Department of Pediatrics at Mount Sinai. “Our study shows that applying an AI algorithm to cameras that continuously monitor infants in the NICU is an effective way to detect neurologic changes early, potentially allowing for faster interventions and better outcomes.”

The research team was surprised by how well Pose AI worked across different lighting conditions (day vs. night vs. in babies receiving phototherapy) and from different angles. They were also surprised that their Pose AI movement index was associated with both gestational age and postnatal age.

“It’s important to note that this approach does not replace the physician and nursing assessments that are critical in the NICU. Rather, it augments these by providing a continuous readout that can then be acted on in a given clinical context,” explained Dr. Richter. “We envision a future system where cameras continuously monitor infants in the NICU, with AI providing a neuro-telemetry strip similar to heart rate or respiratory monitoring, with alert for changes in sedation levels or cerebral dysfunction. Clinicians could review videos and AI-generated insights when needed, offering an intuitive and easily interpretable tool for bedside care.”

The team noted the limitations of the study, including that the AI models were trained on data collected at a single institution, meaning that this algorithm and neurologic predictions need to be evaluated on video data from other institutions and video cameras. The research team plans to test this technology in additional NICUs and to develop clinical trials that will assess its impact on care. They are also exploring its application to other neurological conditions and expanding its use to adult populations.

“At Mount Sinai, we are committed to ensuring that new artificial intelligence possibilities are investigated and leveraged to advance care for our patients,” said Girish N. Nadkarni MD, MPH, System Chief of Data Driven and Digital Medicine, Director of the Mount Sinai Clinical Intelligence Center, Director of The Charles Bronfman Institute for Personalized Medicine and a study co-author. “AI tools are already advancing clinical care across the Mount Sinai Health System, including by shortening length of stay, reducing hospital readmissions, aiding in cancer diagnostics and therapeutic targeting, and delivering real-time care to patients based on physiological data generated from wearables, to name a few. We are excited to now be bringing this non-invasive, safe, and effective AI tool into the NICU to improve outcomes for our smallest, most fragile patients.”

Cardiac arrest, which occurs when the heart malfunctions and abruptly stops beating, is often fatal without quick medical attention such as CPR to increase blood flow to the heart and brain. More than 357,000 out-of-hospital cardiac arrests happen each year in the U.S. with a 9.3% survival rate. “Our findings reinforce that every second counts when starting bystander CPR and even a few minutes delay can make a big difference,” said Evan O’Keefe, M.D., the study’s first author and a cardiovascular fellow at Saint Luke’s Mid America Heart Institute and the University of Missouri-Kansas City. “If you see someone in need of CPR, don’t dwell on how long they’ve been down, your quick actions could save their life.”

The study analyzed nearly 200,000 cases of witnessed out-of-hospital cardiac arrest to determine whether initiating CPR within different time windows, compared to outcomes with no bystander CPR administered, made a difference in survival and brain function after hospital discharge.

“We found that people who received bystander CPR within the first few minutes of their cardiac arrest were much more likely to survive and have better brain function than those who didn’t,” O’Keefe said. “The longer it took for CPR to start, the less survival benefit one received. However, even when CPR was started up to 10 minutes after cardiac arrest, there was still a significant survival benefit compared to individuals who did not receive CPR from a bystander.”

Results also found:

• People who received CPR within two minutes of out-of-hospital cardiac arrest had an 81% higher rate of survival to release from the hospital and 95% higher rate of surviving without significant brain damage compared to people who did not receive bystander CPR.
• Even people who received bystander CPR up to 10 minutes after cardiac arrest were 19% more likely to survive to hospital discharge and 22% more likely to have a favorable neurological outcome than those who did not receive bystander CPR at all.
• For those who did not receive bystander CPR, about 12% survived to be released from the hospital, and more than 9% survived without significant brain damage or major disabilities. When bystander CPR was initiated more than 10 minutes after cardiac arrest, bystander CPR, compared to not receiving the lifesaving assistance, was no longer associated with improved survival.

“These results highlight the critical importance of quick action in emergencies. It suggests that we need to focus on teaching more people how to perform CPR, and we also need to emphasize ways to get help to those suffering cardiac arrest faster,” O’Keefe said. “This might include more widespread CPR training programs, as well as better public access to automated external defibrillators (AEDs) and improved dispatch systems.”

O’Keefe noted that future research could explore how technology (like apps that alert nearby trained bystanders or alert dispatchers to likely cardiac arrest) may help to reduce the time to first intervention, information that could be important for emergency dispatchers and policymakers in the development of public interventions for cardiac arrest.

“This study highlights the need for prompt recognition and treatment of cardiac arrest by bystanders. Time is of the essence when a cardiac arrest occurs, and late interventions can be as ineffective as no intervention. Community education and empowerment are critical for us to save lives,” said American Heart Association volunteer expert Anezi Uzendu, M.D., an interventional cardiologist at the University of Texas Southwestern Medical Center in Dallas and a cardiac arrest survivor.

The American Heart Association urges everyone learn the lifesaving skills of CPR and join its Nation of Lifesavers®, a movement to double survival rates from sudden cardiac arrest by 2030. Being ready to act quickly could be the difference of life or death for someone experiencing a cardiac arrest.

A limitation of the study includes that the average time of arrival for emergency medical technicians (EMTs) to the person having cardiac arrest was roughly 10 minutes. This means that in this study, the people who received bystander CPR 10 minutes after their cardiac arrest were likely being compared to a group receiving professional medical attention.

Study details and background:

• The study identified 160,822 witnessed out-of-hospital cardiac arrests that occurred from 2013-2022. Among the people whose data was analyzed, the average age was 64 years old, and more than 54,000 (about 34%) were women.
• Researchers used data from the Cardiac Arrest Registry to Enhance Survival (CARES), a national, web-based health registry focused on helping communities improve care for and survival of out-of-hospital cardiac arrest.
• The research categorized time to initiation of bystander CPR in two-minute intervals and analyzed the link between each time interval, compared to the group who did not receive CPR, with survival to hospital discharge and favorable neurological survival, or surviving with minor disabilities.

An early and effective immune response is crucial for resolving viral infections and preventing post-infectious complications. The complement system, a pivotal element of antiviral immunity, is a cascade of proteins found in the bloodstream and at mucosal sites, such as the respiratory tract. Activated through three different pathways, complement facilitates the clearance of virus particles by directly inducing their destruction (lysis). To prevent bystander damage to host cells, complement is rapidly inactivated by a set of host molecules referred to as complement regulatory proteins. The new study led by Anna Ohradanova-Repic and colleagues from the Center for Pathophysiology, Infectiology and Immunology at the Medical University of Vienna in collaboration with the team of Heribert Stoiber from the Institute of Virology at the Medical University of Innsbruck shows that SARS-CoV-2 hijacks three of these regulatory proteins, CD55, CD59 and Factor H, and thereby successfully shields itself from complement-mediated lysis.

Hijacking host proteins for effective complement resistance

By propagating SARS-CoV-2 in human cells the researchers discovered that the virus particles acquire the cellular proteins CD55 and CD59. Further experiments showed that SARS-CoV-2 also binds to Factor H, another complement regulatory protein that is primarily found in the bloodstream. Confronting the virus particles with active complement revealed that they are partially resistant to complement-mediated lysis. By removing CD55, CD59 and Factor H from the virus surface or inhibiting their biological functions, the researchers could successfully restore complement-mediated clearance of SARS-CoV-2.

“Through hijacking these three proteins, SARS-CoV-2 can evade all three complement pathways, resulting in reduced or delayed viral clearance by the infected host,” Anna Ohradanova-Repic, the leader of the study explains. Because complement is intricately linked with other components of the immune system, this not only affects virus elimination but can also cause significant inflammation, a core feature of both severe COVID-19 and Long COVID.

“Uncovering immune evasion mechanisms that allow the virus to linger within the host for longer, deepen our understanding of the acute and long-term impacts of SARS-CoV-2 infection,” says first author Laura Gebetsberger.

The scientific team focused its investigations on the GP130 signalling pathway, which researchers expect to have a major potential in the fight against cancer. The background: the signalling pathway, which is mediated by the protein GP130, plays a central role in cell communication and influences the activity of the transcription factor STAT3, which in turn is associated with the development and spread of tumours. Accordingly, blocking the GP130 signalling pathway is currently seen as a great hope in cancer medicine. Yet the current study proves the opposite: tumour growth can be slowed down not by inhibiting but by activating the GP130 signalling pathway in prostate cells.

New hope, especially for aggressive tumours

To achieve these new findings, the researchers investigated genetically modified mice in which GP130 was specifically activated in the prostate. “This allowed us to directly observe the reduction in tumour growth in the cell,” reports Lukas Kenner (Clinical Department of Pathology, MedUni Vienna), who led the study together with Stefan Rose-John (Biochemical Institute, University of Kiel). The results were further backed up by analyses of tissue samples from prostate cancer patients. This showed that high GP130 values correlate with a better survival rate. At the same time, extensive molecular analyses were carried out, including gene expression profiling.

“Our research provides exciting new evidence that the activation of GP130 in prostate cells not only slows tumour growth, but also stimulates the immune system to actively fight the cancer cells,” says Lukas Kenner, summarising the significance of the results, which will now be confirmed in further studies. The research work opens up a promising new therapeutic option, particularly for aggressive prostate cancer, which is still difficult to treat.

Emotional connection enhances interaction in human relationships. Emotional synchronisation in the interaction between a child and a parent is essential for affective attachment. The relationship between a dog and its owner is also based on attachment, but little is known about its physiological mechanisms.

The heart rate variability of a dog and its owner adapt to each other

In a study conducted at the University of Jyväskylä, at the Department of Psychology and Jyväskylä Centre for Interdisciplinary Brain Research, it was found that the heart rate variability of a dog and its owner are interconnected during interaction. Heart rate variability, in other words, the variation in the heartbeat intervals, indicates the state of the autonomic nervous system. High heart rate variability is associated with a state of relaxation and recovery, while low heart rate variability indicates stimulation or strain, such as stress during an exam or sport performance. In this study, the owner’s high heart rate variability was connected to the dog’s high heart rate variability, and vice versa. In addition, the physical activity levels of a dog and its owner mutually adapted to each other during the study.

Different connections for activity and heart rate variability

The connections of heart rate variability and activity levels between a dog and its owner were monitored during specific interaction tasks. Both heart rate and activity level were interconnected between dogs and their owners, but at different times. During free-form resting periods, the owner’s high heart rate variability was connected to the dog’s high heart rate variability. In other words, when the owner was relaxed the dog was also relaxed. Moreover, the owner’s and dog’s activity levels were similar during the given tasks, such as playing. Although it is known that physical activity has an impact on heart rate, the strongest connections of these variables between dog and owner were found in different situations and do not fully explain each other. This suggests that the connection in heart rate variability reflects the synchrony of emotional state rather than of activity levels.

“The interconnection in heart rate variability between the dog and its owner during resting periods may be explained by the fact that in those instances there were no external tasks, but the counterparts could react more to each other’s state in a natural way,” says Doctoral Researcher Aija Koskela.

Owner’s temperament is connected to the dog’s heart rate variability

The study also investigated various background factors for the interconnection of the heart rate variability of the dog and its owner. Bigger dogs had higher heart rate variability. In addition, the dog’s high heart rate variability was also explained by the owner’s negative affectivity, a temperament trait that reflects the person’s tendency to become easily concerned about negative things. This type of owner tends to develop a strong emotional bond with the dog, and therefore the shepherd dogs of this study possibly had a higher sense of safety with these owners.

The dog also influences the owner

A surprising finding in the study was that the owner’s heart rate variability was best explained by the dog’s heart rate variability, even though also the owner’s activity level and body mass index, which are known to impact heart rate, were taken into account in the analysis.

“We exceptionally investigated both a dog’s and its owner’s heart rate and activity level simultaneously, whereas previous studies have commonly focused either on the human’s or the dog’s perspective,” says the leader of the study, Academy Research FellowMiiamaaria Kujala. “The challenging research setting gives a better opportunity to investigate interactive aspects.”

This study indicates that the emotional states of dogs and their owners as well as the reactions of their nervous system become partially adapted to each other during interaction. The same mechanisms that strengthen human affective attachment also seem to support the relationship between a dog and its owner. This study deepens our understanding about interaction between species and about the meaning of emotional connection between dogs and humans.

Interaction research involved dogs bred for cooperation

The study was funded mainly by the Research Council of Finland and the Agria & Svenska Kennelklubben Research Fund. It involved altogether 30 voluntary dog owners with their dogs. The dogs represented breeds refined for cooperating with humans, such as sheep dogs and retrievers. The research findings are in line with previous studies, which have suggested that breeds selected for cooperation are particularly sensitive to react to their owners’ behaviour and personality traits. Next, the project will seek to shed light more specifically on the influential mechanisms involved in this phenomenon.

The study was published on 24 October 2024 in Scientific Reports: Koskela, A., Törnqvist, H., Somppi, S. et al. Behavioral and emotional co-modulation during dog-owner interaction measured by heart rate variability and activity. Sci Rep 14, 25201 (2024).

One sixth of human cancers harbour genetic variations but few studies have established how that affects treatment outcomes. The team sought to answer this question by honing in on an inherited genetic variation that affects patients with leukaemia.

In 2020, leukaemia (cancer of the blood) accounted for approximately 2.5 per cent of all new cancer cases and 3.1 per cent of deaths globally. Of these, chronic myeloid leukaemia (CML) is a subtype that primarily affects the bone marrow, which produces blood cells.

The Duke-NUS scientists, in collaboration with their partners, including Singapore General Hospital and The Jackson Laboratory, developed the first pre-clinical model with a common genetic variation among the population of the East Asian region, which includes Chinese, Japanese and Korean people. About 12 to 15 per cent of people from this region carry an inherited genetic variation in a protein called BCL-2 interacting death mediator (BIM), which is crucial for regulating cell death to eliminate damaged or unwanted cells. Many cancer treatments trigger this process to destroy tumour cells.

The researchers then conducted a series of experiments using their specially designed pre-clinical model, showing that the variation results in the production of alternative versions of the BIM protein, which, in turn, helps cancer cells evade cell death. Consequently, the tumour cells survive longer and are able to multiply more aggressively, contributing to disease progression.

One of the most common treatments for chronic myeloid leukaemia is a class of drugs known as tyrosine kinase inhibitors, with imatinib being one of the most widely used. However, patients with the BIM variation often don’t respond well to imatinib, with fewer cancer cells being killed by the treatment.

Dr Giselle Nah, a research fellow from Duke-NUS’ Cancer and Stem Cell Biology Programme and a first author of the study, said:

“We discovered that leukaemia cells with the BIM variation had higher survival rates compared to those without it. Specifically, these cells were resistant to the cell death that imatinib would typically induce. This resistance allowed the leukaemia to progress more aggressively.”

To dig deeper into the mechanisms at play, the team used advanced profiling techniques to study how different cancer cells depend on various proteins for survival.

Joint first author Dr Yu Mengge, a research fellow from Duke-NUS’ Cancer and Stem Cell Biology Programme, said:

“We found that leukaemia cells with the BIM variation relied heavily on a protein called MCL-1 to stay alive. This important discovery revealed a potential vulnerability in these imatinib-resistant cancer cells that could be targeted with new and more effective treatments.”

Professor Ong Sin Tiong, a clinician-scientist from Duke-NUS’ Cancer and Stem Cell Biology Programme and the study’s senior author, said:

“Based on what we learnt, we tried a new treatment that combined an MCL-1 blocker with imatinib. The results were encouraging, as the combination was much more efficient at killing the resistant leukemia cells than using imatinib alone. This indicates that targeting MCL-1 could help tackle the resistance found in chronic myeloid leukaemia patients with the BIM variation, to reduce the chances of disease progression.”

For patients with this variation, this discovery could be a game-changer.

Duke-NUS Associate Professor Charles Chuah, a Senior Consultant at the Department of Haematology, Singapore General Hospital and National Cancer Centre Singapore, collaborated on the study. He said:

“Getting the right cancer treatment as early as possible is crucial in improving patient outcome and quality of life. Given the prevalence of the BIM variation in the East Asian population, it is crucial to understand its impact on cancer treatment. Our findings suggest that genetic testing for this variant at diagnosis can improve outcomes by identifying patients who may benefit from more aggressive treatments.”

These findings could have significant implications for other cancers, such as certain types of lung cancer, where treatment is administered by triggering the BIM protein to kill tumour cells. The scientists hope to conduct further research in this area to deliver the benefits of precision medicine to more patients.

Duke-NUS is a global leader in medical education and a biomedical research powerhouse, combining basic scientific research with translational know-how to bring a better understanding to common diseases and develop new treatment approaches to improve the lives of people in Singapore and beyond.

Students often appear for high-stakes tests that hold significant weight in determining their futures. One such examination, the Common Test for University Admissions, currently allows examinees using braille an extended examination time of 1.5 times the standard duration. However, with the recent increase in complex questions and questions involving charts and diagrams in such tests, it is necessary to review whether the current accommodations remain adequate.

The researchers assessed the validity of the current time extension for examination questions containing complex tables by measuring the time required to read the text and complex tables. The results showed that 70% of the examinees completed the braille text reading task within 1.5 times the standard duration and 100% completed it within double the duration. However, none of the examinees finished the braille table reading task within 1.5 or even double the extended time. Furthermore, the table reading task revealed considerable individual differences in reading speed, with no correlation observed between this task and braille text reading. This suggests that people who read braille sentences quickly cannot necessarily read braille tables at the same pace.

These findings demonstrate that the current time extension for examinees using braille is insufficient when examination questions include complex tables. This prompts a consideration of how to properly assess the abilities of such examinees and raises the broader question of how to evaluate the skills of each individual regardless of disability status. This research indicates the need to reconsider the current examination framework itself.

This work was supported by the Japan Society for the Promotion of Science (grant number 20H00822).

Bacteria associated with inflammation is found in the gut in higher amounts roughly ten months before patients develop clinical rheumatoid arthritis, a longitudinal study by Leeds researchers has found.

Affecting more than half a million people in the UK, rheumatoid arthritis is a chronic disease that causes swelling, pain and stiffness in the joints because the immune system is mistakenly attacking the body’s healthy cells.

Previous research has linked rheumatoid arthritis to the gut microbiome, which is the ecosystem of microbes in your intestines. But this new study, published today in the Annals of the Rheumatic Diseases, reveals a potential intervention point.

Lead researcher Dr Christopher Rooney, NIHR Academic Clinical Lecturer at the University of Leeds and Leeds Teaching Hospitals NHS Trust, said: “Patients at risk of rheumatoid arthritis are already experiencing symptoms such as fatigue and joint pain, and they may know someone in their family who has developed the disease. As there is no known cure, at-risk patients often feel a sense of hopelessness, or even avoid getting tested.

“This new research might give us a major opportunity to act sooner to prevent rheumatoid arthritis.”

Major opportunity for treatment

Funded by Versus Arthritis, the longitudinal study was conducted on 19 patients at risk of rheumatoid arthritis, with samples taken five times during a 15-month period.

Five of these patients progressed to clinical arthritis, and the research showed they had gut instability with higher amounts of bacteria including Prevotella, which is associated with rheumatoid arthritis, about ten months before progression. The remaining 14, whose disease didn’t progress, had largely stable amounts of bacteria in their gut.

Potential treatments that the researchers want to test at the ten-month window include changes to diet like eating more fibre, taking prebiotics or probiotics, and improving dental hygiene to keep harmful bacteria from periodontal disease away from the gut.

The exact relationship between gut inflammation and rheumatoid arthritis development remains unclear. In a small number of patients within the study, the gut changes occurred before there were any changes to the joints observed by a rheumatologist, but more research is needed to determine whether these influence each other.

Although bacteria is associated with rheumatoid arthritis, the researchers want to make it clear that there is no evidence this is contagious.

Lucy Donaldson, director for research and health intelligence at Versus Arthritis, said: “At Versus Arthritis, we welcome the findings of this study which could give the clinicians of the future a crucial window of opportunity to delay — or even prevent — the onset of rheumatoid arthritis. This success is testament to the dedication of UK researchers who are working to personalise treatment and prevent chronic conditions that have significant impacts on a person’s ability to work, raise families and live independently.”

Years in the making

The research was carried out in collaboration with the National Institute for Health Research Leeds Biomedical Research Centre, under the research themes of Antimicrobial Resistance and Infection and Musculoskeletal Disease.

Leeds Teaching Hospitals NHS Trust, Versus Arthritis and Leeds Hospitals Charity were also partners on the project. Patients at Chapel Allerton Hospital helped to design the research to make stool sampling easier for participants.

The study initially took data from 124 individuals who had high levels of CCP+, an antibody that attacks healthy cells in the blood, which indicates risk of developing rheumatoid arthritis. The researchers compared their samples to 22 healthy individuals and seven people who had a new rheumatoid arthritis diagnosis.

The findings from this larger group showed that the gut microbiome was less diverse in the at-risk group, compared to the healthy control group.

The longitudinal study, which took samples from 19 patients over 15 months, revealed the changes in bacteria at ten months before progression to rheumatoid arthritis.

The Leeds research team will now carry out an analysis of treatments that have already been trialed, to inform future testing of treatments at this potential ten-month intervention point.

The research was published in the November 4 issue of PNAS in the article, “Sensory Artificial Cilia for In Situ Monitoring of Airway Physiological Properties.”

In their paper, the researchers noted that continuously monitoring human airway conditions is crucial for timely interventions, especially when airway stents are implanted to alleviate central airway obstruction in lung cancer and other diseases. In particular, mucus conditions offer important biomarkers for indicating inflammation and stent patency but remain challenging to monitor. Current methods — reliant on computational tomography imaging and bronchoscope inspection — pose risks due to radiation and lack the ability to provide continuous real-time feedback outside of hospitals.

Mimicking the sensing ability of biological cilia, Dong and his team developed novel technology for detecting mucus conditions, including viscosity and layer thickness, which are crucial biomarkers for disease severity.

“The sensing mechanism for mucus viscosity leverages external magnetic fields to actuate a magnetic artificial cilium and sense its shape using a flexible strain-gauge,” the researchers wrote. “Additionally, we report an artificial cilium with capacitance sensing for mucus layer thickness, offering unique self-calibration, adjustable sensitivity, and range, all enabled by external magnetic fields generated by a wearable magnetic actuation system.”

The researchers tested the method by deploying the sensors independently or in conjunction with an airway stent within an artificial trachea and sheep trachea. Sensing signals are transferred wirelessly to a smart phone or the cloud for further data analysis and disease diagnosis.

“The proposed sensing mechanisms and devices pave the way for real-time monitoring of mucus conditions, facilitating early disease detection and providing stent patency alerts, thereby allowing timely interventions and personalized care,” according to the study.

This work was done in collaboration with Vanderbilt University Medical Center faculty members Fabien Maldonado, professor of medicine and thoracic surgery; Caitlin Demarest, assistant professor Thoracic Surgery; and Caglar Oskay, chair of the Department of Civil and Environmental Engineering and Cornelius Vanderbilt Professor of Engineering. Yusheng Wang, the study’s first author, is a third-year Ph.D. student in the Department of Mechanical Engineering.

Earlier this year, Dong was awarded an R21 Trailblazer Award by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) of the National Institutes of Health (NIH) to pursue a project about “Wirelessly Actuated Ciliary Stent for Minimally Invasive Treatment of Cilia Dysfunction.”

The Trailblazer R21 Award supports new and early-stage investigators pursuing research programs that are of high interest to NIBIB, at the interface of life sciences with engineering and the physical sciences.

In a cell-based study, scientists at Washington University School of Medicine in St. Louis have forced glioblastoma cells to display immune system targets, potentially making them visible to immune cells and newly vulnerable to immunotherapies. The strategy involves a combination of two drugs, each already FDA-approved to treat different cancers.

The study is online in the journal Nature Genetics.

“For patients whose tumors do not naturally produce targets for immunotherapy, we showed there is a way to induce their generation,” said co-senior author Ting Wang, PhD, the Sanford C. and Karen P. Loewentheil Distinguished Professor of Medicine and head of the Department of Genetics at WashU Medicine. “In other words, when there is no target, we can create one. This is a very new way of designing targeted and precision therapies for cancer. We are hopeful that in the near future we will be able to move into clinical trials, where immunotherapy can be combined with this strategy to provide new therapeutic approaches for patients with very hard-to-treat cancers.”

To create immune targets on cancer cells, Wang has focused on stretches of DNA in the genome known as transposable elements. In recent years, transposable elements have emerged as a double-edged sword in cancer, according to Wang. His work has shown that transposable elements play a role in causing tumors to develop even as they present vulnerabilities that could be exploited to create new cancer treatment strategies.

For this study, Wang’s team took advantage of the fact that transposable elements naturally can cause a tumor to churn out random proteins that are unique to the tumor and not present in normal cells. Called tumor antigens or neoantigens, these unusual proteins could be the targets for immunotherapies, such as checkpoint inhibitors, antibodies, vaccines and genetically engineered T cell therapies.

Even so, some tumors, including glioblastoma, have few immune targets produced naturally by transposable elements. To address this, Wang and his colleagues, including co-senior author Albert H. Kim, MD, PhD, the August A. Busch Jr. Professor of Neurological Surgery, have demonstrated how to purposely force transposable elements to produce immune system targets on glioblastoma cells that normally lack them.

The researchers used a combination of two drugs that influence the so-called epigenome, which controls which genes are turned on in a cell and to what degree. When treated with the two epigenetic therapy drugs, the tightly packed DNA molecules of the glioblastoma cells unfurled, triggering transposable elements to begin making the unusual proteins that could be used to target the cancer cells. The two drugs were decitabine, which is approved to treat myelodysplastic syndromes, a group of blood cancers; and panobinostat, which is approved for multiple myeloma, a cancer of white blood cells.

Before investigating this strategy in people, the researchers are seeking ways to target the epigenetic therapy so that only the tumor cells are induced to make neoantigens. In the new study, the researchers cautioned that normal cells also produced targets when exposed to the two drugs. Even though normal cells didn’t produce as many neoantigens as the glioblastoma cells did, Wang and Kim said there is a risk of unwanted side effects if normal cells create these targets as well.

In ongoing work, Wang and Kim are investigating how to use CRISPR molecular editing technology to induce specific parts of the genome in cancer cells to produce the same neoantigens from transposable elements that are common across the human population. Such a strategy could give many patients’ tumors — even different cancer types — the same targets that could respond to the same immunotherapy, while sparing healthy cells. There are then multiple possible ways to go after such a shared target, including checkpoint inhibitors, vaccines, engineered antibodies and engineered T cells.

“Immunotherapy has revolutionized the treatment of some specific cancers, such as melanoma,” said Kim, who treats patients at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, and is also the director of the Brain Tumor Center there. “Progress in glioblastoma has been slow by comparison because of how resistant this tumor is to the latest therapeutic strategies. But with recent advancements in immunotherapies and epigenetic therapies that could be used in combination, I’m hopeful that we are on the right path for a similar transformative change in the treatment of glioblastoma.”

People with the syndrome have a slow walking speed and say they have some memory issues, although they do not have a mobility disability or dementia. Called motoric cognitive risk syndrome, the condition can occur before dementia develops.

The study found that people with excessive daytime sleepiness and a lack of enthusiasm to get things done were more likely to develop the syndrome than people without those sleep-related issues. The study does not prove that these sleep-related issues cause the syndrome, it only shows an association.

“Our findings emphasize the need for screening for sleep issues,” said study author Victoire Leroy, MD, PhD, of Albert Einstein College of Medicine in the Bronx, New York. “There’s potential that people could get help with their sleep issues and prevent cognitive decline later in life.”

The study involved 445 people with an average age of 76 who did not have dementia. Participants took questionnaires for sleep at the start of the study. They were asked about memory issues and their walking speed was tested on a treadmill at the start of the study and then once a year for an average of three years.

The sleep assessment asked questions such as how often people had trouble sleeping because they wake up in the middle of the night, cannot fall asleep within 30 minutes, or feel too hot or cold and whether they take medicine to help them sleep. The question to assess excessive daytime sleepiness asks how often people have had trouble staying awake while driving, eating meals or engaging in social activity. The question on enthusiasm asks how much of a problem people have had keeping up enough enthusiasm to get things done.

A total of 177 people met the definition for poor sleepers and 268 met the definition for good sleepers.

At the start of the study, 42 people had motoric cognitive risk syndrome. Another 36 people developed the syndrome during the study.

Of those with excessive daytime sleepiness and lack of enthusiasm, 35.5% developed the syndrome, compared to 6.7% of the people without those problems. Once researchers adjusted for other factors that could affect the risk of the syndrome, such as age, depression and other health conditions, they found that people with excessive daytime sleepiness and lack of enthusiasm were more than three times more likely to develop the syndrome than those who did not have those sleep-related problems.

“More research needs to be done to look at the relationship between sleep issues and cognitive decline and the role played by motoric cognitive risk syndrome,” Leroy said. “We also need studies to explain the mechanisms that link these sleep disturbances to motoric cognitive risk syndrome and cognitive decline.”

A limitation of the study is that participants reported their own sleep information, so they may not have remembered everything accurately.

The study was supported by the National Institute on Aging.

The study, published in Circulation, was carried out by experts from the ProPASS (Prospective Physical Activity, Sitting and Sleep) Consortium, an international academic collaboration led by the University of Sydney and University College London (UCL).

Just five minutes of activity a day was estimated to potentially reduce blood pressure, while replacing sedentary behaviours with 20-27 minutes of exercise per day, including uphill walking, stair-climbing, running and cycling, was also estimated to lead to a clinically meaningful reduction in blood pressure.

Joint senior author Professor Emmanuel Stamatakis, Director of the ProPASS Consortium from the Charles Perkins Centre said: “High blood pressure is one of the biggest health issues globally, but unlike some major causes of cardiovascular mortality there may be relatively accessible ways to tackle the problem in addition to medication.”

“The finding that doing as little as five extra minutes of exercise per day could be associated with measurably lower blood pressure readings emphasises how powerful short bouts of higher intensity movement could be for blood pressure management.”

Hypertension, or a consistent elevated blood pressure level, is one of the biggest causes of premature death globally. Affecting 1.28 billion adults around the world, it can lead to stroke, heart attack, heart failure, kidney damage and many other health problems, and is often described as the ‘silent killer’ due to its lack of symptoms.

The research team analysed health data from 14,761 volunteers in five countries to see how replacing one type of movement behaviour with another across the day is associated with blood pressure.

Each participant used a wearable accelerometer device on their thigh to measure their activity and blood pressure throughout the day and night.

Daily activity was split into six categories: sleep, sedentary behaviour (such as sitting), slow walking, fast walking, standing, and more vigorous exercise such as running, cycling or stair climbing.

The team modelled statistically what would happen if an individual changed various amounts of one behaviour for another in order to estimate the effect on blood pressure for each scenario and found that replacing sedentary behaviour with 20-27 minutes of exercise per day could potentially reduce cardiovascular disease by up to 28 percent at a population level.

First author Dr Jo Blodgett from the Division of Surgery and Interventional Science at UCL and the Institute of Sport, Exercise and Health said: “Our findings suggest that, for most people, exercise is key to reducing blood pressure, rather than less strenuous forms of movement such as walking.

“The good news is that whatever your physical ability, it doesn’t take long to have a positive effect on blood pressure. What’s unique about our exercise variable is that it includes all exercise-like activities, from running for a bus or a short cycling errand, many of which can be integrated into daily routines.

“For those who don’t do a lot of exercise, walking did still have some positive benefits for blood pressure. But if you want to change your blood pressure, putting more demand on the cardiovascular system through exercise will have the greatest effect.”

Professor Mark Hamer, joint senior author of the study and ProPASS Deputy Director from UCL, said: “Our findings show how powerful research platforms like the ProPASS consortium are for identifying relatively subtle patterns of exercise, sleep, and sedentary behaviour, that have significant clinical and public health importance.”

The popularity of this approach presents its own challenges, however: cities can deploy electric buses faster than their power grids can keep up with the increased demand.

For University of Utah engineering professor Xiaoyue Cathy Liu, this challenge is an opportunity — not just to solve the immediate problem of grid stability, but to radically rethink how public transportation systems are integrated into other parts of civic infrastructure.

“Integrating onsite solar power generation and energy storage at bus depots introduces a brand new renewable energy production and management mode,” Liu said, “transforming a public transport depot into an energy hub that produces more electricity than it consumes.”

A professor in Price College of Engineering’s Department of Civil & Environmental Engineering, Liu recently published a study in the journal Nature Energy that analyzes the potential of this approach using data from Beijing’s fleet of electric buses. The international collaboration includes researchers from China’s Beihang University, Sweden’s Chalmers University of Technology and Germany’s Fraunhofer Institute for Systems and Innovation Research ISI.

Beijing’s 27,000 buses form the largest public transportation system in the world. More than 90% of those in service as of 2022 are low- or no-emission vehicles. These battery-powered buses recharge through a network of more than 700 bus depots spread across 6,500 square miles, a substantial piece of physical infrastructure that runs in parallel with the region’s electrical grid. And given the power demands of the vehicles they serve, these depots put a heavy load on that grid, raising the potential for localized brownouts or other disruptions.

Using advanced data science scene techniques, Liu and her colleagues are exploring whether locally generated solar power would be sufficient to counterbalance this demand. Critically, they are also studying the complicated economic factors that would determine this approach’s feasibility.

“More than meeting demand, our simulations show that these depots could net out to be energy producers, further stabilizing the grid,” Liu said.

The study is based on a computer model of the Beijing bus network, replete with real-world data on air temperature and solar irradiance at each depot, recorded over the course of 2020. Combined with the rooftop surface area of each depot, the researchers were able to predict the electric output of solar panels that could be installed there.

Adding to the complexity of this model is the degree of variation between depots, in terms of both supply and demand. With more buses to charge, busier depots can make the most of a day’s sunshine, while more remote depots would need to store or redistribute their excess electricity lest it go to waste.

“We found energy storage to be the most expensive factor in the model, so smarter and strategic charging schedules would need to be implemented,” Liu said. “That responsiveness is critical, as variable energy pricing schemes have such a large impact on the overall economics.”

The researchers aim to further generalize their model, providing a pathway for other countries to estimate the return-on-investment of similarly transforming bus depots and other pieces of civic infrastructure into energy hubs.

When the knee is damaged due to injury or arthritis, performing daily activities like walking, sitting, and running becomes difficult due to extreme pain. In cases of severe damage, knee replacement surgery is recommended by orthopedic surgeons, to reform the damaged parts of the knee and relieve pain by attaining a neutral alignment.

However, this neutral alignment is not always the patient’s original alignment and there is some debate within the orthopedic community on whether restoring the patient’s original alignment can lead to better patient-reported outcomes. In the present study, researchers have attempted to settle this debate and create a comprehensive guide on preoperative planning and execution of knee replacement surgery.

This study is mostly centered around a classification system called the Coronal Plane Alignment of the Knee (CPAK). It categorizes the possible alignments of the knee joint based on two main characteristics. First is the hip-knee-ankle angle; large negative angles cause the knees to be positioned outward, whereas large positive angles cause the knees to point inward. Meanwhile, the second characteristic is the angle of the joint line, which refers to the angle between a line level with the ground and an imaginary line going across the points where the femur meets the tibia.

The research team, which included MD Toshiki Konishi and Associate Professor Satoshi Hamai from the Department of Orthopedic Surgery at Kyushu University Hospital, sought to determine whether changes in the CPAK categorization before and after knee replacement surgery were associated with notable differences in outcomes. To this end, they collected data from 231 patients who received knee replacement surgery for osteoarthritis at Kyushu University Hospital between 2013 and 2019. Using X-ray images, the team determined the CPAK classification and alignment variables of the patients before and after surgery. They also sent a questionnaire to the patients, from which they derived a series of standardized scores related to symptoms, overall satisfaction, activity levels, and quality of life after the operation.

After statistical analysis, the researchers revealed that patients who underwent changes in knee alignment after knee replacement surgery, as determined using the CPAK classification, had significantly worse long-term outcomes. Interestingly, they also found that patients whose joint line angle was tilted to the outside of their knee after surgery (away from the other leg) reported overall worse outcomes as well.

This study demonstrates that precisely replicating a patient’s native alignment during surgery is crucial for ensuring optimal recovery and a higher quality of life. These results could have important implications for how knee replacement surgeries are performed worldwide.

“In future clinical practice, our findings may guide surgeons in preoperative planning and execution of total knee arthroplasty. By aiming to restore the patient’s inherent alignment, patients can achieve superior postoperative outcomes,” explains Konishi. Adding further, he says, “This could help address the challenge of variability in patient outcomes after total knee arthroplasty by providing a more personalized approach to knee alignment, which could become a new standard in orthopedic surgery.”

Highlighting the fact that this was a retrospective study, the research team now aims to take on a prospective approach in their upcoming work. “We plan to incorporate the CPAK classification into preoperative planning, setting each patient’s native knee alignment as the surgical target. Using the robot-assisted technology implemented at our institution, we are now able to perform total knee arthroplasty with high precision, ensuring the accurate reproduction of the preoperative plan,” comments Konishi.

The researchers believe that these efforts will help improve the gold standard of knee replacement surgery, leading to healthier, pain-free, and more active postoperative lives for patients.

The faulty predictions are linked to researchers’ use of AI to assist genome-wide association studies. Such studies scan through hundreds of thousands of genetic variations across many people to hunt for links between genes and physical traits. Of particular interest are possible connections between genetic variations and certain diseases.

Genetics’ link to disease not always straightforward

Genetics play a role in the development of many health conditions. While changes in some individual genes are directly connected to an increased risk for diseases like cystic fibrosis, the relationship between genetics and physical traits is often more complicated.

Genome-wide association studies have helped to untangle some of these complexities, often using large databases of individuals’ genetic profiles and health characteristics, such as the National Institutes of Health’s All of Us project and the UK Biobank. However, these databases are often missing data about health conditions that researchers are trying to study.

“Some characteristics are either very expensive or labor-intensive to measure, so you simply don’t have enough samples to make meaningful statistical conclusions about their association with genetics,” says Qiongshi Lu, an associate professor in the UW-Madison Department of Biostatistics and Medical Informatics and an expert on genome-wide association studies.

The risks of bridging data gaps with AI

Researchers are increasingly attempting to work around this problem by bridging data gaps with ever more sophisticated AI tools.

“It has become very popular in recent years to leverage advances in machine learning, so we now have these advanced machine-learning AI models that researchers use to predict complex traits and disease risks with even limited data,” Lu says.

Now, Lu and his colleagues have demonstrated the peril of relying on these models without also guarding against biases they may introduce. The team describe the problem in a paper recently published in the journal Nature Genetics. In it, Lu and his colleagues show that a common type of machine learning algorithm employed in genome-wide association studies can mistakenly link several genetic variations with an individual’s risk for developing Type 2 diabetes.

“The problem is if you trust the machine learning-predicted diabetes risk as the actual risk, you would think all those genetic variations are correlated with actual diabetes even though they aren’t,” says Lu.

These “false positives” are not limited to these specific variations and diabetes risk, Lu adds, but are a pervasive bias in AI-assisted studies.

New statistical method can reduce false positives

In addition to identifying the problem with overreliance on AI tools, Lu and his colleagues propose a statistical method that researchers can use to guarantee the reliability of their AI-assisted genome-wide association studies. The method helps removing bias that machine learning algorithms can introduce when they’re making inferences based on incomplete information.

“This new strategy is statistically optimal,” Lu says, noting that the team used it to better pinpoint genetic associations with individuals’ bone mineral density.

AI not the only problem with some genome-wide association studies

While the group’s proposed statistical method could help improve the accuracy of AI-assisted studies, Lu and his colleagues also recently identified problems with similar studies that fill data gaps with proxy information rather than algorithms.

In another recently published paper appearing in Nature Genetics, the researchers ring the alarm about studies that over-rely on proxy information in an attempt to establish connections between genetics and certain diseases.

For instance, large health databases like the UK Biobank have a ton of genetic information about large populations, but they don’t have very much data regarding the incidence of diseases that tend to crop up later in life, like most neurodegenerative diseases.

For Alzheimer’s disease specifically, some researchers have attempted to bridge that gap with proxy data gathered through family health history surveys, where individuals can report a parent’s Alzheimer’s diagnosis.

The UW-Madison team found that such proxy-information studies can produce “highly misleading genetic correlation” between Alzheimer’s risk and higher cognitive abilities.

“These days, genomic scientists routinely work with biobank datasets that have hundreds of thousands of individuals, however, as statistical power goes up, biases and the probability of errors are also amplified in these massive datasets,” says Lu. “Our group’s recent studies provide humbling examples and highlight the importance of statistical rigor in biobank-scale research studies.”

Aedes aegypti mosquitoes spread illnesses including dengue, yellow fever and Zika.

Anti-disease programmes breed and release non-biting male mosquitoes that are either sterile or prevent transmission of diseases.

These mass release programmes can be substantially more effective than the widespread spraying of insecticides, as these insects have developed resistance to many commonly employed chemicals.

The new study, by the universities of Exeter and Wageningen, examined how Asaia bacteria affects the development of mosquito larvae.

The results show that Asaia accelerated development time by a day — which could boost mass-rearing schemes that need to produce millions of adults.

“We know that every species, including humans, depends on a ‘microbiome’ — a complex mix of microorganisms living inside the body,” said Professor Ben Raymond, of the Centre for Ecology and Conservation on the University of Exeter’s Penryn Campus in Cornwall.

“Asaia bacteria have been suggested as beneficial parts of mosquito microbiomes, but this has never been rigorously tested in Aedes aegypti.

“We know that Aedes aegypti mosquito larvae can’t develop at all without a microbiome, and our study shows two Asaia species can play a beneficial role.”

The larval period of Aedes aegypti mosquitoes usually lasts about 10 days, so accelerating by a day could be a valuable boost to mass production.

In the study, Asaia bacteria were added to the water where mosquito larvae developed.

Two particular species accelerated larval development.

The mechanism for this is unclear, but it does not appear that these bacteria provided direct nutritional benefits.

Instead, they changed the wider bacterial community, reducing abundance of certain bacteria — including some species that may be slightly parasitic.

Asaia bacteria also remove oxygen — creating conditions that produce hormones to promote development.

Closely related to group A streptococcus (also commonly known as Streptococcus pyogenes), which has been very well studied, little is known about SDSE.

The findings of this study are described in a paper titled “Integrative genomic, virulence, and transcriptomic analysis of emergent Streptococcus dysgalactiae subspecies equisimilis (SDSE) emm type stG62647 isolates causing human infections,” appearing Oct. 17 in the journal mBio, which is published by the American Society for Microbiology in association with the American Academy of Microbiology. James M. Musser, M.D., Ph.D., chair of the Department of Pathology and Genomic Medicine at Houston Methodist, is the corresponding author on the paper.

“Given its great emerging importance to human health, our limited understanding of SDSE molecular pathogenesis is remarkable,” said Jesus M. Eraso, Ph.D., an assistant research professor of pathology & genomic medicine with Houston Methodist and lead author on the study.

To close this knowledge gap, the Houston Methodist team used a sophisticated integrative approach to study 120 human isolates of a particular SDSE subtype, called stG62647. They analyzed the subtype’s genome, where the information of its DNA is stored, its transcriptome, which provides a snapshot of the complete gene expression profile at the time the SDSE cells were collected, and its virulence, which refers to the degree of damage it causes to its host. The stG62647 SDSE strains are important to study because they have been reported to cause unusually severe infections, and understanding the relationships and interplay between these three entities gave the researchers a richer understanding of how it causes disease.

The data from this integrative analysis provided much new data about this important emerging human bacterial pathogen and are useful in vaccine research. It also raised many new questions and generated new hypotheses to be studied in this ongoing line of investigation.

Musser and Eraso’s collaborators on this study were Randall J. Olsen, S. Wesley Long and Ryan Gadd with the Center for Infectious Diseases in the Houston Methodist Research Institute, and Sarrah Boukthir, Ahmad Faili and Samer Kayal from Université Rennes in France.

These studies were funded, in part, by the Fondren Foundation.

The findings also indicate that children living closest to the sea, who are exposed to more dust in the air, may be the most affected.

The study, published in Environmental Research, found that 24% of children in the area have asthma — which is far higher than the national rate of 8.4% for boys and 5.5% for girls. The abnormally high rate raises health experts’ concerns about the children’s health in this predominantly low-income community of color 150 miles southeast of Los Angeles.

Furthermore, experts say, the dust problem is likely to intensify in a hotter climate, with evaporation exposing more and more of the lake bed, or playa, leading to more dust events.

Ironically, successful water conservation efforts are compounding the problem. As state conservationists reduce the agricultural runoff that flows into the Salton Sea, the lake is slowly disappearing. A combination of development and lithium mining may promise more economic opportunities — and an increase in truck traffic likely to kick up more dust and further aggravate respiratory health issues.

“These rural environmental justice communities are facing health consequences due to local dust events,” said first author Jill Johnston, an associate professor of environmental health at USC. “The agricultural industry in Imperial Valley has used excessive amounts of water, but one of the impacts of water conservation is the shrinking of the sea.”

The Salton Sea was created by accident in 1905 by a canal system breach. Until recently, the sea was sustained largely by irrigation runoff from adjacent farmland. Over the past two decades, however, the decreasing waterflow has exposed 16,000 new acres of playa — and a lot of dust. Saline lake beds typically contain various harmful particulates — sulfate, chloride, pesticides and toxic metals such as arsenic, lead and chromium.

To better understand the relationship between airborne dust and respiratory health, researchers recruited 722 school-age children from the predominantly Latino/Hispanic community between 2017 and 2019. Parents and guardians completed a 64-item survey about their child’s health history of the previous 12 months, including episodes of asthma, a daily cough for three months in a row, congestion or excess phlegm for three months in a row.

Researchers then used data from a network of regulatory air monitors to estimate exposures to “dust events” in which hourly concentrations of dust exceeded 150 micrograms per cubic meter. The monitors measure levels of particulate matter in the air, including PM2.5 particles (typically from traffic and combustion) and the larger PM10 particles (typically dust and soil).

The researchers also calculated the distance from the child’s home and the edge of the Salton Sea. Participants living within 7 miles of the sea were considered “close” for the analysis.

The research showed that dust events had a greater impact on wheezing and sleep disturbances among children living closest to the sea. In addition, each deviation increase from the average, annual fine PM2.5 measure resulted in a 3.4 and 3.1 percentage point increase in wheezing and bronchitis symptoms, respectively.

“The community has long suspected that air pollution near the sea may be impacting children’s health,” Johnston said, “but this is the first scientific study to suggest that children living close to the receding shoreline may experience more severe direct health impacts. Protecting public health should be integrated into the mitigation plans.”

In addition to Johnston, other authors included Shohreh Farzan, Elizabeth Kamai, Dayane Dueñas Barahona and Sandrah Eckel, all of USC; Christopher Zuidema and Edmund Seto of the University of Washington; and Luis Olmedo, Esther Bejarano and Christian Torres of Comité Civico del Valle, an Imperial Valley community-based organization.

This work was supported in part by R01ES029598 and 5P30ES007048-21S1 grants from the National Institute of Environmental Health Sciences.

The specific component of fine particle air pollution, or PM2.5, ammonium nitrate, is also implicated in Alzheimer’s and dementia risk in adults, suggesting that PM2.5 may cause neurocognitive harm across the lifespan. Ammonium nitrate forms when ammonia gas and nitric acid, produced by agricultural activities and fossil fuel combustion, respectively, react in the atmosphere.

The findings appear in Environmental Health Perspectives.

“Our study highlights the need for more detailed research on particulate matter sources and chemical components,” said senior author Megan Herting, an associate professor of population and public health sciences at the Keck School of Medicine of USC. “It suggests that understanding these nuances is crucial for informing air quality regulations and understanding long-term neurocognitive effects.”

For the last several years, Herting has been working with data from the largest brain study across America, known as the Adolescent Brain Cognitive Development Study, or ABCD, to understand how PM2.5 may affect the brain.

PM2.5, a key indicator of air quality, is a mixture of dust, soot, organic compounds and metals that come in a range of particle sizes less than 2.5 micrometers in diameter. PM2.5 can travel deep into the lungs, where these particles can pass into the bloodstream, and bypass the blood-brain barrier, causing serious health problems.

Fossil fuel combustion is one of the largest sources of PM2.5, especially in urban areas, but sources like wildfires, agriculture, marine aerosols and chemical reactions are also important.

In 2020, Herting and her colleagues published a paper in which they looked at PM2.5 as a whole, and its potential impact on cognition in children, and did not find a relationship.

For this study, they used special statistical techniques to look at 15 chemical components in PM2.5 and their sources. That’s when ammonium nitrate — which is usually a result of agricultural and farming operations — in the air appeared as a prime suspect.

“No matter how we examined it, on its own or with other pollutants, the most robust finding was that ammonium nitrate particles were linked to poorer learning and memory,” Herting said. “That suggests that overall PM2.5 is one thing, but for cognition, it’s a mixture effect of what you’re exposed to.”

For their next project, the researchers hope to look at how these mixtures and sources may map on to individual differences in brain phenotypes during child and adolescent development.

In addition to Herting, other study authors include Rima Habre, Kirthana Sukumaran, Katherine Bottenhorn, Jim Gauderman, Carlos Cardenas-Iniguez, Rob McConnell and Hedyeh Ahmadi, all of the Keck School of Medicine; Daniel A. Hackman of the USC Suzanne Dworak-Peck School of Social Work; Kiros Berhane of the Columbia University Mailman School of Public Health; Shermaine Abad of University of California, San Diego; and Joel Schwartz of the Harvard T.H. Chan School of Public Health.

The research was supported by grants from the National Institutes of Health [NIEHS R01ES032295, R01ES031074, P30ES007048] and the Environmental Protection Agency [RD 83587201, RD 83544101].

Their findings refute the popular theory in cellular reprogramming that any developed cell can be induced to switch its identity to a completely unrelated cell type through the infusion of transcription factors. The team proposes an alternative theory: there is one rare stem cell type that is unique in its ability to be reprogrammed into different types of cells.

“We believed that most cases of cell reprogramming could be attributed to a rare, multi-potential stem cell that is found throughout the body and lays dormant within populations of mature cells,” said Justin Belair-Hickey, first author on the study and graduate student of U of T’s Donnelly Centre for Cellular and Biomolecular Research. “It was not fully understood why reprogramming tends to be an inefficient process. Our data explain this inefficiency by demonstrating that the neural crest stem cell is one of the few stem cells that can produce the desired reprogrammed cell type.”

The study was published recently in the journal Stem Cell Reports.

Neural crest cells, which can be found below the hair follicle in the skin, are genetically predisposed to develop into neurons. This is not unexpected, as many cell types in the skin originate from the same location in the embryo as neurons: the ectodermal germ layer. The ectoderm is the outermost of the three layers of cells that form during embryonic development.

The team was driven to conduct this study through their own questioning of how experimental data from cellular reprogramming research is interpreted in terms of how flexible the identity of a cell is. This includes theories of how mature cells from one embryonic layer can be directly reprogrammed to mature cells of another embryonic layer, even though the three germ layers are separated by different developmental histories. They hypothesized that cellular reprogramming can only occur from a stem cell to a mature cell, where both come from the same germ layer.

“I think claims about direct reprogramming are either overstated or based on inaccurate interpretations of the data,” said Belair-Hickey. “We set out to demonstrate that the identity of a cell is much more defined and stable than the field of cellular reprogramming has proposed. At first glance, it appears that we’ve found skin cells that can be reprogrammed into neurons, but what we’ve actually found are stem cells in the skin that are derived from the brain.”

Neural crest stem cells are found throughout the body, including in skin, bone and connective tissue. Their distribution throughout the body, ability to be reprogrammed into many types of cells and accessibility within the skin for collection makes them a high-potential candidate for stem cell transplantation to treat disease.

“Neural crest stem cells may have gone unnoticed by others studying cell reprogramming because, while they are widespread throughout the body, they are also rare,” said Derek van der Kooy, principal investigator on the study and professor of molecular genetics at the Donnelly Centre and U of T’s Temerty Faculty of Medicine. “As such, they may have been mistaken for mature cells of various types of tissue that could be reprogrammed into other cell types. I think what we’ve found is a unique group of stem cells that can be studied to understand the true potential of cell reprogramming.”

This research was supported by the Canadian Institutes of Health Research, the Krembil Foundation and Medicine by Design.

The team published their findings in a new study in Plants.

“That finding suggests that azolla is food safe and has the potential to safely feed millions of people due to its rapid growth while free-floating on shallow fresh water without the need for nitrogen fertilizers,” said Daniel Winstead, research technologist in Penn State’s College of Agricultural Sciences and lead author on the earlier study. He works in the labs of Michael Jacobson, professor of ecosystem science and management, and Francesco Di Gioia, assistant professor of vegetable crop science. “Azolla is an amazing plant that can double its biomass in two days and capture nitrogen from the air.”

After the original study published, Winstead said, it was brought to his attention that the cyanobacteria that live inside azolla could produce powerful cyanotoxins that dissuade animals from eating the plant. Cyanotoxins have been linked to neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and Parkinson’s disease, liver and kidney failure, muscle paralysis and other severe health issues. Despite the threat of the toxins and the use and study of azolla, he explained they learned that no scientists had definitively tested for the presence of these toxins in azolla.

“I felt a sense of responsibility to help answer this question because we had just published about azolla’s nutritional quality,” Winstead said. “I didn’t want to be promoting the consumption of a potentially harmful plant. As I was preparing an experimental design, I was contacted by the Azolla Foundation about that organization’s interest in our research. I reached out to them and asked if they knew anyone who was looking into azolla’s toxicity from cyanotoxins.”

Several weeks later he received an email saying a group of researchers was investigating the cyanobacteria-cyanotoxins in azolla question, and they invited Winstead to be a part of the study.

“Together, we analyzed the results and concluded that azolla, and more specifically a cyanobacterium that lives in cavities in the leaves of azolla, do not produce any of the main cyanotoxins,” he said, explaining that the azolla’s cyanobacterium is Nostoc azollae, an endosymbiont or organism that lives within or on the surface of another organism in a mutually beneficial relationship. “More importantly, the known genes required to make these toxins are not even present within the genome of Nostoc azollae.”

According to Winstead, this discovery adds to a growing body of evidence that azolla could be used broadly to solve several global challenges.

“It could help feed many people in need around the world as well as become a new source of biofertilizer and biodiesel,” he said.

Also on the research team were by Jonatha Bujak and Alexandra Bujak, the Azolla Foundation, Blackpool, United Kingdom; Ana Pereira, Joana Azevedo and Vitor Vasconcelos, University of Porto, Portugal; Victor Leshyk, Azolla Biodesign, Sedona, Arizona; Minh Pham Gia, independent researcher, Hanoi, Vietnam; and Timo Stadtlander, The Research Institute of Organic Agriculture, Frick, Switzerland.

Open Philanthropy, Penn State — Research on Emergency Food Resilience project financially supported this research.

Published in Science, the study finds that children who experienced sugar restrictions during their first 1,000 days after conception had up to 35% lower risk of developing Type 2 diabetes and as much as 20% less risk of hypertension as adults. Low sugar intake by the mother prior to birth was enough to lower risks, but continued sugar restriction after birth increased the benefits.

Taking advantage of an unintended “natural experiment” from World War II, researchers at the USC Dornsife College of Letters, Arts and Sciences, McGill University in Montreal, and the University of California, Berkeley, examined how sugar rationing during the war influenced long-term health outcomes.

The United Kingdom introduced limits on sugar distribution in 1942 as part of its wartime food rationing program. Rationing ended in September 1953.

The researchers used contemporary data from the U.K. Biobank, a database of medical histories and genetic, lifestyle and other disease risk factors, to study the effect of those early-life sugar restrictions on health outcomes of adults conceived in the U.K. just before and after the end of wartime sugar rationing.

“Studying the long-term effects of added sugar on health is challenging,” says study corresponding author Tadeja Gracner, senior economist at the USC Dornsife Center for Economic and Social Research. “It is hard to find situations where people are randomly exposed to different nutritional environments early in life and follow them for 50 to 60 years. The end of rationing provided us with a novel natural experiment to overcome these problems.”

Sugar intake during rationing was about 8 teaspoons (40 grams) per day on average. When rationing ended, sugar and sweets consumption skyrocketed to about 16 teaspoons (80 grams) per day.

Notably, rationing did not involve extreme food deprivation overall. Diets generally appeared to have been, in fact, within today’s guidelines set by the U.S. Department of Agriculture and the World Health Organization, which recommend no added sugars for children under two and not more than 12 teaspoons (50g) of added sugar daily for adults.

The immediate and large increase in sugar consumption but no other foods after rationing ended created an interesting natural experiment: Individuals were exposed to varying levels of sugar intake early in life, depending on whether they were conceived or born before or after September 1953. Those conceived or born just before the end of rationing experienced sugar-scarce conditions compared to those born just after who were born into a more sugar-rich environment.

The researchers then identified those born around this time in the U.K. Biobank data collected over 50 years later. Using a very tight birth window around the end of sugar rationing allowed the authors to compare midlife health outcomes of otherwise similar birth cohorts.

While living through the period of sugar restriction during the first 1,000 days of life substantially lowered the risk of developing diabetes and hypertension, for those who were later diagnosed with either of those conditions, onset of disease was delayed by four years and two years, respectively.

Notably, exposure to sugar restrictions in utero alone was enough to lower risks, but disease protection increased postnatally once solids were likely introduced.

The magnitude of this effect is meaningful as it can save costs, extend life expectancy and, perhaps more importantly, quality of life, say the researchers.

In the United States, people with diabetes incur annual medical expenditures of about $12,000 on average. Further, earlier diagnosis of diabetes means significantly shorter life expectancy, with every decade earlier that a diagnosis of diabetes is made cutting three to four years off of life expectancy.

These numbers underscore the value of early interventions that could delay or prevent this disease, the researchers note.

Experts’ concerns about children’s long-term health as they consume excessive amounts of added sugars during their early life, a critical period of development, continue to mount. Adjusting child sugar consumption, however, is not easy — added sugar is everywhere, even in baby and toddler foods, and children are bombarded with TV ads for sugary snacks, say the researchers.

“Parents need information about what works, and this study provides some of the first causal evidence that reducing added sugar early in life is a powerful step towards improving children’s health over their lifetimes,” says study co-author Claire Boone of McGill University and the University of Chicago.

Co-author Paul Gertler of UC Berkeley and the National Bureau of Economics Research adds: “Sugar early in life is the new tobacco, and we should treat it as such by holding food companies accountable to reformulate baby foods with healthier options and regulate the marketing and tax sugary foods targeted at kids.”

This study is the first of a larger research effort exploring how early-life sugar restrictions affected a broader set of economic and health outcomes in later adulthood, including education, wealth, and chronic inflammation, cognitive function and dementia.

As critical responders, macrophages can perceive helpful biotechnology as threats. If not created with the right materials or mechanical forces, these devices can trigger an immune response that can cause inflammation, scar tissue or device failure.

But what is the right material or the right mechanical force? In a meta-analysis co-led by Dr. Abigail Clevenger, a biomedical engineering graduate student at Texas A&M University, researchers emphasize that context matters.

“Not any one force does the same thing to macrophages everywhere in the body,” said Dr. Shreya Raghavan, co-author and biomedical engineering assistant professor. “For example, your lung inflates and deflates, so the macrophage in the lung is already used to those forces and has some adaptations to those mechanics. But what a macrophage in the lung adapts to is different from what a macrophage in the uterus or gut adapts to.”

Now a postdoctoral fellow, Clevenger co-led the article with Dr. Aakanksha Jha, a University of Maryland postdoctoral fellow. Jha’s advisor, Dr. Erika Moore, was also a senior author on the study. The article, published in Trends in Biotechnology, highlights the need to understand macrophage cell behavior to potentially open doors for new or improved biotechnology and targeted immunotherapy treatments.

“When you design immunotherapy for colorectal cancer, for example, you can’t just design a solution in a dish where there’s no mechanics,” said Raghavan. “Mechanics change the way macrophages behave. Your design solutions must take into account that these are mechanosensitive cells. The consequence of not doing so means that the very same macrophage that can help devices function in the body may also perceive harmful tumors as friends and allow them to propagate.”

According to Raghavan, the review critically summarizes advances in research findings in interactions between biotechnologies and macrophages from the past four years.

“We felt like there was a critical mass in scientific advancement that we were excited to put it together,” she said. “Even five years ago, this was a significant knowledge gap, but with integrated tools between biomedical and tissue engineering and molecular and computational biology, there is so much more data. It’s beautiful.”

In a more personal application, Raghavan wears a continuous glucose monitor that she switches out every two weeks due to the immune system response to the foreign materials eventually making the readings unreliable. She hopes the knowledge gained through the review article can help her lab better determine steps for adjusting medical devices — like the continuous glucose monitor — for an improved immune response.

“It’s not a one-size-fits-all; you have to take everything into context, but that’s the power and beauty of engineering,” Raghavan said. “You can break it down and study fundamentals, then build it back up in complexity.”

Researchers from UBC’s Okanagan and Vancouver campuses, as well as the University of Calgary, discovered that delivering CBTi during pregnancy significantly reduces postpartum depressive symptoms after a baby arrives.

“Early intervention is crucial for infant and parental mental health,” says Dr. Elizabeth Keys, an Assistant Professor in UBCO’s School of Nursing and a study co-author. “Our research explores how addressing sleep problems like insomnia can lead to better mental health outcomes for families, helping parents and their children thrive.”

CBTi is a therapeutic intervention that identifies thoughts, behaviors and sleep patterns that contribute to insomnia. Treatment includes challenging or reframing misconceptions and restructuring habits to improve sleep quality.

“CBTi is the gold standard for the treatment of insomnia and has consistently been shown to improve symptoms of depression,” says Dr. Keys. “Its treatment effects are similar to antidepressant medications among adults, but with fewer side effects, and is therefore often preferred by pregnant individuals.”

Sixty-two women assessed for insomnia and depressive symptoms participated in the study — with half randomly assigned to an intervention group and half to a control group.

“We found that CBTi during pregnancy significantly improved sleep and reduced postpartum depressive symptoms for participants,” explains Dr. Keys. “These are enormously encouraging results for anyone that has struggled in those early weeks and months with their newborns.”

Results indicate that effective insomnia treatment during pregnancy may serve as a protective factor against postpartum depression.

“Our study adds to the growing evidence that treating insomnia during pregnancy is beneficial for various outcomes,” Dr. Keys says. “It’s time to explore how we can make this treatment more accessible to pregnant individuals across the country to improve sleep health equity.”

The research highlights the interdisciplinary collaborations between researchers across Canada and UBC’s Vancouver and Okanagan campuses. Dr. Elizabeth Keys is from UBCO, while Dr. Lianne M. Tomfohr-Madsen, a Canada Research Chair in Mental Health and Intersectionality, is based at UBC Vancouver.

Dr. Keys and Dr. Tomfohr-Madsen are lead investigators on the Canadian Institutes of Health Research (CIHR) Sleep Equity Reimagined team and Canadian Sleep Research Consortium members.

A deep dive into the Medicare database of 5.2 million surgeries from 2017 to 2020 for patients 67 and older suggests delaying surgery for three to six months following a heart attack, known as a non-ST-segmented elevation myocardial infarction (NSTEMI).

Researchers aim to identify the “sweet spot” for safely scheduling additional surgical procedures in this high-risk population. The study provides valuable analysis to support changes to decision-making guidelines set more than 20 years ago.

“The data physicians are using for patient care decisions today is outdated. Given the advances in care and the ever-changing mix of patients, clinicians need the latest information,” said Laurent Glance, MD, lead author and professor of Anesthesiology and Perioperative Medicine and Public Health Sciences at the University of Rochester Medical Center (URMC).

The 2014 American College of Cardiology and American Heart Association perioperative guidelines call for waiting 60 days after a heart attack before undergoing an elective noncardiac surgery. The recommendation was based on a study of 500,000 patients between 1999 and 2004.

Most post-surgical deaths or significant complications occur during the first 30 days of recovery and perioperative teams work diligently to prevent them. This new analysis shows a decline in risk during the first 90 days, when it leveled off for the next 180 days.

Aging patients often have multiple acute or chronic conditions, and physicians are challenged to balance their risk of surgical care with their expectations for quality of life.

“Perioperative teams analyze a variety of health and lifestyle factors when we assess a patient’s risk and work to optimize their outcomes,” said Marjorie Gloff, MD, a co-author and director of URMC’s Center for Perioperative Medicine. “It can be frustrating for individuals who suffer with joint pain to postpone a long-awaited knee or hip replacement after surviving a heart attack.”

Additional co-authors include Gloff, Heather Lander, MD, Stewart Lustik, MD, Michael Eaton, MD, Sabu Thomas, MD, of URMC; Mark Sorbero, MS, and Andrew Dick, PhD, of RAND Health; Karen E. Joynt Maddox, MD, MPH, of Washington University; Lee Fleisher, MD, of University of Pennsylvania; and Jingjing Shang, PhD, RN, and Patricia Strong, PhD, RN, of Columbia School of Nursing.

This study was supported by funding from the National Institute of Aging, National Institute of Nursing Research and URMC’s Department of Anesthesiology and Perioperative Medicine.

In order to investigate whether and how nanoplastic particles in the body interact with antibiotics, the research team led by Lukas Kenner (MedUni Vienna), Barbara Kirchner (University of Bonn) and Oldamur Hollóczki (University of Debrecen) linked a common drug with widely used types of plastic. The focus was on the broad-spectrum antibiotic tetracycline, which is used to treat many bacterial infections, such as those of the respiratory tract, skin or intestines. When it came to plastics, the choice fell on polyethylene (PE), polypropylene (PP) and polystyrene (PS), which are ubiquitous components of packaging materials, as well as nylon 6,6 (N66), which is contained in many textiles such as clothing, carpets, sofa covers and curtains. Nanoplastics are smaller than 0.001millimeters and are considered particularly harmful to humans and the environment due to their small size.

Using complex computer models, the team was able to prove that the nanoplastic particles can bind tetracycline and thus impair the effectiveness of the antibiotic. “The binding was particularly strong with nylon,” emphasizes Lukas Kenner, pointing out a largely underestimated danger indoors: “The micro- and nanoplastic load is around five times higher there than outdoors. Nylon is one of the reasons for this: it is released from textiles and enters the body via respiration, for example.”

Danger of antibiotic resistance

As the study results show, the binding of tetracycline to nanoplastic particles can reduce the biological activity of the antibiotic. At the same time, binding to nanoplastics could lead to the antibiotic being transported to unintended sites in the body, causing it to lose its targeted effect and possibly cause other undesirable effects. “Our finding that the local concentration of antibiotics on the surface of the nanoplastic particles can increase is particularly worrying,” reports Lukas Kenner on another detail from the study. This increase in concentration could lead to the development of antibiotic-resistant bacteria. Plastics such as nylon 6,6, but also polystyrene, which bind more strongly to tetracycline, could therefore increase the risk of resistance. “At a time when antibiotic resistance is becoming an ever greater threat worldwide, such interactions must be taken into account,” says Kenner.

The study shows that exposure to nanoplastics is not only a direct health risk, but can also indirectly influence the treatment of diseases. “If nanoplastics reduce the effectiveness of antibiotics, the dosage poses a massive problem,” says Lukas Kenner with a view to future studies looking at the influence of nanoplastics on other drugs.

The study appears in Frontiers in Molecular Neuroscience.

Olfactory dysfunction, often dismissed as a minor inconvenience, may actually be an early sign of various neurological and bodily diseases, as indicated by this research. “The data are particularly interesting because we had previously found that olfactory enrichment can improve the memory of older adults by 226 percent,” said Leon. “We now know that pleasant scents can decrease inflammation, potentially pointing to the mechanism by which such scents can improve brain health.”

This finding, he added, could hold key implications for mitigating symptoms and possibly even reducing the onset of certain diseases through therapeutic olfactory stimulation.

The study delves into the methodical tracking of 139 medical conditions associated with both olfactory loss and heightened inflammation, uncovering insights into a shared pathway linking these factors. Olfactory loss, which often precedes conditions such as Alzheimer’s and Parkinson’s diseases, may serve as an early indicator of disease onset, allowing for more proactive therapeutic approaches.

“It was difficult to track down the studies for so many medical conditions,” said Leon, reflecting on the complexity of linking olfactory loss to such a wide array of disorders. The challenge, he added, underscores the importance of these findings in framing olfactory health as integral to overall well-being.

By showing how olfactory enrichment can mitigate inflammation, this research has laid a foundation for future studies aiming to explore the therapeutic use of scent to address a broader range of medical conditions. “It will be interesting to see if we can ameliorate the symptoms of other medical conditions with olfactory enrichment,” said Leon.

Together with Woo, Leon is now working on a device to deliver olfactory therapy, which could hold promise as a novel, non-invasive way to improve health outcomes.

As science continues to uncover the profound impacts of our senses on health, this research underscores a critical need for further study into olfactory therapies.

Utilizing cutting-edge machine learning and systems biology, researchers analyzed and correlated huge data sets from flies and humans to identify key metabolites that impact lifespan in both species.Results published online in Nature Communicationssuggest that one of the metabolites, threonine, may hold promise as a potential therapeutic for aging interventions.

“These results would not have been possible without this pioneering approach,” says Buck professor Pankaj Kapahi, PhD, senior author of the paper. “There is a lot of data sitting out there that is not being correlated between species. I think this approach could be a game-changer when it comes to identifying potential interventions to improve human health.”

Threonine has been shown to protect against diabetes in mice. The essential amino acid plays an important role in collagen and elastin production and is also involved in blood clotting, fat metabolism and immune function.

The method — simplified

The work began with former Buck postdoc Tyler Hilsabeck, PhD, crunching data (involving metabolomics, phenotypes and genomics) to analyze 120 metabolites in 160 strains of fruit flies on both restricted and normal diets. The goal was to reveal how different genotypes responded to the diets to influence lifespan and healthspan. “This allowed us to find the ‘needles in the haystack’ when it came to identifying relevant metabolites,” Hilsabeck says.

Vikram Narayan, PhD, a postdoctoral fellow then cross-referenced findings with human data from the massive UK Biobank. “Using the human data allowed us to focus on interesting metabolites to those that are conserved in both species. It also allowed us to uncover the impact of those metabolites in humans,” he says. Importantly, the team then brought those relevant metabolites back into the fly to validate results.

The results

In flies, threonine extended lifespan in a strain-and-sex-specific manner. Individuals with higher levels of threonine-related metabolites had longer, healthier lives. “We’re not saying that threonine is going to work in all conditions,” says Kapahi. “Our research shows it works in subsets of both flies and people. I think most of us have stopped expecting to find a ‘magic-bullet’ intervention for aging. Our method provides another way to develop precision medicine for geroscience.”

The results also include findings that were not so positive for both species. Orotate, which is relatively understudied and has been linked with fat metabolism, was negatively associated with aging. In flies orotate counteracted the positive impact of dietary restriction across every strain of the animals. In humans, orotate was linked to a shorter lifespan.

Larger implications

Kapahi hopes the larger research community will begin employing this method. “So many times we find things that work in worms and flies and then we don’t have the resources to move the basic science forward. This approach allows us to say with a lot more certainty that discoveries are going to be relevant in humans.” Kapahi says this method may reduce the need for studies in mice, something he welcomes.

The study was conducted with 50 U.S.-licensed physicians in family medicine, internal medicine and emergency medicine. The research team found that the availability of GPT-4 to physicians as a diagnostic aid did not significantly improve clinical reasoning compared to conventional resources. Other key findings include:

• GPT-4 alone demonstrated significantly better scores in diagnostic performance, surpassing the performance of clinicians using conventional diagnostic online resources and clinicians assisted by GPT-4.
• There was no significant enhancement in diagnostic performance with the addition of GPT-4 when assessing clinicians using GPT-4 against clinicians using conventional diagnostic resources.

“The field of AI is expanding rapidly and impacting our lives inside and outside of medicine. It is important that we study these tools and understand how we best use them to improve the care we provide as well as the experience of providing it,” said Andrew Olson, MD, a professor at the U of M Medical School and hospitalist with M Health Fairview. “This study suggests that there are opportunities for further improvement in physician-AI collaboration in clinical practice.”

These results underline the complexity of integrating AI into clinical practice. While GPT-4 alone showed promising results, the integration of GPT-4 as a diagnostic aid alongside clinicians did not significantly outperform the use of conventional diagnostic resources. This suggests a nuanced potential for AI in healthcare, emphasizing the importance of further exploration into how AI can best support clinical practice. Further, more studies are needed to understand how clinicians should be trained to use these tools.

The four collaborating institutions have launched a bi-coastal AI evaluation network — known as ARiSE — to further evaluate GenAI outputs in healthcare.

Funding for this research was provided by the Gordon and Betty Moore Foundation.

The study, led by UBC and SFU researchers in collaboration with the Medical Research Council (MRC) Unit The Gambia, has the potential to help healthcare workers diagnose babies earlier, including in lower- and middle-income countries (LMICs) where neonatal sepsis is of particular concern. The research, published today in eBiomedicine, is funded by the National Institutes of Health and the Canadian Institutes of Health Research.

“Neonatal sepsis is caused by the body’s irregular response to a severe infection that occurs within the first 28 days of life. Globally, it affects around 1.3 million babies annually, and unfortunately, in LMICs, those rates are higher,” said first author Andy An, a UBC MD/PhD student who completed the research as a doctoral student in the department of microbiology and immunology. “Even when treatment is successful, sepsis can have lifelong effects because it can lead to developmental delay in children, imposing cognitive deficits and long-term health issues. By recognizing it as early as possible, we can treat infants promptly and ideally, head off these harms.”

Neonatal sepsis causes an estimated 200,000 deaths worldwide each year, with the highest rates in LMICs. In Canada, the risk is lower at about one in 200 live births, but higher in prematurely born babies.

Rolling the dice on health

Diagnosing sepsis is challenging for doctors and families. The symptoms can look like many other illnesses, and tests to check if sepsis is present can take several days, aren’t always accurate, and are largely only available in hospitals. The uncertainty can delay urgent treatment with antibiotics.

“Knowing that sepsis is impending would also allow physicians more time to determine the appropriate treatment to use,” said co-senior author Dr. Bob Hancock, professor in the UBC department of microbiology and immunology. “The consequences of neonatal sepsis are so severe in the most vulnerable individuals that providing an early diagnosis to assist and guide physicians could save lives.”

Equitable access to healthcare

The researchers participated in a large study in The Gambia where blood samples were taken from 720 infants at birth. Out of this cohort, 15 babies developed early-onset sepsis.

The researchers used machine learning to map the expression of genes active at birth, in search of biological markers that could predict sepsis.

“We found four genes that, when combined in a ‘signature’, could accurately predict sepsis in newborns nine times out of 10,” said co-senior author Dr. Amy Lee, assistant professor in the SFU department of molecular biology and biochemistry. “This was a unique opportunity where samples were available from all babies in this cohort on the day of birth, meaning we could study the genes expressed in the sepsis babies before they got sick. Most other studies have only published markers that were present when the babies were already ill, and this would therefore not be a predictive signature.”

“The early recognition of sepsis is vital for infants’ survival, and identifying markers that might allow us to ‘predict’ babies at particular risk would be an enormous advantage, since we could then target specific surveillance and treatment of such infants,” said Dr. Beate Kampmann, who led the clinical component of the study at the MRC Unit in The Gambia.

The researchers hope the signature will one day be incorporated not only into PCR tests in hospitals, but also in portable, point-of-care devices.

“There are point-of-care devices available that can test for gene expression, for instance, COVID-19 and influenza, with a single drop of blood. They can operate anywhere with a power source including batteries and can be used by anyone, not just trained healthcare providers,” Dr. Hancock. “These portable devices could be retooled to recognize this ‘signature’ relatively easily and inexpensively.”

The next step for the research would involve a large prospective study to show the signature is successful at predicting sepsis in other populations and prove its methodology, and then the development of point-of-care tools for approval by relevant government bodies.

Dr. Steven Heymsfield, professor of metabolism and body composition, and Dr. M. Cristina Gonzalez, adjunct and visiting professor in metabolism-body composition, both of Pennington Biomedical Research Center, joined colleagues Dr. Carla Prado of the University of Alberta, and Dr. Stuart Phillips of McMaster University on authoring The Lancet commentary, titled “Muscle Matters: The Effects of Medically Induced Weight Loss on Skeletal Muscle.”

The authors emphasize that muscle loss, as measured by decreases in fat-free mass, can account for 25 to 39 percent of total weight lost over a period of 36 to 72 weeks. This rate of muscle decline is significantly higher than what is typically observed with non-pharmacological caloric restriction or normal aging and could lead to unintended negative health consequences.

Despite the promising metabolic benefits associated with GLP-1 receptor agonists, including improvements in fat-to-fat-free tissue ratios, the potential adverse effects of muscle loss are gaining attention. Skeletal muscle plays critical roles not only in physical strength and function but also in metabolic health and immune system regulation.

A decline in muscle mass has been linked to decreased immunity, increased risk of infections, poor glucose regulation, and other health risks. The authors suggest that muscle loss due to weight reduction may exacerbate conditions like sarcopenic obesity, which is prevalent among individuals with obesity and contributes to poorer health outcomes, including cardiovascular disease and higher mortality rates.

While the short-term effects of muscle loss on physical strength and function remain unclear, the commentary calls for future research to explore how reductions in muscle mass might improve muscle composition and quality. The authors stress the need for a multimodal approach to weight loss treatment, combining GLP-1 receptor agonists with exercise and nutritional interventions to preserve muscle mass.

“We have to be mindful of the side effects that we are seeing with the new weight loss medications, such as a person eating less while on the medications and not getting the appropriate amount of dietary vitamins and minerals,” Dr. Heymsfield said. “Also, when a person loses weight, they are not only losing fat, they also lose muscle. We are looking at how that muscle loss can be better managed with consumption of an adequate amount of protein along with an optimum amount of exercise.”

This evolving conversation underscores the importance of ensuring that weight loss interventions promote overall health, including muscle preservation, as part of a comprehensive strategy for treating obesity.

The work is published Oct. 25 in Proceedings of the National Academy of Sciences.

Drosophila have been a favorite subject for geneticists and developmental biologists for over a century.

“Drosophila is such a productive system in many ways,” said Rachel Thayer, a postdoctoral researcher working with Distinguished Professor David Begun at the UC Davis Department of Evolution and Ecology. There are extensive catalogs of cell types and genes for most of the fly’s organ systems. But the female reproductive organs — the uterus, female glands and sperm storage organs — have been mostly left out.

Both humans and insects have internal fertilization, so the female reproductive tract has to deal with foreign material from sperm to sexually transmitted viruses. Insects, like many other female animals including birds and reptiles, have organs that can store viable sperm for long periods.

“We wanted to identify all the cell types and their patterns of gene use for these important organs,” Thayer said.

Thayer and Begun, with coauthors Elizabeth Polston and Jixiang Xu, dissected the reproductive tracts of about 150 flies. They were able to separate cell nuclei into individual droplets and label the RNA from each cell with a sort of barcode. By sequencing the RNA, they were able to identify a profile of gene expression from individual cells and sort them into types.

“We can identify the cell types that express certain genes, and where they come from,” Thayer said.

Previously, there were no cell types from the fly uterus identified with genetic markers. The new study reveals more than 20 different cell types in the uterus and associated organs.

“The most exciting thing to me is to find cell types we had not previously predicted would exist,” Thayer said. “This is previously invisible anatomy.”

Supporting sperm storage

The study found that about 40% of genes for “seminal fluid proteins,” previously identified as being made only in male flies, are also expressed in the female fly, especially in sperm storage organs. They may be key to supporting viable sperm for long periods.

Some seminal fluid proteins are thought to manipulate the female fly in ways that benefit the male, such as by delaying the female from mating again. Such sexual conflicts have been the target of considerable, mostly theoretical, study.

“There is dispute about how big a role these sexual conflicts really play, because sexual reproduction still must be collaborative,” Thayer said. The discovery that many of these proteins are made by both male and female flies means that scientists will have to adjust their thinking about these ideas, Thayer said.

“It does not rule out the possibility of molecular sexual conflict altogether, but it does limit how this could occur,” she said.

While reproduction is, obviously, very different in humans and insects, the fruit fly can be a model for understanding animal reproduction at a fundamental level. For example, the seminal fluid proteins could lead to new ways to culture and store human sperm without freezing, which would benefit fertility treatments.

The most numerous species on Earth, insects pollinate and provide other benefits, as well as destroy crops and carry disease. Better understanding insect reproduction could lead to new control strategies.

Thayer is currently working with isolates of Drosophila from around the world to better understand how the flies are evolving in response to environmental stresses, such as climate change and pesticides.

The work was supported by grants from the National Institutes of Health.

According to the University of Pennsylvania’s Dani Bassett, who recently worked with a collaborative team of researcher to examine the browsing habits of 482,760 Wikipedia readers from 50 different countries, this style of information acquisition is called the “busybody.” This is someone who goes from one idea or piece of information to another, and the two pieces may not relate to each other much.

“The busybody loves any and all kinds of newness, they’re happy to jump from here to there, with seemingly no rhyme or reason, and this is contrasted by the ‘hunter,’ which is a more goal-oriented, focused person who seeks to solve a problem, find a missing factor, or fill out a model of the world,” says Bassett.

In the research, published in the journal Science Advances, Bassett and colleagues discovered stark differences in browsing habits between countries with more education and gender equality versus less equality, raising key questions about the impact of culture on curiosity and learning.

“We observed that countries that had greater inequality, in terms of gender and access to education, had people who were browsing with more intent — seeking closely related information, whereas the people in countries that had more equality were browsing expansively, with more diversity in topics — jumping from topic to topic and collecting loosely connected information,” Bassett says. “While we don’t know exactly why this is, we have our hunches, and we believe these findings will prove useful in helping scientists in our field better understand the nature of curiosity.”

This work builds on a previous study led by assistant professor in the Annenberg School for Communication David Lydon-Staley, who was a postdoctoral researcher in Bassett’s Complex Systems Lab at the time.

In that paper, the team had 149 participants from Philadelphia browse Wikipedia for 15 minutes a day for 21 days. In the course of that study, they identified the two curiosity styles, which were predicted by Perry Zurn, one of the new paper’s coauthors and a professor of philosophy at American University and currently a visiting professor at Cornell University, who studied and analyzed literature from over the last two millennia to home in those these styles of curiosity.

“Beginning this line of work in a small sample allowed us to work out the methods needed to capture the complex information-seeking that accompanies curiosity,” Lydon-Staley says. “Working out those methods then allowed us to scale up and ask whether we could confirm that the styles we observed could be found outside of our sample of Philadelphians.”

Working with Martin Gerlach of the Wikimedia Foundation, who had data of more than two million human browsers, “allowed us to apply our existing methods, and develop new methods, to capture styles of curiosity emerging across 14 different languages of Wikipedia and 50 different countries or territories,” Lydon-Staley says.

The three hunches

The researchers cite three main hypotheses driving the associations between information-seeking approaches and equality.

“One is that it’s possible that countries that have more inequality also have more patriarchal structures of oppression that are constraining the knowledge production approaches to be more Hunter-like,” says Bassett. “Countries that have greater equality, in contrast, are open to a diversity of ideas, and therefore a diversity of ways that we’re engaging in the world. This is more like the busybody — the one that’s moving between ideas in a very open-minded way.”

A second possibility the researchers outline is that browsers go to Wikipedia for different purposes in different countries, citing how someone in a country with higher equality may be going to the site for entertainment or leisure rather than for work.

And the third potential explanation is that people in different countries who come to Wikipedia may have different ages, genders, socioeconomic status, or educational attainment, and that those differences in who’s actually coming to Wikipedia may explain the differences in the browsing patterns.

Making connections

One of the most exciting findings of the study was the confirmation of a third curiosity style — the “dancer,” which had previously only been hypothesized based on Zurn’s research on historical texts.

“The dancer is someone who moves along a track of information but, unlike the busybody, they make leaps between ideas in a creative, choreographed way,” says Zurn. “They don’t jump randomly; they connect different domains to create something new.”

This curiosity style shows a degree of creativity and interdisciplinary thinking, offering a new perspective on how people engage with information. “It’s less about randomness and more about seeing connections where others might not,” Bassett says.

“What this tells us is that people — and likely children — have different curiosity styles, and that might affect how they approach learning,” Bassett says. “A child with a hunter-like curiosity may struggle if assessed using methods that favor the busybody style, or vice versa. Understanding these styles could help us tailor educational experiences to better support individual learning paths.”

Where curiosity may lead next

Looking ahead, the team seeks to explore the factors influencing these curiosity styles.

“One question I’m particularly interested in is whether people browse differently at different times of day — perhaps they’re more hunter-like in the morning and more like busybodies in the evening,” says Bassett.

“This opens up new research avenues, including the role of biological processes in shaping how we seek information,” says Shubhankar Patankar, another author on the paper and a doctoral student in Penn Engineering. He is also keen to understand the implications of the work for AI. “Imparting notions of curiosity to AI systems learning from interactions is an increasingly important area of research,” Patankar says.

The team aims to explore the motivations behind Wikipedia browsing, examining whether users are driven by extrinsic factors, like work, or intrinsic curiosity, like personal interest. Additionally, they are considering expanding their analysis to include other digital platforms where learning and exploration naturally occur.

“Wikipedia is a very special place on the internet,” Lydon-Staley says. “The site features exclusively free content and no commercial advertisements. Much of the rest of the contemporary digital landscape is designed to activate individuals’ buying impulses and customizes our media content. This raises the question of how much we are in charge of where our curiosity takes us in online contexts beyond Wikipedia.”

Dani S. Bassett is the J. Peter Skirkanich Professor at the University of Pennsylvania with a primary appointment in the School of Engineering and Applied Science’s Department of Bioengineering and secondary appointments in the School of Arts & Sciences‘ Department of Physics & Astronomy, Penn Engineering’s Department of Electrical and Systems Engineering, and the Perelman School of Medicine‘s Departments of Neurology and Psychiatry.

Martin Gerlach is a senior research scientist for the Wikimedia Foundation.

David Lydon-Staley is an assistant professor of communication and principal investigator of the Addiction, Health, & Adolescence Lab in the Annenberg School for Communication at Penn.

Shubhankar Patankar is a Ph.D. student at Penn Engineering.

Dale Zhou was a Ph.D. student in the Perelman School of Medicine who is now a postdoctoral researcher at the University of California at Irvine.

Perry Zurn is an associate professor and director of undergraduate studies in philosophy at American University in the College of Arts and Sciences’ Department of Philosophy and Religion.

This research received support from the George E. Hewitt Foundation for Medical Research, the Center for Curiosity, and the National Institute of Health (Grant K01 DA047417).

More and more organizations have come to San Francisco State University’s experts in organizational psychology asking for help doing just that. In response, University researchers developed a tool for job interviews to assess narcissistic grandiosity among potential job candidates. San Francisco State Psychology Professors Kevin Eschleman and Chris Wright and four student researchers led the project, published in the Journal of Personality Assessment.

“We focused on narcissism because it’s one of the most commonly talked about characteristics of people. Really, it represents a lot of things that can go bad in terms of a team,” Eschleman said. “But it’s a characteristic that is very attractive in the short-term. [Narcissists] often have tendencies to be very goal-oriented and are often very successful. There’s a lure to somebody who is high in narcissism.”

The tool developed by the SF State researchers — the Narcissism Interview Scale for Employment (NISE) — is a set of behavioral and situational questions that can be incorporated into a job interview. One question asks respondents to describe their approach to leading a team. Another asks how candidates would procced if they disagree with a plan that the rest of their team likes — and the project requires unanimous consent to move forward. Interviewers are trained to rate candidate responses, providing a more scientific and consistent way to evaluate a candidate’s propensity for narcissistic grandiosity.

The project started four years ago when Eschleman noticed an uptick in organizations asking about effective teams, candidate selection and how to avoid “bad apples.” It’s easy for organizations to be enticed by how a candidate’s skills appear on paper, but failing to properly consider personality might derail team-oriented environments, Eschleman notes. Employees with narcissistic grandiosity tend to have inflated views of self and make self-focused and short term-focused decisions instead of considering long-term organizational needs. They may also abuse and try to protect their sense of power and control, he adds.

“This isn’t a categorical diagnosis,” Eschleman clarified, noting that everyone probably falls somewhere on the continuum of narcissism. “What we’re looking at are people’s consistencies over time. It’s how they view themselves or how others view them consistently over time. Do they engage in these actions consistently?”

The authors acknowledge that this assessment is not a perfect science. There are many other factors in building a successful team and healthy work environment. But they hope their tool will increase the odds for success.

While the researchers have been studying these topics for years, they wanted to make sure their tool was easy to use and could be adapted by different work environments. It is why they focused on job interviews, something accepted and considered appropriate by both organizations and applicants in the hiring process.

Sharon Pidakala (M.S., ’22), one of the study authors, is now a People & Development Manager at Lawyers On Demand in Singapore. Her work involves talent acquisition, culture, development, organizational policies and employee engagement.

“I’ve been grateful to put my research into daily use. It’s really important to make sure that these questions are not outrightly direct because you don’t want it to look like you’re asking someone, ‘Are you a narcissist?'” explained Pidakala, whose SFSU thesis focused on developing the NISE tool. “These questions are raised in a way to make it look favorable for the candidate.”

Pidakala came to SF State specifically to get this type of training. With an undergraduate background in psychology, she sought specialized training in organizational psychology to further refine and expand her expertise in the field.

“Attending SF State and studying organizational psychology has been incredibly valuable, equipping me with versatile skills that can be applied globally,” she said.

To resolve this controversy, Dr. Ruijing Ni, the first author of the study published today in the journal One Earth, and her colleagues at the Max Planck Institute for Chemistry have conducted a comprehensive global meta-analysis with researchers from China, the USA, and Australia. The research team determined the data from 68 epidemiologic studies from 2019 conducted across 22 countries, including those in North America, Western Europe, East Asia, South Asia, and Africa. They conclude that there is now sufficient evidence with high confidence level to support an association between long-term exposure to ambient PM_2.5 and asthma.

11 percent of new cases of asthma in Germany are attributable to particulate matter

“We estimate that globally in 2019, almost a third of asthma cases are attributable to long-term PM_2.5 exposure, corresponding to 63.5 million existing cases and 11.4 million new cases. In Germany, the pollution may have been responsible for 11 percent of new asthma cases, which corresponds to 28,000 people. We also find that the risk of asthma associated with PM_2.5 is much higher in children than in adults, reflecting the age-related vulnerability,” says Dr. Ni.

Typically, the full maturation of lung and immune function is gradually completed until early adulthood. As a result, children may be more susceptible to air pollution exposure, which can lead to airway oxidative stress, inflammation, and hyper-responsiveness, as well as changes in immunological responses and respiratory sensitization to allergens. All these factors play a role in the development of asthma.

Further using these data, the research team established exposure-response curves for both childhood and adult asthma. Such curves are widely employed to quantitatively assess health risks by illustrating the relationship between the level of exposure to a particular substance, e.g., PM_2.5 and the magnitude of the effect it produces, e.g., asthma risk. The exposure-response curves were determined by incorporating evidence from countries and regions across various income levels, which capture the global variation in PM_2.5 exposure. “This initiative is important for quantifying global health effects of air pollution,” comments Prof. Yuming Guo, an epidemiologist from Monash University.

Countries with different income levels and particulate matter pollution considered

Populations in low- and middle-income countries (LMICs) are typically exposed to higher concentrations of air pollution and bear a greater burden of PM_2.5. In contrast, research on the health effects of PM_2.5 has been limited in these regions previously, with the majority of studies conducted in North America and Western Europe. Consequently, attempting a global health impact assessment of PM_2.5 exposure necessitates extrapolating exposure-response associations observed in high-income countries to LMICs. The approach may introduce large uncertainty due to the differences in air pollution sources, healthcare systems, and demographic characteristics between high-income countries and LMICs.

The inclusion of evidence from several LMICs mitigates the limitation in approach and enables the exposure-response curves to be applicable to assess city- to global-scale attributable burden of asthma, as well as asthma health benefits associated with air pollution reductions, e.g., health benefits obtained from policy-driven reductions in air pollution under different scenarios.

“Our findings highlight the urgent need for policymakers to enforce stringent legislation to continuously combat air pollution, while personal protective measures, such as wearing masks, can also help reduce individual exposure and mitigate the risk of asthma,” emphasizes Prof. Yafang Cheng, the corresponding author of the study and the director at the Max Planck Institute for Chemistry.

The study was conducted by researchers from Max Planck Institute for Chemistry (Germany), Institute of Atmospheric Physics at the Chinese Academy of Sciences (China), University of Washington (USA), and Monash University (Australia).

“It’s inconvenient, it’s annoying, but sensations like pain and itch are crucial. They’re ever-present, especially when it comes to skin infections,” says Inclan-Rico, a postdoctoral researcher in the Herbert Lab at Penn’s School of Veterinary Medicine, who has been exploring what he calls “sensory immunity,” the idea that “if you can feel it, you can react to it.” Itch, he explains, is the body’s way of detecting threats such as skin infections before they can take hold.

But in a recent paper published in Nature Immunology, De’Broski Herbert, professor of pathobiology at Penn Vet, and his team flipped that theory on its head. They shed light on how a parasitic worm, Schistosoma mansoni, can sneak into the human body by evading this very defense mechanism, bypassing the itch response entirely. And while there are prophylactic therapeutics for those who may encounter S. mansoni, options for treating someone who has unknowingly been exposed are relatively scant, and these research findings pave the way for addressing this concern.

“These blood flukes, which are among the most prevalent parasites in humans, infecting nearly 250 million people, have seemingly evolved to block the itch, making it easier for them to enter the body undetected,” Inclan says. “So, we wanted to figure out how they do it. What are the molecular mechanisms underlying how they turn off such an essential sensory alarm? And what can this teach us about the sensory apparatus that drives us to scratch a pesky itch?”

Not all reactions are equal

Inclan-Rico says that the research really began when his project revealed that certain strains of mice were more susceptible to infection of S. mansoni. “Specifically, some of the mice had a higher number of parasites successfully traversing throughout body following skin penetration.”

Heather Rossi, a senior research investigator in the Herbert lab and co-author on the study, says that this motivated the team to investigate the neuronal activity at play, with special attention paid to MrgprA3 neurons, which are commonly associated with immunity and itchiness.

They then looked at how a “cousin” of S. mansoni that’s typically found in avian species but has been shown to cause swimmer’s itch in humans, and they found a stark difference between the reaction or lack of it within the mice.

“While avian schistosomes triggered a strong itch response in the skin, S. mansoni was unable to induce this reaction,” Rossi says. “What’s more, when we introduced chloroquine — an anti-malarial drug that’s known to cause pruritus by interacting with MrgprA3 — to the mice treated with S. mansoni antigens, we found that itching was blocked almost entirely.”

A closer look

To further investigate the biochemistry involved in S. mansoni’s workaround for skating past MrgprA3 neurons, the researchers employed a three-legged strategy: Using light to genetically activate neurons on ear skin prior to infection, administering chloroquine, and genetically reducing the population of MrgprA3 neurons in the mice.

“Turns out that activating these neurons blocks the entry,” Inclan-Rico says. “It creates an inflammatory environment, we think, within the skin that prevents the entry and dissemination of the parasites, which is particularly cool.”

Members of the Herbert lab, (Left to right): Ulrich Femoe, Heather Rossi, Adriana Stephenson, Evonne Jean, Annabel Ferguson, De’Broski Herbert, Juan Inclan Rico, Heidi Winters, Camila Napuri, Li-Yin Hung, Olufemi Akinkuotu. (Credit: Adriana Stephenson)

The Herbert lab has been studying parasites that enter the skin, migrate through the layers of connective tissue all the way through until they find a blood vessel, and chart a course towards the lung. There they molt into another larval stage and then use the liver and portal vein to make their way to the intestines as adults where they lay eggs, leading to characteristic symptoms in humans like abdominal swelling, fever, and pain.

“So, as you may imagine, if there are fewer parasites entering the body during initial infection, and also fewer parasites making their way into the lungs,” Inclan-Rico says. “This suggests two things: That the activation of these neurons is blocking the entry of the parasites and it’s also inhibiting their dissemination through the body.” The researchers also found that the mice that had MrgprA3 ablation saw an increased amount of lung parasite infection.

Subcellular crosstalk

Armed with the knowledge that MrgprA3 neurons were involved in blocking the parasites, the team hypothesized that there may be crosstalk between these cells and immune cells, so they began investigating the relationship between these two classes.

“When we activated MrgprA3, it increased the number of macrophages in the skin,” Inclan-Rico says. “These are the white blood cells that typically come in and gobble up infectious elements, and so, when we depleted the macrophages, we saw that this was in fact a causal relationship, that the neurons were functionally linked to the macrophage response because without them the worm infection wasn’t blocked at all.”

Next, the Herbert team sought to find the specific signaling molecules involved and discovered that downstream of MrgprA3 activation the neuropeptide CGRP was released, demonstrating that this neuropeptide plays a key role in neuron-immune cell communication.

“CGRP acts like a messenger between neurons and macrophages,” Inclan-Rico says, “and this signaling triggers the activation of immune cells at the site of infection, which helps contain the parasite.”

However, CGRP wasn’t acting alone as the team found that the nuclear protein IL-33, typically known as an alarm signal released by damaged cells, played a surprising, significant role. When they examined macrophages, they discovered that IL-33 was not just being reduced but was instead acting within the cell nucleus.

“Up until now, people just thought that IL-33 was a nuclear protein, but we didn’t know exactly what it was doing in there. Its role was more thought to be as a secreted factor, either as a consequence of cell death or potentially from immune cells secreting it directly,” Rossi says. “But we did a number of experiments to prove that, in fact, IL-33 in macrophages controls the accessibility of DNA, essentially opening DNA’s tight packaging material and allowing pro-inflammatory cytokines like TNF to be expressed.”

This pro-inflammatory environment is critical for forming a protective barrier that prevents the parasite from advancing farther into the body.

“It’s a two-step process,” Inclan-Rico says. “First, MrgprA3 neurons release CGRP, which signals into macrophages. Then, IL-33 held within the macrophages’ nuclei is greatly reduced, which enhances the inflammatory response and helps block the parasite’s entry.”

Interestingly, they also found that when IL-33 was genetically deleted from macrophages, the protective response induced by itchy neurons was lost.

“This tells us that the neurons are orchestrating this whole defense, but they need the macrophages — and specifically IL-33 in those macrophages — to mount a full immune response,” Herbert says.

Looking ahead, the Herbert lab plans to dive deeper into understanding the mechanisms behind this neuron-immune communication.

“We’re really interested in identifying the molecules that parasites use to suppress the neurons and whether we can harness that knowledge to block parasite entry more effectively,” Herbert says. They also hope to identify other molecules, beyond CGRP and IL-33, that are involved in this signaling pathway.

“If we can pinpoint the exact components that parasites are targeting to evade the itch response, we could develop new therapeutic approaches that not only treat parasitic infections but potentially offer relief for other itch-related conditions like eczema or psoriasis,” Herbert says.

De’Broski R. Herbert is the presidential professor of immunology and a professor of pathobiology at the School of Veterinary Medicine at the University of Pennsylvania.

Juan Manuel Inclan-Rico is a postdoctoral researcher in the Herbert Lab at Penn Vet.

Heather L. Rossi is a senior research investigator in the Herbert Lab at Penn Vet.

Other researchers are Ulrich M. Femoe, Annabel A. Ferguson, Bruce D. Freedman Li-Yin Hung, Xiaohong Liu, Fungai Musaigwa, Camila M. Napuri, Christopher F. Pastore, and Adriana Stephenson of Penn Vet; Wenqin Luo and Qinxue Wu of the Perelman School of Medicine at Penn; Cailu Lin and Danielle R. Reed of the Monell Chemical Senses Center; Petr Horák and Tomáš Macháček of Charles University, Czech Republic; and Ishmail Abdus-Saboor of Columbia University.

The research was supported by the National Institutes of Health (grants T32 AI007532-24, R01 AI164715-01, U01 AI163062-01, P30-AR069589, and R01 AI123173-05 and contract HHSN272201700014I), Charles University (Cooperatio Biology, UNCE24/SCI/011, SVV 260687), and the Czech Science Foundation (GA24-11031S).

“Our new biochip device is low-cost — just a few dollars — and sensitive, which will make accurate disease diagnosis accessible to anyone, whether rich or poor,” said XiuJun (James) Li, Ph.D., a UTEP professor of chemistry and biochemistry. “It is portable, rapid and eliminates the need for specialized instruments.”

Li is the lead author on a new study describing the device; it’s published in Lab on a Chip, a journal that focuses on micro-scale and nanoscale devices.

Li explained that the most commonly used commercial method of cancer biomarker detection, known as ELISA, requires costly instrumentation to work correctly and can take twelve hours or longer to process a sample. This delay is heightened in rural areas in the U.S. or developing countries, he said, because patient samples must be transported to larger cities with specialized instruments, contributing to a higher rate of cancer mortality.

“If you can detect biomarkers early on, before the cancer spreads, you increase a patients’ chance of survival,” Li said. “Any delays in testing, especially in regions that don’t have access to expensive tools and instruments, can be very bad for a patient’s prognosis.”

The device that Li’s team created is microfluidic, which means that it can perform multiple functions using very small amounts of fluids. The device uses an innovative ‘paper-in-polymer-pond’ structure in which patient blood samples are introduced into tiny wells and onto a special kind of paper. The paper captures cancer protein biomarkers within the blood samples in just a few minutes. The paper subsequently changes color, and the intensity of the color indicates what type of cancer is detected and how far it has progressed.

So far, the research has focused on prostate and colorectal cancers, but Li said the method they devised could be applicable to a wide variety of cancer types.

Li said that the device can analyze a sample in an hour — compared to 16 hours using some traditional methods. According to study results, the device is also about 10 times more sensitive than traditional methods even without using specialized instruments. That means the device can detect cancer biomarkers that are present in smaller quantities, typical of cancer in its early stages. A less sensitive device may not pick up on the smaller quantities, Li said.

Before the device is available to the public, Li said the prototype of the device will need to be finalized and the device tested on patients in a clinical trial, which could take several years. It would require final approval by the Food and Drug Administration before it could be used by physicians.

“Dr. XiuJun Li’s innovation significantly improves point-of-care diagnostics by reducing detection times and the need for costly instruments,” said Robert Kirken, dean of the College of Science. “This makes it ideal for resource-limited settings, which will improve early diagnosis and lead to better cancer outcomes. I look forward to seeing what this innovation leads to.”

An additional co-author on the study is Sanjay Timilsina, Ph.D., a former graduate research assistant at UTEP. Li is a member of the Lab on a Chip advisory board.

The predictive model results can help members of the public, water suppliers and regulators understand the potential for PFAS contamination, guide future studies and inform strategic planning for water resources.

USGS scientists are the first to report national estimates of PFAS occurrence in untreated groundwater that supplies water to public and private wells. This research also provides the first estimate of the number of people across the country who are potentially affected by PFAS-contaminated groundwater.

Along with a scientific report, the USGS published an interactive, online map so users can see probability estimates of PFAS occurrence. Note that predictive results are intended to be evaluated at state, regional and national scales rather than at individual household levels. Probability estimates are for the presence of PFAS in groundwater and do not account for any subsequent actions taken by states, municipalities or individuals to treat drinking water. The model does not include estimates of PFAS concentrations; testing is the only way to confirm the presence of contaminants.

Exposure to certain PFAS may lead to adverse health risks in people, according to the U.S. Environmental Protection Agency. PFAS are a group of synthetic chemicals used in a wide variety of common applications, from the linings of fast-food boxes and non-stick cookware to fire-fighting foams and other purposes. PFAS are commonly called “forever chemicals” because many of them do not easily break down and can build up over time, making them a concern for drinking water quality.

“This study’s findings indicate widespread PFAS contamination in groundwater that is used for public and private drinking water supplies in the U.S.,” said Andrea Tokranov, USGS research hydrologist and lead author of this study. “This new predictive model can help prioritize areas for future sampling to help ensure people aren’t unknowingly drinking contaminated water. This is especially important for private well users, who may not have information on water quality in their region and may not have the same access to testing and treatment that public water suppliers do.”

The EPA has established legally enforceable levels, called maximum contaminant levels, for six types of PFAS in drinking water. The EPA regulates public water supplies, and some states have additional regulations for drinking water. Some homes use private water supplies, where residents are responsible for the maintenance, testing and treatment of their drinking water. Those interested in treatment processes and testing options can read EPA’s guidance or contact their state officials or water supplier.

The states with the largest populations relying on public water supplies with potentially contaminated groundwater sources are Florida and California. Regarding private wells, Michigan, Florida, North Carolina, Pennsylvania, New York and Ohio have the largest populations relying on potentially contaminated groundwater.

The study also presents data according to population percentage. In Massachusetts, for example, the source water for 86 to 98% of people who rely on groundwater from public water supplies could be contaminated with PFAS. In Connecticut, the source water for 67 to 87% of the people who rely on groundwater from private wells could be affected. Details by state can be seen in the report’s tables S6 through S8.

“To derive these estimates, the team analyzed 1,238 groundwater samples collected by USGS scientists and determined how factors such as urban development and well depth can impact PFAS occurrence,” continued Tokranov. “With that information, a detailed machine learning model was developed and used to identify which geographic areas have a higher likelihood for contamination. That information was combined with existing USGS research on the number of people in a given area who rely on groundwater for drinking water to establish population estimates.”

Scientists present separate estimates for public and private wells because they typically receive water from different groundwater depths. Public wells using groundwater as the primary water source are usually deeper than private wells.

There are more than 12,000 types of PFAS, not all of which can be detected with current tests; the USGS study tested for the presence of 24 common types. The USGS estimates consider the presence of at least one of those 24 types of PFAS. The most frequently detected compounds were perfluorobutane sulfonate known as PFBS, perfluorooctane sulfonate known as PFOS and perfluorooctanoate known as PFOA.

This research provides a broad outlook for the Lower 48 states and presents state-level estimates. Scientists did not look in detail at specific cities or provide estimates for the types of PFAS present or PFAS concentrations.

Innate immune cells serve as the body’s first line of defense, mobilizing a quick and general attack against invading germs. For germs that evade the body’s innate immune defenses, the second line of attack consists of adaptive immune cells, such as B cells and T cells that rely on their memory of past infections to craft a specific and targeted response. A healthy balance between innate and adaptive immune cells is the hallmark of a youthful immune system — and a key to longevity.

“Our study provides compelling evidence that when a small subset of blood stem cells overproduces innate immune cells, this drives the aging of the immune system, contributes to disease, and ultimately shortens the lifespan,” said Lu, who is an associate professor of stem cell biology and regenerative medicine, biomedical engineering, medicine, and gerontology at USC, and a Leukemia & Lymphoma Society Scholar. Lu is also a member of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, and the USC Norris Comprehensive Cancer Center at the Keck School of Medicine of USC. “Our findings suggest that restraining the small subset of blood stem cells that are overproducing innate immune cells could be an effective way to delay immune aging.”

In the study, first author Anna Nogalska and her colleagues found striking differences in how quickly the immune system ages — even among lab mice with the same genetic background raised in identical conditions. By the advanced age of 30 months, delayed aging mice retained a youthful balance of innate and adaptive immune cells. However, early aging mice showed a big increase in innate immune cells relative to adaptive immune cells.

By tracking the individual blood stem cells responsible for producing both innate and adaptive immune cells, the scientists discovered the subset of blood stem cells primarily responsible for the age-associated imbalance of the immune system. Specifically, the scientists observed that thirty to forty percent of blood stem cells dramatically changed their preference for producing innate versus adaptive immune cells as the mice aged.

In delayed agers, the subset of blood stem cells decreased their production of innate immune cells, protecting against the effects of aging. Among delayed agers, there was an increase in gene activity related to blood stem cells’ regulation and response to external signals — which might keep their production of innate immune cells in check. When the scientists used CRISPR to edit out these genes, blood stem cells reversed their natural tendency and produced more innate immune cells instead of adaptive immune cells — like in the early agers.

In contrast, in early agers, the subset of blood stem cells shifted towards producing more innate immune cells, which, in excess, lead to many diseases of aging. Accordingly, in these early agers, the scientists found an increase in gene activity related to the proliferation of blood stem cells and the differentiation of innate immune cells. When the scientists used CRISPR to edit out these early aging genes, blood stem cells produced more adaptive immune cells instead of innate immune cells — becoming more similar to those in the delayed agers.

Importantly, delayed agers tended to live longer than early agers.

“In the elderly human population, the immune system often tips into producing an overabundance of innate immune cells, which can contribute to diseases such as myeloid leukemia and immune deficiencies,” said Nogalska, senior scientist and lab manager in the Lu Lab. “Our study suggests how we might promote a more youthful immune system to combat these common diseases of aging.”

Additional co-authors are Jiya Eerdeng, Samir Akre, Mary Vergel-Rodriguez, Yeachan Lee, Charles Bramlett, Adnan Y. Chowdhury, Bowen Wang, Colin G. Cess, and Stacey D. Finley from USC.

Ninety percent of the project was supported by federal funding from the National Institutes of Health (grants R00-HL113104,R01HL138225, R35HL150826, and 1F31HL149278-01A1) and the National Cancer Institute (grant P30CA014089). Additional funding came from the California Institute for Regenerative Medicine (grant EDUC4-12756R) and the Leukemia & Lymphoma Society (grant LLS-1370-20).

Good balance, muscle strength and an efficient gait contribute to people’s independence and well-being as they age. How these factors change, and at what rate, can help clinicians develop programs to ensure healthy aging. Individually, people can train their balance without special equipment and work on maintaining it over time.

In this study, 40 healthy, independent people over 50 underwent walking, balance, grip strength and knee strength tests. Half of the participants were under 65; the other half were 65 and older.

In the balance tests, participants stood on force plates in different situations: on both feet with eyes open, on both feet with eyes closed, on the non-dominant leg with eyes open, and on the dominant leg with eyes open. In the one-legged tests, participants could hold the leg they weren’t standing on where they wanted. The tests were 30 seconds each.

Standing on one leg — specifically the nondominant leg — showed the highest rate of decline with age.

“Balance is an important measure because, in addition to muscle strength, it requires input from vision, the vestibular system and the somatosensory systems,” says Kenton Kaufman, Ph.D., senior author of the study and director of the Motion Analysis Laboratory at Mayo Clinic. “Changes in balance are noteworthy. If you have poor balance, you’re at risk of falling, whether or not you’re moving. Falls are a severe health risk with serious consequences.”

Unintentional falls are the leading cause of injuries among adults who are 65 and older. Most falls among older adults result from a loss of balance.

In the other tests:

• Researchers used a custom-made device to measure participants’ grip. For the knee strength test, participants were in a seated position and instructed to extend their knee as forcefully as possible. Both the grip and knee strength tests were on the dominant side. Grip and knee strength showed significant declines by decade but not as much as balance. Grip strength decreased at a faster rate than knee strength, making it better at predicting aging than other strength measures.
• For the gait test, participants walked back and forth on an 8-meter, level walkway at their own pace and speed. Gait parameters didn’t change with age. This was not a surprising result since participants were walking at their normal pace, not their maximum pace, Dr. Kaufman says.
• There were no age-related declines in the strength tests that were specific to sex. This indicates that participants’ grip and knee strength declined at a similar rate. Researchers did not identify sex differences in the gait and balance tests, which suggests that male and female subjects were equally affected by age.

Dr. Kaufman says people can take steps to train their balance. For example, by standing on one leg, you can train yourself to coordinate your muscle and vestibular responses to maintain correct balance. If you can stand on one leg for 30 seconds, you are doing well, he says.

“If you don’t use it, you lose it. If you use it, you maintain it,” Dr. Kaufman says. “It’s easy to do. It doesn’t require special equipment, and you can do it every day.”

Funding for this study includes the Robert and Arlene Kogod Professorship in Geriatric Medicine and W. Hall Wendel Jr. Musculoskeletal Professorship.

The findings, published in Cell Chemical Biology, lay the groundwork for developing tailored dietary strategies to help anti-cancer medications better kill malignant cells.

“We want to make cancer treatment more effective,” said Evan Lien, Ph.D., an assistant professor at VAI and the study’s corresponding author. “The best way to do this is by understanding how cancer cells behave and identifying ways to break through their defenses. Our findings are an important step toward evidence-based diets that could one day augment existing therapies.”

Fats are critical nutrients required for healthy function. Cancer cells hijack normal cellular processes and steal resources like fats, which then act as fuel for sick cells to grow and spread.

The study focused on ferroptosis, a type of cell death that occurs when fat molecules in cancer cells experience damage. In recent years, targeting ferroptosis has emerged as an increasingly promising avenue for developing new anti-cancer strategies.

Many of the mechanisms that enable cancer cells to grow uncontrollably also allow them to avoid cellular quality control processes that usually kill and remove sick cells. Ferroptosis can be an exception, which makes it a potentially powerful tool to leverage in cancer treatment.

Using cell models, Lien and his team showed that removing cancer cells’ access to fats makes them highly sensitive to ferroptosis and, by extension, drugs that induce ferroptosis.

The findings are promising, Lien says, but much more work is needed to replicate the discovery in other models of cancer. He and his team also are investigating if the type and amount of fat can be manipulated through diet to make ferroptosis inducers work more effectively.

“Diet is something that’s relatively easy to modify,” Lien said. “We’re not there yet, but the thing we’re most excited about is how we might be able to use what we learn to one day design diets tailored to different types of treatment. That could be transformative.”

Authors include Kelly H. Sokol, Cameron J. Lee, Thomas J. Rogers, Ph.D., Althea Waldhart, Abigail E. Ellis, Samuel R. Daniels, Rae J. House, Ph.D., Xinyu Ye, Mary Olsenavich, Amy Johnson, Benjamin R. Furness, and Ryan D. Sheldon, Ph.D. of VAI; and Sahithi Madireddy of the Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology.

When a virus attacks, the body’s immune response has two basic layers of defense: the innate and the adaptive immune systems. While the adaptive immune system grows stronger against a specific pathogen as the body is exposed to it multiple times and which forms the basis of vaccinations, the innate immune system is an assortment of molecular mechanisms that work against a broad range of pathogens at a basic level. The Kobe University virologist SHOJI Ikuo says, “The new coronavirus, however, is so infectious that we wondered what clever mechanisms the virus employs to evade the innate immune system so effectively.”

Shoji’s team previously worked on the immune response to hepatitis viruses and investigated the role of a molecular tag called “ISG15” the innate immune system attaches to the virus’s building blocks. Having learned that the novel coronavirus has an enzyme that is especially effective in removing this tag, he decided to use his team’s expertise to elucidate the effect of the ISG15 tag on the coronavirus and the mechanism of the virus’s countermeasures.

In a paper in the Journal of Virology, the Kobe University-led team is now the first to report that the ISG15 tag gets attached to a specific location on the virus’s nucleocapsid protein, the scaffold that packages the pathogen’s genetic material. For the virus to assemble, many copies of the nucleocapsid protein need to attach to each other, but the ISG15 tag prevents this, which is the mechanism behind the tag’s antiviral action. “However, the novel coronavirus also has an enzyme that can remove the tags from its nucleocapsid, recovering its ability to assemble new viruses and thus overcoming the innate immune response,” explains Shoji.

The novel coronavirus shares many traits with the SARS and MERS viruses, which all belong to the same family of viruses. And these viruses, too, have an enzyme that can remove the ISG15 tag. However, Shoji’s team found that their versions are less efficient at it than the one in the novel coronavirus. And in fact, it has been reported recently that the previous viruses’ enzymes have a different primary target. “These results suggest that the novel coronavirus is simply better at evading this aspect of the innate immune system’s defense mechanism, which explains why it is so infectious,” says Shoji.

But understanding just why the novel coronavirus is so effective also points the way to developing more effective treatments. The Kobe University researcher explains: “We may be able to develop new antiviral drugs if we can inhibit the function of the viral enzyme that removes the ISG15 tag. Future therapeutic strategies may also include antiviral agents that directly target the nucleocapsid protein, or a combination of these two approaches.”

This research was funded by the Kansai Economic Federation, the Hyogo Science and Technology Association (grant 3501) and the Ministry of Education, Culture, Sports, Science and Technology Japan (grant 18042-203556). It was conducted in collaboration with researchers from Universitas Gadjah Mada, Niigata University, the University of Yamanashi, Hokkaido University and Osaka University.

The research, led by a team of Stanford psychologists, published Oct. 21 in Proceedings of the National Academy of Sciences (PNAS).

“One of the hardest things for groups of people who face stigma, including previously incarcerated people, is that other Americans don’t perceive their experiences very accurately,” said Jamil Zaki, the paper’s senior author and a professor of psychology in the School of Humanities and Sciences (H&S). “One way to combat that lack of empathy for stigmatized groups of people is to get to know them. This is where media comes in, which has been used by psychologists for a long time as an intervention.”

Studying how narrative persuades

The paper incorporates Zaki’s earlier research on empathy with the scholarship of his co-author, Stanford psychologist Jennifer Eberhardt, who has studied the pernicious role of racial bias and prejudice in society for over three decades.

The idea for the study emerged from a conversation Eberhardt had with one of the executive producers of the film Just Mercy, which is based on the book by the lawyer and social justice activist Bryan Stevenson. Stevenson’s book focuses on his efforts at the Equal Justice Initiative to overturn the sentence of Walter McMillian, a Black man from Alabama who in 1987 was sentenced to death for the murder of an 18-year-old white girl, despite overwhelming evidence showing his innocence. The film vividly portrays the systemic racism within the criminal justice system and illustrates how racial bias tragically impacts the lives of marginalized individuals and their families, particularly Black Americans, as they navigate a flawed legal system.

It was around the time of the movie’s release that Eberhardt, who is a professor of psychology in H&S, the William R. Kimball Professor of Organizational Behavior in the Graduate School of Business, and a faculty director of Stanford SPARQ, published her book, Biased: Uncovering the Hidden Prejudice That Shapes What We See, Think, and Do (Viking, 2019), which grapples with many of the same issues as Just Mercy.

On her book tour, she met with many different people, including one of Just Mercy’s executive producers. He approached her with a question originally posed to him by former U.S. President Barack Obama, who had recently watched the film at a private screening. Obama wondered whether watching it could change the way neurons fired in people’s brains.

“I told this producer we don’t have to sit and wonder — this is a question that we can answer through rigorous research,” said Eberhardt. “This paper is a first step in that direction.”

Eberhardt connected with Zaki, and together they designed a study to examine how Just Mercy might change how people think about people who have been pushed to the margins of society.

To measure how watching the film might shape a person’s empathy toward formerly incarcerated people, the researchers asked participants before and after they watched the movie to also watch a set of one- to three-minute-long videos that featured men who had been incarcerated in real life. Participants were asked to rate what they thought these men were feeling as they shared their life stories. These ratings were then measured against what the men actually told the researchers they felt when recounting their experiences.

Opening minds and hearts

The study found that after watching Just Mercy, participants were more empathetic toward those who were formerly incarcerated than those in the control condition.

Their attitudes toward criminal justice reform were also swayed.

The researchers asked participants whether they would sign and share a petition that supported a federal law to restore voting rights to people with a criminal record. They found that people who watched Just Mercy were 7.66% more likely than participants in the control condition to sign a petition.

The study underscores the power of storytelling, Eberhardt said. “Narratives move people in ways that numbers don’t.”

In an early study Eberhardt co-authored, she found that citing statistics on racial disparities is not enough to lead people to take a closer look at systems — in fact, she found that presenting numbers alone can possibly backfire. For example, highlighting racial disparities in the criminal justice system can lead people to be more punitive, not less, and to be more likely to support the punitive policies that help to create those disparities in the first place.

As Eberhardt and Zaki’s study has shown, what does change people’s minds are stories — a finding consistent with a previous study Zaki conducted that found how watching a live theater performance can impact how people perceive social and cultural issues in the U.S.

The psychologists also found that their intervention works regardless of the storyteller’s race, and it had the same effect regardless of people’s political orientation.

“When people experience detailed personal narratives it opens their mind and heart to the people telling those narratives and to the groups from which those people come from,” Zaki said.

New research from the University of Washington investigated responses to sweetened beverage taxes using the purchasing behavior of approximately 400 households in Seattle, San Francisco, Oakland and Philadelphia — all of which recently introduced beverage taxes. The study was published online Sept. 30 in Health Economics.

Researchers found that after the tax was introduced, lower-income households decreased their purchases of sweetened beverages by nearly 50%, while higher-income households reduced purchases by 18%. Since previous studies have shown that lower-income individuals consume sweetened beverages at a higher-than-average rate, these results suggest the taxes could help reduce health disparities and promote population health.

“If households reduce their sugar intake, they will experience health benefits,” said Melissa Knox, co-author and UW associate teaching professor of economics. “Sweetened beverages are one of the largest sources of sugar in the American diet. They have all kinds of health consequences and don’t really provide any nutrition. The idea with the tax is that lower-income people, because they reduce their intake more, receive greater health benefits than the higher-income households.”

Using Nielsen Consumer Panel, researchers followed the households for a year before and after the tax was implemented in their city. Consumers were given a handheld scanner to report their purchases.

The results showed that households experienced price increases for taxed beverages, with the difference persisting for at least one year post-tax. Price increases were largest for lower-income households — a 22% increase in sweetened beverage prices versus 11% for higher-income households. After the tax was implemented, lower-income households saw a 47% decline in purchases of sweetened beverages. Researchers didn’t observe a post-tax increase in cross-border shopping.

“We also looked at untaxed beverages and found that lower-income households are substituting with untaxed beverages,” Knox said. “They’re using some of their money to go buy a different beverage, rather than buying a candy bar instead of buying a Coke.”

Policy makers are particularly interested in the response of lower-income consumers due to their higher consumption on average of sweetened beverages and concerns that the taxes are regressive.

Previous research from the UW found that lower-income and higher-income households paid about the same amount toward the tax, which means lower-income households spent a higher proportion of their income. But the study also showed more dollars went toward funding programs that benefit lower-income communities than those households paid in taxes. The annual net benefit to lower-income communities ranged from $5.3 million to $16.4 million per year across three U.S. cities.

More past research from the UW found the tax was also associated with declines in childhood body mass index among children in Seattle compared to a well-matched comparison group.

“Together, this body of work suggests the tax is having the intended health benefits and this new evidence gives reason to believe health benefits could be larger for households with lower incomes,” said Jessica Jones-Smith, co-author and UW professor of health systems and population health.

The research was funded by the UW’s Royalty Research Fund and the Robert Wood Johnson Foundation. Partial support was provided by a Eunice Kennedy Shriver National Institute of Child Health and Human Development research infrastructure grant.

Rett syndrome is caused by mutations of the MECP2 gene located on the X chromosome. Children with Rett initially show typical development before symptoms start.

The symptoms vary widely. They include loss of hand function, breathing difficulties and seizures that affect the child’s ability to speak, walk, and eat. Rett is less common in males, but when they are affected, symptoms are typically more severe and present earlier than in females.

The study, published in Communications Biology, analyzed the cerebral cortices of male and female mice with and without MECP2 mutation at three timepoints: before symptoms, when symptoms started, and during late disease stage. It looked at gene expression in 14 different cell types.

“In an X-linked dominant disorder such as Rett, it is important to know that females do not just have less severe symptoms than males. Their condition is different,” said Janine LaSalle, lead author of the study and professor of microbiology and immunology at UC Davis Health. “That is why it is important to study female mouse models of Rett. They are more relevant for developing treatments.”

Most studies use male mouse models for Rett syndrome. These models have an engineered deletion of key MECP2 gene elements. This disables the production of MeCP2 protein in all cells, as males have only one X chromosome.

In humans with Rett, this type of MECP2 gene deletion does not exist. All the cells in females with Rett have an MECP2 mutation inherited from one parent on the X chromosome, but only half of the cells express the mutant gene. This means the other half of the cells with a wild-type copy of MECP2 inherited from the other parent expresses normal MeCP2 protein.

Thus, the brain of a girl with Rett syndrome has a mosaic-like distribution of cells expressing wild-type MeCP2 and cells expressing mutant MeCP2 protein.

“When we separated the two types of cells in the brain, we could see that the wild-type expressing cells are really dysregulated,” LaSalle said.

Mosaic brains and the seesaw effect in dysregulated genes

Gene regulation is the process of turning genes on and off. Dysregulated genes are either over expressing or under expressing, which means they are producing more or less of certain functional proteins. In the female mouse model with Rett syndrome, this gene impairment went in stages. The researchers called this “the seesaw effect.”

The authors studied the wild-type expressing cells of mosaic female Rett mouse brain. They found changes to gene responses in excitatory neurons before symptoms started, in inhibitory neurons when symptoms started, and then in astrocytes at a later stage.

“There was a back-and-forth oscillation where it seems like the genes are trying to reach homeostasis or balance in the brain. This idea of the seesaw homeostasis is important to look at over time, as the symptoms progress,” LaSalle said.

LaSalle explained that the wild-type expressing cells are trying to counteract the effects from the mutant expressing cells. By doing so, they become dysregulated themselves. The wild-type cells start expressing genes up and down. This dysregulation is worse in the beginning and then it stabilizes as Rett progresses.

Finding balance as disease progresses

The study found an unusual disease progression. One can start out with normal infancy, regress, then plateau, and then regress again and then finally plateau. Plateauing resembles a state of homeostasis, a stabilization of symptoms over time.

“We expected the number of impaired genes to go along with the increased symptoms. To our surprise, the females actually had more dysregulated genes at the pre-symptomatic stage than they did later on,” LaSalle said.

The study also found that females overall had more dysregulated genes and at different disease stages compared to males. This suggests that males are not just experiencing a more severe version of Rett. Importantly, this study confirmed that the use of a female mouse model is a better representation of Rett syndrome in females.

The study also examined various gene pathways. A pathway is like taking a diverse group of genes and putting them into a functional group. If the human body is a factory, a pathway would be a team within the factory. For example, a team would be keeping the heart rate normal. Another would be working on the sleep-wake cycle.

The study showed a link between the MECP2 mutation and the Alzheimer’s pathway as well as various addiction pathways.

“In genomics, we have moved from looking at one gene at a time to thinking about groups of genes that act together in pathways. The findings point to different pathways, which means MECP2 mutation may have relevance to other diseases beyond Rett syndrome,” LaSalle explained.

This study was supported by multiple National Institutes of Health grants (1R01AA027075, 1S10OD010786-01, P50 HD103526, P30 ES023513), the National Cancer Institute grant (P30 CA093373) and Astrios Cell Sorter grant (S10 OD018223). UC Davis co-authors include Osman Sharifi, Dag Yasui, Viktoria Haghani, Kari Neier, Sophia Hakam, Keith Fraga, Ian Korf, Gerald Quon and Nelson Johansen.

The findings are published October 15 in Journal of General Internal Medicine.

IMGs, or those who graduated from a medical school located outside the U.S. and Canada, now make up a quarter of all licensed physicians in the U.S. This population has been shown to specialize in primary care at a higher rate than U.S. medical graduates, especially in underserved areas across the country. However, their citizenship status, which differentially affects their ability to enter and remain in the U.S. after medical school, can impact which specialties they enter and where they ultimately practice medicine.

“IMGs have made significant contributions to the U.S. health care system, as they are more likely to work in high-need, underserved areas,” says Tarun Ramesh, lead author of the study and research fellow at the Harvard Pilgrim Health Care Institute. “Because various factors threaten their ability or wish to continue their contributions, it’s crucial that we understand how their citizenship status impacts which specialty and practice location they choose to better aid policymakers in adapting interventions to incentivize entering primary care practice, especially in rural and shortage-facing areas.”

Researchers studied 15,133 new physicians who accepted a job offer from 2010 to 2019 using the New York Resident and Fellows Exit Survey. The study sample included 8,177 U.S. medical graduates; 2,753 U.S. citizen IMGs; 1,057 permanent resident IMGs; and 3,146 noncitizen non-permanent resident IMGs. The study assessed three distinct outcomes: whether a new physician chose to practice primary care; whether a new primary care physician chose to work in a rural area; and whether a new primary care physician chose to work in a health professional shortage area.

The team found that citizenship status has significant effects on IMGs’ choices of specialties and practice locations, confirming that the role played by IMGs in the US health care system differs by their citizenship status. Compared to U.S. medical graduates, the team found that US citizen IMGs were five times, permanent resident IMGs seven times, and noncitizen non-permanent resident IMGs nine times more likely to enter primary care compared to US medical graduates. They also identified two distinct trends: a declining proportion of noncitizen non-permanent resident IMGs entering primary care and increased likelihood of their practicing in rural areas and health professional shortage area.

“The role that IMGs play in bolstering health care options in underserved areas shouldn’t be overlooked,” said senior author Hao Yu, Harvard Medical School associate professor of population medicine at the Harvard Pilgrim Health Care Institute. He adds, “While visa incentive programs may drive non-citizen, non-permanent resident IMGs to practice in these areas, our findings show that more nuanced efforts are needed to make primary care a more attractive specialty.”

The authors suggest that further research is needed to better understand differences in subspeciality, salaries, job satisfaction, and incentives among U.S. citizen, permanent resident, and noncitizen non-permanent resident IMGs, in addition to evaluating new state laws offering provisional licensing pathways for IMGs to practice medicine.

The study, published today in Current Biology, investigates the neural foundations of behavioural innovation in Heliconius butterflies, the only genus known to feed on both nectar and pollen. As part of this behaviour, they demonstrate a remarkable ability to learn and remember spatial information about their food sources — skills previously connected to the expansion of a brain structure called the mushroom bodies, responsible for learning and memory.

Lead author Dr Max Farnworth from the University of Bristol’s School of Biological Sciences explained: “There is huge interest in how bigger brains may support enhanced cognition, behavioural precision or flexibility. But during brain expansion, it’s often difficult to disentangle effects of increases in overall size from changes in internal structure.”

To answer this question, the study authors delved deeper into the changes that occurred in the neural circuits that support learning and memory in Heliconius butterflies. Neural circuits are quite similar to electrical circuits as each cell has specific targets that they connect with, and assembles a net with its connections. This net then elicits specific functions by constructing a circuitry.

Through a detailed analysis of the butterfly brain, the team discovered that certain groups of cells, known as Kenyon cells, expanded at different rates. This variation led to a pattern called mosaic brain evolution, where some parts of the brain expand while others remain unchanged, analogous to mosaic tiles all being very different from each other.

Dr Farnworth explained: “We predict that because we see these mosaic patterns of neural changes, these will relate to specific shifts in behavioural performance — in line with the range of learning experiments which show that Heliconius outperform their closest relatives in only very specific contexts, such as long-term visual memory and pattern learning.”

To feed on pollen, Heliconius butterflies need to have efficient routes of feeding, as pollen plants are quite rare.

Project supervisor and co-author, Dr Stephen Montgomery said: “Rather than having a random route of foraging, these butterflies apparently choose fixed routes between floral resources — akin to a bus route. The planning and memory processes needed for this behaviour are fulfilled by the assemblies of neurons inside the mushroom bodies, hence why we’re fascinated by the internal circuitry throughout. Our results suggest that specific aspects of these circuits have been tweaked to bring about the enhanced capacities of Heliconius butterflies.”

This study contributes to the understanding on how neural circuits change to reflect cognitive innovation and change. Examining neural circuits in tractable model systems such as insects promises to reveal genetic and cellular mechanisms common to all neural circuits, thus potentially bridging the gap, at least on a mechanistic level, to other organisms such as humans.

Looking ahead, the team plans to explore neural circuits beyond the learning and memory centres of the butterfly brain. They also aim to increase the resolution of their brain mapping to visualise how individual neurons connect at an even more granular level.

Dr Farnworth said: “I was really fascinated by the fact that we see such high degrees of conservation in brain anatomy and evolution, but then very prominent but distinct changes.”

“This is a really fascinating and beautiful example of a layer of biodiversity we don’t usually see, the diversity of brain and sensory systems, and the ways in which animals are processing and using the information provided by the environment around them” concluded Dr Montgomery.

Breast canceris a significant global public health challenge, with 2.3 million new cases and 700,000 deaths every year. Approximately 80% of patients with primary breast cancer can be cured, if they are diagnosed and treated promptly. However, in many cases, the cancer has already spread to other parts of the body, or metastasized, at the time of diagnosis.

Metastatic cancer is incurable and accounts for more than 90% of cancer-related deaths. Currently, there are no reliable in vitro models to study how breast cancer spreads to secondary organs such as bone, lung, liver or brain. Now, researchers from the Precision Nanomaterials Group at Tampere University and the Cancer Molecular Biology Lab at Izmir Institute of Technology have used lab-on-a-chip platforms to create a physiologically relevant metastasis model to study the factors controlling breast cancer bone metastasis.

“Breast cancer most frequently spreads to bone, with an estimated rate of 53%, resulting in severe symptoms such as pain, pathological bone fractures, and spinal cord compressions. Our research provides a laboratory model that estimates the likelihood and mechanism of bone metastasis occurring within a living organism. This advances the understanding of molecular mechanisms in breast cancer bone metastasis and provides the groundwork for developing preclinical tools for predicting bone metastasis risk,” says Burcu Firatligil-Yildirir, postdoctoral researcher at Tampere University and the first author of the paper.

According to Nonappa, Associate Professor and leader of the Precision Nanomaterials Group at Tampere University, developing sustainable in vitro models that mimic the complexity of the native breast and bone microenvironment is a multidisciplinary challenge.

“Our work shows that physiologically relevant in vitro models can be generated by combining cancer biology, microfluidics and soft materials. The results open new possibilities for developing predictive disease, diagnostic and treatment models,” he says.

The Precision Nanomaterials Group at Tampere University develops various in vitro cancer metastasis disease and diagnostic models.

The team has found that a class of protective proteins known as MANF plays a role in the process that keep cells efficient and working well.

The findings appear in the journal Proceedings of the National Academy of Sciences.

Our cells make proteins and discard them after they perform their jobs. This efficient, continuous maintenance process is known as cellular homeostasis. However, as we age, our cells’ ability to keep up declines.

Cells can create proteins incorrectly, and the cleanup process can become faulty or overwhelmed. As a result, proteins can clump together, leading to a harmful buildup that has been linked to such diseases as Alzheimer’s and Parkinson’s.

“If the cells are experiencing stress because this protein aggregation has started, the endoplasmic reticulum, which is where proteins are made and then released, gets the signal to stop making these proteins,” explains biology professor Bhagwati Gupta, who supervised the research.

“If it can’t correct the problem, the cell will die, which ultimately leads to degeneration of the neurons and then neurodegenerative diseases that we see.”

Previous studies, including one from McMaster, had shown that MANF protects against increased cellular stress. The team set out to understand how this happens by studying microscopic worms known as C. elegans. They created a system to manipulate the amount of MANF in C. elegans.

“We could literally see where MANF was expressed in the worms because they are translucent. We could see it in all different tissues. Within these tissues, MANF was present in structures known as lysosomes which are associated with lifespan and protein aggregation,” said Shane Taylor, now a post-doctoral fellow at the University of British Columbia who worked on the project for his PhD while at McMaster.

The team discovered that MANF plays a key role in the cell’s disposal process by helping to break down the accumulated proteins, keeping cells healthier and clutter-free.

Increasing MANF levels also activates a natural clean-up system within cells, helping them function better for longer.

“Although our research focused on worms, the findings uncover universal processes. MANF is present in all animals, including humans. We are learning fundamental and mechanistic details that could then be tested in higher systems,” said Taylor.

To develop MANF as a potential therapy, researchers want to understand what other players MANF interacts with.

“Discovering MANF’s role in cellular homeostasis suggests that it could be used to develop treatments for diseases that affect the brain and other parts of the body by targeting cellular processes, clearing out these toxic clumps in cells and maintaining their health,” said Gupta.

“The central idea of aging research is basically can we make the processes better and more efficient. By understanding how MANF works and targeting its function, we could develop new treatments for age-related diseases. We want to live longer and healthier. These kinds of players could help that.”

Published in the journal Aging Cell on October 18, 2024, in collaboration with researchers from the National Institutes of Health (NIH) and Duke University, the study identified a protein linked to the cardiovascular health of animal models with progeria that could translate to human treatments. Heart failure and stroke are the most common causes of death for people with HGPS, who typically have a life expectancy between 6 and 20 years old.

These new findings from the lab of UMD Cell Biology and Molecular Genetics Professor Kan Cao are “highly promising,” according to lead author and biological sciences Ph.D. student Sahar Vakili.

“This could pave the way for new treatments targeting cardiovascular complications in HGPS, which are currently a major cause of mortality in the affected children,” Vakili said. “Beyond progeria, insights gained from this research might also be applicable to other age-related diseases where endothelial dysfunction plays a role.”

Sometimes called the “Benjamin Button disease,” HGPS causes a variety of symptoms associated with aging, including skin wrinkling, joint stiffness, and the loss of hair and body fat. The disease stems from a mutation in the LMNA(lamin A) gene, which produces a protein that helps to keep cells healthy.

To better understand how progeria causes cardiovascular complications, the research team looked at endothelial cells. These cells line the body’s vascular system — including the heart — and control substances moving in and out of the bloodstream. When endothelial cells malfunction, it can lead to an array of conditions, including cardiovascular disease, stroke, blood clots and atherosclerosis (buildup of plaque inside the arteries).

More specifically, the researchers wanted to understand the signals sent by endothelial cells that ultimately lead to HGPS-related cardiovascular disease. For the first time, the team discovered that Angiopoietin-2 (Ang2) — a protein that regulates the formation of new blood vessels and the flow of substances through blood vessel walls — is significantly impaired in individuals with progeria, affecting the overall function of their endothelial cells.

The researchers discovered they could use Ang2 to “rescue” endothelial cells, improving their health despite dysfunction stemming from HGPS. It enhanced the formation of blood vessels, normalized cell migration and even restored nitric oxide levels, which are crucial for a healthy vascular system.

“Ang2 treatment also improves endothelial cell signaling to vascular smooth muscle cells, suggesting it could be a potential therapy for vascular dysfunctions in HGPS,” Vakili said.

Current treatments for HGPS can help reduce the risk of fatal complications like heart attack and stroke, but they do not target the underlying disease. Cao explained that their research is unlikely to offer a definitive progeria cure, but it could buy patients more time by improving their health in other ways.

“While Ang2 only has receptors on the endothelial cells, it may have a broader beneficial impact on additional tissue types beyond cardiovascular systems, such as bone and fat tissues, since blood vessels are essential for our body to transport nutrients, oxygen and waste,” said Cao, who started studying progeria during her postdoc in 2005, just two years after the cause of progeria was discovered.

As a next step, Cao plans to conduct a follow-up study in collaboration with a group at the NIH to explore different methods of administering Ang2 to animal models with progeria.

While the work is ongoing, Cao is confident that each new study will bring researchers closer to identifying a cure.

“We are getting really close to a cure for progeria,” she said. “Research-wise, we are pushing hard, and I can see the light at the end of the tunnel.”

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social interaction and communication, and restricted and repetitive patterns of behavior, interests and activities. ASD is nearly four times more prevalent among males than females, but the reason for this disparity is not well understood.

One common hypothesis involves the difference in sex chromosomes between males and females — typical females have two X chromosomes, while typical males have one X and one Y chromosome.

“A leading theory in the field is that protective factors of the X chromosome lower autism risk in females,” said Matthew Oetjens, Ph.D., assistant professor at Geisinger’s Autism & Developmental Medicine Institute.

The Geisinger research team, led by Dr. Oetjens and Alexander Berry, Ph.D., staff scientist, sought to determine the effects of the X and Y chromosomes on autism risk by examining ASD diagnoses in people with an abnormal number of X or Y chromosomes, a genetic condition known as sex chromosome aneuploidy.

The team analyzed genetic and ASD diagnosis data on 177,416 patients enrolled in the Simons Foundation Powering Autism Research (SPARK) study and Geisinger’s MyCode Community Health Initiative. They found that individuals with an additional X chromosome had no change in ASD risk, but that those with an additional Y chromosome were twice as likely to have an ASD diagnosis. This suggests a risk factor associated with the Y chromosome instead of a protective factor associated with the X chromosome.

“While these may seem like two sides of the same coin, our results encourage us to look for autism risk factors on the Y chromosome instead of limiting our search to protective factors on the X chromosome,” Dr. Berry said. “However, further research is needed to identify the specific risk factor associated with the Y chromosome.”

This analysis also confirms prior work by showing that the loss of an X or Y chromosome, known as Turner syndrome, is associated with a large increase in ASD risk. Further research is needed to determine whether the ASD risk factors associated with sex chromosome aneuploidy explains the sex difference in ASD prevalence.

Researchers found 10 ‘target’ PFAS (perfluoroalkyl substances) — chemicals which do not break down in nature — in tap and bottled water available for consumption in major cities in the UK and China. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) were detected in over 99% of samples of bottled water sourced from 15 countries around the world.

They observed significant differences in PFAS concentrations between tap water samples from Birmingham, UK, and Shenzhen, China, with Chinese tap water found to have higher concentrations of PFAS compared to UK tap water.

However, the study demonstrates that measures such as boiling and/or activated carbon filtration — typically using a ‘jug’ water filter — can substantially reduce PFAS concentrations in drinking water, with removal rates ranging from 50% to 90% depending on the PFAS and treatment type.

Publishing their findings today (17 October) in ACS ES&T Water, researchers from the University of Birmingham, Southern University of Science and Technology, Shenzhen, and Hainan University, Haikou, reveal a wide range of PFAS contamination for target PFAS, starting at 63% of bottled waters tested.

Co-author Professor Stuart Harrad, from the University of Birmingham, commented: “Our findings highlight the widespread presence of PFAS in drinking water and the effectiveness of simple treatment methods to reduce their levels. Either using a simple water filtration jug or boiling the water removes a substantial proportion of these substances.

“While current PFAS levels in most water samples are not a major health concern, ongoing monitoring and regulation are crucial to protect public health. We provide valuable data on the presence of PFAS in drinking water alongside practical solutions to mitigate consumer exposure via drinking water. This is a significant step towards ensuring safer drinking water for communities worldwide.”

Bottled water from various countries showed varying levels of PFAS, with natural mineral water containing higher concentrations than purified water, but the concentrations were generally below health advisory levels set by regulatory agencies.

Co-author Professor Yi Zheng, from Southern University of Science and Technology, commented: “Increased awareness about the presence of PFAS in both tap and bottled water can lead to more informed choices by consumers, encouraging the use of water purification methods.

Our findings also suggest that the potential health risks of PFAS in drinking water may be influenced by lifestyle and economic conditions, highlighting the need for future research to further explore these factors from a socio-economic perspective.”

Except for comparisons between natural mineral and purified water, the researchers observed no significant difference in target PFAS concentrations between glass and plastic or still and sparkling bottled water.

While concentrations of most individual PFAS were well below corresponding health-based reference values, average PFOS concentrations in tap water samples from Shenzhen, China exceeded the maximum contaminant level (MCL) of 4 ng/L newly promulgated by the US Environmental Protection Agency (USEPA) in 2024.

Researchers purchased 112 bottled water samples from local shops and online supermarkets in the UK and China including 89 still and 23 sparkling waters in either plastic or glass bottles. The samples covered 87 brands with water sources originating from 15 countries in Asia, Europe, North America, and Oceania

They collected 41 tap water samples from homes in Birmingham and the nearby cities of Worcester, Coventry, and Derby — provided by two suppliers: South Staffordshire Water and Seven Trent Water, with a further 14 tap water samples collected from homes in Shenzhen, China.

PFAS are used widely in industry, in fire-fighting foams, and consumer products from waterproof clothing and school uniforms to personal care products because of their water and stain repellent properties. While some have been banned by government regulation, others are still widely used and their toxic effects not yet fully investigated.

The chemicals are already known to enter the body in different ways, for example being breathed in, ingested via food or drinking water, or absorbed through the skin. They are known to cause adverse health effects such as a lowered immune response to vaccination, impaired liver function, decreased birth weight, and increased risk of some cancers.

The scientists were investigating the hippocampus, a brain area that plays a key role in memory in humans and mice. Specifically, they focused on the CA2 region, which is significant for social memory, the ability to remember other individuals, and the CA1 region, which is important for remembering places.

In this new study, the researchers for the first time reveal that CA1 and CA2 respectively encode the locations and individuals linked with a threatening experience. The results show that, beyond simply recognizing individuals, CA2 helps record more complex aspects of social memory: in this case, whether another individual is safe or risky. The scientists published their findings on October 15 in the journal Nature Neuroscience.

“It’s vital to all species that live in social communities, including mice and humans, to have social memories that can help one avoid future experiences with others that might prove harmful while keeping ourselves open to individuals who may be beneficial,” saidPegah Kassraian, PhD, a postdoctoral research fellow in the Siegelbaum lab and lead author of the new study. “Fearful memories are important for survival and help to keep us safe.”

To investigate where fearful social memories originate in the brain, Dr. Kassraian and her colleagues gave individual mice a choice. They could scamper to one place, meet another mouse that was unknown to them, and receive a mild foot shock (much like a static electricity zap people might get after walking on a carpet and touching a doorknob). Scurrying in the opposite direction to meet a different stranger was safe. Normally, the mice quickly learned to avoid the strangers and locations that were associated with the shocks, and these memories lasted for at least 24 hours.

To determine where in the hippocampus these memories were stored, the researchers genetically altered the mice to enable them to selectively suppress the CA1 or CA2 regions. Surprisingly, turning off each region had very different effects. When the scientists silenced CA1, the mice could no longer remember where they were zapped, but they could still remember which stranger was associated with the threat. When they silenced CA2, the mice remembered where they were shocked, but became indiscriminately afraid of both strangers they met.

These new findings reveal that CA2 helps mice remember whether past encounters with others were threatening or safe. The results also are consistent with prior research detailing how CA1 is home to place cells, which encode locations.

Previous research has implicated CA2 in various neuropsychiatric conditions such as schizophrenia and autism. The new study suggests that further investigating CA2 might help scientists better understand social anxiety, post-traumatic stress disorder and other conditions that can lead to social withdrawal.

“It’s possible that social withdrawal symptoms are related to an inability to discriminate between who is a threat and who is not,” said Dr. Siegelbaum, who is also a professor and chair of the department of neuroscience at Columbia’s Vagelos College of Physicians and Surgeons. “Targeting CA2 could be a useful way of diagnosing or treating disorders linked with a fear of others.”

The paper, “The hippocampal CA2 region discriminates social threat from social safety,” was published online in Nature Neuroscience on October 15, 2024.

The full list of authors includes Pegah Kassraian, Shivani K. Bigler, Diana M. Gilly, Neilesh Shrotri, Anastasia Barnett, Heon-Jin Lee, W. Scott Young, and Steven A. Siegelbaum.

The authors report no conflicts of interest.

A team of researchers led by Prof. Dr. Alexander Eggel from the Department for BioMedical Research (DBMR) at the University of Bern and the Department of Rheumatology and Immunology, Bern University Hospital, and Prof. Dr. Thomas Kaufmann from the Institute of Pharmacology at the University of Bern, developed an alternative test in 2022. It mimics the allergic reaction in a test tube and thus offers an attractive alternative to standard tests. The researchers from Bern have now investigated the effectiveness of the test on samples from children and adolescents with confirmed peanut allergy and a healthy control group in a clinical study in collaboration with partners from the Hospital for Sick Kids in Toronto, Canada. They were able to show that the new test has a higher diagnostic accuracy than the methods used so far. The study was recently published in the European Journal for Allergy and Clinical Immunology (Allergy).

Mast cell activation test as appropriate alternative

“The most common food allergies are type I allergies. They develop when the body produces immunoglobulin E (IgE) antibodies in response to substances that are actually harmless (allergens),” explains Alexander Eggel. These antibodies bind to specific receptors on the mast cells, which are immune cells that play an important role in allergic reactions and inflammation. They are mainly located in the tissue, for example, in the intestinal mucosa, and are prepared for and sensitized to the allergen by binding to the antibodies. Upon renewed contact with the allergen, it binds directly to the mast cells loaded with antibodies, activating them and triggering an allergic reaction. ”In the Hoxb8 mast cell activation test (Hoxb8 MAT), which we developed, mast cells grown in the laboratory are brought into contact with blood serum from allergic patients. The mast cells bind the IgE antibodies from the serum and are sensitized by them. We can then stimulate the mast cells with different amounts of the allergens to be tested,” says Eggel. Quantifying the activated mast cells suggests how allergic a patient is to the allergen tested without needing to consume the food.

Higher diagnostic accuracy than standard tests

The study used serum samples from a total of 112 children and adolescents who had already participated in a study in Canada and for whom clear diagnostic data on their peanut allergy status were available. The mast cells cultured in the laboratory were sensitized with their serum and then stimulated with peanut extract. “The cell-based test was easy to carry out and worked perfectly. All samples were measured within two days, which was very fast,” says Thomas Kaufmann. The results showed that a large number of sera from allergic patients exhibited allergen dose-dependent activation, while almost all samples from the non-allergic control subjects did not activate the mast cells. “An exceptionally high diagnostic accuracy of 95% could be calculated from these data,” Eggel adds.

In addition, the data measured in the study were analyzed in direct comparison with other diagnostic methods established at the hospital. It was found that the Hoxb8 MAT test had significantly higher accuracy than the standard measurement of allergen-specific IgE antibodies in the blood or the frequently used skin test. “Comparison with other clinical tests was crucial to determine which of them reflected the patients’ allergic reaction best. The new mast cell activation test has the advantage that it is functional and therefore incorporates many parameters that are important for triggering the allergy,” says Thomas Kaufmann, adding: “The new test is also based on stable blood serum, which can be drawn using simple blood sampling and then stored in the freezer. This eliminates the challenging logistical obstacles that arise with other methods.” The study also showed that the Hoxb8 MAT test leads to less false negative results.

“What has been shown in this study on the diagnosis of peanut allergies can also be applied to other allergies in a simple way. The technology is a perfect example of how basic research from the University of Bern can be brought to the clinical practice, and might ultimately simplify life for patients and physicians,” concludes Eggel.

While public discourses often focus on international migration, existing scientific evidence indicates that when climatic factors drive migration, it often results in short distance moves within national borders. However, there is a lack of scientific studies examining climate-induced internal migration across different countries. The new study, published in Nature Climate Change, used census microdata from 72 countries spanning the period from 1960 to 2016 to provide the first worldwide assessment of how environmental stress affects migration within national borders.

“Our analysis shows that internal migration — which we defined as movement between subnational regions within a country — increases in regions affected by drought and aridification, especially in hyper-arid and arid regions. The effects are most pronounced in agriculturally dependent and rural areas, where livelihoods are highly vulnerable to changing climate conditions. Many climate-induced migrants move to urban areas, contributing to the accelerated urbanization trends observed in numerous countries,” explains lead author Roman Hoffmann, who leads the Migration and Sustainable Development Research Group at IIASA.

The analysis revealed regional differences in impacts. The effects of drought and aridification were, for example, found to be strongest in parts of Africa, the Middle East, South America, South Asia, and Southern Europe, where agricultural livelihoods are prevalent and the climate is already dry. In these regions, the combination of economic hardship and environmental challenges creates strong incentives for migration.

Globally, the findings indicate overall more mobility in wealthier areas where migration constraints may be lower. Within countries, it is typically poorer regions that tend to have higher outmigration rates toward wealthier areas when they are affected by climatic stress. In addition to regional differences, the study also documents major heterogeneities in migration patterns across population groups. In less developed countries, younger working-age adults (15-45) with medium levels of education are most likely to migrate in response to drought and increased aridity. In wealthier countries, older populations across all education levels show stronger migration patterns.

“As climate change continues to increase the frequency and severity of droughts and water scarcity worldwide, more populations will face pressures to seek better living conditions. Our work underscores the need for policies that address both the drivers of migration and the consequences for destination regions. Adequate infrastructure, health services, and social support systems are critical in urban areas that are increasingly absorbing climate-induced migrants,” notes coauthor Guy Abel, a researcher in the IIASA Migration and Sustainable Development Research Group.

Additionally, the research highlights the importance of supporting vulnerable populations, including those who cannot migrate due to resource constraints. Policies that promote livelihood diversification, social safety nets, and resilience-building in affected communities can help mitigate forced migration and displacement, while also protecting those who remain.

Although the study represents a major step forward in understanding the links between climate change and internal migration, the authors also acknowledge the challenges posed by limited and non-comparable migration data. The dataset used in the study, extracted from census microdata, provides a robust longitudinal view on internal migration for a large number of countries. At the same time, it does not capture other forms of movement, including temporal or short-distance mobility, which are also highly relevant in the context of climate change.

“As climate change continues to reshape migration trends, more comprehensive data and continued research will be essential for developing targeted interventions and policy solutions to address the complex relationship between environmental factors and human mobility. Our work highlights the urgent need for a holistic approach to policy development that accounts for both spatial and social differences, recognizing the complex and context-dependent nature of migration dynamics,” concludes coauthor Raya Muttarak, a researcher in the IIASA Migration and Sustainable Development Research Group and professor of Demography and the Department of Statistical Sciences at the University of Bologna, Italy.

Infertility is a growing problem and the number of in vitro fertilisation procedures is increasing rapidly. It is already known that women who become pregnant by assisted reproduction techniques have an increased risk of preeclampsia, repeated miscarriages and the baby being born prematurely and with a lower birth weight. Yet, the reasons behind this have not been fully understood.

“Before a planned in vitro fertilisation, the man’s sperm sample is analysed for concentration, motility and morphology. But there are men who, according to this analysis, have normal sperm, but still have reduced fertility,” says Amelie Stenqvist, lecturer at Lund University. She received her PhD from Lund and now works as a specialist in gynaecology and obstetrics at Skåne University Hospital in Malmö.

Around 20-30 per cent of babies born through in vitro fertilisation have fathers with damaged DNA in their sperm, as shown by elevated levels of DNA fragmentation. The DNA fragmentation index (DFI) is a measure of the amount of strand breaks in the DNA and is used to provide important new information about male fertility. Sperm with DNA damage may still be fertile, but the chances of fertilisation are lower and if the percentage of DFI exceeds 30 per cent, the chances of natural conception are close to zero.

Although current in vitro techniques mean that men with a high DFI can become fathers, until now very little has been known about the impact of DNA fragmentation on pregnancy and the health of the baby. It has been difficult to research the topic because the DFI value is not included in the standard measurements currently taken by Sweden’s fertility clinics. It also requires a large study population and access to national medical registries.

“Since half of the placenta’s DNA comes from the father and placental development and function play a central role in preeclampsia, we wanted to investigate whether a high percentage of DNA damage in the sperm affected the risk of preeclampsia,” says Aleksander Giwercman.

He is a professor of reproductive medicine at Lund University, a consultant at Skåne University Hospital in Malmö and one of the researchers behind ReproUnion**. Aleksander Giwercman also led a research study that included 1,660 children conceived through IVF and ICSI at the Reproductive Medicine Centre in Malmö over the period 2007-2018*.

The results showed that in the 841 couples who underwent IVF, a DFI of over 20 per cent doubled the risk of the woman developing preeclampsia (10.5 per cent) and also increased the risk of premature birth. In the IVF group with a DFI below 20 per cent, there was a 4.8 per cent risk of preeclampsia, which is comparable to pregnancies that occur naturally. For couples undergoing ICSI, there was no association with preeclampsia.

“Today, DFI analysis is only performed at some fertility clinics in Sweden, but we think that it should be introduced as standard at all clinics. It can give couples answers as to why they are not getting pregnant and can influence the chosen method of assisted fertilisation. Not only that, our latest results show that a DFI analysis could be used to identify high-risk pregnancies,” says Aleksander Giwercman.

What makes this finding even more interesting is that high DNA fragmentation in sperm is linked to the overall health of the father and is potentially treatable. Most DNA damage is caused by oxidative stress, which is an imbalance between harmful molecules and the antioxidants that protect cells. Other factors that increase DNA fragmentation include the man’s age, smoking, obesity and infections.

“The next step is to identify which group of men respond best to methods to prevent and treat sperm DNA damage, and to test these methods to prevent pregnancy complications,” concludes Amelie Stenqvist.

Protein degrader molecules are heralding a revolution in drug discovery, with more than 50 drugs of this type currently being tested in clinical trials for patients with diseases for which no other options exist.

The Centre for Targeted Protein Degradation (CeTPD) at the University of Dundee is one of the world’s leading centres for research into how protein degraders work and how they can most effectively be put to use for a new generation of drugs.

Now researchers have revealed previously invisible levels of detail and understanding of how the protein degraders work, which in turn is allowing for even more targeted use of them at the molecular level.

PhD student Charlotte Crowe, together with Dr Mark Nakasone, Senior Postdoctoral Scientist at CeTPD, used a technique called cryo-electron microscopy (cryo-EM), which enables scientists to see how biomolecules move and interact with each other.

This works by flash-freezing proteins and using a focused electron beam and a high-resolution camera to generate millions of 2D images of the protein. They then used sophisticated software and artificial intelligence (AI) models which allowed them to generate 3D snapshots of the degrader drugs working in action.

Their latest research is published in the journal Science Advances and is expected to constitute a landmark contribution to research in the field of TPD and ubiquitin mechanisms.

“We have reached a level of detail where we can see how these protein degraders work and can be deployed [to recruit the disease-causing protein ] and target the ‘bull’s eye’, in molecular terms,” said Charlotte Crowe, who carried out the research together with a wider team of Dundee researchers.

“Protein degrader molecules work in a way that is fundamentally different from the way conventional drugs work. However, until recently the exact details of how this process works at the molecular level had remained elusive.

“Proteins are typically a few nanometres large, which is 1 billionth of a metre, or 1 millionth of the width of a hair. So being able to ‘see’ them in action has not been possible, up until now.

“We have now been able to build a moving image of how it all happens, which means we can more specifically control the process with an incredible level of detail.”

Professor Alessio Ciulli, Director of CeTPD and one of the world leaders in the field of targeted protein degradation, said, “This is incredibly exciting work and opens up the possibility of even more effectively targeted drugs able to finally treat some diseases which up until now have been too difficult to tackle.”

How it works

Proteins are essential for our cells to function properly, but when these do not work correctly they can cause disease.

Targeted protein degradation involves redirecting protein recycling systems in our cells to destroy the disease-causing proteins.

Protein degraders work by capturing the disease-causing protein and making it stick like a glue to the cellular protein-recycling machinery, which then tags the protein as expired in order to destroy it.

The tag is a small protein called ubiquitin, which effectively gets fired at the disease-causing protein like a bullet. In order for the process to work effectively, ubiquitin must hit the right spots on the target protein so that it gets tagged effectively. The new work by the Dundee team enables them to see how the bullet hits the proverbial bull’s eye.

Working with a protein degrader molecule called MZ1, which was developed in the Ciulli laboratory at Dundee, and using high-end mass spectrometry, they were able to identify exactly where on the target protein the vital ‘tags’ are added.

The work shows how degrader drugs hold onto and position disease-causing proteins, making them good targets for receiving ubiquitin molecules (ie. “ubiquitin-atable”) which then leads to their destruction inside the cell.

Protein degradation efficiency and productivity is dependent on the degrader molecule’s ability to hold tight onto the disease-causing protein, and in a position where it can most effectively act. This latest research paints a bull’s eye and holds it steady enough for the molecule to be accurately targeted.

Professor Ciulli said this and other recently published papers were contributing to rapid development of an exciting field of science and drug discovery.

“This rapidly expanding field is fascinating and complementary articles on how this cellular protein-recycling machinery works to fire ubiquitin molecules at target proteins were recently published by the laboratories of biochemists Brenda Schulman (Max-Planck Institute of Biochemistry) and Gary Kleiger (University of Nevada, Las Vegas).

“Our collective work provides a leap forward in understanding that will accelerate development of new TPD drugs in future.”

The work by a team led by Hideto Takahashi, director of the IRCM’s synapse development and plasticity research unit, in collaboration with Steven Connor’s team at York University and Masanori Tachikawa’s team at Japan’s Tokushima University is published in The EMBO Journal.

Although defects in synapse organization are linked to many neuropsychiatric conditions, the mechanisms responsible for this organization are poorly understood. The new study’s findings could provide valuable therapeutic insights, the researchers believe.

Two goals are important to bear in mind with this research, said Takahashi, an associate research medical professor in molecular biology and neuroscience at UdeM.

“One is to uncover novel molecular mechanisms for brain cell communication,” he said. “The other is to develop a new unique animal model of anxiety disorders displaying panic disorder- and agoraphobia-like behaviors, which helps us develop new therapeutic strategies.”

Understanding the mechanisms

Mental illnesses, such as anxiety disorders, autism and schizophrenia are among the leading health disorders in Canada and worldwide. Despite their prevalence, drug development and treatment for many of these illnesses have proven to be very challenging, due to the complexity of the brain. Scientists have therefore strived to understand the underlying mechanisms that lead to cognitive disorders in order to advance therapeutic strategies.

The junctions between two brain cells (neurons) are called synapses, which are essential for neuronal signal transmission and brain functions. Defects in excitatory synapses, which activate signal transmission to target neurons, and those in synaptic molecules predispose to many mental illnesses.

Takahashi’s team has previously discovered a new protein complex within the synaptic junction, called TrkC-PTPσ, which is only found in excitatory synapses. The genes coding for TrkC (NTRK3) and PTPσ (PTPRS) are associated with anxiety disorders and autism, respectively. However, the mechanisms by which this complex regulates synapse development and contributes to cognitive functions are unknown.

The work carried out in the new study by first author Husam Khaled, a doctoral student in Takahashi’s laboratory, showed that the TrkC-PTPσ complex regulates the structural and functional maturation of excitatory synapses by regulating the phosphorylation, a biochemical protein modification, of many synaptic proteins, while disruption of this complex causes specific behavioral defects in mice.

Building blocks of the brain

Neurons are the building blocks of the brain and the nervous system that are responsible for sending and receiving signals that control the brain and body functions. Neighboring neurons communicate through synapses, which act like bridges that allow the passage of signals between them.

This process is essential for proper brain functions such as learning, memory and cognition. Defects in synapses or their components can disrupt communication between neurons, and lead to various brain disorders.

By generating mice with specific genetic mutations that disrupt the TrkC-PTPσ complex, Takahashi’s team uncovered the unique functions of this complex. They demonstrated that this complex regulates the phosphorylation of many proteins involved in synapse structure and organization.

High-resolution imaging of the mutant mice brains revealed abnormal synapse organization, and further study of their signaling properties showed an increase in inactive synapses with defects in signal transmission. Observing the behavior of the mutant mice, the scientists saw that they exhibited elevated levels of anxiety, especially enhanced avoidance in unfamiliar conditions, and impaired social behaviors.

In a new study, Field Museum researchers collaborated with scientists at the University of Illinois Urbana-Champaign on an in-depth analysis of hairs carefully extracted from the lions’ broken teeth. The study used microscopy and genomics to identify some of the species the lions consumed. The findings are reported in the journal Current Biology.

The original discovery of the hairs occurred in the early 1990s, when Thomas Gnoske, a collections manager at the Field Museum, found the lions’ skulls in storage and examined them for signs of what they had consumed. He was the first to determine that they were fully grown older adult males — despite being maneless. He also was the first to notice that thousands of broken and compacted hairs had accumulated in exposed cavities in the lions’ damaged teeth during their lifetimes.

In 2001, Gnoske and Julian Kerbis Peterhans, a professor at Roosevelt University and Field Museum adjunct curator, first reported on the damaged condition of the teeth — which they hypothesized may have contributed to the lions’ predation of humans — and the presence of hairs embedded in broken and partially healed teeth. A preliminary analysis of some of the hairs suggested that they were from eland, impala, oryx, porcupine, warthog and zebra.

In the new study, Gnoske and Peterhans facilitated a new examination of some of the hairs. Co-authors Ogeto Mwebi, a senior research scientist at the National Museums of Kenya; and Nduhiu Gitahi, a researcher at the University of Nairobi, conducted the microscopic analysis of the hairs. U. of I. postdoctoral researcher Alida de Flamingh led a genomic investigation of the hairs with U. of I. anthropology professor Ripan S. Malhi. They focused on a separate sample of four individual hairs and three clumps of hairs extracted from the lions’ teeth.

Malhi, de Flamingh and their colleagues are developing new techniques to learn about the past by sequencing and analyzing ancient DNA preserved in biological artifacts. Their work in partnership with Indigenous communities has yielded numerous insights into human migration and the pre- and postcolonial history of the Americas. They have helped develop tools for determining the species and geographic origins of present-day and ancient tusks of African elephants. They have advanced efforts to isolate and sequence DNA from museum specimens and have traced the migration and genomic history of dogs in the Americas.

In the current work, de Flamingh first looked for, and found, familiar hallmarks of age-related degradation in what remained of the nuclear DNA in the hairs from the lions’ teeth.

“To establish the authenticity of the sample we’re analyzing, we look to see whether the DNA has these patterns that are typically found in ancient DNA,” she said.

Once the samples were authenticated, de Flamingh focused on mitochondrial DNA. In humans and other animals, the mitochondrial genome is inherited from the mother and can be used to trace matrilineal lineages through time.

There are several advantages to focusing on mtDNA in hair, the researchers said. Previous studies have found that hair structure preserves mtDNA and protects it from external contamination. MtDNA also is much more abundant than nuclear DNA in cells.

“And because the mitochondrial genome is much smaller than the nuclear genome, it’s easier to reconstruct in potential prey species,” de Flamingh said.

The team built a database of mtDNA profiles of potential prey species. This reference database was compared with mtDNA profiles obtained from the hairs. The researchers took into account the species suggested in the earlier analysis and those known to be present in Tsavo at the time the lions were alive.

The researchers also developed methods for extracting and analyzing the mtDNA from the hair fragments.

“We were even able to get DNA from fragments that were shorter than the nail on your pinky finger,” de Flamingh said.

“Traditionally, when people want to get DNA from hairs, they’ll focus on the follicle, which is going to have a lot of nuclear DNA in it,” Malhi said. “But these were fragments of hair shafts that were more than 100 years old.”

The effort yielded a treasure trove of information.

“Analysis of hair DNA identified giraffe, human, oryx, waterbuck, wildebeest and zebra as prey, and also identified hairs that originated from lions,” the researchers reported.

The lions were found to share the same maternally inherited mitochondrial genome, supporting early reports theorizing that they were siblings. Their mtDNA also was consistent with an origin in Kenya or Tanzania.

The team found that the lions had consumed at least two giraffes, along with a zebra that likely originated in the Tsavo region.

The discovery of wildebeest mtDNA was surprising because the nearest population of wildebeests in the late 1890s was about 50 miles away, the researchers said. Historical reports, however, noted that the lions left the Tsavo region for about six months before resuming their rampage on the bridge-builders’ camp.

The absence of buffalo DNA and the presence of only a single buffalo hair — identified using microscopy — was surprising, de Flamingh said. “We know from what lions in Tsavo eat today that buffalo is the preferred prey,” she said.

“Colonel Patterson kept a handwritten field journal during his time at Tsavo,” Kerbis Peterhans said. “But he never recorded seeing buffalo or indigenous cattle in his journal.”

At the time, the cattle and buffalo populations in this part of Africa were devastated by rinderpest, a highly contagious viral disease brought to Africa from India by the early 1880s, Kerbis Peterhans said.

“It all but wiped out cattle and their wild relatives, including cape buffalo,” he said.

The mitogenome of the human hair has a broad geographic distribution and the scientists declined to describe or analyze it further for the current study.

“There may be descendants still in the region today and to practice responsible and ethical science, we are using community-based methods to extend the human aspects of the larger project,” they wrote.

The new findings are an important expansion of the kinds of data that can be extracted from skulls and hairs from the past, the researchers said.

“Now we know that we can reconstruct complete mitochondrial genomes from single hair fragments from lions that are more than 100 years old,” de Flamingh said.

There were thousands of hairs embedded in the lions’ teeth, compacted over a period of years, the researchers said. Further analyses will allow the scientists to at least partially reconstruct the lions’ diet over time and perhaps pinpoint when their habit of preying on humans began.

Malhi also is an affiliate of the Carl R. Woese Institute for Genomic Biology at the U. of I.

The National Science Foundation and U.S. Department of Agriculture supported this research.

Understanding the situation affects how we recognize emotions

In the 1970s, the theory was put forward that the face is the window to our emotions. Researcher Paul Ekman described basic emotions such as fear, anger, disgust, joy and sadness using typical facial expressions, which were found to be similar across all cultures. “However, in recent years it’s become increasingly obvious that there are many situations in life where a typical facial expression is not necessarily the key piece of information that guides our assessment of other people’s feelings,” points out Newen and cites the following example: “People almost universally rate a typical facial expression of fear as anger when they have the background knowledge that the assessed person’s been turned away by a waiter even though they’d demonstrably reserved a table.” In such a situation, people expect the person to be angry, and this expectation determines the perception of their emotion, even if their facial expression would typically be attributed to a different emotion.

“In addition, we can sometimes recognize emotions even without seeing the face; for example, the fear experienced by a person who’s being attacked by a snarling dog, even though we only see them from behind in a stance of freeze or fright,” illustrates Berio.

Recognizing an emotion is part of our overall impression of a person

Berio and Newen propose that recognizing emotions is a sub-process of our ability to form an overall impression of a person. In doing so, people are guided by certain characteristics of the other person, for example physical appearance characteristics such as skin color, age and gender, cultural characteristics such as clothing and attractiveness as well as situational characteristics such as facial expression, gestures and posture.

Based on such characteristics, people tend to quickly assess others and immediately associate social status and even certain personality traits with them. These associations dictate how we perceive other people’s emotions. “If we perceive a person as a woman and they show a negative emotion, we’re more likely to attribute the emotion to fear, whereas with a man it’s more likely to be read as anger,” as Berio points out.

Background information is included in the assessment

In addition to the perception of characteristics and initial associations, we also hold detailed person images that we use as background information for individuals in our social circle — family members, friends and colleagues. “If a family member suffers from Parkinson’s, we learn to assess the typical facial expression of this person, which seems to indicate anger, as neutral, because we are aware that a rigid facial expression is part of the disease,” says Berio.

The background information also includes person models of typical occupational groups. “We hold stereotypical assumptions about the social roles and responsibilities of for example doctors, students and workmen,” says Newen. “We generally perceive doctors as less emotional, for example, which changes the way we assess their emotions.”

In other words, people make use of the wealth of characteristics and background knowledge to assess the emotion of another person. Only in rare cases do they read the emotion from a person’s facial expression alone. “All this has implications for emotion recognition using artificial intelligence (AI): It will only be a reliable option when AI doesn’t rely solely on facial expressions, which is what most systems currently do,” says Newen.

On October 8th, KAIST (represented by President Kwang-Hyung Lee) announced that Professor Yoonsu Park’s research team from the Department of Chemistry successfully developed technology that enables the easy editing and correction of oxygen atoms in furan compounds into nitrogen atoms, directly converting them into pyrrole frameworks, which are widely used in pharmaceuticals.

This research was published in the scientific journal Science on October 3rd under the title “Photocatalytic Furan-to-Pyrrole Conversion.”

Many drugs have complex chemical structures, but their efficacy is often determined by a single critical atom. Atoms like oxygen and nitrogen play a central role in enhancing the pharmacological effects of these drugs, particularly against viruses.

This phenomenon, where the introduction of specific atoms into a drug molecule dramatically affects its efficacy, is known as the “Single Atom Effect.” In leading-edge drug development, discovering atoms that maximize drug efficacy is key.

However, evaluating the Single Atom Effect has traditionally required multi-step, costly synthesis processes, as it has been difficult to selectively edit single atoms within stable ring structures containing oxygen or nitrogen.

Professor Park’s team overcame this challenge by introducing a photocatalyst that uses light energy. They developed a photocatalyst that acts as a “molecular scissor,” freely cutting and attaching five-membered rings, enabling single-atom editing at room temperature and atmospheric pressure — a world first.

The team discovered a new reaction mechanism in which the excited molecular scissor removes oxygen from furan via single-electron oxidation and then sequentially adds a nitrogen atom.

Donghyeon Kim and Jaehyun You, the study’s first authors and candidates in KAIST’s integrated master’s and doctoral program in the Department of Chemistry, explained that this technique offers high versatility by utilizing light energy to replace harsh conditions. They further noted that the technology enables selective editing, even when applied to complex natural products or pharmaceuticals. Professor Yoonsu Park, who led the research, remarked, “This breakthrough, which allows for the selective editing of five-membered organic ring structures, will open new doors for building libraries of drug candidates, a key challenge in pharmaceuticals. I hope this foundational technology will be used to revolutionize the drug development process.”

The significance of this research was highlighted in the Perspective section of Science, a feature where a peer scientist of prominence outside of the project group provides commentary on an impactful research.

This research was supported by the National Research Foundation of Korea’s Creative Research Program, the Cross-Generation Collaborative Lab Project at KAIST, and the POSCO Science Fellowship of the POSCO TJ Park Foundation.

“As a physician, I help to care for children who have the most severe symptoms, and as a researcher, I’m driven to understand why they become so sick,” said corresponding author Melody G. Duvall, MD, PhD, of the Division of Pulmonary and Critical Care Medicine at Brigham and Women’s Hospital (BWH) and the Division of Critical Care Medicine at Boston Children’s Hospital. “NK cells are important first responders during viral infection — but they can also contribute to lung inflammation. Interestingly, our findings fit with data from some studies in COVID-19, which reported that patients with the most severe symptoms also had increased NK cells in their airways. Together with previous studies, our data link NK cells with serious viral illness, suggesting that these cellular pathways merit additional investigation.”

Duvall and colleagues, including lead author Roisin B. Reilly of the Division of Pulmonary and Critical Care Medicine at BWH, looked at samples from 47 children critically ill with RSV, analyzing immune cells found in their airways and peripheral blood. Compared to uninfected children, those with severe illness had elevated levels of NK cells in their airways and decreased NK cells in their blood. In addition, they found that the cells themselves were altered, both in appearance and in their ability to perform their immunological function of killing diseased cells.

Duvall and co-authors have previously described a post-pandemic surge in pediatric RSV infections. While clinicians can only provide supportive care to the most severely sick children, vaccines to prevent RSV are now available for children 19 months and younger, adults 60 years and over, and people who are pregnant.

The researchers argue that a sizable proportion of drugs and other compounds can bind to melanin pigments in the skin, leading to differences in how bioavailable and efficacious these drugs and other compounds are in people with varying skin tones.

“Our review paper concludes that melanin, the pigment responsible for skin color, shows a surprising affinity for certain drug compounds,” said Simon Groen, an assistant professor of evolutionary systems biology in the Institute of Integrative Genome Biology at the University of California, Riverside, and a coauthor on the paper. “Melanin’s implications for drug safety and dosing have been largely overlooked, raising alarming questions about the efficacy of standard dosing since people vary a lot in skin tones.”

According to Groen and coauthor Sophie Zaaijer, a consultant and researcher affiliated with UC Riverside who specializes in diversity, equity, and inclusion (DEI) in preclinical R&D and clinical trials, current FDA guidelines for toxicity testing fail to adequately address the impact of skin pigmentation on drug interactions.

“This oversight is particularly concerning given the push for more diverse clinical trials, as outlined in the agency’s Diversity Action Plan,” Zaaijer said. “But current early-stage drug development practices still primarily focus on drug testing in white populations of Northern European descent.”

In one example, the researchers found evidence of nicotine affinity for skin pigments, potentially affecting smoking habits across people with a variety of skin tones and raising questions about the efficacy of skin-adhered nicotine patches for smoking cessation.

“Are we inadvertently shortchanging smokers with darker skin tones if they turn to these patches in their attempts to quit?” Groen said.

Groen and Zaaijer propose utilizing a new workflow involving human 3D skin models with varying pigmentation levels that could offer pharmaceutical companies an efficient method to assess drug binding properties across different skin types.

“Skin pigmentation should be considered as a factor in safety and dosing estimates,” Zaaijer said. “We stand on the brink of a transformative era in the biomedical industry, where embracing inclusivity is not just an option anymore but a necessity.”

According to the researchers, skin pigmentation is just one example. Genetic variations among minority groups can lead to starkly different drug responses across races and ethnicities, affecting up to 20% of all medications, they said.

“Yet, our molecular understanding of these differences remains very limited,” Zaaijer said.

The researchers acknowledge that transformations enhancing inclusivity — encompassing race, ethnicity, sex, and age — demand a comprehensive overhaul of all FDA guidelines on clinical endpoints to align with the FDA’s Diversity Action Plan.

“It’s a monumental task, requiring clear lines of communication between academics, industry researchers, clinicians, and regulators,” Zaaijer said. “The future of medicine relies on our capacity to connect these currently isolated operational teams.”

The researchers point out that a shift towards inclusive drug development is set to take place as instigated by a new law, the Food and Drug Omnibus Reform Act, enacted in 2022.

“The FDA published their draft guidelines recently,” Zaaijer said. “Once final in a few months, they will mandate considering patient diversity in clinical trials and preclinical R&D. The next step is to provide guidance on what pharmacokinetic variables should be tested in drug R&D pipelines in their pursuit to equitable drugs.”

The researchers hope to activate the pharmaceutical industry and academia to start doing systematic experimental evaluations in preclinical research in relation to skin pigmentation and drug kinetics.

They also encourage patients, their advocacy groups, and clinical trial participants to ask questions related to ancestry-specific drug efficacy and safety, such as, “Has this drug been tested to see if it’s safe for people from different ancestral backgrounds, including mine?” Clinicians and pharmaceutical representatives should be able to provide an easy-to-understand document outlining the results of the various tests, the researchers said.

They acknowledge that in the current state of drug development this will be hard.

“In terms of risk profile testing, drugs are most often tested on one or a few human cell models that mostly come from donors of Northern European descent,” Zaaijer said. “Drugs are then tested in a rodent model. If these tests are successful, drug companies push the drug through to clinical trials. But are drugs ready to be given to a diverse patient group if they haven’t first been tested, for example, on human cell models of different ancestries? Would you bungee jump off a bridge if you know the ropes have not been tested for your weight category? Unlikely. So why is this currently acceptable with drugs?”

Groen explained that in different ancestral backgrounds certain genetic variants are more prevalent. Those variants can affect how a drug is metabolized and how it behaves in a body, he said.

“If different ancestral backgrounds are taken into consideration in the early stages of drug discovery, then diverse groups of people may have more trust in the drug development process and enroll in clinical trials because they will be better informed of any potential associated risks,” he said.

The results are important because, while the left- and right-handed versions, or enantiomers, of chemical compounds have identical chemical properties, they differ in how they react in the human body. Developing cost-effective ways to synthesize only the version with a desired biological effect is critical to medicinal chemistry.

In a study published in the Oct. 11 issue of the journal Science, the researchers describe how their chemical synthesis method can quickly, efficiently and in a scalable manner produce a sample that is purely one enantiomer of a mirror-image pair of molecules, as opposed to a mixture of the two. The new method involves adding prenyl groups — molecules made of five carbon atoms — to enones by means of a newly developed catalyst in one step in the synthesis process.

“Adding a prenyl group is the way nature assembles these molecules, but it has been challenging for scientists to replicate this successfully,” said Dr. Filippo Romiti, assistant professor of chemistry and biochemistry in the School of Natural Sciences and Mathematics at UT Dallas and a corresponding author of the study.

“Nature is the best synthetic chemist of all; she’s way ahead of us. This research represents a paradigm shift in the way we can now synthesize large quantities of biologically active molecules and test them for therapeutic activity,” said Romiti, who is also a Cancer Prevention & Research Institute of Texas (CPRIT) Scholar.

Naturally occurring compounds are a significant source of potential new medicines, but because they often occur only in minute quantities, scientists and pharmaceutical companies must develop methods to synthesize larger amounts to test in the lab or to manufacture into drugs.

In their study, the researchers demonstrated how incorporating their new chemical reaction resulted in a synthesis process that reached completion in about 15 minutes at room temperature, which is more energy-efficient than having to heat or cool substances significantly during a reaction.

Romiti collaborated with researchers at Boston College, the University of Pittsburgh and the University of Strasbourg in France to develop the new chemical reaction. Romiti’s role involved creating the synthesis process.

The researchers developed their method as part of an effort to synthesize polycyclic polyprenylated acylphloroglucinols (PPAPs), which are a class of more than 400 natural products with a broad spectrum of bioactivity, including combatting cancer, HIV, Alzheimer’s disease, depression, epilepsy and obesity.

Romiti and his colleagues demonstrated a proof of concept by synthesizing enantiomers of eight PPAPs, including nemorosonol, a chemical derived from a Brazilian tree that has been shown by other researchers to have antibiotic activity.

“For 20 years, we’ve known that nemorosonol is antimicrobial, but which enantiomer is responsible? Is it one or both?” Romiti said. “It could be that one version has this property, but the other does not.”

Romiti and his colleagues tested their nemorosonol enantiomer against lung and breast cancer cell lines provided by Dr. John Minna, director of the Hamon Center for Therapeutic Oncology Research at UT Southwestern Medical Center.

“Our entantiomer of nemorosonol had pretty decent effects against cancer cell lines,” Romiti said. “This was very interesting and could only have been discovered if we had access to large quantities of a pure entantiomeric sample to test.”

Romiti said more research will be needed to confirm whether one nemorosonol enantiomer is specifically antimicrobial and the other anticancer.

The study results could impact drug discovery and translational medicine in several ways. In addition to informing scalable and more efficient drug-manufacturing processes, the findings will enable researchers to make more efficiently natural product analogs, which are optimized versions of the natural product that are more potent or selective in how they work in the body.

“We developed this process to be as pharma-friendly as possible,” Romiti said. “This is a new tool for chemists and biologists to study 400 new drug leads that we can make, plus their analogs, and test their biological activity. We now have access to potent natural products that we previously could not synthesize in the lab.”

Romiti said the next step will be to apply the new reaction to the synthesis of other classes of natural products, in addition to PPAPs. In August he received a five-year, $1.95 million Maximizing Investigators’ Research Award for Early Stage Investigators from the National Institute of General Medical Sciences, a component of the National Institutes of Health (NIH), to continue his work in this area.

In addition to CPRIT, the research was supported by funding from the National Science Foundation and from the NIH (2R35GM130395, 2R35GM128779) to co-corresponding authors and chemistry professors Dr. Peng Liu at the University of Pittsburgh and Dr. Amir Hoveyda at Boston College.

With MS, the body’s immune system attacks myelin, the fatty, white substance that insulates and protects the nerves. MS is chronic and can be unpredictable and disabling.

“People with MS undergo an increased number of tests to monitor MS, making it more likely to detect other diseases,” said study author Emmanuelle Leray, PhD, of Rennes University in France. “We found an association between some types of cancer and MS which may have different explanations depending on a person’s age and the types of cancer. Overall, our study found the increased risk of cancer was quite small.”

For the study, researchers reviewed 10 years of data in the French national health care database. Researchers identified 140,649 people with MS and matched them for factors such as age, sex and residence to 562,596 people without MS. All participants were cancer free three years before the study. They were followed for an average of eight years.

During the study, 8,368 people with MS and 31,796 people without MS developed cancer.

Researchers determined there were 799 cancers per 100,000 person-years for people with MS and 736 cancers per 100,000 person-years for people without MS. Person-years represent both the number of people in the study and the amount of time each person spends in the study.

Researchers found people with MS had a 6% increased risk of developing any type of cancer regardless of age, sex and residence. They also found cancer risk was higher in those under 55 and lower in people 65 and older when compared to people without MS.

Researchers then looked at cancer types. People with MS had a 71% increased risk for bladder cancer, a 68% increased risk for brain cancer and a 24% increased risk for cervical cancer. However, they also had a 20% lower risk of prostate cancer, a 10% lower risk of colorectal cancer and a 9% lower risk of breast cancer.

“While our study found a higher risk for brain cancer, it may be due in part to earlier detection in those with MS since they regularly have brain scans which may detect cancers earlier, before a person has symptoms,” said Leray. “Frequent urinary tract infections in people with MS and the use of immunosuppressant drugs may contribute to their higher risk of bladder and cervical cancers.”

Leray added, “The lower risk for colorectal and breast cancers may be due in part to fewer people with MS getting screened for cancer in older age when they may be experiencing more MS symptoms. More research is needed, including studies that look at more closely at how cancer screenings may play a role.”

A limitation of the study was that researchers were unable to adjust for factors such as education, income, smoking and alcohol consumption since this information was not available in the national database.

The study was supported by the Rennes Institute of Clinical Neurosciences and the EDMUS-ARSEP Foundation.

Now, new research reveals that these tiny suitors are leveraging a flexible network of modular brain circuits to quickly adapt to different mating signals. The study, published in Nature, is the first to describe how diverse species of fruit flies plug new sensory inputs, such as pheromones, into a set of basic brain circuits without needing to develop new neural pathways from scratch.

The findings offer a larger framework for understanding how brain wiring can change to influence behavioral evolution. “The diversity of behaviors across the animal kingdom is enormous, but the underlying mechanisms of how nervous systems are shaped by evolution have been very difficult to unravel,” says Vanessa Ruta, head of the Laboratory of Neurophysiology and Behavior. “Here we uncovered what we believe is a key neural mechanism that gives brain circuits the flexibility to rewire across species.”

Plug-and-play

One of the great mysteries of behavioral evolution is how, as species diversify, brain circuits keep pace with the rapid changes in social signals that allow individuals to find their ideal mates. Courtship behaviors, for instance, evolve quickly, making it difficult to imagine that the fly brain completely reinvents itself every time a new pheromone enters the Drosophila repertoire.

But until now, it was not possible to identify where evolution acts in the nervous system to alter behavior, and so the key features of what makes such circuits so adaptable remained a mystery. Ruta’s group turned to fruit flies, where closely related species share similar brains but rely on vastly different cues for mating rituals. D. simulans, for instance, mainly relies on visual cues to find a mate, while D. yakuba evolved a novel capacity to use pheromones to find a mate even in complete darkness. These and other variations presented an opportunity to study how similar brains detect and perceive different social cues.

“We started looking for parts of the brain that might be primed for flexibility,” says Rory Coleman, first author on the study and a postdoctoral fellow in the Ruta lab. “We were searching for features that might make the circuit intrinsically adaptable, potential evolutionary hotspots driving behavioral diversification.”

After comparing pheromone-sensing circuits across multiple species — using behavioral assays, genetic tools, neuroimaging, and CRISPR genome editing — they ultimately singled out sensory neurons in the male forelegs and P1 neurons in the higher brain as key to modulating courtship across species. The team found that the basic neural building blocks of male mating behaviors, such as the P1 neurons, are present across species, but different sensory signals can be flexibly wired into this node. This allows fly species to develop different mating strategies without rewiring their entire brains.

For instance, the researchers found that P1 neurons were activated in response to entirely different types of pheromones in D. melanogaster and D. yakuba. Yet the role of P1 neurons in initiating courtship was still conserved across both species. “One important discovery from our work is that there are discrete nodes within the brains of each of these species that can flexibly integrate new sensory modalities,” Ruta says. “This flexibility allows conserved nodes like the P1 neurons to still initiate courtship in different species but respond to the distinct cues of their females.”

A social brain

This research falls under the umbrella of Rockefeller’s Price Family Center for the Social Brain, an initiative focusing on understanding the neuronal, cellular, and molecular foundations of social behavior. In addition to shedding light on flexibility in the face of new sensory inputs, the present work also illustrates an experimental approach for studying how social behaviors evolve across species. “Our results demonstrate that Drosophila is a powerful system for studying behavioral evolution,” Ruta says.

By examining how variations in neural circuits shape behaviors like mating, the lab hopes to advance our understanding of the complex interplay between brain function and social behaviors, providing a framework for understanding how social circuits are built to produce adaptive behaviors in the human brain. And while the brain structures of flies and humans differ substantially, it is likely some of the underlying principles of how neural circuits evolve and adapt are conserved across species

“We hope that comparative evolutionary studies like this one will reveal the core rules shaping how neural circuits have been built across the animal kingdom, including in humans,” Coleman says. “Many neurological disorders are thought to arise from the miswiring of circuits” Ruta adds. “By examining neural circuits through the lens of evolution, we hope to shed light on which neural motifs can change and how they can be altered, not through the ravages of disease, but as a consequence of evolutionary selection.”

In a new Northwestern University-led study, microbiologists found that showerheads and toothbrushes are teeming with an extremely diverse collection of viruses — most of which have never been seen before.

Although this might sound ominous, the good news is these viruses don’t target people. They target bacteria.

The microorganisms collected in the study are bacteriophage, or “phage,” a type of virus that infects and replicates inside of bacteria. Although researchers know little about them, phage recently have garnered attention for their potential use in treating antibiotic-resistant bacterial infections. And the previously unknown viruses lurking in our bathrooms could become a treasure trove of materials for exploring those applications.

The study will be published Wednesday (Oct. 9) in the journal Frontiers in Microbiomes.

“The number of viruses that we found is absolutely wild,” said Northwestern’s Erica M. Hartmann, who led the study. “We found many viruses that we know very little about and many others that we have never seen before. It’s amazing how much untapped biodiversity is all around us. And you don’t even have to go far to find it; it’s right under our noses.”

An indoor microbiologist, Hartmann is an associate professor of civil and environmental engineering at Northwestern’s McCormick School of Engineering and a member of the Center for Synthetic Biology.

The return of ‘Operation Pottymouth’

The new study is an offshoot of previous research, in which Hartmann and her colleagues at University of Colorado at Boulder characterized bacteria living on toothbrushes and showerheads. For the previous studies, the researchers asked people to submit used toothbrushes and swabs with samples collected from their showerheads.

Inspired by concerns that a flushing toilet might generate a cloud of aerosol particles, Hartmann affectionately called the toothbrush study, “Operation Pottymouth.”

“This project started as a curiosity,” Hartmann said. “We wanted to know what microbes are living in our homes. If you think about indoor environments, surfaces like tables and walls are really difficult for microbes to live on. Microbes prefer environments with water. And where is there water? Inside our showerheads and on our toothbrushes.”

Diversity and opportunities

After characterizing bacteria, Hartmann then used DNA sequencing to examine the viruses living on those same samples. She was immediately blown away. Altogether, the samples comprised more than 600 different viruses — and no two samples were alike.

“We saw basically no overlap in virus types between showerheads and toothbrushes,” Hartmann said. “We also saw very little overlap between any two samples at all. Each showerhead and each toothbrush is like its own little island. It just underscores the incredible diversity of viruses out there.”

While they found few patterns among all the samples, Hartmann and her team did notice more mycobacteriophage than other types of phage. Mycobacteriophage infect mycobacteria, a pathogenic species that causes diseases like leprosy, tuberculosis and chronic lung infections. Hartmann imagines that, someday, researchers could harness mycobacteriophage to treat these infections and others.

“We could envision taking these mycobacteriophage and using them as a way to clean pathogens out of your plumbing system,” she said. “We want to look at all the functions these viruses might have and figure out how we can use them.”

Most microbes ‘will not make us sick’

But, in the meantime, Hartmann cautions people not to fret about the invisible wildlife living within our bathrooms. Instead of grabbing for bleach, people can soak their showerheads in vinegar to remove calcium buildup or simply wash them with plain soap and water. And people should regularly replace toothbrush heads, Hartmann says. Hartmann also is not a fan of antimicrobial toothbrushes, which she said can lead to antibiotic-resistant bugs.

“Microbes are everywhere, and the vast majority of them will not make us sick,” she said. “The more you attack them with disinfectants, the more they are likely to develop resistance or become more difficult to treat. We should all just embrace them.”

The study, “Phage communities in household-related biofilms correlate with bacterial hosts but do not associate with other environmental factors,” was supported by Northwestern University.

Proponents of AI envision the technology helping to manage health care supply chains, monitor disease outbreaks, make diagnoses, interpret medical images, and even reduce equity gaps in access to care by compensating for healthcare worker shortages. But others are sounding the alarm about issues like privacy rights, racial and gender biases in models, lack of transparency in AI decision-making processes that could lead to patient care mistakes, and even the potential for insurance companies to use AI to discriminate against people with poor health.

Which types of impacts these tools ultimately have will depend upon the manner in which they are developed and deployed. In a paper for the journal Social Science & Medicine, Vitale and her coauthor, University of British Columbia doctoral candidate Leah Shipton, conducted an extensive literature analysis of AI’s current trajectory in health care. They argue that AI is positioned to become the latest in a long line of technological advances that ultimately have limited impact because they engage in a “politics of avoidance” that diverts attention away from, or even worsens, more fundamental structural problems in global public health.

For example, like many technological interventions of the past, most AI being developed for health focuses on treating disease, while ignoring the underlying determinants of health. Vitale and Shipton fear that the hype over unproven AI tools could distract from the urgent need to implement low-tech but evidence-based holistic interventions, like community health workers and harm reduction programs.

“We have seen this pattern before,” Vitale said. “We keep investing in these tech silver bullets that fail to actually change public health because they’re not dealing with the deeply rooted political and social determinants of health, which can range from things like health policy priorities to access to healthy foods and a safe place to live.”

AI is also likely to continue or exacerbate patterns of harm and exploitation that have historically been common in the biopharmaceutical industry. One example discussed in the paper is that the ownership of and profit from AI is currently concentrated in high-income countries, while low- to middle-income countries with weak regulations may be targeted for data extraction or experimentation with the deployment of potentially risky new technologies.

The paper also predicts that lax regulatory approaches to AI will continue the prioritization of intellectual property rights and industry incentives over equitable and affordable public access to new treatments and tools. And since corporate profit motives will continue to drive product development, AI companies are also likely to follow the health technology sector’s long-term trend of overlooking the needs of the world’s poorest people when deciding which issues to target for investment in research and development.

However, Vitale and Shipton did identify a bright spot. AI could potentially break the mold and create a deeper impact by focusing on improving the health care system itself. AI could be used to allocate resources more efficiently across hospitals and for more effective patient triage. Diagnostic tools could improve the efficiency and expand the capabilities of general practitioners in small rural hospitals without specialists. AI could even provide some basic yet essential health services to fill labor and specialization gaps, like providing prenatal check-ups in areas with growing maternity care deserts.

All of these applications could potentially result in more equitable access to care. But that result is far from guaranteed. Depending on how and where these technologies are deployed, they could either successfully backfill gaps in care where there are genuine health worker shortages or lead to unemployment or precarious gig work for existing health care workers. And unless the underlying causes of health care worker shortages are addressed — including burnout and “brain drain” to high-income countries — AI tools could end up providing diagnosis or outbreak detection that is ultimately not useful because communities still lack the capacity to respond.

To maximize benefits and minimize harms, Vitale and Shipton argue that regulation must be put in place before AI expands further into the health sector. The right safeguards could help to divert AI from following harmful patterns of the past and instead chart a new path that ensures future projects will align with the public interest.

“With AI, we have an opportunity to correct our way of governing new technologies,” Shipton said. “But we need a clear agenda and framework for the ethical governance of AI health technologies through the World Health Organization, major public-private partnerships that fund and deliver health interventions, and countries like the United States, India, and China that host tech companies. Getting that implemented is going to require continued civil society advocacy.”

Expectations shape our perception, profoundly influencing how we interpret the world. Positive expectations about sensory stimuli can alleviate distress and reduce pain through what’s known as the placebo effect, while negative expectations may heighten anxiety and exacerbate pain. In the new study, Luo, Kishida, and colleagues investigated the impact of the hedonic aspect of expectations on subjective experiences.

Specifically, the researchers measured neurobehavioral responses to the taste of hot sauce among individuals with a wide range of taste preferences. In total, 47 participants completed the tasks while undergoing functional magnetic resonance imaging scanning. The researchers identified participants who liked versus those who strongly disliked spicy flavors and provided contextual cues about the spiciness of the sauce to be tasted. That way, they were able to dissociate the effects of positive and negative expectations from sensory stimuli (i.e., visual and taste stimuli), which were the same across all participants.

The results showed that positive expectations lead to modulations in the intensity of subjective experience. These modulations were accompanied by increased activity in brain regions previously linked to pleasure, information integration, and the placebo effect, including the anterior insula, dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex. By contrast, negative expectations decreased hedonic experience and increased neural activity in the Neurological Pain Signature network.

Taken together, these findings demonstrate that hedonic aspects of one’s expectations asymmetrically shape how the brain processes sensory input and associated behavioral reports of one’s subjective experiences of intensity, pleasure, and pain. The results suggest a dissociable impact of hedonic information. While positive expectations facilitate higher-level information integration and reward processing, negative expectations prime lower-level processes related to pain and emotions. According to the authors, this study demonstrates the powerful role of hedonic expectations in shaping subjective reality and suggests potential avenues for consumer and therapeutic interventions targeting expectation-driven neural processes.

The authors add, “Our study highlights how hedonic expectations shape subjective experiences and neural responses, offering new insights into the mechanisms behind pain perception.”

Published in the journal PNAS, their findings could pave the way for new approaches to treating disorders related to our body clock.

CK1δ regulates circadian rhythms by tagging other proteins involved in our biological clock to fine-tune the timing of these rhythms. In addition to modifying other proteins, CK1δ itself can be tagged, thereby altering its own ability to regulate the proteins involved in running the body’s internal clock.

Previous research identified two distinct versions of CK1δ, known as isoforms δ1 and δ2, which vary by just 16 building blocks or amino acids right at the end of the protein in a part called the C-terminal tail. Yet these small differences significantly impact CK1δ’s function. While it was known that when these proteins are tagged, their ability to regulate the body clock decreases, no one knew exactly how this happened.

Using advanced spectroscopy and spectrometry techniques to zoom in on the tails, the researchers found that how the proteins are tagged is determined by their distinct tail sequences.

Howard Hughes Medical Institute Investigator Professor Carrie Partch from the Department of Chemistry & Biochemistry at the University of California, Santa Cruzand corresponding author of the study explained:

“Our findings pinpoint to three specific sites on CK1δ’s tail where phosphate groups can attach, and these sites are crucial for controlling the protein’s activity. When these spots get tagged with a phosphate group, CK1δ becomes less active, which means it doesn’t influence our circadian rhythms as effectively. Using high-resolution analysis, we were able to pinpoint the exact sites involved — and that’s really exciting.”

Having first studied this protein more than 30 years ago while investigating its role in cell division, Professor David Virshup, the director of the Cancer and Stem Cell Biology Programme at Duke-NUS and co-corresponding author of the study, elaborated:

“With the technology we have available now, we were finally able to get to the bottom of a question that has gone unanswered for more than 25 years. We found that the δ1 tail interacts more extensively with the main part of the protein, leading to greater self-inhibition compared to δ2. This means that δ1 is more tightly regulated by its tail than δ2. When these sites are mutated or removed, δ1 becomes more active, which leads to changes in circadian rhythms. In contrast, δ2 does not have the same regulatory effect from its tail region.”

This discovery highlights how a small part of CK1δ can greatly influence its overall activity. This self-regulation is vital for keeping CK1δ activity balanced, which, in turn, helps regulate our circadian rhythms.

The study also addressed the wider implications of these findings. CK1δ plays a role in several important processes beyond circadian rhythms, including cell division, cancer development, and certain neurodegenerative diseases. By better understanding how CK1δ’s activity is regulated, scientists could open new avenues for treating not just circadian rhythm disorders but also a range of conditions.

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, commented:

“Regulating our internal clock goes beyond curing jet lag — it’s about improving sleep-quality, metabolism and overall health. This important discovery could potentially open new doors for treatments that could transform how we manage these essential aspects of our daily lives.”

The researchers plan to further investigate how real-world factors, such as diet and environmental changes, affect the tagging sites on CK1δ. This could provide insights into how these factors affect circadian rhythms and might lead to practical solutions for managing disruptions.

Duke-NUS is a global leader in medical education and biomedical research, driving breakthroughs that transcend scientific exploration for the benefit of our communities. By merging scientific research with translational methods, the School deepens our understanding of prevalent diseases and develop innovative new treatment approaches.

Some of these environmental phenols are known to have cardiac toxicities. Now, an interdisciplinary study involving four University of Cincinnati College of Medicine professors is revealing their adverse impact on the heart’s electrical properties, and the research has been published in the journal Environmental Health.

“This is the first study to look at the impact of phenol exposure on cardiac electrical activity in humans,” said Hong-Sheng Wang, PhD, professor in the Department of Pharmacology, Physiology and Neurobiology and the study’s lead author.

Researchers used data from the Fernald Community Cohort, which includes nearly 10,000 people who lived near the former U.S. Department of Energy uranium processing site at Fernald, outside Cincinnati, and participated in the Fernald Medical Monitoring Program between 1990 and 2008.

Much of the cohort did not experience exposure to uranium beyond the radiation received by the general population. Wang and his team used their data, including biological samples and medical records, in the study so uranium exposure would not be a factor in the findings — making them relevant to the general population. Because urine samples and electrocardiograms, or EKGs, were collected on the same day, the results were significant for analyzing exposure to environmental phenols.

The EKGs, which measure cardiac electrical activities, were read by board-certified physicians, and the urine samples were sent to the Centers for Disease Control and Prevention for exposure analysis.

One goal of the study was to identify any changes in EKG parameters associated with environmental phenol exposure.

The heart is driven by electrical activity, so anything affecting its electrical properties can have a detrimental impact and possibly result in arrhythmias.

The research concluded higher exposure to some environmental phenols is associated with altered cardiac electrical activity.

Researchers found higher exposure to BPA, BPF and BPA+F in women is associated with a longer PR interval, a delay in the time it takes for electrical signals to move from the atria at the top of the heart to the ventricles.

“Our findings were highly sex-specific,” said Wang. In women, researchers identified an association with longer QRS duration, or contraction of the ventricles, and dysfunction of the electrical impulses of the heart.

“It was particularly pronounced in women with higher body mass indexes,” said Wang.

In men, researchers found higher exposure to triclocarban (TCC), an antimicrobial agent, led to longer QT intervals in the heart — meaning the heart’s electrical system is taking too long to recharge, a situation that can contribute to heart rhythm dysfunction. TCC has since been banned in the United States.

Wang also pointed out that typical exposure levels alone are unlikely to cause clinically significant heart disease in healthy people.

“These were not dramatic changes that we observed, but moderate changes to cardiac electrical activity,” he said. “However, they were particularly pronounced in certain subpopulations.”

He said the altered cardiac activity could exacerbate existing heart disease or arrhythmias in a patient, especially older adults or those with other risk factors.

“Now there are new chemicals out there, so the next step would be to examine these newer environmental chemicals and to focus on their impact on an individual level in those who are predisposed to heart disease,” said Wang.

Other contributors in this study included Susan Pinney, PhD, FACE, professor of epidemiology in the Department of Environmental and Public Health Sciences; Jack Rubinstein, MD, FACC, professor of clinical cardiology in the Department of Internal Medicine; and Changchun Xie, PhD, professor in the Department of Biostatistics, Health Informatics and Data Sciences.

This study was funded by grants from the National Institute of Environmental Health and the University of Cincinnati Center for Environmental Genetics.

Of 236 patients who received cilta-cel infusions at 16 U.S. medical centers in 2022, 89% saw their cancer respond to the treatment and 70% had a complete response, meaning there was no detectable cancer after the treatment. These numbers are comparable to the results of the phase II CARTITUDE-1 trial that led to cilta-cel’s approval by the U.S. Food and Drug Administration (FDA), which showed a 98% response rate and an 83% complete response rate.

Most notable and encouraging, according to researchers, was that over half of the patients included in the new study would have been ineligible to participate in CARTITUDE-1.

“Even though in the real world a majority of patients are not as fit in terms of performance status, organ function, or baseline blood counts as they were in the clinical trial that led to FDA approval [of this therapy], these patients can do very well,” said Surbhi Sidana, MD, the study’s lead author and associate professor at Stanford University School of Medicine. “We saw very high response rates that appeared to be durable, despite over half of the patients not meeting [the trial’s] eligibility criteria. The response rates and time until progression of myeloma or death due to any reason was within the range of results observed in the clinical trial.”

Multiple myeloma is a cancer affecting plasma cells, a type of white blood cell. Currently about 40% of people diagnosed with multiple myeloma do not survive five years, and the prognosis is poorest in patients who do not see their cancer eradicated with standard treatments (refractory) or who see their cancer return after an initial response (relapsed). Two CAR-T therapies, where a patient’s own immune cells are removed, genetically altered, and then infused back into the body to attack and kill cancer cells, have been approved for use in these patients.

Cilta-cel was approved in 2022 for use in patients whose multiple myeloma had not been eradicated or had relapsed after four or more previous lines of therapy; the approval was expanded to earlier lines of treatment in April 2024. The new study focused on patients who had received treatment under the initial approval indication for heavily pre-treated patients. For the new study, researchers retrospectively analyzed outcomes among 255 patients who began the process of receiving cilta-cel in March through December of 2022. The study participants had undergone a median of six prior lines of therapy — and up to 18 lines of therapy — without seeing a lasting response.

Of the 255 patients who started the process of receiving cilta-cel, 236 (about 92%) underwent the full treatment. In addition to analyzing response rates of the whole study population, researchers examined outcomes among several subgroups. They found that patients who received the CAR T-cell product within the range specified by the FDA had a higher response rate (with 94% seeing a response overall and 76% seeing a complete response) compared with the one-fifth of patients whose CAR T cells did not fully conform to the quality standards specified by the FDA.

Researchers also examined a subgroup that included patients who had received prior therapies targeting B cell maturation antigen (BCMA), a protein found on multiple myeloma cells. Since cilta-cel targets BCMA, patients who had previously received such therapies were excluded from the CARTITUDE-1 trial. Researchers found that the 14% of study participants who fell into this category did show lower response rates than those who had not previously received BCMA targeted therapies, with the difference being most pronounced in patients who had received BCMA targeted therapies more recently. This suggests that further studies could help elucidate how the timing of cilta-cel and other BCMA targeted therapies may affect outcomes. The researchers also identified other key patient and disease characteristics that were associated with a lower likelihood of survival or a higher likelihood of disease progression.

Overall, rates of serious side effects were similar to those reported in previous clinical trials. The study found that three-quarters of those who received cilta-cel infusions experienced cytokine release syndrome (CRS), a common CAR-T side effect that can be severe, but only 5% experienced events of grade 3 or higher. Overall, 14% of study participants experienced neurotoxicity and 10% experienced delayed neurotoxicity; 2% experienced Parkinsonism.

“Delayed neurotoxicity is predominantly seen with cilta-cel [compared with other CAR-T therapies], and that’s another trade-off we should still be aware of,” said Dr. Sidana.

The study also found a relatively high rate of death (10%) unrelated to patients’ cancer, mostly from infections or CRS, suggesting that there may be room for improvement in decreasing infection risks and managing CRS.

As a retrospective, real-world study, the study did not include a control group and there may have been discrepancies in outcomes assessment and reporting among the 16 centers that contributed data. Researchers suggested that additional studies could help to identify opportunities to reduce serious side effects and determine whether using cilta-cel earlier during cancer treatment could help to lower the risk of toxicity.

The study, led by first author Debanjan Bhattacharya, PhD, was recently published in the journal Cancers.

Research background

According to the American Cancer Society, lung cancer is the leading cause of cancer death in the United States, accounting for about one in five cancer deaths. Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, making up approximately 80% to 85% of all lung cancer cases.

Up to 40% of lung cancer patients develop brain metastases during the course of the disease, and these patients on average survive between eight and 10 months following diagnosis.

Current standard of care treatments for lung cancer that spreads to the brain include surgical resection and stereotactic brain radiosurgery, and whole brain irradiation is standard in patients with more than 10 metastatic brain lesions.

“Lung cancer brain metastasis is usually incurable, and whole brain radiation treatment is palliative, as radiation limits therapy due to toxicity,” said Bhattacharya, research instructor in the Department of Neurology and Rehabilitation Medicine in UC’s College of Medicine. “Managing potential side effects and overcoming resistance to radiation are major challenges when treating brain metastases from lung cancer. This highlights the importance of new treatments which are less toxic and can improve the efficacy of radiation therapy, are less expensive, and can improve the quality of life in patients.”

Research focus

Bhattacharya and his colleagues at UC focused on AM-101, a synthetic analog in the class of benzodiazepine drugs first developed by James Cook, a medicinal chemist at the University of Wisconsin-Milwaukee. Prior to this study, AM-101’s effect in non-small cell lung cancer was unknown.

AM-101 is a particularly useful drug in the context of brain metastases in NSCLC, Bhattacharya said, as benzodiazepines are known to be able to pass through the blood-brain barrier that protects the brain from potential harmful invaders that can also block some drugs from reaching their target in the brain.

Research results

The team found AM-101 activated GABA(A) receptors located in the NSCLC cells and lung cancer brain metastatic cells. This activation triggers the “self-eating” process of autophagy where the cell recycles and degrades unwanted cellular parts.

Specifically, the study showed that activating GABA(A) receptors increases the expression and clustering of GABARAP and Nix (an autophagy receptor), which boosts the autophagy process in lung cancer cells. This enhanced “self-eating” process of autophagy makes lung cancer cells more sensitive to radiation treatment.

Using animal models of lung cancer brain metastases, the team found AM-101 makes radiation treatment more effective and significantly improves survival. Additionally, the drug was found to slow down the growth of the primary NSCLC cells and brain metastases.

In addition to making radiation more effective, adding AM-101 to radiation treatments could allow for lower radiation doses, which could reduce side effects and toxicity for patients, Bhattacharya said. The team is now working toward opening Phase 1 clinical trials testing the combination of AM-101 and radiation both in lung cancer within the lungs and lung cancer that has spread to the brain.

Bhattacharya began this research while working in the lab of former UC researchers Soma Sengupta and Daniel Pomeranz Krummel, who are now at the University of North Carolina at Chapel Hill. Bhattacharya credits their mentorship and the collaboration with other experts within UC and across multiple academic research institutions in the United States.

Bhattacharya also emphasizes the role of shared university research resources that helped the study move forward. He dedicates this work to his father, who died in 2021 while he was in the early phases of the research.

“The entire work, along with revision experiments, was done at the University of Cincinnati, and this reflects the strong collaborative effort between multiple teams. I am grateful to the Department of Neurology and Rehabilitation Medicine for the overall support in completion of this study,” he said. “My father’s passing motivated me to work harder to complete this project, as he had known about my research and wanted to see me succeed.”

In the study, published in the October issue of the journal Brain, researchers observed that ophthalmic acid binds to and activates calcium-sensing receptors in the brain, reversing the movement impairments of Parkinson’s mouse models for more than 20 hours.

The disabling neurogenerative disease affects millions of people worldwide over the age of 50. Symptoms, which include tremors, shaking and lack of movement, are caused by decreasing levels of dopamine in the brain as those neurons die. L-dopa, the front-line drug for treatment, acts by replacing the lost dopamine and has a duration of two to three hours. While initially successful, the effect of L-dopa fades over time, and its long-term use leads to dyskinesia — involuntary, erratic muscle movements in the patient’s face, arms, legs and torso.

“Our findings present a groundbreaking discovery that possibly opens a new door in neuroscience by challenging the more-than-60-year-old view that dopamine is the exclusive neurotransmitter in motor function control,” said co-corresponding author Amal Alachkar, School of Pharmacy & Pharmaceutical Sciences professor. “Remarkably, ophthalmic acid not only enabled movement, but also far surpassed L-dopa in sustaining positive effects. The identification of the ophthalmic acid-calcium-sensing receptor pathway, a previously unrecognized system, opens up promising new avenues for movement disorder research and therapeutic interventions, especially for Parkinson’s disease patients.”

Alachkar began her investigation into the complexities of motor function beyond the confines of dopamine more than two decades ago, when she observed robust motor activity in Parkinson’s mouse models without dopamine. In this study, the team conducted comprehensive metabolic examinations of hundreds of brain molecules to identify which are associated with motor activity in the absence of dopamine. After thorough behavioral, biochemical and pharmacological analyses, ophthalmic acid was confirmed as an alternative neurotransmitter.

“One of the critical hurdles in Parkinson’s treatment is the inability of neurotransmitters to cross the blood-brain barrier, which is why L-DOPA is administered to patients to be converted to dopamine in the brain,” Alachkar said. “We are now developing products that either release ophthalmic acid in the brain or enhance the brain’s ability to synthesize it as we continue to explore the full neurological function of this molecule.”

Team members also included doctoral student and lab assistant Sammy Alhassen, who is now a postdoctoral scholar at UCLA; lab specialist Derk Hogenkamp; project scientist Hung Anh Nguyen; doctoral student Saeed Al Masri; and co-corresponding author Olivier Civelli, the Eric L. and Lila D. Nelson Chair in Neuropharmacology — all from the School of Pharmacy & Pharmaceutical Sciences — as well as Geoffrey Abbott, professor of physiology & biophysics and vice dean of basic science research in the School of Medicine.

The study was supported by a grant from the National Institute of Neurological Disorders and Stroke under award number NS107671 and the Eric L. and Lila D. Nelson Chair in Neuropharmacology.

Alachkar and Civelli are inventors on a provisional patent that covers products related to ophthalmate and calcium-sensing receptors in motor function.

“In the past, researchers would ask participants to recall what they were doing when they lost their balance, but memory can be unreliable,” said Madigan. “With this new method, participants record their experiences immediately after an incident, providing much more accurate and detailed information.”

The findings were recently published in the Journal of American Geriatrics Society and highlight how voice-recorders captured the moment when participants, who averaged around 72 years of age, lost their balance. The study concludes that among older adults, voice recorders are effective at capturing the circumstances and context in which they lost their balance and potentially fell, without relying on recall later.

Partners:

• Michael Madigan, professor with the Grado Department of Industrial and Systems Engineering at Virginia Tech
• Neil Alexander, director, VA Ann Arbor Health Care System GRECC; University of Michigan: Ivan Duff Collegiate Professor of Geriatric and Palliative Medicine, Department of Internal Medicine; Research Professor, Institute of Gerontology

Real-world insight

In this study, 30 participants wore voice recorders on their wrists over the course of three weeks, and in the event of balance loss, turned them on to record answers to these key questions:

• When and where did the balance loss occur?
• What were they doing at the time?
• How did they attempt to regain their balance — did they grab a railing, take steps, or sit down?
• Why do they think they lost their balance?
• Did they fall?

This immediate, self-reported data was analyzed by Madigan and his team. Instead of waiting to meet with researchers after losing their balance, participants could reflect on what happened in the moment.

“We’re trying to better understand the circumstances in which people lose their balance,” Madigan said. “This process doesn’t require people to think back weeks or months to an incident, especially when memory can be unreliable.”

Participant experience

Maria Moll, a retired epidemiologist and study participant, found the research particularly meaningful, especially as someone in her 70s who remains physically active. After a friend experienced a fall, Moll became more interested in contributing to balance-loss prevention research.

“I’ve always been interested in physical fitness and balance, especially as I age,” said Moll. “This study made me more mindful of my movements, particularly during more challenging activities like hiking.”

The future of real-world data collection

Looking ahead, the team plans to expand the study to larger groups and combine the data with other lab-based measurements. By doing so, they hope to identify individuals who are most at risk of balance loss and develop strategies to proactively address those risks.

“We want to give clinicians the tools to intervene before a fall occurs,” said Madigan. “This method can provide more reliable, detailed information that helps us understand not just how people lose their balance, but why.”

Atrial fibrillation, commonly called AFib or AF, causes about 1 in 7 strokes, according to the U.S. Centers for Disease Control and Prevention, and is associated with a significant increase in the risk of morbidity and mortality. More than 12 million people are expected to have AFib by 2030, according to the American Heart Association, and current treatment paradigms remain inadequate, researchers say.

Proteins involved in physiological processes of the heart have been a target of research for AFib for some time. Until recently, most research suggested that treating AFib through inhibition of specific small-conductance calcium-activated potassium channels, or SK channels, could either reduce or worsen arrhythmias under different conditions.

“Our study used pioneering experimental and computational approaches to decipher how the human SK2 channel can be dynamically co-regulated. The study is especially timely considering inhibitors of SK channels are currently in clinical trials to treat AFib, making further insight into their regulatory mechanisms paramount,” said Nipavan Chiamvimonvat, MD, chair of the Department of Basic Medical Sciences at the U of A College of Medicine — Phoenix.

The paper, “Atomistic Mechanisms of the Regulation of Small Conductance Ca2+-Activated K+ channel (SK2) by PIP2,” was published in the journal Proceedings of the National Academy of Sciences.

The research team examined the role of a lipid — phosphatidylinositol 4,5-bisphosphate, or PIP2 — in regulating the SK2 channel. PIP2 is an integral component of all plant and animal cell membranes and acts as a messenger for a variety of signaling pathways in the body.

“Because PIP2 plays such an essential role in multiple ion channels, regulating cardiac ion channels through PIP2 presents a new mechanism for the lipid regulation of cardiac excitability and function,” said computational biologist Ryan Woltz, PhD, the paper’s co-first author and an assistant research professor at the College of Medicine — Phoenix.

Currently, SK channels are the only known potassium channels that are upregulated in heart failure, and their regulation plays a critical role in cardiac excitability and how disturbances in the heart’s rhythm develop.

“Since PIP2 is known to be dysregulated in heart failure, our study provides critical translational insights into possible mechanisms of cardiac arrhythmias in heart failure,” said co-first author Yang Zheng, PhD, a postdoctoral research fellow at the College of Medicine — Phoenix.

Using comparative modeling, the research team generated human SK2 channel models in closed, intermediate and open states. They then used molecular dynamics simulations to explore the molecular mechanisms of SK2 channel modulation by PIP2.

“Structural insights from our study will be useful to design novel inhibitors of SK2 channels to treat cardiac arrhythmias,” said Vladimir Yarov-Yarovoy, PhD, a professor at UC Davis Health.

Co-senior author Igor Vorobyov, PhD, an associate professor at UC Davis Health, said the team is already using similar computational approaches to study other SK channel subtypes.

“I am thrilled to participate in this collaborative multi-university and multidisciplinary research study and looking forward to a continued collaboration,” Vorobyov said. “We are currently working on applying a similar pioneering experimental/computational approach to modulation of SK channels by drug molecules, which may enhance or inhibit function of these ion channels and can be used as prospective treatment options for AFib and other cardiovascular diseases.”

A new study by researchers at the University of Arizona College of Medicine — Phoenix and the University of California Davis Health identified a new target for developing a therapy to treat atrial fibrillation, the most common type of abnormal heart rhythm.

Atrial fibrillation, commonly called AFib or AF, causes about 1 in 7 strokes, according to the U.S. Centers for Disease Control and Prevention, and is associated with a significant increase in the risk of morbidity and mortality. More than 12 million people are expected to have AFib by 2030, according to the American Heart Association, and current treatment paradigms remain inadequate, researchers say.

Proteins involved in physiological processes of the heart have been a target of research for AFib for some time. Until recently, most research suggested that treating AFib through inhibition of specific small-conductance calcium-activated potassium channels, or SK channels, could either reduce or worsen arrhythmias under different conditions.

“Our study used pioneering experimental and computational approaches to decipher how the human SK2 channel can be dynamically co-regulated. The study is especially timely considering inhibitors of SK channels are currently in clinical trials to treat AFib, making further insight into their regulatory mechanisms paramount,” said Nipavan Chiamvimonvat, MD, chair of the Department of Basic Medical Sciences at the U of A College of Medicine — Phoenix.

The paper, “Atomistic Mechanisms of the Regulation of Small Conductance Ca2+-Activated K+ channel (SK2) by PIP2,” was published in the journal Proceedings of the National Academy of Science.

The research team examined the role of a lipid — phosphatidylinositol 4,5-bisphosphate, or PIP2 — in regulating the SK2 channel. PIP2 is an integral component of all plant and animal cell membranes and act

Atrial fibrillation, commonly called AFib or AF, causes about 1 in 7 strokes, according to the U.S. Centers for Disease Control and Prevention, and is associated with a significant increase in the risk of morbidity and mortality. More than 12 million people are expected to have AFib by 2030, according to the American Heart Association, and current treatment paradigms remain inadequate, researchers say.

Proteins involved in physiological processes of the heart have been a target of research for AFib for some time. Until recently, most research suggested that treating AFib through inhibition of specific small-conductance calcium-activated potassium channels, or SK channels, could either reduce or worsen arrhythmias under different conditions.

“Our study used pioneering experimental and computational approaches to decipher how the human SK2 channel can be dynamically co-regulated. The study is especially timely considering inhibitors of SK channels are currently in clinical trials to treat AFib, making further insight into their regulatory mechanisms paramount,” said Nipavan Chiamvimonvat, MD, chair of the Department of Basic Medical Sciences at the U of A College of Medicine — Phoenix.

The paper, “Atomistic Mechanisms of the Regulation of Small Conductance Ca2+-Activated K+ channel (SK2) by PIP2,” was published in the journal Proceedings of the National Academy of Sciences.

The research team examined the role of a lipid — phosphatidylinositol 4,5-bisphosphate, or PIP2 — in regulating the SK2 channel. PIP2 is an integral component of all plant and animal cell membranes and acts as a messenger for a variety of signaling pathways in the body.

“Because PIP2 plays such an essential role in multiple ion channels, regulating cardiac ion channels through PIP2 presents a new mechanism for the lipid regulation of cardiac excitability and function,” said computational biologist Ryan Woltz, PhD, the paper’s co-first author and an assistant research professor at the College of Medicine — Phoenix.

Currently, SK channels are the only known potassium channels that are upregulated in heart failure, and their regulation plays a critical role in cardiac excitability and how disturbances in the heart’s rhythm develop.

“Since PIP2 is known to be dysregulated in heart failure, our study provides critical translational insights into possible mechanisms of cardiac arrhythmias in heart failure,” said co-first author Yang Zheng, PhD, a postdoctoral research fellow at the College of Medicine — Phoenix.

Using comparative modeling, the research team generated human SK2 channel models in closed, intermediate and open states. They then used molecular dynamics simulations to explore the molecular mechanisms of SK2 channel modulation by PIP2.

“Structural insights from our study will be useful to design novel inhibitors of SK2 channels to treat cardiac arrhythmias,” said Vladimir Yarov-Yarovoy, PhD, a professor at UC Davis Health.

Co-senior author Igor Vorobyov, PhD, an associate professor at UC Davis Health, said the team is already using similar computational approaches to study other SK channel subtypes.

“I am thrilled to participate in this collaborative multi-university and multidisciplinary research study and looking forward to a continued collaboration,” Vorobyov said. “We are currently working on applying a similar pioneering experimental/computational approach to modulation of SK channels by drug molecules, which may enhance or inhibit function of these ion channels and can be used as prospective treatment options for AFib and other cardiovascular diseases.”

A new study by researchers at the University of Arizona College of Medicine — Phoenix and the University of California Davis Health identified a new target for developing a therapy to treat atrial fibrillation, the most common type of abnormal heart rhythm.

Atrial fibrillation, commonly called AFib or AF, causes about 1 in 7 strokes, according to the U.S. Centers for Disease Control and Prevention, and is associated with a significant increase in the risk of morbidity and mortality. More than 12 million people are expected to have AFib by 2030, according to the American Heart Association, and current treatment paradigms remain inadequate, researchers say.

Proteins involved in physiological processes of the heart have been a target of research for AFib for some time. Until recently, most research suggested that treating AFib through inhibition of specific small-conductance calcium-activated potassium channels, or SK channels, could either reduce or worsen arrhythmias under different conditions.

“Our study used pioneering experimental and computational approaches to decipher how the human SK2 channel can be dynamically co-regulated. The study is especially timely considering inhibitors of SK channels are currently in clinical trials to treat AFib, making further insight into their regulatory mechanisms paramount,” said Nipavan Chiamvimonvat, MD, chair of the Department of Basic Medical Sciences at the U of A College of Medicine — Phoenix.

The paper, “Atomistic Mechanisms of the Regulation of Small Conductance Ca2+-Activated K+ channel (SK2) by PIP2,” was published in the journal Proceedings of the National Academy of Science.

The research team examined the role of a lipid — phosphatidylinositol 4,5-bisphosphate, or PIP2 — in regulating the SK2 channel. PIP2 is an integral component of all plant and animal cell membranes and acts as a messenger for a variety of signaling pathways in the body.

“Because PIP2 plays such an essential role in multiple ion channels, regulating cardiac ion channels through PIP2 presents a new mechanism for the lipid regulation of cardiac excitability and function,” said computational biologist Ryan Woltz, PhD, the paper’s co-first author and an assistant research professor at the College of Medicine — Phoenix.

Currently, SK channels are the only known potassium channels that are upregulated in heart failure, and their regulation plays a critical role in cardiac excitability and how disturbances in the heart’s rhythm develop.

“Since PIP2 is known to be dysregulated in heart failure, our study provides critical translational insights into possible mechanisms of cardiac arrhythmias in heart failure,” said co-first author Yang Zheng, PhD, a postdoctoral research fellow at the College of Medicine — Phoenix.

Using comparative modeling, the research team generated human SK2 channel models in closed, intermediate and open states. They then used molecular dynamics simulations to explore the molecular mechanisms of SK2 channel modulation by PIP2.

“Structural insights from our study will be useful to design novel inhibitors of SK2 channels to treat cardiac arrhythmias,” said Vladimir Yarov-Yarovoy, PhD, a professor at UC Davis Health.

Co-senior author Igor Vorobyov, PhD, an associate professor at UC Davis Health, said the team is already using similar computational approaches to study other SK channel subtypes.

“I am thrilled to participate in this collaborative multi-university and multidisciplinary research study and looking forward to a continued collaboration,” Vorobyov said. “We are currently working on applying a similar pioneering experimental/computational approach to modulation of SK channels by drug molecules, which may enhance or inhibit function of these ion channels and can be used as prospective treatment options for AFib and other cardiovascular diseases.”

Although a lifetime of immune-suppressing medicine is the standard regimen for transplant recipients, this comes with considerable dangers and side effects, including susceptibility to infection and decreased efficacy of vaccines.

Now, breakthrough research from a new University of Virginia biomedical engineering professor who recently joined both the School of Engineering and Applied Science and the School of Medicine is helping pioneer a new way for the body to accept transplanted organs without compromising the immune system.

Evan Scott is the Thomas A. Saunders III Family Jefferson Scholars Foundation Distinguished University Professor and David Goodman Family Bicentennial Professor of Nanomedicine in the biomedical engineering department, a joint program of UVA’s School of Engineering and Applied Science and School of Medicine, which he joins after 11 years at Northwestern University.

Scott is the co-author of a new article in the journal Proceedings of the National Academy of Science,describing a study in which Scott and fellow researchers used nanoparticles to make the cells of transplanted hearts in mice resistant to attack by their immune system.

“What we’re trying to do is modify the immune system in a controlled and therapeutic way, so that one day transplant patients won’t have to continuously take the immunosuppressive drugs that they do today, with all the risks they entail,” Scott said.

Beyond the area of transplant, Scott’s new lab at UVA will continue this line of research, which could have implications for other areas that deal with immune rejection, such as diabetes, cell therapy, and autoimmune disorders. He’ll also lead UVA’s Institute for Nanoscale Scientific and Technological Advanced Research, or NanoSTAR, as a part of the new Paul and Diane Manning Institute of Biotechnology.

“Evan’s innovative work with nanoparticles represents the kind of forward-thinking science that can reshape entire medical fields. We are thrilled to have him join our UVA community,” said Jennifer L. West, Dean of the School of Engineering and Saunders Family Professor of Engineering.

The Immune System’s Dilemma: Friend or Foe?

There are about 4,000 heart transplants in the United States each year, and the number is on the rise. However, in a significant percentage of cases, the body rejects the transplanted organ, misclassifying it as a threat and sending in the immune system to attack.

Existing treatments focus on one of two paths: suppressing the immune system so that it will not attack — but leaving the patient’s immune system compromised to viral and bacterial threats — or by building tolerance, which helps the body accept the new organ.

Scott and his lab are focused on the second approach; in the new study, he and his coauthors tried to rewire the cellular-level instructions that cause an immune system to attack a new organ, essentially retraining the immune system to tolerate the new cells.

The Role of Myeloid Cells in Organ Rejection

The body’s immune system uses a wide range of white blood cell types to address a diversity of threats and functions, including pathogenic infection, cancer and wound healing. Myeloid cells circulating in the blood stream are a particularly versatile white blood cell, capable of changing into several different forms as required by the task at hand. When they detect a threat, myeloid cells called monocytes can transform into inflammatory macrophages — attack cells that deal with intruders.

Targeting HIF-2α: A New Therapeutic Strategy

Dr. Scott’s long-term collaborator, Dr. Edward Thorp, discovered that these inflammatory macrophages didn’t always develop in response to transplanted cells. They found that a particular protein, HIF-2α, influenced this process, as it was present in the hearts of mice who accepted the transplant, but not present in those that rejected the new heart.

For researchers, this meant that the protein could be therapeutically targeted and used to signal to the host’s immune system that the newly transplanted heart cells were OK and do not need to be attacked, preventing the monocytes from transforming into inflammatory macrophages.

The research team therefore developed nanoparticles encapsulating the drug Roxadustat, which increases the levels of HIF-2α in monocyte. Since the spleen serves as a reservoir for monocytes, this organ was targeted by the nanoparticles to modify circulating white blood cells and maximize the effect of the therapy. This strategy ensured that a sufficient amount of circulating monocytes were modified to signal the immune system to specifically leave the transplanted heart cells alone while allowing the immune system itself to remain otherwise fully functional.

In the study, mice who received the treatment showed significantly better ability to accept their transplanted hearts.

“We specifically targeted the delivery of the drug directly to the spleen, which proved highly effective. This ability to modify how circulating monocytes respond to their environment has an immense and broad therapeutic potential for treating a variety of different disorders,” Scott said.

The advantage of this new technique is that it can create brain activation without the use of an implanted device in the brain to deliver physical light, according to Manuel Gomez-Ramirez, an assistant professor of brain and cognitive sciences and with the University’s Del Monte Institute for Neuroscience, and the senior author of the study, which appears in the journal NeuroImage.

“BL-OG is an ideal method for noninvasively teasing apart neural circuits in the brain,” says Emily Murphy, the first author of the study and manager of the Haptics Lab, led by Gomez-Ramirez. “There are still so many things to learn about the structure and function of distinct brain areas and neuronal cell types that will help us understand how healthy brains function.”

How to turn on a light — without a switch

To turn on light in the brain, researchers need a few tools. The first one is optogenetics, an established research technique that uses light to activate or inactivate cells in the brain. The next tool is bioluminescence, the same chemical reaction that gives a firefly its glow, which provides the light optogenetics needs to work.

Combining these tools creates the material needed for BL-OG. But in order to work, BL-OG still needs something to “turn on” the light. The organic substance luciferin, when combined with bioluminescence, creates light that activates the optogenetics and modulates cellular response in the brain without an incision. Previous work by Gomez-Ramirez has shown that the chemical luciferin is harmless to the body.

The researchers in the Haptics Lab tested this combination. They put BL-OG into a pre-determined brain region in mice. They then injected luciferin through a vein in the animal’s tail to activate the targeted cells in the brain. They found that BL-OG effects occur rapidly in the brain, but that these effects could be controlled by scaling the dosage of the luciferin in the animal.

‘Fine-tuning’ bioluminescent optogenetics

“The advantage of this technique is we can create brain activation without a cable. There is less risk for infection and other things to go awry because it is a noninvasive method,” Gomez-Ramirez says. “If we want to standardize this technique in the lab, and potentially in the clinic, it is critical to map all the important parameters around using it. These latest findings allow us to now work on fine-tuning the desired effects of BL-OG based on need and requirements.”

Researchers were also able to track the neuromodulation effects of BL-OG through the bioluminescent activity, another potential feature of this method that could provide insight into how the brain works.

The Alfred P. Sloan Foundation supported this research.

New research led by University of Utah mathematicians and climate scientists is generating fresh models for understanding two critical processes in the sea ice system that have profound influences on global climate: the flux of heat through sea ice, thermally linking the ocean and atmosphere, and the dynamics of the marginal ice zone, or MIZ, a serpentine region of the Arctic sea ice cover that separates dense pack ice from open ocean.

In the last four decades since satellite imagery became widely available, the width of the MIZ has grown by 40% and its northern edge has migrated 1,600 kilometers northward, according to Court Strong, a professor of atmospheric sciences.

“It has also shifted toward the pole while the size of the sea ice pack has declined,” said Strong, a co-author on one of two studies published by U scientists in recent weeks. “Most of these changes have happened in the fall, around the time when sea ice reaches its seasonal minimum.”

A tale of two studies, one north and one south

This study, which adapts a phase transition model normally used for alloys and binary solutions on laboratory scales to MIZ dynamics on the scale of the Arctic Ocean, appears in Scientific Reports. A second study, published in the Proceedings of the Royal Society A and based on field research in the Antarctic, developed a model for understanding the thermal conductivity of sea ice. The issue cover featured a photo exposing regularly spaced brine channels in the bottom few centimeters of Antarctic sea ice.

Ice covering both polar regions has sharply receded in recent decades thanks to human-driven global warming. Its disappearance is also driving a feed-back loop where more of the sun energy’s is absorbed by the open ocean, rather than getting reflected back to space by ice cover.

Utah mathematics professors Elena Cherkaev and Ken Golden, a leading sea ice researcher, are authors on both studies. The Arctic study led by Strong examines the macrostructures of sea ice, while the Antarctic study, led by former Utah postdoctoral researcher Noa Kraitzman, gets into its micro-scale aspects.

Sea ice is not solid, but rather is more like a sponge with tiny holes filled with salty water, or brine inclusions. When the ocean water below interacts with this ice, it can set up a flow that allows heat to move more quickly through the ice, just as when you stir a cup of coffee, according to Golden. Researchers in the Antarctic study used advanced mathematical tools to figure out how much this flow boosts heat movement.

The thermal conductivity study also found that new ice, as opposed to the ice that remains frozen year after year, allows more water flow, thereby enabling greater heat transfer. Current climate models could be underestimating the amount of heat moving through the sea ice because they don’t fully account for this water flow. By improving these models, scientists can better predict how fast sea ice melts and how this affects the global climate.

While the aspects of ice investigated in the two studies are quite different, the mathematical principles for modeling them are the same, according to Golden.

“The ice not a continuum. It’s a bunch of floes. It’s a composite material, just like the sea ice with the tiny brine inclusions, but this is water with ice inclusions,” said Golden, describing the Arctic’s marginal ice zone. “It’s basically the same physics and math in a different context and setting, to figure out what are the effective thermal properties on the big scale given the geometry and information about the floes, which is analogous to giving detailed information about the brine inclusions at the sub-millimeter scale.”

Golden is fond of saying what happens in the Arctic does not stay in the Arctic. Changes in the MIZ are certainly playing out elsewhere in the world in the form of disrupted climate patterns, so it is critical to understand what it’s doing. The zone is defined as that part of the ocean surface where 15% to 80% is covered by sea ice. Where the ice cover is greater than 80% it is considered pack ice and less than 15% it’s considered to be the outer fringes of open ocean.

A troubling picture from space

“The MIZ is the region around the edge of the sea ice, where the ice gets broken into smaller chunks by waves and melting,” Strong said. “Changes in the MIZ are important because they affect how heat flows between the ocean and atmosphere, and the behavior of life in the Arctic, from microorganisms to polar bears, and navigating humans.”

With the advent of quality satellite data beginning in the late 1970s, scientific interest in the MIZ has grown, since now its changes are easily documented. Strong was among those who figured out how to use imagery shot from space to measure the MIZ and document alarming changes.

“Over the past several decades, we’ve seen the MIZ widen by a dramatic 40%,” Strong said.

For years, scientists have scrutinized sea ice as a so-called “mushy layer.” As a metal alloy melts or solidifies from liquid, either way it passes through a porous or mushy state where the liquid and solid phases coexist. Freezing salt water is similar, resulting in a pure ice host with liquid brine pockets, which is particularly porous or mushy in the bottom few centimeters nearest the warmer ocean, with vertical channels called “chimneys” in mushy layer language.

Strong’s team tested whether previously modeled mushy layer physics could be applied to the vast reaches of the MIZ. According to the study, the answer is yes, potentially opening a fresh look at a part of the Arctic that is in constant flux.

In short, the study proposed a new way of thinking about the MIZ, as a large-scale phase transition region, similar to how ice melts into water. Traditionally, melting has been viewed as something that happens on a small scale, like at the edges of ice floes. But when the Arctic is viewed in its entirety, the MIZ can be seen as a broad transition zone between solid, dense pack ice and open water. This idea helps explain why the MIZ is not just a sharp boundary, but rather a “mushy” region where both ice and water coexist.

“In climate science, we often use very complex models. This can lead to skillful prediction, but can also make it difficult to understand what’s happening physically in the system,” Strong said. “The goal here was to make the simplest possible model that can capture the changes we’re seeing in the MIZ, and then to study that model to gain insight into how the system works and why it’s changing.”

The focus in this study was to understand the MIZ’s seasonal cycle. The next step will be applying this model to better understand what drives MIZ trends observed over the past few decades.

A University of California, Davis, research team systematically analyzed 40 empirical studies, the majority of which had found that outdoor air pollution is associated with differences in children’s brains. These differences include volumes of white matter, which is associated with cognitive function, connections throughout the brain and even early markers for Alzheimer’s.

The study, “Clearing the Air: A systematic review of studies on air pollution and childhood brain outcomes to mobilize policy change,” was published this month in Developmental Cognitive Neuroscience.

“We’re seeing differences in brain outcomes between children with higher levels of pollution exposure versus lower levels of pollution exposure,” said Camelia Hostinar, an associate professor of psychology and the study’s corresponding author.

Children and teens are especially vulnerable to air pollution because their brains and bodies are still developing. They tend to spend more time outdoors, and their bodies absorb more contaminants relative to their bodyweight than adults, researchers said.

Outdoor air pollution and brain development

This study surveyed 40 published, peer-reviewed studies that all included measures of outdoor air pollution and brain outcomes for children at various ages, from newborns up to 18-year-old adults. The majority of studies came from the United States, Mexico and Europe, with one each from Asia and Australia.

The studies ranged in how they measured brain differences. Some used advanced scanning methods like magnetic resonance imaging, or MRI. Others tested changes in chemical compounds that aid in brain function and health. Some studies looked for tumors in the brain or central nervous system.

Studies from Mexico City that compared children from high- and low-pollution areas found significant differences in brain structure.

Each study included measures of air pollution linked to the child’s address or neighborhood, which showed that the children’s brain differences were observed in places with high levels of air pollution as well as places that met local air pollution standards.

“A lot of these studies include children in places with air pollutant levels that are well below limits set by U.S. or European regulations,” said Anna Parenteau, a Ph.D. student in psychology at UC Davis and the study’s co-first author.

Outdoor air pollution

Sources of outdoor air pollution include coal-fired plants, wildfires and many other sources near where people live. This systematic review is unique because most others have focused on how air pollution affects adults or animals, researchers said.

“We can’t necessarily apply findings from adults and assume that it’s going to be the same for children,” said Johnna Swartz, an associate professor of human ecology and co-author on the study. “We also have to look more at different developmental windows because that might be really important in terms of how air pollution might impact these brain outcomes.”

To establish a causal link between outdoor air pollution and differences in the brain, the research team looked to experimental research on animals. That research showed that pollution does lead to many of the same outcomes identified by the studies in this review, including markers for Alzheimer’s disease.

“A lot of researchers working on brain development, whether it’s autism, Alzheimer’s or something else, really discounted for a long time the environmental factors,” said Anthony Wexler, a professor at UC Davis and director of its Air Quality Research Center. “They argued that it’s genetic or some other factor other than exposure to air pollution. That’s changed a lot recently because of all this research literature.”

Reducing harm

This systematic review proposed steps for both parents and policymakers to protect their children from outdoor air pollution by, for example, adding air filters to homes and schools near freeways.

“We listed air purifiers as one of the policy recommendations, and that is something that could be subsidized or provided in schools and other places where children spend a lot of time,” said Hostinar. “These can be quite effective.”

Researchers can also incorporate measures of air pollution into studies related to brain health or other health outcomes.

“Anybody collecting data from human participants on brain outcomes or cardiovascular outcomes or anything else could easily add questions to assess air pollution exposure, such as obtaining their addresses,” said Sally Hang, a Ph.D. student in psychology and the study’s first co-author.

Plasticizers are chemical compounds that make materials more flexible. They are used in a wide variety of products ranging from lunchboxes and shower curtains to garden hoses and upholstery.

“It’s not just for drinking straws and grocery bags,” said David Volz, environmental sciences professor at UC Riverside, and corresponding author of a paper about the study published in the journal Environmental Research.

Previous California monitoring programs focused on plasticizers called ortho-phthalates, some of which were phased out of manufacturing processes due to health and environmental concerns. Less research has focused on the health effects of their replacements, called non-ortho-phthalates.

This study revealed the presence of both types of plasticizers in the air throughout Southern California.

“The levels of these compounds are through the roof,” Volz said. “We weren’t expecting that. As a result, we felt it was important for people to learn about this study.”

The National Institute of Environmental Health Sciences also wants to increase the visibility of this study, one of only a few to document the phthalates’ presence in the air of urban environments. The institute’s monthly newsletter, Environmental Factor, highlights the study in their October 2024 issue.

The researchers tracked two groups of UCR undergraduate students commuting from different parts of Southern California. Both groups wore silicone wristbands designed to collect data on chemical exposures in the air.

The first group wore their wristbands for five days in 2019, and the second group wore two different wristbands for five days each in 2020. Both groups wore the bands continuously, all day, as they went about their activities. At the end of the data collection period, the researchers chopped the wristbands into pieces, then analyzed the chemicals they contained.

In a previous paper, the team focused on TDCIPP, a flame-retardant and known carcinogen, picked up in the wristbands. They saw that the longer a student’s commute, the higher their exposure to TDCIPP.

Unlike TDCIPP, which most likely migrates out of commuters’ car seats into dust, the team cannot pinpoint the origin of the plasticizers. Because they are airborne, rather than bound to dust, the wristbands could have picked them up anywhere, even outside the students’ cars.

For every gram of chopped-up wristband, the team found between 100,000 and 1 million nanograms of three phthalates, DiNP, DEHP, and DEHT. Ten total plasticizers were measured, but the levels of these three stood out.

Both DiNP and DEHP are included on California’s Proposition 65 list, which contains chemicals known to cause cancer, birth defects, or other reproductive harm. DEHT was introduced as an alternative, but its effects on human health have not been well studied.

This study suggests that introducing DEHT also has not done much to reduce the public’s level of exposure to DiNP or DEHP. Levels of all three chemicals found by Volz and his team were similar to those found by researchers in unrelated studies conducted on the East Coast.

Despite differences in climate, the air on both coasts is likely carrying similar levels of phthalates.

“No matter who you are, or where you are, your daily level of exposure to these plasticizer chemicals is high and persistent,” Volz said. “They are ubiquitous.”

To Volz, studies like this one amplify the need to find alternatives to plastic. As plastics degrade, these compounds and others like them are leaching out into the environment and into the body.

“The only way to decrease the concentration of plasticizers in the air is to decrease our production and consumption of materials containing plasticizers,” he said.

In a new clinical trial, researchers at the Salk Institute and University of California San Diego School of Medicine found that time-restricted eating — also known as intermittent fasting — could offer significant health benefits to adults with metabolic syndrome. Patients who ate within a consistent eight-to-ten-hour window each day for three months saw improvements in several markers of blood sugar regulation and metabolic function compared to those who received standard treatments.

“Our bodies actually process sugars and fats very differently depending on the time of day,” says Salk Professor Satchidananda Panda, co-corresponding author of the study and holder of the Rita and Richard Atkinson Chair. “In time-restricted eating, we are re-engaging the body’s natural wisdom and harnessing its daily rhythms to restore metabolism and improve health.”

The TIMET study is the first to evaluate the benefits of a customized time-restricted eating schedule in patients taking medication for metabolic syndrome. The results were published on September 30, 2024, in Annals of Internal Medicine.

“For many patients, metabolic syndrome is the tipping point that leads to serious and chronic diseases like diabetes and heart disease,” says co-corresponding author Pam Taub, professor of medicine at the UC San Diego School of Medicine and a cardiologist at UC San Diego Health. “There is an urgent need for more effective lifestyle interventions that are accessible, affordable, and sustainable for the average American.”

Western diets high in sugar, salt, and fat, combined with increasingly sedentary lifestyles, are thought to have contributed to the rising rates of metabolic dysfunction. While the initial recommendation may be to “eat less and move more,” these lifestyle changes are difficult for most people to sustain long-term. The researchers say time-restricted eating offers a more practical approach accessible to a wider range of patients, including those already on medication.

“Unlike expensive pharmaceuticals like Ozempic, which require lifetime use, time-restricted eating is a simple lifestyle change that doesn’t cause side effects and can be maintained indefinitely,” says first author Emily Manoogian, a staff scientist in Panda’s lab at Salk. “Patients appreciate that they don’t have to change what they eat, just when they eat.”

In the new study, time-restricted eating protocols were customized to each participant’s eating habits, sleep/wake schedules, and personal commitments. The resulting regimen had them reduce their eating window to a consistent eight to ten hours per day, beginning at least one hour after waking up and ending at least three hours before going to sleep. Manoogian says this personalized approach made the intervention easier for patients to complete, compared to other intermittent fasting studies, which typically assign the same strict time window to all participants.

The TIMET study also accepted participants who were on medication for metabolic syndrome — a group usually excluded from such trials. This makes it the first study to measure the benefits of time-restricted eating in addition to existing standard-of-care pharmacological treatments.

In the study, 108 adults with metabolic syndrome were randomly sorted into either the time-restricted eating group or the control group. Both groups continued to receive standard-of-care treatments and underwent nutritional counseling on the Mediterranean diet. Participants also logged their meals using the myCircadianClock mobile app, developed at Salk.

After three months, patients who had completed the time-restricted eating regimen showed improvements in key markers of cardiometabolic health, including blood sugar and cholesterol. They also saw lower levels of hemoglobin A1c, a marker of long-term blood sugar control. This reduction was similar in scale to what is typically achieved through more intensive interventions by the National Diabetes Prevention Program.

The time-restricted eating group also showed 3-4% greater decreases in body weight, body mass index (BMI), and abdominal trunk fat, a type of fat closely linked to metabolic disease. Importantly, these participants did not experience significant loss of lean muscle mass, which is often a concern with weight loss.

The TIMET trial adds to a growing body of evidence supporting the use of time-restricted eating as a practical, low-cost intervention to improve cardiometabolic health. The promising results suggest that healthcare providers could consider recommending the lifestyle intervention to patients with metabolic syndrome as a complement to existing treatments, though additional long-term studies are needed to determine whether time-restricted eating can sustain these benefits and ultimately reduce the risk of chronic disease.

Other authors include Monica O’Neal, Kyla Laing, and Nikko R. Gutierrez of Salk, and Michael J. Wilkinson, Justina Nguyen, David Van, Ashley Rosander, Aryana Pazargadi, Jason G. Fleischer, and Shahrokh Golshan of UC San Diego.

The work was supported by the National Institutes of Health (R01DK118278, R01CA258221, P30CA014195, UL1TR001442), the Robert Wood Johnson Foundation (76014), and the Larry L. Hillblom Foundation Postdoctoral Fellowship.

To answer this question, an international team of neuroscientists, neurosurgeons, and neurologists joined forces. Doris Dijksterhuis and Matthew Self from Pieter Roelfsema’s group looked together with their colleagues at the brain activity of patients with epilepsy. As part of their treatment, these patients were implanted with depth electrodes in their hippocampus, a brain area involved in learning and memory. The research team took advantage of this and conducted additional tests with them.

“We can measure the activity of individual brain cells in the hippocampus while the patient performs a task,” says Matthew Self. In the hippocampus, there are cells that respond to a specific person, so-called “concept cells.” A well-known example is the “Jennifer Aniston cell,” which becomes active when you see a photo of Jennifer Aniston, hear her name or read the words “Jennifer Aniston.” We wondered if these cells also become active when you only read a pronoun, like ‘he’ or ‘she’. Are these cells able to link the pronoun to the right person?

Shrek cell

Doris Dijksterhuis: “To test this, we first showed the patients many photos until we found a cell that responded to one particular image. For example, we found a cell that responded to an image of ‘Shrek’ but not to other images. We call this cell a ‘Shrek concept cell’. When patients later read a sentence like: “Shrek and Fiona were having dinner. He poured out some wine.” the ‘Shrek’ cell indeed responded to the word “Shrek,” but also to the pronoun ‘He.’ This is interesting because such a pronoun can mean something entirely different in another sentence. For example, in the sentence ‘Donald Trump and Kamala Harris were having dinner. He poured out some wine,’ the same pronoun, ‘He’, refers to Donald Trump, and therefore the Shrek cell will not react. Individual hippocampal cells track who the pronoun refers to in a dynamic, flexible way.”

Self: “We had the participants answer a question at the end of the sentences about who performed the action. We could predict whether the patients would give the correct answer based on the activity of the individual concept cells. To make it a bit more challenging, we also added some trick questions, with two people of the same gender: “Jennifer Aniston and Kamala Harris walked into a bar. She sat at the table.” The patient had to decide themselves who performed the action. We observed that patients tended to choose the person that evoked the most activity in the hippocampus at the start of the sentence. This could be based on chance fluctuations in activity on a trial-by-trial basis or an internal preference for one of the two characters in the sentence.”

The bigger picture

Dijksterhuis: “The hippocampus is important for learning and memory, but it remains unclear how the hippocampus is involved in the interaction between memory and language. How do we remember what we’ve read? When you think of something you’ve read, you have different concepts that together create the story. Pronouns help us to understand who did what in the story and cells in the hippocampus encode these actions into our memory. Ultimately, we want to know how an entire memory is formed and represented in the brain.”

“It is of great value that this group of patients has given their permission to participate in our research. We can only very rarely measure the activity of single brain cells in people who are reading and it is impossible to study these processes in animals. When we get the chance, we try to get as much out of it as possible.”

Source: Science

Substrates in biological cells need to be continuously transported inwards and outwards across the cell membrane to ensure the survival of the cells and enable them to perform their function. However, not all substrates that move through the body should be allowed to enter the cells. And some of these transport processes need to be controllable so that they only occur at a particular time or under specific conditions in order to trigger a cell function.

The role of these active and specialised transport channels is assumed by so-called transport proteins, or transporters for short, a wide variety of which are integrated into the cell membranes. A transport protein comprises a large number of individual amino acids, which together form a complex three-dimensional structure.

Each transporter is tailored to a specific molecule — the so-called substrate — or a small group of substrates. But which exactly? Researchers are constantly searching for matching transporter-substrate pairs.

Professor Dr Martin Lercher from the research group for Computational Cell Biology and corresponding author of a study, which has now been published in PLOS Biology: “Determining which substrates match which transporters experimentally is difficult. Even determining the three-dimensional structure of a transporter — from which it may be possible to identify the substrates — is a challenge, as the proteins become unstable as soon as they are isolated from the cell membrane.”

“We have chosen a different — AI-based — approach,” says Dr Alexander Kroll, lead author of the study and postdoc in the research group of Professor Lercher. “Our method — which is called SPOT — used more than 8,500 transporter-substrate pairs, which have already been experimentally validated, as a training dataset for a deep learning model.”

To enable a computer to process the transporter proteins and substrate molecules, the bioinformaticians in Düsseldorf first convert the protein sequences and substrate molecules into numerical vectors, which can be processed by AI models. After completion of the learning process, the vector for a new transporter and those for potentially suitable substrates can be entered into the AI system. The model then predicts how likely it is that certain substrates will match the transporter.

Kroll: “We have validated our trained model using an independent test dataset where we also already knew the transporter-substrate pairs. SPOT predicts with an accuracy above 92% whether an arbitrary molecule is a substrate for a specific transporter.”

SPOT thus suggests highly promising substrate candidates. “This enables us to limit the search scope for experimenters to a significant degree, which in turn speeds up the process of identifying which substrate is a definite match for a transporter in the laboratory,” says Professor Lercher, explaining the link between bioinformatic prediction and experimental verification.

Kroll adds: “And this applies for any arbitrary transport protein, not just for limited classes of similar proteins, as is the case in other approaches to date.”

There are various potential application areas for the model. Lercher: “In biotechnology, metabolic pathways can be modified to enable the manufacture of specific products such as biofuels. Or drugs can be tailored to transporters to facilitate their entry into precisely those cells in which they are meant to have an effect.”

They also showed that aspirin was able to improve hormone deficiency symptoms in mice with this condition.

People with mutations in a gene called Sox3 develop hypopituitarism, where the pituitary gland doesn’t make enough hormones. It can result in growth problems, infertility and poor responses of the body to stress.

In research published today in PLOS Genetics, the scientists at the Crick removed Sox3 from mice, causing them to develop hypopituitarism around the time of weaning (starting to eat solid food).

They found that mutations in Sox3 largely affect the hypothalamus in the brain, which instructs the pituitary gland to release hormones. However, the gene is normally active in several brain cell types, so the first task was to ask which specific cells were most affected by its absence.

The scientists observed a reduced number of cells called NG2 glia, suggesting that these play a critical role in inducing the pituitary gland cells to mature around weaning, which was not known previously. This could explain the associated impact on hormone production.

The team then treated the mice with a low dose of aspirin for 21 days. This caused the number of NG2 glia in the hypothalamus to increase and reversed the symptoms of hypopituitarism in the mice.

Although it’s not yet clear how aspirin had this effect, the findings suggest that it could be explored as a potential treatment for people with Sox3 mutations or other situations where the NG2 glia are compromised.

An incidental discovery revealed the role of gut bacteria in hormone production

When the National Institute for Medical Research (NIMR) merged with the Crick in 2015, mouse embryos were transferred from the former building to the latter, and this included the mice with Sox3 mutations.

When these mice reached the weaning stage at the Crick, the researchers were surprised to find that they no longer had the expected hormonal deficiencies.

After exploring a number of possible causes, lead author Christophe Galichet compared the microbiome — bacteria, fungi and viruses that live in the gut — in the mice from the Crick and mice from the NIMR, observing several differences in its makeup and diversity. This could have been due to the change in diet, water environment, or other factors that accompanied the relocation.

He also examined the number of NG2 glia in the Crick mice, finding that these were also at normal levels, suggesting that the Crick-fed microbiome was somehow protective against hypopituitarism.

To confirm this theory, Christophe transplanted faecal matter retained from NIMR mice into Crick mice, observing that the Crick mice once again showed symptoms of hypopituitarism and had lower numbers of NG2 glia.

Although the exact mechanism is unknown, the scientists conclude that the make-up of the gut microbiome is an example of an important environmental factor having a significant influence on the consequences of a genetic mutation, in this case influencing the function of the hypothalamus and pituitary gland.

Christophe Galichet, former Senior Laboratory Research Scientist at the Crick and now Research Operations Manager at the Sainsbury Wellcome Centre, said: “It was a huge surprise to find that changes in the gut microbiome reversed hypopituitarism in the mice without Sox3. It’s reinforced to me how important it is to be aware of all variable factors, including the microbiome, when working with animals in research and how nurture can influence nature.”

Robin Lovell-Badge, Group Leader of the Stem Cell Biology and Developmental Genetics Laboratory at the Crick, said: “Hypopituitarism can result from trauma as well as rare mutations, and it can have some profound effects on health in general. As well as suggesting potential options for treatment, our work reinforces how important the gut-brain link is. The next step for this research will be to work out exactly how aspirin and the microbiome influence NG2 glia, and then study this effect in people so we can see if these relatively accessible interventions could help treat hypopituitarism.”

A team led by scientists at UC Riverside, UC Irvine, and Yale School of Medicine has now designed a new drug against malaria and identified its mechanism of action. The researchers found the drug, called MED6-189, is effective against drug-sensitive and drug-resistant P. falciparum strains in vitro as well as in a humanized mouse model (the mice were engineered to have human blood).

The researchers report in the journal Science this week that MED6-189 works by targeting and disrupting not only the apicoplast, an organelle found in P. falciparum cells, but also the vesicular trafficking pathways. They found that this dual mode of action prevents the pathogen from developing resistance, making the drug a highly effective antimalarial compound and a promising new lead in the fight against malaria.

“Disruption of the apicoplast and vesicular trafficking blocks the parasite’s development and thus eliminates infection in red blood cells and in our humanized mouse model of P. falciparum malaria,” said Karine Le Roch, a professor of molecular, cell and systems biology at UCR and the paper’s senior author. “We found MED6-189 was also potent against other zoonotic Plasmodium parasites, such as P. knowlesi and P. cynomolgi.“

MED6-189 is a synthetic compound inspired by a compound extracted from marine sponges. The lab of Christopher Vanderwal, a professor of chemistry and pharmaceutical sciences at UC Irvine, synthesized the compound.

“Many of the best antimalarial agents are natural products, or are derived from them,” he said. “For example, artemisinin, initially isolated from the sweet wormwood plant, and analogues thereof, are critically important for treatment of malaria. MED6-189 is a close relative of a different class of natural products, called isocyanoterpenes, that seem to target multiple pathways in P. falciparum. That is beneficial because had only one pathway been targeted, the parasite could develop resistance to the compound more quickly.”

When researchers at GSK, a pharmaceutical company in Spain, administered MED6-189 to the mice infected with P. falciparum, they found it cleared the mice of the parasite. In collaboration with Choukri Ben Mamoun, a professor of medicine and microbial pathogenesis at the Yale School of Medicine, the team also tested the compound against P. knowlesi, a parasite that infects monkeys, and found it worked as intended, clearing the monkey’s parasite-infected red blood cells.

Next, the team plans to continue the optimization of MED6-189 and further confirm the modified compound’s mechanisms of action using a systems biology approach. Systems biology is a biomedical research approach to understanding the larger picture of a biological system. It offers researchers a way to examine how different living organisms and cells interact at larger scales.

Le Roch, Vanderwal, and Ben Mamoun were joined in the research by fellow scientists at the Stowers Institute for Medical Research in Kansas City, Missouri; GSK; and the University of Georgia.

The research was supported by a grant to Le Roch, Vanderwal, and Ben Mamoun and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. At UCR, Le Roch directs the Center for Infectious Disease and Vector Research.

The title of the research paper is “A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking in P. falciparum Malaria.”

They published their findings today (Sept. 26) in JAMA Network Open.

“The cause of SUID is believed to be multi-factorial. Even with education about safe sleep environments and the back-to-sleep campaign encouraging parents to put babies to sleep on their backs, there’s still a high rate of SUID,” said Emma Guare, a fourth-year medical student at Penn State College of Medicine and first author of the paper. “It’s been hypothesized that there might be a link between infection and SUID and we wanted to better understand that connection, particularly as endemic infection rates shifted during the pandemic.”

In 2022, approximately 3,700 infants died unexpectedly in the United States, according to the Centers for Disease Control and Prevention (CDC). SUID is an umbrella term for unexpected death of an infant under the age of one year from known and unknown causes. SIDS is a type of SUID that occurs during sleep and where the cause of death is not known, even after a full investigation, and accounts for roughly one-third of SUID cases.

The research team examined the rate of both SUID and SIDS during the COVID-19 pandemic and compared it to the immediate period prior to the pandemic. Between March 1, 2018, and Dec. 31, 2021, there were 14,308 cases of SUID, based on national data on mortality provided by the CDC.

The research team found that the risk of SUID and SIDS increased during the pandemic when they compared monthly cases to the pre-pandemic period. The greatest increase was observed in 2021 when rates for SUID and SIDS increased 9% and 10%, respectively, compared to the pre-pandemic period. There was a notable shift in SUID rates from June to December 2021, when the monthly rate of SUID increased between 10% and 14% compared to pre-pandemic levels.

Measures put in place to mitigate the pandemic also interrupted the spread of respiratory illnesses like RSV, keeping rates low during 2020. However, as these measures were lifted during the second year of the pandemic, seasonal respiratory viruses began to circulate more widely at unexpected times and with more intensity.

While there were few RSV-related hospitalizations in 2020, cases surged between June and December 2021, an “off-season” for RSV, which typically is active between October and April. This seasonal shift in RSV closely mirrored the monthly changes in SUID that were observed in 2021.

“We don’t know what makes babies who die from SUID or SIDS more vulnerable, whether it’s genetics or something else. It could be that infections like RSV amplify those factors and make them more vulnerable,” said co-author Erich Batra, associate professor of pediatrics and family and community medicine at Penn State College of Medicine. “With RSV in particular, there have been questions about whether RSV causes more apnea, when you stop breathing temporarily, than other viruses and if that contributes to an environment conducive to SUID.”

The team noted that further research is needed to better understand the role of infection in SUID and SIDS and whether infections like RSV may contribute to a portion of SUID and SIDS cases.

“Practicing safe sleep practices is just as important, if not more important when babies are sick,” Batra said. He encouraged caregivers to continue to place babies to sleep on their backs, avoid soft bedding and not share a bed.

Other Penn State College of Medicine authors on the paper include Catharine Paules, associate professor of medicine; Vernon Chinchilli, Distinguished Professor of Public Health Sciences; Paddy Ssentongo, assistant professor of public health sciences; and Rong Zhao, doctoral student in biostatistics.

Hemophilia is a genetic disorder that limits the blood’s ability to clot and affects around 30,000 people in the United States, mostly males. Left untreated, it can cause spontaneous bleeding, particularly internal bleeding into the joints, which, over time, can cause painful joint damage and mobility issues. Hemophilia B is caused by a lack of clotting factor IX. The gene therapy enables the liver to create factor IX, which allows the blood to clot and protects patients from frequent bleeds.

“What we saw from patients in this study was that within a few days of receiving the gene therapy infusion, it took root, and their bodies started making factor IX for the first time in their lives,” said study investigator and lead author Adam Cuker, MD, MS, section chief for Hematology, and clinical director of the Penn Blood Disorders Center and the Penn Comprehensive Hemophilia Program. “We always want to be careful about using the word ‘cure’ especially until we have longer follow-up data, but for many of these patients, it’s been life changing.”

After at least one year of follow-up, participants in the study had an average 71 percent reduction in bleed rate after receiving the gene therapy, compared to the year prior, when they were treated with prophylactic infusions of factor IX, the standard treatment for the disease. More than half of the 45 patients in the study did not have any bleeds after receiving gene therapy.

FDA-approved gene therapies available at Penn Medicine

Based on the results of this study, the FDA approved the gene therapy (fidanacogene elaparvovec) in April 2024. Cuker was the site lead for the clinical trial at Penn Medicine, which was one of the top-enrolling sites for the study. It represents the second form of gene therapy approved to treat hemophilia B. The first such therapy (etranacogene dezaparvovec-drlb) was approved in November 2022, and Penn Medicine is one of several medical centers in the United States where this treatment is available to patients.

Gene therapies have very specific guidelines that determine eligibility and require specialized knowledge to carry out patient screening and selection, education about treatment risks and benefits, and post-therapy monitoring. Penn Medicine offers access to numerous clinical trials for gene therapy and expertise in administering FDA-approved gene therapies.

In the current study, the most common adverse effect was related to an immune system attack on liver cells that were targeted by the gene therapy, which can render the gene therapy ineffective, if not quickly treated. In the study, affected patients were treated with steroids to limit this immune reaction. Patients in the study will continue to be followed for at least five years to monitor potential long-term side effects.

Life-changing impact

For patients with hemophilia B, the current standard of care of ongoing prophylactic infusions of factor IX is generally effective, but burdensome. Depending on the specific product, a patient may require regular infusions anywhere from once every two weeks up to several times a week. Most patients learn how to put their own IV in to be able to complete their infusions at home. The goal of this prophylactic treatment is to regularly give the body enough factor IX to prevent bleeds, though they still occur. By contrast, the new gene therapy only requires a single dose, and most patients in the study did not need to resume prophylactic factor IX treatments.

“We hear from people born with hemophilia that — even if their disease is well-managed — there’s this burden that’s always in the back of their mind. The frequent infusions, the cost of treatment, the need to plan for infusions when traveling, what happens if they do experience a bleed, and so on, is always there,” Cuker said. “Now that we have patients who were treated on this study and are essentially cured of their hemophilia, they’re telling us about realizing a new, ‘hemophilia-free state of mind.’ As a physician, it’s amazing to see my patients so happy with their new reality.”

The study was supported by Pfizer. Cuker has previously served as a paid consultant for Pfizer.

The findings show the psychedelic DOI (2,5-dimethoxy-4-iodoamphetamine) lessened anxiety in mice and rats while activating the ventral hippocampus and so-called fast-spiking interneurons there.

“It hasn’t been known what brain areas and cell types are involved when psychedelics suppress anxiety,” said Alex Kwan, associate professor of biomedical engineering at Cornell University and senior author of the study, which published today in the journal Neuron. “The idea is that if we know the neurobiology involved, we can design some better drug that would target these pathways.”

“The work provides an understanding of the cellular trigger for the psychedelic-induced relief of anxiety,” said Vidita Vaidya, senior professor of biological sciences at the Tata Institute of Fundamental Research in Mumbai, and the paper’s corresponding author.

The pathway in the ventral hippocampus — a brain structure involved in social memory, emotion and affect — does not appear to cause the hallucinations that are a hallmark of DOI, suggesting that some of the therapeutic effects of psychedelics — including reducing PTSD, depression and anxiety — may be isolated within discrete brain circuits, Vaidya said.

“That opens up the possibility to design psychedelic inspired drugs that target anxiety without evoking potent hallucinations,” she added.

The study builds on earlier research that identified abnormal hyperactivity in the ventral hippocampus when an animal is anxious, particularly neurons that communicate with the amygdala, the major processing center for emotions.

“There’s a hint that in the anxiety state, these cells are active, and maybe the drug works by then silencing some of these,” Kwan said.

In a first-of-its-kind study, researchers from EMBL Heidelberg’s Typas, Bork, Zimmermann, and Savitski groups, and many EMBL alumni, including Kiran Patil (MRC Toxicology Unit Cambridge, UK), Sarela Garcia-Santamarina (ITQB, Portugal), André Mateus (Umeå University, Sweden), as well as Lisa Maier and Ana Rita Brochado (University Tübingen, Germany), compared a large number of drug-microbiome interactions between bacteria grown in isolation and those part of a complex microbial community. Their findings were recently published in the journal Cell.

For their study, the team investigated how 30 different drugs (including those targeting infectious or noninfectious diseases) affect 32 different bacterial species. These 32 species were chosen as representative of the human gut microbiome based on data available across five continents.

They found that when together, certain drug-resistant bacteria display communal behaviours that protect other bacteria that are sensitive to drugs. This ‘cross-protection’ behaviour allows such sensitive bacteria to grow normally when in a community in the presence of drugs that would have killed them if they were isolated.

“We were not expecting so much resilience,” said Sarela Garcia-Santamarina, a former postdoc in the Typas group and co-first author of the study, currently a group leader in the Instituto de Tecnologia Química e Biológica (ITQB), Universidade Nova de Lisboa, Portugal. “It was very surprising to see that in up to half of the cases where a bacterial species was affected by the drug when grown alone, it remained unaffected in the community.”

The researchers then dug deeper into the molecular mechanisms that underlie this cross-protection. “The bacteria help each other by taking up or breaking down the drugs,” explained Michael Kuhn, Research Staff Scientist in the Bork Group and a co-first author of the study. “These strategies are called bioaccumulation and biotransformation respectively.”

“These findings show that gut bacteria have a larger potential to transform and accumulate medicinal drugs than previously thought,” said Michael Zimmermann, Group Leader at EMBL Heidelberg and one of the study collaborators.

However, there is also a limit to this community strength. The researchers saw that high drug concentrations cause microbiome communities to collapse and the cross-protection strategies to be replaced by ‘cross-sensitisation’. In cross-sensitisation, bacteria which would normally be resistant to certain drugs become sensitive to them when in a community — the opposite of what the authors saw happening at lower drug concentrations.

“This means that the community composition stays robust at low drug concentrations, as individual community members can protect sensitive species,” said Nassos Typas, an EMBL group leader and senior author of the study. “But, when the drug concentration increases, the situation reverses. Not only do more species become sensitive to the drug and the capacity for cross-protection drops, but also negative interactions emerge, which sensitise further community members. We are interested in understanding the nature of these cross-sensitisation mechanisms in the future.”

Just like the bacteria they studied, the researchers also took a community strategy for this study, combining their scientific strengths. The Typas Group are experts in high-throughput experimental microbiome and microbiology approaches, while the Bork Group contributed with their expertise in bioinformatics, the Zimmermann Group did metabolomics studies, and the Savitski Group did the proteomics experiments. Among external collaborators, EMBL alumnus Kiran Patil’s group at Medical Research Council Toxicology Unit, University of Cambridge, United Kingdom, provided expertise in gut bacterial interactions and microbial ecology.

As a forward-looking experiment, authors also used this new knowledge of cross-protection interactions to assemble synthetic communities that could keep their composition intact upon drug treatment.

“This study is a stepping stone towards understanding how medications affect our gut microbiome. In the future, we might be able to use this knowledge to tailor prescriptions to reduce drug side effects,” said Peer Bork, Group Leader and Director at EMBL Heidelberg. “Towards this goal, we are also studying how interspecies interactions are shaped by nutrients so that we can create even better models for understanding the interactions between bacteria, drugs, and the human host,” added Patil.

In recent research published in the journal PLOS ONE, USC and Australian researchers explored the powerful effect of repetition on people’s beliefs.

In two rounds studies, they found that even the strongest believers in climate science — those categorized as “alarmed” believers — felt that the skeptical and pro-climate beliefs seemed more true when they encountered them a second time.

“It could take as little as a single repetition to make someone feel as though a claim were true,” said Norbert Schwarz, a study co-author and provost professor of psychology at USC Dornsife College of Letters, Arts and Sciences and USC Marshall School of Business. “It’s certainly concerning, especially when you consider how many people are exposed to both truthful and false claims and either spread them or are persuaded by them to make decisions that might affect the planet..”

Truthiness

According to psychology research, people are more likely to feel statements are true if those statements reflect their own beliefs.

However, their perceptions can be changed if they encounter repeated statements. The more they are exposed to those statements, the more valid the statements seem. Psychologists refer to this as “truthiness” — or, more formally — the “illusory truth effect.”

The team of researchers wondered how people who said they firmly believe in climate science would respond when they encountered climate-skeptical statements.

The researchers worked with 52 participants in the first round of study and 120 in the second. Almost all of the participants — except for 10% — believed in and endorsed climate science — evidence that humans are mainly responsible for climate change.

In both studies, the participants were asked to rate the truth of a series of statements that were climate-skeptical, supportive of climate-science, or weather-related filler statements. Fifteen minutes later, they reviewed another round of claims — half of which turned out to repeat the earlier statements. The participants then rated these claims on a six-point scale ranging from “definitely true” to “definitely false.”

In the second round, the participants also were asked to determine if the claim seemed scientific or climate-skeptic.

Most of the participants (90%) supported climate science. They ranged from “concerned” people, who believe climate change is a problem, but take little action, to “alarmed” people who report the highest level of concern about climate change. Less than 10% assumed that climate change is not an important problem.

Independent of the strength of their convictions, the climate science believers considered all of the claims, including those that opposed their own beliefs in climate science, more valid when they were repeated. This was true even among the so-called “alarmed” participants, who were strongest climate science believers.

“People find claims of climate skeptics more credible when they have been repeated just once,” said the study’s lead author, Mary Jiang, of The Australian National University. “Surprisingly, this increase in belief as a result of repetition occurs even when people identify as a strong endorser of climate science.”

Schwarz noted that the study indicates that there is a benefit to amplifying messages if they are truthful and reinforce action such as healthy behaviors. But repetition can also be harmful if the messages repeat falsehoods.

“In short, this study emphasizes what we have learned over the years, and that is: We should not repeat false information. Instead, we must repeat what is true so that it becomes familiar and more likely to be believed,” Schwarz said.

Steven Banik, assistant professor of chemistry in the School of Humanities and Sciences and institute scholar at Sarafan ChEM-H at Stanford University, and his lab have developed a new method to help force misplaced proteins back to their proper homes within cells. The method involves rewiring the activity of naturally occurring shuttles to help move proteins to different parts of the cell. The team has devised a new class of molecules called “targeted relocalization activating molecules” or TRAMs that convince these natural shuttles to take different cargo — like the proteins that get exported from the nucleus in some cancers — along for the ride. Published in Nature on Sept. 18, this strategy could lead to a therapeutic to correct the protein misplacement associated with diseases, and also to create new functions in cells.

“We are taking proteins that are lost and bringing them back home,” said Banik.

Shuttles and passengers

Our cells contain many compartments, like the nucleus, the secure home of DNA, or the mitochondria, where energy is produced. In between all these compartments is the cytoplasm. All throughout the cell’s many locations are proteins. They are responsible for all sorts of actions — building and breaking molecules, contracting muscles, sending signals — but for them to function properly, they have to do their respective actions in the right place.

“Cells are really crowded places,” said Banik. “Proteins are whizzing through the crowd passing by all kinds of other molecules like RNA, lipids, other proteins. So a protein’s function is limited by what it can do and by its proximity to other molecules.”

Diseases will sometimes take advantage of this need for proximity by mutating proteins that might otherwise be able to protect a cell from damage. These kinds of mutations are like putting the wrong address on a package, tricking proteins into going where they would never go in healthy cells.

Sometimes, this movement makes the protein stop working altogether. Proteins that act on DNA, for instance, will not find any DNA in the cytoplasm and float off doing nothing. Other times, this movement leads to a protein becoming a bad actor. In ALS, for example, a mutation sends a certain protein, called FUS, out of the nucleus and into the cytoplasm, where it aggregates into toxic clumps and eventually kills the cell.

Banik and his team wondered whether they could combat this purposeful misplacement of proteins by using other proteins as shuttles to carry passenger proteins to their proper home. But these shuttles often have other functions, so the team would need to convince the shuttle to take on cargo and transport it to a new place.

To do this, Banik and his team developed a new kind of two-headed molecule called a TRAM. One head is designed to stick to the shuttle, and the other is designed to stick to the passenger. If the shuttle is strong enough, it will carry the passenger to its rightful place.

Along for the ride

The team focused on two promising types of shuttles, one that drags proteins into the nucleus, and another that exports proteins from the nucleus. Christine Ng, a chemistry graduate student and first author on the paper, designed and built TRAMs that hitch together shuttle and passenger. If a passenger in the cytoplasm ended up in the nucleus, they would know their TRAM had worked.

The first challenge was immediate: there were no reliable methods to measure the amount of a protein in a specific location in individual cells. So Ng developed a new method to quantify the amount and location of passenger proteins within a cell at a given time. A chemist by training, she had to learn new skills of microscopy and computational analysis to do this.

“Nature is inherently complex and interconnected, so it’s crucial to have interdisciplinary approaches,” said Ng. “Borrowing logic or tools from one field to address a problem in another field often results in very exciting ‘what if’ questions and discoveries.”

Next, she put it to the test. Her TRAMs successfully moved passenger proteins into and out of the nucleus, depending on the shuttle they used. These early experiments helped her generate some basic “rules” for design, like how strong a shuttle had to be to overcome the passenger’s tendency to pull in another direction.

The next challenge was whether they could design TRAMs that could be medicines, ones that reverse disease-causing protein movement. First, they created a TRAM that would relocalize FUS, the protein that gets shipped out of the nucleus and forms dangerous granules in ALS patients. After treating cells with their TRAM, the team saw that FUS was transported back into its natural home in the nucleus, and that the toxic clumps decreased and the cells were less likely to die.

They then turned their attention to a well-known mutation in mice that makes them more resistant to neurodegeneration. The mutation, famously studied by the late Ben Barres and others, causes a certain protein to travel away from the nucleus down the axon in neurons.

The team wondered if they could build a TRAM that would mimic the protective effect of the mutation, taking the protein for a ride down to the end of the axon. Their TRAM not only moved the target protein down the axon, but also made the cell more resistant to stress that mimics neurodegeneration.

In all these examples, the team faced an ongoing challenge: Designing the passenger-targeting head of the TRAM is difficult because scientists have not yet identified all the possible molecules that could bind to their target passengers. To get around this, the team used genetic tools to install a sticky tag onto these passengers. In the future, though, they hope that they will be able to find naturally occurring sticky pieces on these passengers, and develop TRAMs into new kinds of medicines.

Though they focused on two shuttles, the method is generalizable to any other shuttles, like those that push things to the cell surface, where communication with other cells occurs.

And beyond sending mutated proteins back to where they belong, the team also hopes that TRAMs could be used to send healthy proteins to parts of the cell that they cannot normally access, creating new functions that we do not yet know are possible.

“It’s exciting because we are just starting to learn the rules,” said Banik. “If we shift the balance, if a protein suddenly has access to new molecules in a new part of the cell at a new time, what will it do? What functions could we unlock? What new piece of biology could we understand?”

Banik is also a member of Bio-X and of the Wu Tsai Human Performance Alliance. Other Stanford co-authors include Aofei Liu, a former graduate student in chemistry, and Bianxiao Cui, the Job and Gertrud Tamaki Professor of Chemistry. Cui is a member of Bio-X, the Cardiovascular Institute, and the Wu Tsai Neurosciences Institute, and is a faculty fellow of Sarafan ChEM-H. This work was supported by an A*STAR fellowship and by the NIH/NIGMS.

The approach, detailed in the journal Cell Stem Cell, uses patients’ own tumor cells that replicate the unique characteristics of a patient’s tumor allowing scientists to quickly screen a large number of drugs in order to identify personalized treatments that can target this rare and diverse group of cancers.

“Sarcoma is a rare and complex disease, which makes conducting clinical trials to identify effective treatments particularly challenging. Some of the rarer subtypes lack standard treatment altogether. Even when multiple therapy options are available, there is often no reliable, data-driven method to determine the best course of action for an individual patient. Choosing the most effective treatment is akin to searching for a needle in a haystack,” said Dr. Alice Soragni, the senior author of the study and assistant professor in the department of Orthopaedic Surgery at the David Geffen School of Medicine at UCLA. “Testing drugs with patient-derived tumor organoids has potential to help predict how a patient may respond to treatment, with the goal of improving patient outcomes for diseases where treatment options are often limited.”

While sarcomas, which can develop in the bones or soft tissues like muscles and adipose tissue, only account for less than 1% of all cancers, they carry a high mortality rate, particularly among young people. The rarity and diversity of sarcoma types — more than 100 distinct subtypes — makes them particularly difficult to study. Responses to conventional therapies can vary widely between patients, making it challenging to determine the most effective course of action for each individual.

To determine whether organoids could enhance the understanding of how a patient’s tumor might respond to specific drugs or combinations, the team assembled a biobank of 294 samples from 126 UCLA patients diagnosed with 25 different subtypes of bone and soft tissue sarcoma. While tumor organoids have been widely used to study carcinomas, this study is the first of its scale to extend organoid development to sarcoma.

The team successfully created tumor organoids from over 110 samples and conducted detailed histopathological and molecular analyses to confirm that the organoids retained the key characteristics of the original tumors. These organoids were then subjected to high-throughput drug screening using the mini-ring pipeline developed by Soragni and her team, enabling the testing of hundreds of drugs in a 3D format within a short timeframe.

Using this process, the team was able to identify at least one potentially effective U.S. Food and Drug Administration (FDA)-approved treatment for 59% of the samples tested. Additionally, they found the drug responses observed in the lab matched how the patients themselves responded to treatment for a small number of cases, suggesting that these organoids could be a powerful tool for guiding clinical decisions.

“We’ve shown that it’s possible to generate sarcoma organoids quickly — within a week after surgery or biopsy — and use them to screen a large number of drugs, including FDA-approved therapies and other treatments currently in clinical trials,” said Soragni.

“This gives us the ability to identify which drugs are most likely to work for a particular patient, which is crucial for a disease as complex as sarcoma, where genomic precision medicine has often fallen short,” added study author Dr. Noah Federman, the Glaser Family Endowed Chair and director of the UCLA Health Jonsson Comprehensive Cancer Center’s Pediatric Bone and Soft Tissue Sarcoma Program.

In addition, the study demonstrated that a large-scale, functional precision medicine program could be implemented within a single institution, offering a streamlined and scalable model for organoid-based testing.

“Organoids provide a tangible way to match patients with the most promising therapies and this could be a game-changer for sarcoma patients,” said Dr. Nicholas Bernthal, chair and executive medical director of the Department of Orthopaedic Surgery at UCLA. “We’re optimistic that this approach will lead to better, more personalized care for those who need it most.”

Following the results of this study, the UCLA team will validate the findings in a larger clinical trial that is aimed at confirming the effectiveness of the organoid-based approach in predicting treatment responses in patients with osteosarcoma, the most common type of bone cancer that mainly affects children and young adults.

Soragni, Federman and Bernthal are all members of the UCLA Health Jonsson Comprehensive Cancer Center. The study’s first authors are Ahmad Shihabi, a project scientist in the Soragni laboratory; Peyton Tebon, a visiting project scientist; and Huyen Thi Lam Nguyen, a graduate student. Other UCLA authors are Sara Sartini, Ardalan Davarifar, Alexandra Jensen, Miranda Diaz-Infante, Hannah Cox, Alfredo Enrique Gonzalez, Summer Swearingen, Helena Winata, Sorel Fitz-Gibbon, Takafumi Yamaguchi, Jae Jeong, Sarah Dry, Arun Singh, Bartosz Chmielowski, Joseph Crompton, Fritz Eilber, Scott Nelson, Paul Boutros and Jane Yanagawa.

The study was supported by grants from the National Cancer Institute, the Alan B. Slifka Foundation, David Geffen School of Medicine at UCLA and the UCLA Health Jonsson Comprehensive Cancer Center.

“Therapies that use the patient’s immune system to fight their disease have a lot of potential to change how patients are treated. However, one of the biggest problems in the field right now is that these immunotherapies work well only in a small fraction of patients,” Elise Alspach, Ph.D., assistant professor of molecular microbiology and immunology at SLU, senior author on the paper.

Alspach and her team aimed to understand what determines good T-cell responses in patients, why some patients seem to have better T-cell responses than others, and why some patients respond well to immunotherapies. Research findings recently published in Cancer Immunology Research show that a protein called CXCL13 that has recently been linked to immunotherapy response in patients is more highly expressed in females than males. Additionally, Alspach and her team found that CXCL13 expression is a better marker of immunotherapy response in females than in males.

Alspach and her team used single-cell RNA sequencing in human datasets to understand more about differences in how male and female immune systems respond to tumors. Single-cell RNA sequencing allows scientists to learn what’s happening inside individual cells. Using this technology, Alspach and her team determined that T-cells that infiltrate female tumors are highly activated and ready to identify tumor cells and kill them. They also noted immune suppressive T-cells present more frequently in male tumors than in female tumors.

Alspach and her team discovered that there is growing evidence that the male sex is associated with a better response to immunotherapy, which she said appears to contrast with their work and recently published papers showing that females mount stronger immune responses against their tumors.

“We currently don’t understand why males would respond better than females to immune targeting therapies, but this interesting juxtaposition highlights the need for more research into the variable of sex in the immune response against cancer,” Alspach said.

Alspach said the potential of immunotherapy is revolutionary as it mediates tumor rejection in patients and induces long-term remission.

“When we get infected with a virus, the immune system generates a population of cells that can remember that virus and do a better job of eliminating it from your body, so the immune system does the same thing against tumors,” she said. “The memory response against that tumor partly generates long-term remissions that we see in patients treated with immunotherapies.”

Before the advent of immunotherapies, Alspach said cancer treatments were hard on the body and not tumor-specific or, in the case of small molecule drugs that targeted specific proteins inside tumor cells, frequently become resistant to therapies. Current immunotherapies are typically much better tolerated in more patients, and patients can maintain a higher quality of life because the immune system can be educated to specifically target the tumor rather than all the tissues in the body.

Because immune responses against tumors are different between the sexes, Alspach and her colleagues concluded that it makes sense to potentially design different treatments for male versus female patients. In the future, she hopes more appropriate therapeutic strategies will be devised to target the pathways that mediate better tumor control in ways that benefit individual patients.

This research was possible thanks to a recent investment in single-cell RNA sequencing technology at Saint Louis University, allowing researchers to bring us closer to new cures.

Additional authors include Richard J. DiPaolo, Ph.D.; Ryan M. Teague, Ph.D.; Michelle Brennan, Ph.D.; David DeBruin; Chinye Nwokolo; Katey S. Hunt; Alexander Piening; Maureen J. Donlin; and Stephen T. Ferris, Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine.

Several years ago, MIT researchers showed that administering a series of escalating doses of an HIV vaccine over a two-week period could help overcome a part of that challenge by generating larger quantities of neutralizing antibodies. However, a multidose vaccine regimen administered over a short time is not practical for mass vaccination campaigns.

In a new study, the researchers have now found that they can achieve a similar immune response with just two doses, given one week apart. The first dose, which is much smaller, prepares the immune system to respond more powerfully to the second, larger dose.

This study, which was performed by bringing together computational modeling and experiments in mice, used an HIV envelope protein as the vaccine. A single-dose version of this vaccine is now in clinical trials, and the researchers hope to establish another study group that will receive the vaccine on a two-dose schedule.

“By bringing together the physical and life sciences, we shed light on some basic immunological questions that helped develop this two-dose schedule to mimic the multiple-dose regimen,” says Arup Chakraborty, the John M. Deutch Institute Professor at MIT and a member of MIT’s Institute for Medical Engineering and Science and the Ragon Institute of MIT, MGH and Harvard University.

This approach may also generalize to vaccines for other diseases, Chakraborty notes.

Chakraborty and Darrell Irvine, a former MIT professor of biological engineering and materials science and engineering and member of the Koch Institute for Integrative Cancer Research, who is now a professor of immunology and microbiology at the Scripps Research Institute, are the senior authors of the study, which appears in Science Immunology. The lead authors of the paper are Sachin Bhagchandani PhD ’23 and Leerang Yang PhD ’24.

Neutralizing antibodies

Each year, HIV infects more than 1 million people around the world, and some of those people do not have access to antiviral drugs. An effective vaccine could prevent many of those infections. One promising vaccine now in clinical trials consists of an HIV protein called an envelope trimer, along with a nanoparticle called SMNP. The nanoparticle, developed by Irvine’s lab, acts as an adjuvant that helps recruit a stronger B cell response to the vaccine.

In clinical trials, this vaccine and other experimental vaccines have been given as just one dose. However, there is growing evidence that a series of doses is more effective at generating broadly neutralizing antibodies. The seven-dose regimen, the researchers believe, works well because it mimics what happens when the body is exposed to a virus: The immune system builds up a strong response as more viral proteins, or antigens, accumulate in the body.

In the new study, the MIT team investigated how this response develops and explored whether they could achieve the same effect using a smaller number of vaccine doses.

“Giving seven doses just isn’t feasible for mass vaccination,” Bhagchandani says. “We wanted to identify some of the critical elements necessary for the success of this escalating dose, and to explore whether that knowledge could allow us to reduce the number of doses.”

The researchers began by comparing the effects of one, two, three, four, five, six, or seven doses, all given over a 12-day period. They initially found that while three or more doses generated strong antibody responses, two doses did not. However, by tweaking the dose intervals and ratios, the researchers discovered that giving 20 percent of the vaccine in the first dose and 80 percent in a second dose, seven days later, achieved just as good a response as the seven-dose schedule.

“It was clear that understanding the mechanisms behind this phenomenon would be crucial for future clinical translation,” Yang says. “Even if the ideal dosing ratio and timing may differ for humans, the underlying mechanistic principles will likely remain the same.”

Using a computational model, the researchers explored what was happening in each of these dosing scenarios. This work showed that when all of the vaccine is given as one dose, most of the antigen gets chopped into fragments before it reaches the lymph nodes. Lymph nodes are where B cells become activated to target a particular antigen, within structures known as germinal centers.

When only a tiny amount of the intact antigen reaches these germinal centers, B cells can’t come up with a strong response against that antigen.

However, a very small number of B cells do arise that produce antibodies targeting the intact antigen. So, giving a small amount in the first dose does not “waste” much antigen but allows some B cells and antibodies to develop. If a second, larger dose is given a week later, those antibodies bind to the antigen before it can be broken down and escort it into the lymph node. This allows more B cells to be exposed to that antigen and eventually leads to a large population of B cells that can target it.

“The early doses generate some small amounts of antibody, and that’s enough to then bind to the vaccine of the later doses, protect it, and target it to the lymph node. That’s how we realized that we don’t need to give seven doses,” Bhagchandani says. “A small initial dose will generate this antibody and then when you give the larger dose, it can again be protected because that antibody will bind to it and traffic it to the lymph node.”

T-cell boost

Those antigens may stay in the germinal centers for weeks or even longer, allowing more B cells to come in and be exposed to them, making it more likely that diverse types of antibodies will develop.

The researchers also found that the two-dose schedule induces a stronger T-cell response. The first dose activates dendritic cells, which promote inflammation and T-cell activation. Then, when the second dose arrives, even more dendritic cells are stimulated, further boosting the T-cell response.

Overall, the two-dose regimen resulted in a fivefold improvement in the T-cell response and a 60-fold improvement in the antibody response, compared to a single vaccine dose.

“Reducing the ‘escalating dose’ strategy down to two shots makes it much more practical for clinical implementation. Further, a number of technologies are in development that could mimic the two-dose exposure in a single shot, which could become ideal for mass vaccination campaigns,” Irvine says.

The researchers are now studying this vaccine strategy in a nonhuman primate model. They are also working on specialized materials that can deliver the second dose over an extended period of time, which could further enhance the immune response.

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the National Institutes of Health, and the Ragon Institute of MIT, MGH, and Harvard.

The findings, published Sept. 20 in the journal Science Immunology, offer a mechanistic understanding for how cells respond to heat and could explain how chronic inflammation contributes to the development of cancer.

The impact of fever temperatures on cells is a relatively understudied area, said Jeff Rathmell, PhD, Cornelius Vanderbilt Professor of Immunobiology and corresponding author of the new study. Most of the existing temperature-related research relates to agriculture and how extreme temperatures impact crops and livestock, he noted. It’s challenging to change the temperature of animal models without causing stress, and cells in the laboratory are generally cultured in incubators that are set at human body temperature: 37 degrees Celsius (98.6 degrees Fahrenheit).

“Standard body temperature is not actually the temperature for most inflammatory processes, but few have really gone to the trouble to see what happens when you change the temperature,” said Rathmell, who also directs the Vanderbilt Center for Immunobiology.

Graduate student Darren Heintzman was interested in the impact of fevers for personal reasons: Before he joined the Rathmell lab, his father developed an autoimmune disease and had a constant fever for months on end.

“I started thinking about what an increased set point temperature like that might do. It was intriguing,” Heintzman said.

Heintzman cultured immune system T cells at 39 degrees Celsius (about 102 degrees Fahrenheit). He found that heat increased helper T cell metabolism, proliferation and inflammatory effector activity and decreased regulatory T cell suppressive capacity.

“If you think about a normal response to infection, it makes a lot of sense: You want effector (helper) T cells to be better at responding to the pathogen, and you want suppressor (regulatory) T cells to not suppress the immune response,” Heintzman said.

But the researchers also made an unexpected discovery — that a certain subset of helper T cells, called Th1 cells, developed mitochondrial stress and DNA damage, and some of them died. The finding was confusing, the researchers said, because Th1 cells are involved in settings where there is often fever, like viral infections. Why would the cells that are needed to fight the infection die?

The researchers discovered that only a portion of the Th1 cells die, and that the rest undergo an adaptation, change their mitochondria, and become more resistant to stress.

“There’s a wave of stress, and some of the cells die, but the ones that adapt and survive are better — they proliferate more and make more cytokine (immune signaling molecules),” Rathmell said.

Heintzman was able to define the molecular events of the cell response to fever temperatures. He found that heat rapidly impaired electron transport chain complex 1 (ETC1), a mitochondrial protein complex that generates energy. ETC1 impairment set off signaling mechanisms that led to DNA damage and activation of the tumor suppressor protein p53, which aids DNA repair or triggers cell death to maintain genome integrity. Th1 cells were more sensitive to impaired ETC1 than other T cell subtypes.

The researchers found Th1 cells with similar changes in sequencing databases for samples from patients with Crohn’s disease and rheumatoid arthritis, adding support to the molecular signaling pathway they defined.

“We think this response is a fundamental way that cells can sense heat and respond to stress,” Rathmell said. “Temperature varies across tissues and changes all the time, and we don’t really know what it does. If temperature changes shift the way cells are forced to do metabolism because of ETC1, that’s going to have a big impact. This is fundamental textbook kind of stuff.”

The findings suggest that heat can be mutagenic — when cells that respond with mitochondrial stress don’t properly repair the DNA damage or die.

“Chronic inflammation with sustained periods of elevated tissue temperatures could explain how some cells become tumorigenic,” Heintzman said, noting that up to 25% of cancers are linked to chronic inflammation.

“People ask me, ‘Is fever good or bad?'” Rathmell added. “The short answer is: A little bit of fever is good, but a lot of fever is bad. We already knew that, but now we have a mechanism for why it’s bad.”

The research was supported by the National Institutes of Health (grants R01DK105550, R01HL136664, R01CA217987, R01HL118979, R01AI153167, R01CA245134, T32AI112541, T32DK101003, T32AR059039, K00CA253718), Lupus Research Alliance, Waddell Walker Hancock Cancer Discovery Fund, and National Science Foundation.

The answer, according to archaeologists from the University of Colorado Boulder: It’s complicated. In a new study, the team drew on a wide range of evidence — from medical studies of modern equestrians to records of human remains across thousands of years.

The researchers concluded that horseback riding can, in fact, leave a mark on human skeletons, such as by subtly altering the shape of the hip joint. But those sorts of changes on their own can’t definitively reveal whether people have ridden horses during their lives. Many other activities, even sitting for long periods of time, can also transform human bones.

“In archaeology, there are vanishingly few instances in which we can tie a particular activity unequivocally to skeletal changes,” said Lauren Hosek, lead author of the study and an assistant professor in the Department of Anthropology at CU Boulder.

She and her colleagues reported their findings Sept. 20 in the journal Science Advances.

The results may have implications for researchers who study the origins of when humans first domesticated horses — and also cast doubt on a long-standing theory in archaeology known as the Kurgan hypothesis.

The first equestrians

The research lies at the center of what is among the old debates in archaeology, said William Taylor, a co-author of the new study and curator of archaeology at the CU Museum of Natural History.

He explained that the earliest, incontrovertible evidence of humans using horses for transport comes from the region around the Ural Mountains of Russia. There, scientists have uncovered horses, bridles and chariots dating back to around 4,000 years ago.

But the Kurgan hypothesis, which emerged in the early 20th century, argues that the close relationship between humans and horses began much earlier. Proponents believe that around the fourth millennium B.C., ancient humans living near the Black Sea called the Yamnaya first began galloping on horseback across Eurasia. In the process, the story goes, they may have spread a primordial version of the languages that would later evolve into English, French and more.

“A lot of our understanding of both the ancient and modern worlds hinges on when people started using horses for transportation,” Taylor said. “For decades, there’s been this idea that the distribution of Indo-European languages is, in some way, related to the domestication of the horse.”

Recently, scientists have pointed to human remains from the Yamnaya culture dating back to about 3500 B.C. as a key piece of evidence supporting the Kurgan hypothesis. These ancient peoples, the group argued, showed evidence of wear and tear in their skeletons that likely came from riding horses.

Hips can lie

But, in the new study, Hosek and Taylor argue that the story isn’t so simple.

Hosek has spent a lot of time poring over human bones to learn lessons about the past. She explained that the skeleton isn’t static but can shift and change shape over an individual’s lifetime. If you pull a muscle, for example, a reaction can emerge at the site where the muscle attaches to the underlying bone. In some cases, the bone can become more porous or raised ridges may form.

Reading those sorts of clues, however, can be murky at best. The hip joint is one example.

Hosek noted that when you flex your legs at the hip for long periods of time, including during long horse rides, the ball and socket of the hip joint may rub together along one edge. Over time, that rubbing can cause the round socket of the hip bone to become more elongated, or oval in shape. But, she said, other activities can cause the same kind of elongation.

Archaeological evidence shows that humans used cattle, donkeys and even wild asses for transport in some areas of western Asia centuries before they first tamed horses. Ancient peoples likely yoked these beasts of burden to pull carts or even smaller, two-wheeled vehicles that looked something like a chariot.

“Over time, this repetitive, intense pressure from that kind of jostling in a flexed position could cause skeletal changes,” Hosek said.

She’s seen similar changes, for example, in the skeletons of Catholic nuns from the 20th century. They never rode horses, but did take long carriage rides across the American West.

Ultimately, Hosek and Taylor say that human remains on their own can’t be used to put a date on when people first started riding horses — at least not with currently available science.

“Human skeletons alone are not going to be enough evidence,” Hosek said. “We need to couple that data with evidence coming out of genetics and archaeology and by looking at horse remains, too.”

Taylor added that the picture doesn’t look good for the Kurgan hypothesis:

“At least for now, none of these lines of evidence suggest that the Yamnaya people had domestic horses.”

The method, published this week in the Journal of Archaeological Science, examines two immune proteins found embedded in human tooth enamel: immunoglobulin G, an antibody that fights infection, and C-reactive protein, which is present during inflammation in the body.

“These proteins are present in tooth enamel, and they are something we can use to study the biological and potentially the emotional health of past human populations,” said Tammy Buonasera, an assistant professor at the University of Alaska Fairbanks and lead author of the paper. “Analysis of immune proteins in enamel has not been done before and this opens the door to studying disease and health in the past in a more targeted way than we can today.

The study began when Buonasera was a research associate at the University of California, Davis. She and collaborators, including representatives from local Indigenous tribes, tested for the presence and amount of the proteins in tooth enamel from three groups of people:

• Ancestral Ohlone people from a mission outpost dating to the late 1700s and early 1800s in the San Francisco Bay Area. Their skeletons were inadvertently discovered during a 2016 construction project in the area. Tribal descendants gave permission for their teeth to be used in the study.
• European settlers from the late 1800s buried at a San Francisco city cemetery.
• Modern-day military cadets who donated wisdom teeth.

The research team then cross-referenced the levels of the two proteins with the known history and experiences of each of the populations. Native peoples in the California mission system experienced high rates of mortality, intense stress and introduced infectious diseases. European settlers from the 1800s had shorter lifespans than present-day populations but, as a group, were assumed to have experienced lower degrees of stress and disease than the Ohlone group. It was assumed that the present-day military cadets experienced better health and nutrition than both archaeological groups.

The researchers found a close correspondence between evidence for high levels of stress and disease in the Indigenous population and high levels of the two proteins in their teeth. Protein levels were much higher than those in the other two groups tested.

“We see certain individuals, especially children, with very high levels of immunoglobulins, which the body uses to battle disease, and C-reactive protein, which people produce when they are under stress,” said Jelmer Eerkens, an anthropology professor at University of California, Davis and one of the corresponding authors on the paper. “It’s heartbreaking to think about children who may have lost their parents and family to disease, were thrown into a new cultural environment they didn’t understand, and how it affected their well-being.”

Buonasera said this new way of looking at teeth could allow scientists a more detailed look at historical and prehistoric human experiences, for several reasons.

The first is that teeth form during different windows in a human’s development, starting in utero and continuing through late adolescence or early adulthood. That growth over time in each tooth is analogous to the rings in a tree.

“So, it has the potential to provide us with a record — from birth to early adulthood — of a person’s health status,” Buonasera said.

Second, immune proteins within tooth enamel could provide more specific information about health than scientists can get from looking at structural changes to bone or teeth. Many illnesses do not leave a visible trace on the skeleton, while proteins in teeth may record responses to illness or inflammation.

Finally, tooth enamel tends to degrade much slower than other tissues in the body. That means there’s potential to learn from the proteins in the teeth of ancient humans, providing a timeline of human wellness that stretches back thousands of years.

Beyond gaining new insight into the lives of ancient humans, the method has potential to fuel discoveries about the effects of stress, disease and lifestyle on modern humans as well, she said.

“Without trying to overstate things too much, looking at stresses and immune responses in past populations could provide points of comparison with modern lifestyles that can be especially valuable because you have that depth of time,” Buonasera said.

In addition to being the first to examine serum proteins trapped in enamel, the study is also innovative because of the accuracy the new method provides, said Glendon Parker, an adjunct associate professor at UC Davis and one of the co-authors of the paper.

“We see the approach Tammy and her team have taken to be relevant in many contexts, for this and other questions,” Parker said. “These new tools will give us further insight into the lives of past peoples. It is an exciting time for bio-anthropology as these tools become available.”

Their study recently published in the journal JAMA Health Forum shows that policies requiring coverage of a 12-month supply of short-acting hormonal contraception — most commonly the birth control pill — have not been fully implemented, resulting in no substantial increases nationally in year-long prescription orders. This leaves many patients at an increased risk for unintended pregnancy.

A common cause for decreased effectiveness with the pill is breaks in use, often due to running out of a prescription or a lapse in obtaining a refill. However, dispensing a longer-term supply of contraception — six or 12 months — is linked to improved continuous use, fewer breaks in coverage and health system savings.

“The decision of when or if to become pregnant is deeply personal,” said Maria Rodriguez, M.D., M.P.H., professor of obstetrics and gynecology in the OHSU School of Medicine and director of the OHSU Center for Reproductive Health Equity. “It shouldn’t be impacted by a delay in getting to your pharmacy for a refill, or a pill package running out while on vacation.”

To address this barrier, policymakers in 19 states have enacted 12-month contraceptive supply policies, which require insurers to cover the cost of dispensing a full year of coverage at once per prescription. However, OHSU researchers found that these policies have not been fully implemented and have failed to change current prescribing practices.

Using a difference-in-difference model, which compares changes in outcomes over time between populations, researchers looked at oral pill, patch and ring contraception prescriptions among nearly 4.8 million female Medicaid enrollees ages 18 to 44 in 36 states — 11 states with the 12-month supply policy, and 25 without. Researchers found that in 10 of the 11 states with the policy, an increase in the proportion of contraception dispensed was smaller than one percentage point — meaning just a nominal improvement in year-long prescription orders.

“Our findings suggest a significant gap in knowledge both for patients and prescribers, and we hope this serves as a call to action to make 12-month supplies the standard prescribing practice,” Rodriguez said. “This is low-hanging fruit for improving birth control access, especially for people who live in states with more restrictions on reproductive health care.”

For coverage policies to be effective, insurance companies must comply with and be held accountable for following the revised coverage guidelines, Rodriguez said. Similarly, clinicians would need to change their standard prescribing patterns to write for an extended supply of contraception, and pharmacists would need to dispense the full supply.

The research team says full implementation of these policies will require outreach to contraceptive users, prescribers, pharmacists and payers, as well as enforcement from state governments. A federal policy mandating coverage of a 12-month supply is another strategy to support access, as it would require all insurers, including private payers, to cover 12-month contraception supplies.

Rodriguez encourages patients to feel empowered to ask about their contraceptive options and advocate for choices that are the best fit their personal preferences, lifestyle and family planning goals.

“In our current health care landscape, where reproductive rights are constantly under attack, it’s critical to remove barriers and ensure broad access to contraception,” Rodriguez said. “We need providers to be following this prescribing practice as their default and patients to know that it’s their right to ask for it.”

“The results of our trial demonstrate the clear safety and efficacy of pomalidomide to treat bleeding in HHT, giving these patients a much-needed effective treatment option,” said first author Hanny Al-Samkari, MD, the Peggy S. Blitz Endowed Chair in Hematology/Oncology at Massachusetts General Hospital, Associate Professor of Medicine at Harvard Medical School, classical hematologist and principal investigator at the Mass General Cancer Center. “While much work is still needed to develop additional treatments for HHT, the PATH-HHT study serves as proof of principle that we can develop effective drugs to treat this awful disease.”

Patients with HHT suffer from severe, recurrent nose bleeding that severely reduces their health-related quality of life and results in unemployment and social isolation. They also endure chronic gastrointestinal bleeding, which results in severe anemia and dependence on intravenous iron infusions and blood transfusions. They can additionally suffer from vascular malformations in internal organs, like the brain, lungs, and liver, that can cause life-threatening bleeding, strokes, and heart complications.

The PATH-HHT study is a National Institutes of Health-sponsored clinical trial that enrolled patients at 11 centers, including MGH. The trial evaluated pomalidomide to treat disease manifestations in HHT, focusing on the severe nosebleeds that affect almost all patients with this disease. The primary outcome achieved significant improvements in longitudinal nosebleed severity over time in the pomalidomide group versus the placebo group. Additionally, the investigators found substantial improvements in HHT-specific quality of life in patients receiving pomalidomide compared with those receiving placebo.

The PATH-HHT study was intended to enroll 159 participants but because it eclipsed its prespecified threshold for efficacy, it was closed to enrollment early.

“When you do a clinical trial, closing early for efficacy is the best possible outcome,” said Al-Samkari.

The most common side-effects of pomalidomide were neutropenia, constipation, and rash, but these were mostly mild and manageable. The authors note that additional studies will be needed to define the mechanisms of action of pomalidomide in HHT — that is, why the drug works for this condition. Future studies will also be needed to determine if the drug could have similar effects in patients with gastrointestinal bleeding or other HHT complications.

Massachusetts General Hospital is a HHT Center of Excellence, as certified by the Cure HHT Foundation, and serves over 500 families with HHT throughout Massachusetts and the rest of New England, plus upstate New York. People additionally travel from far and wide to participate in clinical trial opportunities within the MGH HHT Center. The Center is co-directed by Al-Samkari and Josanna Rodriguez-Lopez, MD, from the Division of Pulmonary and Critical Care Medicine.

“As you can imagine, for a neglected but serious disease with no approved therapies, we had great interest in the PATH-HHT study from patients, and enrolled over 50 patients into this important trial,” Al-Samkari said. “This success would not have been possible without the efforts of Pamela Hodges, NP, PhD and the incredible research nurses, coordinators, and associates within the Mass General Cancer Center, as well as my colleagues throughout MGH HHT Center. It has also been my great pleasure to work with Dr. Keith McCrae at the Cleveland Clinic to contribute to this multicenter effort. As a multisystem disease, HHT is very much a team sport.”

The MIND diet is a combination of the Mediterranean and DASH diets. It includes green leafy vegetables like spinach, kale and collard greens along with other vegetables. It recommends whole grains, olive oil, poultry, fish, beans and nuts. It prioritizes berries over other fruits and recommends one or more servings of fish per week.

“With the number of people with dementia increasing with the aging population, it’s critical to find changes that we can make to delay or slow down the development of cognitive problems,” said study author Russell P. Sawyer, MD, of the University of Cincinnati in Ohio and member of the American Academy of Neurology. “We were especially interested to see whether diet affects the risk of cognitive impairment in both Black and white study participants.”

The study involved 14,145 people with an average age of 64. Of participants, 70% were white and 30% were Black. They were followed for an average of 10 years.

Participants filled out a questionnaire on their diet over the past year. Researchers looked at how closely the foods people were eating matched the MIND diet.

One point was given for each of the following: three or more daily servings of whole grains; six or more weekly servings of green leafy vegetables; one or more daily servings of other vegetables; two or more weekly servings of berries; one or more weekly servings of fish; two or more weekly servings of poultry; three weekly servings of beans; five daily servings of nuts; four or fewer weekly servings of red meat; one or fewer weekly servings of fast or fried foods; one or more weekly servings of olive oil; and one or fewer tablespoons of butter or margarine daily; five or fewer weekly servings of pastries and sweets; and one glass per day of wine. The total points possible was 12.

Researchers then divided participants into three groups. The low group had an average diet score of five, the middle group had an average score of seven and the high group had an average score of nine.

Thinking and memory skills were measured at the beginning and end of the study.

During the study, cognitive impairment developed in 532 people, or 12% of 4,456 people in the low diet group; in 617 people, or 11% of 5,602 people in the middle group; and in 402 people, or 10% of the 4,086 people in the high group.

After adjusting for factors such as age, high blood pressure and diabetes, researchers found people in the high group had a 4% decreased risk of cognitive impairment compared to those in the low group.

When looking at male and female participants, researchers found a 6% decreased risk of cognitive impairment for female participants who most closely followed the diet but no decreased risk for male participants.

Researchers also looked at how quickly people’s thinking skills declined as they developed problems. They found that people who more closely followed the MIND diet declined more slowly than those who did not, and that association was stronger in Black participants than in white participants.

“These findings warrant further study, especially to examine these varying impacts among men and women and Black and white people, but it’s exciting to consider that people could make some simple changes to their diet and potentially reduce or delay their risk of cognitive issues,” said Sawyer.

A limitation of the study was it included only older Black and white people so results may not be the same for other populations.

The study was funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging.

A new study contradicts that belief with the discovery that species of flies living in the two distinct visual habitats have significantly different navigation tactics. The researchers made the discovery by putting fruit flies in a contraption that let them interact with virtual objects in a manner similar to the holodeck on the TV show “Star Trek: The Next Generation.”

Flying fruit flies have two jobs: to head toward interesting things, but also stay steady during flight. As in humans, vision helps them move straight and stay stable while orienting toward enticing objects. These two tasks are not complementary. Looking at interesting things interrupts the vision needed to stay stable. But the brain manages to process visual signals in such a way that the flies can accomplish both tasks.

“Visual stability is important — try to stand on one foot with your eyes closed,” said Mark Frye, the corresponding author of a paper published in Current Biology and a professor of integrative biology and physiology at UCLA. “If you want to look at interesting things, you have to briefly override the part of your vision that directs balance, and you risk falling over.”

Urban fruit flies, Drosophila melanogaster, live in a rich visual environment and can stabilize the background surrounding the objects around which they need to orient themselves. But in the desert, what few objects Mojave fruit flies, Drosophila mojavensis, encounter are likely to be the ones they are interested in, such as cactuses, but they also compose the scenery they need to use to stay stable.

To test how different environments affected the balance between navigation and stability in both species, the researchers devised a system that let the flies interact with virtual objects while tracking their body and eye movements with a camera. They glued a tiny steel pin to the fly’s back and connected it to a magnet suspended from the top of a round, drum-like device. Another magnet at the bottom of the drum created a magnetic field that held the pin exactly in position, while allowing the fly to rotate on the horizontal plane within the drum.

The walls of the drum were completely covered with LED lights and a computer created different moving shapes in various sizes and orientations using the lights. The fly could choose how to interact with these virtual objects. One of the objects was a vertical bar that looked like a natural feature, such as a tree trunk. This was designed to test how the fly would use the bar and background to navigate.

“We know exactly where she’s looking at because we’re tracking her body and head with a video camera. We also control exactly what the LED visual display is doing so we can recreate the fly’s eye view of the experiment,” Frye said.

The desert flies ignored the background and steered to smoothly follow the bar, centering it on their visual midline, while the urban flies did not. Desert and urban flies alike made rapid eye movements, called saccades, to follow objects that moved along a continuous path. Desert flies, however, relied more heavily on smooth fixation of the vertical bar, followed up by a flurry of saccades to catch up with fast-moving bars.

This pattern is similar to how our own eyes track moving objects.

“When our eyes track a fast-moving object, like a cow passing us by from a boring train ride, we tend to see smooth continuous eye movements, but only if the object is moving slowly relative to us. As we speed by faster, our eyes switch to rapid saccades to keep up,” said Martha Rimniceanu, a doctoral candidate at UCLA and the lead author of the study. “We were excited to find different use of smooth eye movements and saccades in closely related fly species. We believe this is an adaptation for the structure of their native visual environment.”

The desert flies responded to the bar moving across a stationary background by employing a ‘fixate and saccade’ strategy to track the bar smoothly. Urban flies smoothly fixated on the background, not the bar, and oriented toward the bar with saccades that overrode smooth stability.

“Basically, the desert flies fixate on the bar for balance and stability while also orienting toward it as an interesting object. The urban flies smoothly fixated on the background for balance, then used rapid saccades exclusively to navigate toward the bar,” Frye said.

The research showed that regardless of whether two species are closely related or not, their visual environment determined their visual navigation tactics.

Fruit flies are often used in experiments probing visual perception and processing. The finding that not all species of fruit fly navigate their environment the same way expands the possibilities for what scientists can learn. Desert fruit fly visual navigation more closely resembles that of humans than the urban fruit fly does, for example, and they could be used as a model for learning more about vision in humans. The information can also be used to aid development of autonomous vehicles.

“We can tailor research to the questions we have, rather than being limited to what the fly will give us,” Frye said.

Many people who use fentanyl become trapped in their addiction out of fear and a low tolerance for the withdrawal symptoms, which include muscle cramps, nausea, chills, sweats and intense cravings.

They can’t stop using fentanyl, and they also have trouble starting either of the two medications, methadone and buprenorphine, that can dramatically reduce their risk of overdose death.

Research findings published Aug. 29 in Addiction Science & Clinical Practice may offer hope. A pilot study showed that a small amount of ketamine can reduce or eliminate the withdrawal symptoms associated with quitting fentanyl.

“The main takeaway is that we have found an easier way for people trapped in the grip of fentanyl addiction to get started in treatment,” said Dr. Lucinda Grande, a clinical assistant professor of family medicine at the University of Washington School of Medicine. She was the study’s lead author.

“Methadone can be difficult to access due to strict federal regulations, and starting buprenorphine can cause severe withdrawal symptoms before those who start it become stabilized,” added study co-author Dr. Tom Hutch. He is the medical director of the opioid treatment program at We Care Daily Clinics in Auburn, Wash. “Ketamine, at an imperceptibly low dose, helps bridge that gap.”

Over 14 months, Grande and colleagues in Auburn and Olympia prescribed ketamine to 37 fentanyl-addicted patients whose fear of withdrawal symptoms had deterred them from trying buprenorphine. Twenty-four patients actually tried the drug, and 16 completed the transition to buprenorphine.

Most patients reported a reduction or elimination of withdrawal symptoms after each ketamine dose, the effect of which lasted for hours. Of the last 12 who completed the transition, 92% remained in treatment for at least 30 days.

Patients placed a ketamine lozenge or syrup under the tongue. The 16 mg dose is a small fraction of that typically used for anesthesia, the main clinical role of ketamine for 50 years, according to Grande. That dosage also is less than half of the smallest ketamine dose prescribed for depression treatment, an increasingly common use of this medication.

Researchers monitored patients daily or almost daily, and refined the treatment strategy based on patient response and prescriber experience.

Grande developed the concept after she learned that emergency-medicine physician and coauthor Dr. Andrew Herring of Oakland, California, used a higher, sedating dose of ketamine successfully in his emergency department to resolve a patient’s severe case of withdrawal from fentanyl addiction.

Grande is a primary-care and addiction doctor in practice near Olympia who, in the past dozen years, has used low-dose ketamine to treat more than 600 patients for chronic pain and depression.

Ketamine has gained prominence in the news since actor Matthew Perry of the sitcom “Friends” overdosed on the drug and drowned. Perry had undergone high-dose ketamine treatment for depression, news reports have suggested.

“Our study underscores the enormous potential of this medication for addressing important health problems such as depression, chronic pain and now fentanyl-use disorder,” said Grande. Ketamine’s positive attributes have been overshadowed by Perry’s death, she said.

Grande hopes this pilot study’s results will be confirmed by larger studies. “I am excited about these results,” she said. “This is a wonderful opportunity to save lives.”

Wild animals may also experience adversity early in life, but the effect on their survival and longevity is unknown. While a similar tool could help scientists conserve animal populations by identifying the most influential stressors to mitigate, few populations have been studied over a long enough time to get the data needed to develop a CAI for that species.

UCLA biologists are changing that by creating the first cumulative adversity index for yellow-bellied marmots, based on 62 years of continuous data collection at the Rocky Mountain Biological Laboratory in Colorado. This is the second-longest study of individually marked mammals in the world. The new study, published in Ecology Letters, offers detailed steps for scientists with large datasets for other species to create their own CAI.

The index they developed identified some predictable but also surprising stressors with significant effects on marmot survival and longevity. For example, it was no surprise a late start of the growing season reduced survival because marmots must gain weight during the summer for their 7- to 8-month hibernation. But the finding that summer drought had no effect was unexpected. Predation also played a smaller-than-anticipated role. Not surprisingly, a mother’s death played a large role — but it still did even if it occurred after the pup was weaned. That may be because pups live with their mother for a full year after weaning.

To create the index, doctoral student Xochitl Ortiz-Ross selected data for female marmots born after 2001 — when the researchers started quantifying physiological stress — that remained in one of the studied colonies until 2019, to guarantee an accurate record of their pedigree, age and lifetime experiences. Males typically disperse while females remain in the area where they are born, so biologists can observe females during their lifespan.

This population of marmots spans a 984-foot (300-meter) elevation change that divides the population into up-valley and down-valley groups, with different environmental and demographic conditions. The scientists trap individuals in the population biweekly from spring through late summer, when the marmots are active, collecting behavioral, morphological and physiological data.

Ortiz-Ross identified the following ecological, demographic and maternal measures of adversity, all of which can affect if a pup survives its first year: late start of season; summer drought; predation pressure; large litters; male-biased litters; late weaning; poor maternal mass; high maternal stress; and maternal loss. She wanted to find out if these factors had any effect on the length of an individual’s lifespan after the first year.

These variables were fed into computer models that quantified standard, mild, moderate and acute adversity. All models yielded similar results. Moderate and acute cumulative adversity decreased the odds of pup survival by 30% and 40%, respectively. Pup survival odds were significantly higher up-valley for all models, while maternal loss decreased survival odds in all models and by up to 64% in the moderate adversity model. Poor maternal mass decreased chances of survival by 77% only in the moderate adversity model, while late weaning decreased odds by 33% only in the standardized and raw models. Surprisingly, drought increased odds of survival across all but the acute adversity model, with the greatest effect observed in the moderate adversity model.

The average adult lifespan was 3.8 years, but acute CAIs tripled the risk of adverse effects on life expectancy.

“We found that a CAI effectively captures short-term survival risk in yellow-bellied marmots, and even in the long term, increased adversity early in life lowered the adult lifespan,” Ortiz-Ross said. “Positive effects didn’t cancel out earlier adverse ones, suggesting that adversity does accumulate in marmots and can’t be fully recovered by positive experiences.”

The results supported the hypothesis that a CAI can be a useful tool to evaluate the long-term survival impact of multiple early life stressors in yellow-bellied marmots.

“What we’re facing in terms of biodiversity management is death by a thousand cuts. We typically study one factor at a time: humans, predators, climate and so forth,” said Daniel Blumstein, co-author and professor of ecology and evolutionary biology. “But these impacts occur together and have a cumulative effect. We need a way to figure out which of these stressors — or which combination — has the biggest cumulative effect, and our research shows the CAI can do that for marmots.”

For example, conservation plans targeting this marmot population might target the down-valley group which surprisingly, fared a little worse, and on reducing maternal mortality and improving the health of mothers. But they might not need to target reducing predation or countering the effects of summer drought; these did not turn out to be as important as expected.

Preterm birth, defined as a live birth before 37 weeks of pregnancy, is the second-leading cause of infant mortality in the United States, and one that disproportionately affects Black and Hispanic birthing people. While individual-level factors such as poverty, age, and health status may contribute to racial/ethnic disparities in preterm birth, researchers believe there are broader structural challenges that may be driving the racial gap in this all-too-common birth complication.

A new study led by Boston University School of Public Health (BUSPH) examined preterm births in Massachusetts, where 1 in 11 live births are premature, and found that the social characteristics of a birthing parent’s neighborhood is associated with their risk of experiencing an early delivery.

Published in JAMA Network Open, the study found that more than half of Black and Hispanic infants were born into very low-opportunity neighborhoods, and that babies born into these neighborhoods had a 16-percent greater risk of being born preterm. Researchers assessed neighborhood opportunity level based on a variety of educational, health, environmental, and socioeconomic characteristics identified in the Childhood Opportunity Index (COI), a widely used composite measure that currently includes 44 indicators by census tract.

The study sheds new light on the health consequences of structural racism and historically discriminatory practices — such as redlining and disproportionate exposures to pollutants — that continue to shape modern-day neighborhood conditions and circumstances. Because neighborhood social opportunity is inequitably distributed by race and ethnicity, the COI serves as a valuable measure of both historic and ongoing structural racism, the researchers say.

“Our findings suggest that the context of social opportunity has an impact on children’s health before they are even born, and may in part be a driver of persistent racial and ethnic inequities in preterm birth,” says study lead and corresponding author Dr. Candice Belanoff, clinical associate professor of community health sciences at BUSPH. “The effect remained after we controlled for factors such as maternal/birthing parent health and individual social position.”

Dr. Belanoff and colleagues from BUSPH, Simmons SSW, the University of Illinois, Chicago (UIC), and Brandeis University (Brandeis) utilized Massachusetts birth certificate data by census tract for more than 260,000 singleton infants born in the Boston, Springfield, and Worcester metropolitan areas from February 2011 to December 2015, to explore possible links between neighborhood opportunity levels and preterm births.

Preterm birth was highest among Black infants at 8.4 percent, followed by Hispanic infants at 7.3 percent, Asian or Pacific Islander infants at 5.8 percent, and White infants at 5.8 percent. Compared to White and Asian or Pacific Islander infants, Black and Hispanic infants were approximately 54 percent more likely to be born into very low child opportunity neighborhoods, compared to White infants (11.8 percent) and Asian or Pacific Islander infants (19.6 percent) Similarly, Black and Hispanic infants were also least likely to be born into very high child opportunity neighborhoods, at 6 percent and 6.7 percent, respectively.

“While many lower opportunity neighborhoods are rich cultural hubs and locations of incredible community activism and power, they still suffer the effects of economic exclusion, they are still closer to toxic environmental exposures, and they still generally feature fewer of the resources that help people flourish across the life course,” Dr. Belanoff says.

“This is why it is important to look beyond the individual if we are ever going to reduce or eliminate the racial/ethnic gap in birth outcomes,” says study senior author Dr. Joanna Almeida, professor and Eva Whiting White Endowed Chair at Simmons SSW. “We need to address the inequitable distribution of resources and access to neighborhood opportunity in order to move the needle on racial and ethnic inequities in preterm birth.”

Phospholipids are usually distributed unevenly across the cell membrane, with some types staying on the inside and others on the outer side. However, cells need to change this distribution quickly in response to environmental or internal signals. The process of moving phospholipids from one side of the membrane to the other, known as phospholipid scrambling, can expose specific phospholipids to the outside of the cell. This exposure is important for several functions, including blood clotting and the removal of unwanted cells.

The new research, published in Nature Communications, identified protein complexes that play an essential role in this process. “We discovered that when calcium is incorporated into cells, a specific protein complex, including the ion channel Tmem63b and the vitamin B1 transporter Slc19a2, triggers phospholipid scrambling,” explains Professor Jun Suzuki, who led the study.

Calcium serves as a signal that can activate various cellular processes such as ion channel gating and phospholipid scrambling when it enters the cell. “When Tmem63b was deleted, the cells lost calcium-induced phospholipid scrambling activity” says Han Niu, the study’s first author. “Conversely, certain genetic mutations in the Tmem63b gene linked to diseases like epilepsy and anemia lead to continuous activation of phospholipid scrambling, even without calcium stimulation.”

The researchers also found that Kcnn4, a potassium channel activated by calcium, influences this process. When either Slc19a2 or Kcnn4 was missing, phospholipid scrambling decreased. This shows that Tmem63b, Slc19a2, and Kcnn4 work together to regulate phospholipid scrambling.

Earlier studies by Suzuki and colleagues had identified other proteins involved in phospholipid scrambling, but they couldn’t explain all cases. The new discovery shows that Tmem63b and Slc19a2 work together as a pair bound together to trigger this process, whereas the other proteins work as pairs made of two copies of the same protein.

The team also found that changes in the tension of the cell’s plasma membrane might help activate the Tmem63b/Slc19a2 complex. When calcium enters the cell and potassium ions leave by Kcnn4, it can cause the cell to shrink. This shrinkage can cause changes in the cell membrane tension, facilitating activation of Tmem63b with increase in intracellular calcium. This activation mechanism could explain how neuronal cells and red blood cells adapt to environmental changes through phospholipid scrambling.

The researchers hope that their findings will lead to new treatments for diseases in which phospholipid scrambling is disrupted, including epilepsy and anemia.

Dr. Mohammadi, an Associate Professor with the School of Engineering, says their latest work, dubbed the iValve, is their most advanced yet and combines the best of both technologies — mechanical and tissue — when it comes to replacement heart valves.

“Tissue valves generally perform better than mechanical valves because of their shape, but last only 15 to 20 years on average, which would require another replacement. Mechanical valves can last a lifetime, but do not perform as well as tissue valves, requiring patients to take daily anticoagulants,” says Dr. Mohammadi.

“We have produced a new mechanical heart valve that combines the best of both worlds — offering the performance of tissue valves with the long-lasting durability of mechanical valves. We believe this valve could make life easier and safer for patients,” he adds.

The breakthrough valve was made possible through an international collaboration with ViVitro Labs and independent consultants Lawrence Scotten and Rolland Siegel. The research was funded by Angeleno Medical and published this month in the Journal of Biomechanics.

“This is the only valve of its kind to be designed and built in Canada,” notes Dr. Mohammadi. “We are incredibly proud of this valve as an example of the engineering innovation coming from UBC and Canada.”

Dr. Mohammadi also says while mechanical heart valve replacements have long been in use, the long-standing challenge has been to perfect the technology for the smallest hearts — tiny infants.

“What is particularly exciting about the iValve, is that it was specifically designed for high-heart-rate applications, such as in pediatric patients,” explains Dr. Mohammadi.

Now that their prototype performs well in mechanical lab tests, the researchers will bring it to animal and clinical trials. If all goes well, they hope the iValve could be ready for those trials within two years.

In the meantime, they will also be using the technology and techniques to develop new valves.

“This valve is designed to allow blood flow to the aorta, which is the body’s largest artery, and the blood vessel that carries oxygen-rich blood away from the heart throughout your body,” explains Mohammadi. “Next, we will take what we have learned and develop one for the mitral valve. That valve is responsible for making sure that blood flows from your left atrium to your left ventricle. It also ensures that blood doesn’t flow backward between those two chambers.”

Heart Valve Performance Lab Manager Dr. Dylan Goode is excited about what the future holds for the iValve — and for the benefits it could bring to patients.

Dr. Goode began working with Dr. Mohammadi in 2018 while completing his Master of Applied Science in Mechanical Engineering. Recently, he successfully defended his doctoral dissertation, which documents his design work, fabrication and testing of the iValve.

“We have shown that the iValve can provide the structural benefits of a mechanical heart valve and last a patient’s lifespan while providing improved hemodynamic performance, meaning an improvement of the way in which blood flows through vessels.”

Dr. Goode notes the new iValve could also mean a major improvement in lifestyle for these patients who endure a routine of regular anticoagulant therapy — blood thinners — which can increase their risk of severe bleeding, blood clots or damage to tissues and organs if blood flow is impeded.

That’s the groundbreaking finding from a new study published in the Journal of Physiology that shows for the first time that maternal obesity alters a critical thyroid hormone in the fetal heart, disrupting its development.

Consuming a high-fat, sugary diet during pregnancy also increases the likelihood of the unborn baby becoming insulin resistant in adulthood, potentially triggering diabetes and causing cardiovascular disease. This is despite babies being a normal weight at birth.

University of South Australia researchers identified the link by analysing tissue samples from the fetuses of pregnant baboons fed a high-fat, high-energy diet in a biomedical research institute in the United States. They then compared this to fetuses from baboons on a control diet.

Lead author, University of South Australia PhD candidate Melanie Bertossa, says the findings are significant because they demonstrate a clear link between an unhealthy diet high in saturated fats and sugar, and poor cardiovascular health.

“There has been a long-standing debate as to whether high-fat diets induce a hyper- or hypothyroid state in the fetal heart. Our evidence points to the latter,” Bertossa says.

“We found that a maternal high-fat, high-energy diet reduced concentrations of the active thyroid hormone T3, which acts like a switch around late gestation, telling the fetal heart to start preparing for life after birth. Without this signal, the fetal heart develops differently.”

Bertossa says that diets high in fat and sugar can alter the molecular pathways involved in insulin signalling and critical proteins involved in glucose uptake in the fetal heart. This increases the risk of cardiac insulin resistance, often leading to diabetes in adulthood.

“You’re born with all the heart cells you will ever have. The heart doesn’t make enough new heart muscle cells after birth to repair any damage, so changes that negatively impact these cells before birth could persist for a lifetime.

“These permanent changes could cause a further decline in heart health once children reach adolescence and adulthood when the heart starts to age.”

Senior author, UniSA Professor of Physiology Janna Morrison, says the study demonstrates the importance of good maternal nutrition in the leadup to pregnancy, not only for the mother’s sake but also for the health of the baby.

“Poor cardiac outcomes were seen in babies that had a normal birth weight — a sign that should guide future clinical practice,” Prof Morrison says.

“Cardiometabolic health screening should be performed on all babies born from these types of pregnancies, not just those born too small or too large, with the goal being to detect heart disease risks earlier.”

Prof Morrison says that if rising rates of high-fat sugary diets are not addressed, more people will develop health complications such as diabetes and cardiovascular disease, which could result in shorter life spans in the decades ahead.

“Hopefully, with the knowledge we have now about the negative health impacts of obesity, there is potential to change this trajectory.”

The researchers are currently undertaking long-term studies of babies born to women on high- fat high-energy diets to track their health over decades.

The results of the trial, dubbed the DESTINY-Breast12 study, were presented today at the European Society of Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain, and published simultaneously in a paper in the journal Nature Medicine.

The findings point to T-DXd as a valuable new treatment option for patients with a particularly challenging form of cancer, researchers say. “As many as half of patients with HER2-positive breast cancer develop brain metastases, which often has a poorer prognosis than breast cancer that hasn’t spread to the brain,” says Nancy Lin, MD, leader of the trial and senior author of the study in Nature Medicine. Lin is the associate chief of the Division of Breast Oncology, Dana-Farber, Susan F. Smith Center for Women’s Cancers, and the director of the Metastatic Breast Cancer Program. Localized therapies such as surgery, radiosurgery, and radiation therapy to the brain, are used to treat brain metastases, but the disease usually progresses in the central nervous system — the brain and spinal cord — within six to 12 months of treatment.

Trastuzumab deruxtecan consists of the drug deruxtecan — a chemotherapy agent — linked to an antibody that targets the HER2 protein on breast cancer cells. Trastuzumab itself is a mainstay treatment of HER2-positive breast cancer that has spread to other parts of the body, including the brain. But as with treatments directed specifically at the brain, patients receiving trastuzumab usually have their disease progress, often in the central nervous system.

“Additional systemic therapies for patients with brain metastases are urgently needed,” Lin remarks.

The DESTINY-Breast12 trial involved 504 patients with HER-2 positive breast cancer treated at 78 cancer centers in Western Europe, Japan, Australia, and the U.S. Two hundred sixty-three participants had active or stable brain metastases and 241 had no brain metastases. All had received at least one therapy before enrolling in the trial.

After a median follow-up of 15.4 months, progression-free survival of participants with brain metastases — the length of time patients lived with the cancer before it worsened — was a median of 17.3 months, investigators found. 12- month progression-free survival was 61.6%. Seventy-one percent of participants had an intracranial objective response — a measurable decrease of their cancer in the central nervous system. As expected, there was also a high rate of response in tumors outside of the central nervous system in patients with or without brain metastases. Ninety percent of patients in both groups were alive a year after beginning T-DXd treatment.

The side effects associated with T-DXd were consistent with those reported in previous studies and included nausea, constipation, neutropenia (low levels of a type of white blood cells), fatigue, and anemia. Interstitial lung disease (ILD), a known risk of T-DXd, was observed at similar rates to prior studies, and vigilance to this potentially fatal side effect remains critical.

“Our data show that T-DXd has substantial and durable activity within the brain in patients with HER2-positive breast cancer that has metastasized there,” Lin says. “These results support the use of the drug going forward in this patient population.”

“In patients with obesity who were prescribed semaglutide or liraglutide, we found that long-term weight reduction varied significantly based on the medication’s active agent, treatment indication, dosage and persistence with the medication,” said Hamlet Gasoyan, Ph.D., lead author of the study and a researcher with Cleveland Clinic’s Center for Value-Based Care Research.

Semaglutide (sold under the brand names Wegovy and Ozempic) and liraglutide (sold under the brand names Saxenda and Victoza) are glucagon-like peptide-1 receptor agonists, or GLP-1 RA medications. Those FDA-approved medications help lower blood sugar levels and promote weight loss.

Obesity is a complex chronic disease that affects more than 41% of the U.S. adult population. Clinical trials have shown that anti-obesity medications are effective; however, there is limited data in real-world settings regarding the factors associated with long-term weight change and clinically significant weight loss.

In this study, the researchers identified key factors that were associated with long-term weight loss of patients with obesity. They also indicated the elements that were linked to the probability of achieving 10% or more weight loss.

This retrospective cohort study included 3,389 adult patients with obesity who initiated treatment with injectable semaglutide or liraglutide between July 1, 2015, and June 30, 2022. Follow-up ended in July 2023.

At the start of the study, the median baseline body mass index among study participants was 38.5; 82.2% had type 2 diabetes as treatment indication. Among the patients, 68.5% were white, 20.3% were Black, and 7.0% were Hispanic. More than half of the participants were female (54.7%). Most of the patients received treatment for type 2 diabetes. Overall, 39.6% were prescribed semaglutide for type 2 diabetes, 42.6% liraglutide for type 2 diabetes, 11.1% semaglutide for obesity, and 6.7% liraglutide for obesity.

Results show that one year after the initial prescription’s fill, weight change was associated with the following factors:

• Persistence with medication. On average, patients who were persistent with the medication at one year experienced -5.5% weight change versus -2.8% among patients who had 90-275 medication coverage days within the first year and -1.8% among those with less than 90 covered days.

Researchers found that four in 10 patients (40.7%) were persistent with their medication one year after their initial prescription’s fill. The proportion of patients who were persistent with semaglutide was 45.8% versus 35.6% in patients receiving liraglutide.

Among patients who persisted with their medication at 12 months, the average reduction in body weight was -12.9% with semaglutide for obesity, compared to -5.9% with semaglutide for type 2 diabetes. The reduction in body weight was -5.6% with liraglutide for obesity, compared to -3.1% with liraglutide for type 2 diabetes.

Studies have shown that achieving sustained weight loss of 10% or more provides clinically significant health benefits. With that in mind, Dr. Gasoyan and colleagues looked at the proportion of patients who achieved 10% or more weight reduction.

Overall, 37.4% of patients receiving semaglutide for obesity achieved 10% or more body weight reduction compared to 16.6% of patients receiving semaglutide for type 2 diabetes. In comparison, 14.5% of those receiving liraglutide for obesity achieved 10% or more body weight reduction versus 9.3% of those receiving liraglutide for type 2 diabetes.

Among patients who persisted with their medication one year after their initial prescriptions, the proportion who achieved 10% or more weight reduction was 61% with semaglutide for obesity, 23.1% with semaglutide for type 2 diabetes, 28.6% with liraglutide for obesity, and 12.3% with liraglutide for type 2 diabetes.

Based on the study’s multivariable analysis that accounted for relevant socio-demographic and clinical variables, the following factors were associated with higher odds of achieving 10% or more weight reduction one year after the initial prescriptions:

“Our findings could help inform patients and providers regarding some of the key factors that are associated with the probability of achieving sustained weight loss of a magnitude large enough to provide clinically significant health benefits,” said Dr. Gasoyan. “Having real-world data could help manage expectations regarding weight reduction with GLP-1 RA medications and reinforce that persistence is key to achieve meaningful results.”

In a previous study, Dr. Gasoyan and colleagues looked at the factors influencing the long-term use of anti-obesity medications. Future research will continue to explore patients’ persistence and health outcomes with GLP-1 RA medications. ?

Dr. Gasoyan is supported by a grant from the National Cancer Institute.

The investigational mRNA cancer immunotherapy is targeted for patients with lung cancer, melanoma and other solid tumours. Nineteen patients with advanced stage cancers received between one and nine doses of the immunotherapy treatment. Scientists have found the immunotherapy created an immune response against cancer and was well tolerated, with adverse events including fatigue, injection site pain and fever.

Results from the Phase I trial, also the first-in-human study of the therapy, are being presented on Saturday, 14^th September at the European Society of Medical Oncology conference in Barcelona by the UK Chief Investigator of the trial from King’s College London and Guy’s and St Thomas’ NHS Foundation Trust. The trial is sponsored by Moderna.

The mRNA immunotherapy is just one of many cancer vaccines entering clinical trials around the world. The therapy works by presenting common markers of tumours to patients’ immune systems, training them to recognise and fight cancer cells that express them and potentially eliminate cells that could supress the immune system.

The Phase I trial was designed to test the safety and tolerability of the immunotherapy, and secondary and tertiary objectives were to assess the radiographic and immunological responses.

Eight out of sixteen patients who could have their responses evaluated were able to demonstrate their tumour size did not grow and no new tumours appeared.

Data also showed the mRNA immunotherapy could activate the immune system in many patients, generating immune cells in the blood that could recognise the two proteins of interest (PD-L1 and IDO1). Researchers were able to show in some patients that the immunotherapy can increase levels of important immune cells that can kill cancer cells as well as reduced levels of other immune cells that can prevent the immune system from fighting cancer.

The results should be treated with caution, say the study authors, as the sample size was small and the primary objective of the study was to test for safety and determine the optimal dose of the immunotherapy. However, these promising early results support further research into mRNA-4359.

The trial continues to recruit patients with melanoma and lung cancer in combination with the immunotherapy drug pembrolizumab to provide more information on the safety and efficacy of the therapy.

The UK’s Chief Investigator of the trial Dr Debashis Sarker, a Clinical Reader in Experimental Oncology at King’s College London and a consultant in medical oncology at Guy’s and St Thomas’ NHS Foundation Trust, said: “This study evaluating an mRNA cancer immunotherapy is an important first step in hopefully developing a new treatment for patients with advanced cancers.

“We have shown that the therapy is well tolerated without serious side effects and can stimulate the body’s immune system in a way that could help to treat cancer more effectively. However, as this study has only involved a small number of patients to date, it’s too early to say how effective this could be for people with advanced stage cancer.

“The trial continues to recruit patients with melanoma and lung cancers and is a huge international effort across the UK, USA, Spain and Australia.”

Kyle Holen, M.D., Moderna’s Senior Vice President and Head of Development, Therapeutics and Oncology, said: “We are encouraged by the Phase 1 results of mRNA-4359, which demonstrate its potential to elicit strong antigen-specific T-cell responses while maintaining a manageable safety profile.

“This novel approach could be a key component in shifting the tumour microenvironment toward a more immune-permissive state, offering potential hope for patients with advanced solid tumours.”

The new findings are published in the Journal of Exposure Science and Environmental Epidemiology.

“Although the cohort in our study was small, the findings are significant because they show children and adults in agricultural regions of the San Joaquin Valley of California continue to be exposed to pesticides and herbicides. This is despite efforts to decrease their use,” said Deborah H. Bennett, first author of the study. Bennett is a professor of environmental health at the UC Davis School of Medicine’s Department of Public Health Sciences.

As a heavily agricultural state, California uses millions of pounds of chemical pesticides.

According to data from the California Department of Pesticide Regulation, in 2022, five of the top six counties in California that used the most pounds of pesticides were in the San Joaquin Valley. Those include Fresno, Kern, Tulare, San Joaquin and Madera counties.

Backpack sensors sampled air participants were breathing

The researchers recruited 31 adults and 11 children who lived in three small agricultural towns in the San Joaquin Valley. They gave them backpacks with two special air-collection tubes on the shoulder straps. The location of the tubes allowed researchers to sample the air the participants were breathing.

Each participant wore the backpacks for 1-3 days, eight to 14 hours per day. The combined air sampling took place over a total of 92 days.

When the researchers analyzed the results, they found that seven adults (22% of adult participants) and one school-aged child were exposed to detectable levels of at least one pesticide.

The pesticides found by the sensors on the backpacks include:

• 1,3-dichloropropene, a pesticide used to eradicate parasitic worms
• Chlorpyrifos, a pesticide in use since the 1960s that has been linked to neurologic damage in children
• Pyrimethanil, a fungicide used to prevent mold and mildew
• , an insecticide used to prevent insects
• Penthiopyrad, a fungicide to prevent mold and mildew
• Trifluralin, an herbicide used to control grasses and weeds

When the samples were collected, chlorpyrifos was no longer approved for use in California. Previous research showed that chlorpyrifos has numerous adverse health effects, including acting as a developmental neurotoxin in children and sensitive populations.

Although the toxicity of compounds like chlorpyrifos is known, others are understudied. For example, studies of penthiopyrad in zebrafish found exposure to the chemical resulted in developmental deformities. However, studies of penthiopyrad have not been conducted in mammals, so the potential effects on humans are unknown.

“We need to expand community measuring and monitoring of chemicals routinely used in agriculture,” Bennett said. “New studies are also needed to evaluate the potential toxicity of the chemicals people in California’s agricultural communities are routinely exposed to.”

Participants in this study served as citizen scientists, going about their normal days while wearing the backpacks to collect the samples.

“Many people in agricultural communities are very concerned about pesticide exposure,” said Jane Sellen from Californians for Pesticide Reform, who was a co-author of the study. “They were happy to work with the scientists to collect this much needed data. Even with a small sample size, the results were alarming but not surprising.”

Rebecca Moran, Christopher P. Alaimo and Thomas M. Young of UC Davis are also co-authors on the study.

The project was funded through the California Air Resources Board Community Air Grant (19-CAUP-11) and by the National Institute of Environmental Health Sciences (2P30 ES023513).

The study is part of a continuing assessment of multiple generations of Mexican-origin families living in the United States called the California Families Project. This was the first of these studies to look at how the adolescents’ physiology and relationships worked together to support positive development across the teen years, researchers said.

“We give a lot of attention to adolescents’ problems, and of course that’s important, but we also need to learn more about what helps youths to thrive and live better lives as kind and caring adults,” said Paul Hastings, professor of psychology and the lead author of the paper.

Hastings said the research is important when one considers that in California more than half of children and adolescents identify as Latino or Latinx, and the majority of these families identify Mexico as their country of origin. The people studied were living in Northern California at the time.

The study found that family support predicted the youths’ helpful and compassionate actions toward people they were close to, whereas youths who had good friend support systems became more engaged in volunteer work and other helpful community actions by 19 years of age. In addition, adolescents with physiology that prepared them to be sensitive to others were more likely to be empathic, helpful and kind.

The study was published in Developmental Psychology, a journal of the American Psychological Association, in August.

Researchers looked at 229 Mexican-origin adolescents from fifth grade onward (ages 10 through 19), with data collected from 2006 through 2016. They assessed adolescents’ electrocardiography (heart rate activity), their socialization in relationships with family and friends, and multiple aspects of their prosocial tendencies, including empathy, helpfulness, kindness and civic engagement with their communities.

The study was performed by researchers conducting individual assessments using questionnaires, behavioral tasks, and physiological monitoring of the youths’ ability to manage their physiological arousal. Youths reported on social support they received from family and friends in surveys between ages 10 to 16. They then had their baseline respiratory sinus arrhythmia, or RSA, measured at 17. Empathy and prosocial behavior were assessed at ages 17 and 19.

“The unique benefit of having supportive friendships was evident for emerging adults’ engagement in broader community-oriented prosocial behaviors,” researchers wrote.

“This finding suggests that feeling secure and connected may be particularly important for youths to be prepared to engage with the broader community,” Hastings said.

Additional authors of the paper include Jonas Miller, University of Connecticut; Davis G. Weissman, California State University Dominguez Hills; Gustavo Carlo, UC Irvine; and from UC Davis, Richard W. Robins (psychology), Amanda E. Guyer (human ecology), and Ryan T. Hodge (human development).

The research was supported by the National Institute of Mental Health and the National Institute on Drug Abuse.

The information was published in the New England Journal of Medicine.

Until March 2024, H5N1 had not been detected in 1,337 wastewater samples analyzed by the team. But from March 4 to July 15 (the end of data collection for this article), H5N1 was detected in 10 of 10 cities, 22 of 23 sites, and 100 of 399 samples. However, the abundance of H5N1 in wastewater samples collected over time did not correlate with influenza-related hospitalizations over the same time period, so the risk to the public was extremely low.

UTHealth Houston and Baylor established the wastewater testing program as part of the Texas Epidemic Public Health Institute (TEPHI).

The sequencing protocol used by the team can detect genetic changes that might indicate an adaptation of the virus to mammals, perhaps even humans. Lack of clinical burden in humans and genomic information suggested that the source of the virus load found in wastewater during that time span came from animal origins. But continued surveillance is critical for monitoring any evolutionary adaptations that would indicate the potential for it to jump to humans, the researchers concluded.

Lead authors of the journal letter were Michael J. Tisza, PhD, assistant professor of molecular virology and microbiology at Baylor; Blake Hanson, PhD, assistant professor in the Center for Infectious Diseases at UTHealth Houston School of Public Health; Eric Boerwinkle, PhD, director of TEPHI and the dean, Kozmetsky Family Chair in Human Genetics, and M. David Low Chair in Public Health of the School of Public Health; and Anthony W. Maresso, PhD, the Joseph L. Melnick Chair of Virology at Baylor. Boerwinkle and Hanson are also members of The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences.

The team detects viruses in wastewater by using a viral probe capture set targeting thousands of viral species or variants. Since May 2022, TEPHI has detected more than 400 human and animal viruses, several of which (SARS-CoV-2, influenza, and mpox) have correlated to clinical case data in the population.

Letter co-authors from UTHealth Houston included Kristina Mena, PhD, the Jane Dale Owen Chair in Environmental Health Protection; Anna Gitter, PhD; Fuqing Wu, PhD; Janelle Rios, MPH, PhD; and Jennifer Deegan, MPAff. From Baylor College of Medicine: Justin Clark, PhD; Li Wang, MD, PhD; Katelyn Payne, BS, Matthew Ross, PhD; Sara Javornik Cregeen, PhD; Juwan Cormier, PhD; Vasanthi Avadhanula, PhD; Austen Terwilliger, PhD; Pedro Piedra, MD; Joseph Petrosino, PhD. John Balliew, with the El Paso Water Utility, was also a co-author.

While light pollution is associated with increased risk of some disorders and diseases, this is the first time it had been associated with Alzheimer’s disease.

The study was conducted at Rush University System for Health and published in Frontiers in Neuroscience.

“Our research shows that there is an association in the U.S. between Alzheimer’s disease prevalence and exposure to light at night, particularly in those under the age of 65,” said lead investigator, Robin Voigt-Zuwala, PhD, an associate professor?at Rush. “Nightly light pollution — a modifiable environmental factor — may influence risk for Alzheimer’s.”

High U.S. light levels

While legislation in some states aims to reduce light pollution, levels of nighttime light remain high in many parts of the country.

In studying light pollution maps, researchers looked at the lower 48 states and incorporated medical data associated with Alzheimer’s disease risk factors and divided the groups by light intensity. In the five groups, they found that light intensity was correlated with Alzheimer’s disease prevalence even when some well-established disease factors were not.

While the cause is unknown, higher nighttime light intensity was associated with a greater Alzheimer’s disease prevalence than any other risk factor examined in the study for those under the age of 65, suggesting that younger people may be more sensitive to the effects of light exposure at night.

“Certain genes can influence early-onset Alzheimer’s,and these same genes may cause increased vulnerability to the effects of nighttime light exposure,” Voigt-Zuwala explained. “Additionally, younger people are more likely to live in urban areas and have lifestyles that may increase exposure to light at night.”

Reducing light exposure

Exposure to light influences the body’s natural sleep-wake pattern, which is called a circadian rhythm. Exposure to light at night can disrupt a person’s circadian rhythm, which can promote inflammation and make a person less resilient and more prone to disease. Researchers did not examine light inside the home at night or how it might impact health.

Voigt-Zuwala said, “The good news is that simple changes can be made with minimal effort to reduce exposure to light at night — adding black out curtains or sleeping with an eye mask.”

The research results are limited to a subset of the population and further testing is needed to better understand the connection between evening outdoor light and Alzheimer’s disease.

“I practice in diverse conditions and contexts. I practice hungry, tired, angry and happy. I practice different songs at different speeds and sometimes with different pianos,” said Manavbasi, a graduate student researcher at the Beckman Institute for Advanced Science and Technology. “It’s the variety of practice that makes me a better performer.”

Variety may also make us better learners, according to recent research conducted by Manavbasi and his colleagues at the University of Illinois Urbana-Champaign.

The researchers observed that varied practice, not repetition, primed older adults to learn a new working memory task. Their findings, which appear in the journal Intelligence, propose diverse cognitive training as a promising whetstone for maintaining mental sharpness as we age.

“People often think that the best way to get better at something is to simply practice it over and over again, but robust skill learning is actually supported by variation in practice,” said lead investigator Elizabeth A. L. Stine-Morrow, a Beckman researcher and professor emerita of educational psychology at Illinois.

“While the importance of diversity in practice has been well established in the area of motor learning, our study demonstrated that this principle applies to the development of mental skills as well,” she said.

In their 1978 study, Kerr and Booth found that children who practiced tossing a beanbag at a target from a set distance were less likely to hit their marks than children who had practiced throwing from several different distances. On a larger scale, researchers have observed varied preparation to beget high-level performance in athletics and academics alike.

“World-class athletes who specialize in one sport are more likely to have had early experience with multiple sports than their national-class counterparts, and Nobel laureates are more likely to have more early study and work experiences outside of their discipline compared to nationally acclaimed award winners,” Stine-Morrow said.

She wondered how this concept translates to cognitive training. If learning were a sport, does a diverse training regimen raise the level of play?

The researchers narrowed their focus to working memory, or the cognitive ability to hold one thing in mind while doing something else.

“We chose working memory because it is a core ability needed to engage with reality and construct knowledge,” Stine-Morrow said. “It underpins language comprehension, reasoning, problem-solving and many sorts of everyday cognition.”

Because working memory often declines with aging, Stine-Morrow and her colleagues recruited 90 Champaign-Urbana locals aged 60-87.

At the beginning and end of the study, researchers assessed the participants’ working memory by measuring each person’s reading span: their capacity to remember information while reading something unrelated. The researchers asked participants to read and comprehend a series of logical and illogical sentences (e.g., “Headwear worn by royalty is called a crown,” or “An animal with orange and black stripes is a zebra”), each paired with a letter of the alphabet. Participants who recalled the letters in the correct order generally have a stronger working memory, the researchers said.

Between the reading span assessments, participants completed four weeks of cognitive training. For the first two weeks, participants trained on one of four practice regimens: the reading span task itself, a new working memory activity, multiple working memory activities and a control task unrelated to working memory. For the latter two weeks, all participants practiced a variation of the reading span task.

The participants who practiced with multiple working memory activities showed the most improvement on the reading span assessment from beginning to end, outperforming those who had rehearsed the reading span task for all four weeks.

Though ultimately the most improved, the mixed practice group was not immediately outperforming the others, the researchers noticed.

“They needed to work for it,” Stine-Morrow said. “Mixed practice did not directly lead to better performance; it led to better learning. That group was the slowest to improve on the reading span task, but they ultimately reached the highest peak.”

One reason that varied practice may promote skill development is because of the principle of mutualism, or “mutual growth among closely related abilities,” Stine-Morrow said.

These results provide early evidence for the concept of mutualism and show promise for improving working memory later in life.

“With this study, we have demonstrated the broad principle of mutualism through the small lens of how it applies to working memory,” Stine-Morrow said. “If you scale up this principle and combine it with different kinds of skills, that could demonstrate broader effects.”

Because of limitations caused by the COVID-19 pandemic, participants used their home computers and iPads provided by the research team to complete all portions of the study remotely.

“We are grateful to the folks in the Chambana community who support our research, especially in this case, where they had to fit these activities into their lives over the course of four weeks. Most people thought the activities were challenging, but fun, and treated them as a game they wanted to win,” Stine-Morrow said.

Kimberly Kaphingst, ScD, research director of the Genetic Counseling Shared Resource and co-leader of the Cancer Control and Population Sciences Program at Huntsman Cancer Institute, and professor of communication at the U, says the results of the BRIDGE (Broadening the Reach, Impact, and Delivery of Genetic Services) trial could help expand patient access to genetic care.

According to the American Cancer Society, up to 10% of all cancers may be caused by inherited genetic changes.

“There’s a substantial number of people who have an inherited cancer syndrome. The vast majority don’t know it,” says Kaphingst. “As we are getting better at recognizing people who are in need of genetic testing, we were very interested as a team in coming up with sustainable and scalable ways to actually provide those types of genetic services.”

The current standard of care model for genetic testing involves a two-appointment process. Patients first meet with a genetic counselor for a pre-test appointment, during which they discuss their family history, as well as the risks, benefits, and limitations of testing. If patients choose to proceed with testing, they schedule a second appointment to analyze the results with the counselor.

The BRIDGE trial used an algorithm to find patients at higher risk for inherited cancer syndromes based on their self-reported family health histories.

Researchers then divided more than 3,000 Utah and New York participants into two groups — one pursuing the standard two-appointment model, and the other engaging with a chatbot designed and scripted to provide genetics education instead of having a pre-test appointment with a genetic counselor.

Participants in the chatbot group were sent a message through MyChart, an online patient health portal, recommending genetic services and providing a link to launch a chatbot. They then received information about genetic testing and were able to ask questions to help them decide if they should proceed with testing.

Researchers found outcomes between the two groups were equally likely to complete genetic testing, demonstrating that a chatbot is a viable alternative to the traditional model.

“Our goal wasn’t to see if the chatbot was better or for worse. The question was, is this another model that we can use to offer genetic services to patients and have similar outcomes. For a lot of people, the chatbot model provided enough information,” says Kaphingst. “The chatbot can take some of the burden off genetic counselors and help provide genetic testing to more patients who are eligible.”

Researcher and genetic counselor Rachelle Chambers, MS, CGC, manager of the High-Risk Cancer Genetics Program at NYU Langone Perlmutter Cancer Center, says the promising results of this equivalency trial are crucial as knowledge of and demand for genetic testing is on the rise.

“Twenty years ago, we were testing for a handful of cancer-related genes, like BRCA1 and BRCA2, which can lead to an increased risk for breast and ovarian cancer. Now, we might analyze 100 different genes linked to cancers,” says Chambers. “From my perspective as a genetic counselor, there are not enough genetic specialists to meet the increased demand of patients that could benefit from this type of testing.”

Patients who know they are genetically more likely to develop cancer can be proactive in prevention, through increased screenings, taking medications, pursuing surgery to reduce risk, and changing personal behaviors.

The results of the BRIDGE trial have been published in JAMA Network Open.

The trial was co-led by Saundra Buys, MD, Huntsman Cancer Institute investigator and professor in the department of medicine at the U, and Meenakshi Sigireddi, MD, assistant professor of medicine at NYU Grossman School of Medicine. Additional Huntsman Cancer Institute collaborators include Wendy Kohlmann, MS, now at the U.S. Department of Veterans Affairs, Sarah Colonna, MD, Whitney F. Espinel, CGC, MS, Amanda Gammon, MS, CGC, Josh Schiffman, MD, professor of pediatrics at the U, Kensaku Kawamoto, MD, PhD, MHS, FACMI, FAMIA, professor of clinical informatics at the U, Guilherme Del Fiol, MD, PhD, FACMI, professor of biomedical informatics at the U, and David Wetter, PhD, MS, professor of population health sciences at the U. Michael Flynn, MD, adjunct assistant professor at the U, and Rachel Hess, MD, MS, professor of population health sciences at the U, also contributed to the study.

This study was supported by the National Institutes of Health/National Cancer Institute through U01CA232826, which was part of the Inherited Cancer Syndrome Collaborative, P30 CA02014; and Huntsman Cancer Foundation.

“Framing climate change action as a way to protect and preserve patriotic values and familiar ways of life can improve climate awareness and motivate action across the American political spectrum,” says Katherine Mason, a New York University doctoral student and the lead author of the study, which appears in the Proceedings of the National Academy of Sciences (PNAS). “This approach encourages people to see climate action as a way to celebrate and sustain cherished cultural traditions, rather than having to relinquish or replace them.”

The findings, which stem from an experiment involving 50,000 participants across 60 countries, showed such messaging had similar, though smaller, effects among liberals in some nations, including France and Chile, and among conservatives in Israel and Chile. However, it backfired among conservatives in other nations — notably, Belgium, Germany, and Russia.

Overall, the results are at odds with much of today’s pro-environment messaging, which often centers on doomsday scenarios, overhauling our socioeconomic system, or radically altering our consumption habits.

“It is crucial to avoid triggering…existential threats, insofar as these can motivate system defensiveness and backlash against pro-environmental initiatives,” write the authors, who also included John Jost, a professor in NYU’s Department of Psychology, and Madalina Vlasceanu, an NYU assistant professor at the time of the study and now at Stanford University.

In the PNAS study, participants were informed they would be asked to read some information, report on their beliefs and behaviors, and write a small paragraph. To ensure a common understanding of climate change, they were given the following definition: “Climate change is the phenomenon describing the fact that the world’s average temperature has been increasing over the past 150 years and will likely be increasing more in the future.”

Participants assigned to the control condition then read a literary passage from Charles Dickens’ 1861 novel Great Expectations, which made no references to the climate. In the “framing” condition, participants read a message aimed at increasing feelings of connection to the existing social system, linking the nation’s “way of life” to natural and cultural traditions and communicating that climate change poses a threat that requires patriotic, pro-environmental action to “protect and preserve” the national heritage “as it should be.” The message, which was accompanied by photographs of cities, natural resources, people, and flags, was tailored to include country-specific terms.

Participants in the control and framing conditions were then asked to answer questions pertaining to belief in climate change, support for pro-environmental policies, and willingness to share climate information on social media.

Among US participants, those who read the patriotic/status quo message showed increased belief in climate change, more support for pro-environmental policies, and a greater willingness to share climate information on social media relative to the control group. Moreover, this message was similarly effective for conservatives and liberals.

“Climate change is a challenge that must urgently be tackled,” says Mason. “Our approach tested the ways to communicate information about climate change that resonates with people’s pre-existing values and beliefs. Crucially, these results suggest that messages aligning with preferences maintaining the status quo may improve climate awareness and action among not only conservatives — whose attitudes are most in sync with such messages — but also among liberals.”

In the paper, the researchers offer a detailed analysis of findings from other nations, outlining similarities and differences from the US sample and possible reasons for them.

Katherine Mason was supported by the National Science Foundation Predoctoral Award at the time the research was conducted (DGE-2234660).

As you are reading this story, your brain is involved in multiple behaviors.

Perhaps you are moving your arm to grab a cup of coffee, while reading the article out loud for your colleague, and feeling a bit hungry. All these different behaviors, such as arm movements, speech and different internal states such as hunger, are simultaneously encoded in your brain. This simultaneous encoding gives rise to very complex and mixed-up patterns in the brain’s electrical activity. Thus, a major challenge is to dissociate those brain patterns that encode a particular behavior, such as arm movement, from all other brain patterns.

For example, this dissociation is key for developing brain-computer interfaces that aim to restore movement in paralyzed patients. When thinking about making a movement, these patients cannot communicate their thoughts to their muscles. To restore function in these patients, brain-computer interfaces decode the planned movement directly from their brain activity and translate that to moving an external device, such as a robotic arm or computer cursor.

Shanechi and her former Ph.D. student, Omid Sani, who is now a research associate in her lab, developed a new AI algorithm that addresses this challenge. The algorithm is named DPAD, for “Dissociative Prioritized Analysis of Dynamics.”

“Our AI algorithm, named DPAD, dissociates those brain patterns that encode a particular behavior of interest such as arm movement from all the other brain patterns that are happening at the same time,” Shanechi said. “This allows us to decode movements from brain activity more accurately than prior methods, which can enhance brain-computer interfaces. Further, our method can also discover new patterns in the brain that may otherwise be missed.”

“A key element in the AI algorithm is to first look for brain patterns that are related to the behavior of interest and learn these patterns with priority during training of a deep neural network,” Sani added. “After doing so, the algorithm can later learn all remaining patterns so that they do not mask or confound the behavior-related patterns. Moreover, the use of neural networks gives ample flexibility in terms of the types of brain patterns that the algorithm can describe.”

In addition to movement, this algorithm has the flexibility to potentially be used in the future to decode mental states such as pain or depressed mood. Doing so may help better treat mental health conditions by tracking a patient’s symptom states as feedback to precisely tailor their therapies to their needs.

“We are very excited to develop and demonstrate extensions of our method that can track symptom states in mental health conditions,” Shanechi said. “Doing so could lead to brain-computer interfaces not only for movement disorders and paralysis, but also for mental health conditions.”

Researchers from the University of Utah are attempting to get a handle on this question and the latest findings are concerning.

Sediments in the lake’s exposed playa are potentially more harmful than other major dust sources affecting the Wasatch Front’s air quality, according to a study published online recently in the journal Atmospheric Environment.

These sediments, when aerosolized, show higher levels of reactivity and bioavailability when compared to sediments collected from other spots upwind of Utah’s major population center along the Wasatch Front. Chemical analysis also indicated the presence of numerous metals, and levels of arsenic and lithium that exceed the U.S. Environmental Protection Agency’s soil residential regional screening levels.

“You’re talking about a very large dust source located next to a very large population, and you’ve got elevated levels of manganese, iron, copper and lead. Lead is a concern for developmental reasons,” said senior author Kerry Kelly, a professor of chemical engineering. “Manganese, iron and copper, these are transition metals and are known to be very irritating to your lungs. Once you get irritation, that can lead to this whole inflammatory response. And that’s part of the problem with particulate matter and it’s adverse health effects like asthma.”

The Great Salt Lake is a terminal body receiving runoff from a vast drainage basin spanning northern Utah and parts of three other states. Metals from natural sources and human disturbances are pushed into lake from inflows or atmospheric deposition, and these materials accumulate in the lakebed. The potential for harmful dust pollution has become a priority for Utah state officials, who issued a list of priorities aimed at tackling the problem.

Another recent study led by sociology professor Sara Grineski found dust from the lakebed disproportionately affects disadvantaged neighborhoods in Salt Lake County.

In a separate forthcoming study led by U biologist Michael Werner’s lab, another team of researchers characterized levels of toxic metals deposited in submerged lakebed sediments sampled during the lake’s record low-water year of 2021, noting how these levels have changed since the years of Utah’s mining era. Concentrations of some metals, such as lead and zinc, appear to have decreased, likely a reflection of the decline in the region’s mining activity, while mercury levels surprisingly have increased.

Researchers cautioned that they can’t conclude whether these pollutants are actually being blown into populated areas during wind events because the monitoring equipment to capture that dust has yet to be adequately deployed downwind of the lake. Most high-wind events arrive from the southwest, blowing for several hours off the lake north into Weber or Box Elder County, before shifting to the south as the front passes through.

To conduct the published study, Kerry Kelly’s lab, which specializes in air quality, teamed up with researchers in the U’s College of Science. They examined previously collected sediment samples from the Great Salt Lake, comparing them with sediments from other dust sources in the Great Basin, namely Sevier Lake, Fish Springs Lake and West Desert in western Utah and Tule Lake in northeastern California. These places are known to contribute to dust pollution reaching Salt Lake City.

In recent years, co-author Kevin Perry, a professor of atmospheric sciences, has systematically gathered exposed lakebed sediments, logging hundreds of miles on a bike. His prior research has identified “hotspots” on the playa that appear to be enriched with potentially toxic elements.

Only 9% of the exposed lakebed, or 175 square kilometers (about 43,000 acres), is emitting dust from areas where lakebed crusts are disturbed, according to Perry. The rest of the playa is covered in a natural hardened layer that keeps the sediments in place. Perry’s ongoing research examines what happens to the playa crusts over time. He said his initial findings indicate the broken layers reset fairly easily, suggesting the playa’s threat to air quality may not be as dire as previously thought.

The latest study is the first to analyze the dust’s “oxidative potential,” a measure of its ability to react with oxygen.

“When you breathe in something that’s really reactive, it’s going to interact with the cells inside your lungs and it’s going to cause damage,” Kelly said.

In the lab, the team aerosolized the sediment samples to isolate the particles that are small enough to inhale and lodge in lung tissue, those smaller than 10 micrometers or PM10.

These particles were captured on filters and further analyzed using a method called inductively coupled mass plasma mass spectrometry to determine their elemental makeup and other tests to determine their oxidative potential (OP) and bioaccessibility.

“We devised a way to dissolve the metals using increasingly caustic acids to figure out at what level these metals leaching from the particles,” Perry said. “It turns out that the dust from Great Salt Lake has more leachable metals that are bioavailable than we would wish.”

Meanwhile, high OP was detected in dust associated with certain metals, including copper, manganese, iron and aluminum.

New research led by Stanford Medicine has found that it can — if a therapy is matched with the right patients. In a study of adults with both depression and obesity — a difficult-to-treat combination — cognitive behavioral therapy that focused on problem solving reduced depression in a third of patients. These patients also showed adaptative changes in their brain circuitry.

Moreover, these neural adaptations were apparent after just two months of therapy and could predict which patients would benefit from long-term therapy.

The findings add to evidence that choosing treatments based on the neurological underpinnings of a patient’s depression — which vary among people — increases the odds of success.

The same concept is already standard practice in other medical specialties.

“If you had chest pain, your physician would suggest some tests — an electrocardiogram, a heart scan, maybe a blood test — to work out the cause and which treatments to consider,” said Leanne Williams, PhD, the Vincent V.C. Woo Professor, a professor of psychiatry and behavioral sciences, and the director of Stanford Medicine’s Center for Precision Mental Health and Wellness.

“Yet in depression, we have no tests being used. You have this broad sense of emotional pain, but it’s a trial-and-error process to choose a treatment, because we have no tests for what is going on in the brain.”

Williams and Jun Ma, MD, PhD, professor of academic medicine and geriatrics at the University of Illinois at Chicago, are co-senior authors of the study published Sept. 4 in Science Translational Medicine. The work is part of a larger clinical trial called RAINBOW (Research Aimed at Improving Both Mood and Weight).

Problem solving

The form of cognitive behavioral therapy used in the trial, known as problem-solving therapy, is designed to improve cognitive skills used in planning, troubleshooting and tuning out irrelevant information. A therapist guides patients in identifying real-life problems — a conflict with a roommate, say — brainstorming solutions and choosing the best one.

These cognitive skills depend on a particular set of neurons that function together, known as the cognitive control circuit.

Previous work from Williams’ lab, which identified six biotypes of depression based on patterns of brain activity, estimated that a quarter of people with depression have dysfunction with their cognitive control circuits — either too much or too little activity.

The participants in the new study were adults diagnosed with both major depression and obesity, a confluence of symptoms that often indicates problems with the cognitive control circuit. Patients with this profile generally do poorly on antidepressants: They have a dismal response rate of 17%.

Of the 108 participants, 59 underwent a year-long program of problem-solving therapy in addition to their usual care, such as medications and visits to a primary care physician. The other 49 received only usual care.

They were given fMRI brain scans at the beginning of the study, then after two months, six months, 12 months and 24 months. During the brain scans, the participants completed a test that involves pressing or not pressing a button according to text on a screen — a task known to engage the cognitive control circuit. The test allowed the researchers to gauge changes in the activity of that circuit throughout the study.

“We wanted to see whether this problem-solving therapy in particular could modulate the cognitive control circuit,” said Xue Zhang, PhD, a postdoctoral scholar in psychiatry who is the lead author of the study.

With each brain scan, participants also filled out standard questionnaires that assessed their problem-solving ability and depression symptoms.

Working smarter

As with any other depression treatment, problem-solving therapy didn’t work for everyone. But 32% of participants responded to the therapy, meaning their symptom severity decreased by half or more.

“That’s a huge improvement over the 17% response rate for antidepressants,” Zhang said.

When researchers examined the brain scans, they found that in the group receiving only usual care, a cognitive control circuit that became less active over the course of the study correlated with worsening problem-solving ability.

But in the group receiving therapy, the pattern was reversed: Decreased activity correlated with enhanced problem-solving ability. The researchers think this may be due to their brains learning, through the therapy, to process information more efficiently.

“We believe they have more efficient cognitive processing, meaning now they need fewer resources in the cognitive control circuit to do the same behavior,” Zhang said.

Before the therapy, their brains had been working harder; now, they were working smarter.

Both groups, on average, improved in their overall depression severity. But when Zhang dug deeper into the 20-item depression assessment, she found that the depression symptom most relevant to cognitive control — “feeling everything is an effort” — benefited from the more efficient cognitive processing gained from the therapy.

“We’re seeing that we can pinpoint the improvement specific to the cognitive aspect of depression, which is what drives disability because it has the biggest impact on real-world functioning,” Williams said.

Indeed, some participants reported that problem-solving therapy helped them think more clearly, allowing them to return to work, resume hobbies and manage social interactions.

Fast track to recovery

Just two months into the study, brain scans showed changes in cognitive control circuit activity in the therapy group.

“That’s important, because it tells us that there is an actual brain change going on early, and it’s in the time frame that you’d expect brain plasticity,” Williams said. “Real-world problem solving is literally changing the brain in a couple of months.”

The idea that thoughts and behaviors can modify brain circuits is not so different from how exercise — a behavior — strengthens muscles, she added.

The researchers found that these early changes signaled which patients were responding to the therapy and would likely improve on problem-solving skills and depression symptoms at six months, 12 months and even one year after the therapy ended, at 24 months. That means a brain scan could be used to predict which patients are the best candidates for problem-solving therapy.

It’s a step toward Williams’ vision of precision psychiatry — using brain activity to match patients with the therapies most likely to help them, fast-tracking them to recovery.

“It’s definitely advancing the science,” Zhang said. “But it’s also going to transform a lot of people’s lives.”

Researchers from University of Washington, University of Pittsburgh School of Medicine and The Ohio State University also contributed to the work.

The study received funding from the National Institutes of Health (grants UH2 HL132368, UH3 HL132368 and R01 HL119453).

The research, led by scientists at Stanford Medicine and the University of California, San Francisco, is part of a larger effort to identify low-risk, low-cost ways to treat one of the most common health problems women face as they age.

After 12 weeks of a low-impact yoga program, study participants had about 65% fewer episodes of incontinence. Women in a control group doing stretching and strengthening exercises experienced a similar benefit over the same time period. The benefits are on par with the effects of medications used to address incontinence, the researchers said.

“Our study was testing the kind of yoga that just about anyone can do, with modifications for different physical abilities,” said the study’s senior author, Leslee Subak, MD, chair of obstetrics and gynecology at Stanford Medicine. “What I love about it is that it’s safe, inexpensive, doesn’t require a doctor and accessible wherever you live.” Because the trial was conducted partly during the COVID-19 pandemic, many participants received their yoga or exercise instruction via online meetings, exercising in their own homes, she noted.

The study’s lead author is Alison Huang, MD, professor of medicine, urology, and epidemiology and biostatistics at UCSF.

Urinary incontinence, which affects more than half of middle-aged women and up to 80% of 80-year-olds, can lead to a variety of other problems, from social isolation to bone fractures caused by falls. But there is help.

“Part of the problem is that incontinence is stigmatized; we don’t talk about it,” said Subak, the Katharine Dexter McCormick and Stanley McCormick Memorial Professor III. “Or we hear folklore about this being normal when you get older. In fact, it’s very common but it’s not inevitable, and we have very effective ways of treating it.”

Addressing a common problem

Incontinence deserves good treatment because of the many ways it interferes with people’s lives.

“It takes away independence,” Subak said. “My patients will say, ‘I can’t stay with my kids or grandkids because I’m afraid I’ll wet the bed, and I can’t talk about it; it’s too embarrassing.'”

Patients may avoid activities that could boost their well-being, such as exercising and seeing friends. They are more likely to be admitted to a nursing home and to suffer certain serious medical problems such as hip fractures.

“Incontinence and overactive bladder are among the biggest risk factors for falls and fractures among older women,” Subak said. “You’re rushing to the bathroom at night — with the lights off — tripping and falling, and breaking a hip.”

Some factors that contribute to risk for incontinence can’t be changed, such as aging or having had children. But others are modifiable.

“A lot of my research has focused on weight loss and physical activity, which in fact are effective treatments,” Subak said. She became interested in studying yoga as a treatment after some of her patients told her it helped them.

Being active helps

The study compared two 12-week exercise programs: 121 participants were randomly assigned to yoga, and 119 to a physical conditioning control group. The participants were women with urinary incontinence that caused symptoms at least once a day. They were 45 to 90 years old, with a mean age of 62.

In the yoga program, participants learned 16 hatha yoga poses intended to strengthen the pelvic floor, via two 90-minute sessions per week. The pelvic floor consists of the muscles that form the base of the pelvis and hold its organs — including the bladder and urethra — in place. Participants were also asked to practice yoga for at least one hour per week outside of class and to maintain a practice log.

Participants in the control group spent an equal amount of time in exercise classes, but their classes focused on nonspecific stretching and strengthening exercises that did not engage the pelvic floor. They were also asked to practice for an additional hour per week and keep a practice log.

The study began with in-person classes, then transitioned to a videoconference format when the COVID-19 pandemic lockdowns began.

Participants recorded when they leaked urine and classified whether each episode was urgency incontinence, when an overactive bladder causes a person to feel the need to urinate more often than usual, or stress incontinence, in response to pressure in the abdomen, such as from coughing or sneezing. They also answered standard questionnaires about their bladder function.

At the beginning of the study, the participants had an average of 3.4 episodes of urinary incontinence per day, including 1.9 urgency-type episodes and 1.4 stress-type episodes.

By the end of the 12-week programs, participants in the yoga group were experiencing 2.3 fewer episodes of incontinence per day, on average. Those in the physical conditioning group were experiencing 1.9 fewer episodes per day.

The two treatments are about equally effective, with both approaches reducing episodes of incontinence by around 60%, and the benefits from both treatments are meaningful, Subak said. Patients who would like to try these approaches can search for low-impact Iyengar yoga or low-impact exercise classes in their communities or online, she said, adding that instructors should be able to adapt the activity to participants’ physical limitations.

“I’m impressed that exercise did so well and impressed that yoga did so well,” Subak said. “One of the take-home messages from this study is ‘Be active!'”

Other nonsurgical treatments for incontinence, including medications, typically result in a 30% to 70% improvement in symptoms, she noted.

If a patient asked whether yoga could help with incontinence, “I would say that I think it’s a great idea to try it if you’re interested,” Subak said. “It’s very low risk, and there’s potential for benefit not only for incontinence but also for your general well-being.”

The study was funded by the National Institutes of Health (grants R01AG050588, R01DK116712-04S1 and K24AG068601). Researchers from Yale University and San Francisco State University also contributed to the study.

Nearly 7 million Americans are living with Alzheimer’s disease, the fifth leading cause of death among those 65 and older. The disease will carry an estimated $360 billion in health care costs this year alone, according to the Alzheimer’s Association.

Researchers led by Duke Han, professor of psychology and family medicine at USC Dornsife, aimed to better understand the link between early Alzheimer’s disease and financial vulnerability by using high-powered MRI to examine the brains of 97 study participants over age 50.

The scientists focused on the entorhinal cortex, a region that acts as a relay station between the hippocampus — the brain’s learning and memory center — and the medial prefrontal cortex, which regulates emotion, motivation and other cognitive functions. It is often the first region to show changes in Alzheimer’s disease, typically becoming thinner as the disease progresses.

None of the study participants, age 52 to 83, showed clinical signs of cognitive impairment, but all underwent MRI scans to measure the thickness of their entorhinal cortex.

In addition, the researchers used a standardized tool called a Perceived Financial Exploitation Vulnerability Scale (PFVS) to assess the participants’ financial awareness and their susceptibility to poor financial decisions, which they term “financial exploitation vulnerability,” or FEV.

By comparing the adults’ FEV with the thickness of their entorhinal cortex, Han and the team found a significant correlation: Those more vulnerable to financial scams had a thinner entorhinal cortex.

This was especially true for participants age 70 and older. Previous research has linked FEV to mild cognitive impairment, dementia and certain molecular brain changes associated with Alzheimer’s disease.

Han, who holds a joint appointment at Keck School of Medicine of USC, says the findings provide crucial evidence supporting the idea that FEV could be a new clinical tool for detecting cognitive changes in older adults — changes that are often difficult to detect.

“Assessing financial vulnerability in older adults could help identify those who are in the early stages of mild cognitive impairment or dementia, including Alzheimer’s disease,” Han said. He added, however, that financial vulnerability alone is not a definitive indicator of Alzheimer’s disease or other cognitive decline. “But assessing FEV could become part of a broader risk profile,” he said.

Han also noted several limitations of the study. Most participants were older, white, highly educated women, making it difficult to generalize the findings to a more diverse population. Additionally, while the study found a link between entorhinal cortex thickness and FEV, it does not prove one. Finally, the study does not include specific measures of Alzheimer’s disease pathology.

These limitations leave open the possibility that the relationship between FEV and entorhinal cortex thinning could be explained by other factors. Accordingly, Han said that more research, including long-term studies with diverse populations, is needed before FEV can be considered a reliable cognitive assessment tool.

The innovative framework, dubbed scAMF (Single-cell Analysis via Manifold Fitting), was developed by a team of scientists led by Associate Professor Zhigang Yao from the Department of Statistics and Data Science at the NUS Faculty of Science. The framework employs advanced mathematical techniques to fit a low-dimensional manifold within the high-dimensional space where the gene expression data are measured. By doing so, scAMF effectively reduces noise while preserving crucial biological information. This allows for more accurate characterisation of cell types and states.

This research was done in collaboration with Professor Yau Shing-Tung at Tsinghua University. Their findings have been published in the Proceedings of the National Academy of Sciences on 3 September 2024.

Harnessing manifold fitting techniques to overcome hurdles in data analysis

Single-cell RNA sequencing has become a crucial tool in genomic research, offering unprecedented insights into cellular diversity and disease mechanisms. However, the inherent noise in scRNA-seq data, arising from both biological variability and technical errors, has long posed challenges for accurate analysis. Traditional scRNA-seq analysis methods, including genomic imputation approaches, graph-based methods, and deep learning-based algorithms, often struggle to accurately characterise cell relationships due to inherent noise.

The scAMF framework represents a significant step forward in overcoming these limitations. It operates on the principle of fitting a low-dimensional manifold within the ambient space of gene expression data, effectively reducing noise while preserving crucial information. At the heart of scAMF lies the manifold fitting module which effectively denoises scRNA-seq data by unfolding their distribution in the ambient space. This technique aims to reconstruct a smooth manifold within the original space where the data is measured, capturing the low-dimensional structure of the data in a manner that minimizes information loss and effectively eliminates noise.

The key innovation of scAMF lies in its ability to improve the spatial distribution of the data, bringing gene expression vectors of cells from the same type closer together while maintaining clear separation between different cell types. This enhancement leads to more precise and reliable clustering in subsequent analyses.

“Our approach effectively denoises scRNA-seq data by fitting a low-dimensional manifold in the high-dimensional space,” explained Assoc Prof Yao. “This method significantly improves the accuracy of cell type classification and the clarity of data visualisation.”

The scAMF method employs a unique combination of data transformation, manifold fitting using shared nearest neighbor metrics, and unsupervised clustering validation. When compared to other methods, scAMF demonstrates superior performance in several key areas, including more effective noise reduction, improved clustering accuracy, better preservation of biological information, competitive computational efficiency, clearer visualisation, and robust performance across diverse datasets. These improvements position scAMF as a powerful new tool in single-cell analysis, potentially enabling researchers to uncover previously hidden cellular heterogeneity and rare cell populations.

Future work — Driving greater understanding of cellular diversity and function

Building on the success of scAMF, the research team is now developing a novel framework for constructing high-resolution, multiscale cell atlases. This new approach aims to overcome current methodological limitations in cell atlas construction, such as challenges in identifying small cell populations and outdated unsupervised learning techniques.

A key focus is the development of a multi-resolution cell analysis framework based on scAMF. This advanced framework aims to identify rare cell populations and contribute to the construction of comprehensive cell atlases. The multi-resolution approach will allow researchers to analyse cellular heterogeneity at various levels of granularity, from broad cell types to subtle subpopulations. This is particularly crucial for identifying rare cell types that may be overlooked by conventional analysis methods.

“Our ongoing work has already shown promising results across numerous benchmark datasets, revealing novel biological insights,” Assoc Prof Yao noted. “We’ve applied it to the Human Brain Cell Atlas and identified new subtypes and marker genes for various cell types.”

This ongoing research promises to push the boundaries of single-cell analysis even further, potentially revolutionising our understanding of cellular diversity and function across various biological systems.

The results of the ELVIS-Kids randomised controlled trial were presented by Professor Steve Cunningham from Child Life and Health, University of Edinburgh, UK.

He said: “Children have up to 10 to 12 upper respiratory tract infections, what we refer to as colds, per year, which have a big impact on them and their families. There are medicines to improve symptoms, such as paracetamol and ibuprofen, but no treatments that can make a cold get better quicker.”

ELVIS-Kids Chief Investigator Dr Sandeep Ramalingam, consultant virologist, NHS Lothian, Edinburgh, UK, had noted that salt-water solutions are often used by people in South Asia, as nasal irrigation and gargling, to treat a cold and wanted to explore if this clinical benefit could be replicated in a large study.

The research team recruited 407 children aged up to six years to a study where they were given either hypertonic saline ~2.6% (salt-water) nasal drops or usual care when they developed a cold. Overall, 301 children developed a cold; for 150 of these, their parents were given sea salt and taught to make and apply salt-water nose drops to the children’s noses (three drops per nostril, a minimum of four times per day, until well) and 151 children had usual cold care.

Professor Cunningham explains: “We found that children using salt-water nose drops had cold symptoms for an average of six days where those with usual care had symptoms for eight days. The children receiving salt water nose drops also needed fewer medicines during their illness.

“Salt is made up of sodium and chloride. Chloride is used by the cells lining the nose and windpipes to produce hypochlorous acid within cells, which they use to defend against virus infection. By giving extra chloride to the lining cells this helps the cells produce more hypochlorous acid, which helps suppress viral replication, reducing the length of the virus infection, and therefore the duration of symptoms.”

When children got salt-water nose drops, fewer households reported family members catching a cold (46% vs 61% for usual care). Eighty-two per cent of parents said the nose drops helped the child get better quickly and 81% said they would use nose drops in the future.

Professor Cunningham added: “Reducing the duration of colds in children means that fewer people in their house also get a cold, with clear implications for how quickly a household feels better and can return to their usual activities like school and work etc.

“Our study also showed that parents can safely make and administer nose drops to their children and therefore have some control over the common cold affecting their children.”

Professor Alexander Möeller is Head of the ERS Paediatric Assembly and Head of the Department for Respiratory Medicine at the University Children’s Hospital Zurich, Switzerland, and was not involved in the research. He said: “This is an important study that is the first of its kind to investigate the impact of salty nose drops in children with colds. Although most colds usually don’t turn into anything serious, we all know how miserable they can be, especially for young children and their families.

“This extremely cheap and simple intervention has the potential to be applied globally; providing parents with a safe and effective way to limit the impact of colds in their children and family would represent a significant reduction in health and economic burden of this most common condition.”

The team hope to further investigate the effect of saltwater nose drops on wheeze during colds, after initial results from this study showed that children who received the drops had significantly fewer episodes of wheeze (5% vs 19%).

“Bats have gained a bad reputation as being something to fear, especially after reports of a possible linkage with the origins Covid-19,” says study author Eyal Frank, an assistant professor at the Harris School of Public Policy. “But bats do add value to society in their role as natural pesticides, and this study shows that their decline can be harmful to humans.”

Frank compared the effect of bat die-offs on pesticide use in counties that experienced those bat population declines to counties that were likely unaffected by the wildlife disease. He found that when the bat populations declined, farmers increased their use of pesticides by about 31 percent. Because pesticides have been linked to negative health impacts, Frank next tested to see if the increased use of pesticides corresponded with an increase in infant mortality — a common marker to study the health impacts of environmental pollution. Indeed, when farmers increased their use of pesticides, the infant mortality rate rose by almost 8 percent. This corresponds to an additional 1,334 infant deaths. Or, for every 1 percent increase in pesticides, there was a 0.25 percent increase in the infant mortality rate.

The study also found that pesticides aren’t as good at preventing pests as bats. The quality of the crops likely declined, as farmers’ revenue from crop sales decreased by nearly 29 percent. Combining this revenue loss with the expense of the pesticides, farmers in communities that experienced the bat die-offs lost $26.9 billion dollars between 2006 and 2017. Adding onto those losses the $12.4 billion in damages from infant mortality, the total societal cost from the bat die-offs in these communities amounted to $39.6 billion.

“When bats are no longer there to do their job in controlling insects, the costs to society are very large — but the cost of conserving bat populations is likely smaller,” says Frank. “More broadly, this study shows that wildlife adds value to society, and we need to better understand that value in order to inform policies to protect them.”

For the first time, an interdisciplinary study has applied the theory of entropy to tourism, finding that travel could have positive health benefits, including slowing down the signs of ageing.

Entropy is classified as the general trend of the universe towards death and disorder. The entropy perspective suggests that tourism could trigger entropy changes, where positive experiences might mitigate entropy increase and enhance health, while negative experiences may contribute to entropy increase and compromise health.

“Ageing, as a process, is irreversible. While it can’t be stopped, it can be slowed down,” ECU PhD candidate Ms Fangli Hu said.

Ms Hu noted that positive travel experiences could enhance individuals’ physical and mental wellness through exposure to novel environments, engagement in physical activities and social interaction, and the fostering of positive emotions. These potential benefits have been acknowledged through practices such as wellness tourism, health tourism, and yoga tourism.

“Tourism isn’t just about leisure and recreation. It could also contribute to people’s physical and mental health,” Ms Hu added.

Travel therapy: Slowing down the clock

Travel therapy could serve as a groundbreaking health intervention when viewed through an entropy lens, she added. As an important aspect of the environment, positive travel experiences may help the body sustain a low-entropy state by modulating its four major systems.

Tourism typically exposes people to new surroundings and relaxing activities, and novel settings can stimulate stress responses and elevate metabolic rates, positively influencing metabolic activities and the body’s self-organising capabilities. These contexts may also trigger an adaptive immune system response.

Ms Hu said that this reaction improves the body’s ability to perceive and defend itself against external threats.

“Put simply, the self-defence system becomes more resilient. Hormones conducive to tissue repair and regeneration may be released and promote the self-healing system’s functioning.”

Leisurely travel activities might help alleviate chronic stress, dampen overactivation of the immune system, and encourage normal functioning of the self-defence system. Engaging in recreation potentially releases tension and fatigue in the muscles and joints. This relief helps maintain the body’s metabolic balance and increases the anti-wear-and-tear system’s effectiveness. Organs and tissues can then remain in a low-entropy state,” Ms Hu explained.

Travel encompasses physical activities such as hiking, climbing, walking, and cycling. Physical exertion can boost metabolism, energy expenditure, and material transformation, all of which help coordinate self-organising systems.

“Participating in these activities could enhance the body’s immune function and self-defence capabilities, bolstering its hardiness to external risks. Physical exercise may also improve blood circulation, expedite nutrient transport, and aid waste elimination to collectively maintain an active self-healing system. Moderate exercise is beneficial to the bones, muscles, and joints in addition to supporting the body’s anti-wear-and-tear system,” Ms Hu said.

On the flip side, the research has pointed out that tourists could face challenges such as infectious diseases, accidents, injuries, violence, water and food safety issues, and concerns related to inappropriate tourism engagement.

“Conversely, tourism can involve negative experiences that potentially lead to health problems, paralleling the process of promoting entropy increase. A prominent example is the public health crisis of COVID-19.”

Researchers from the University of Exeter — in partnership with the University of Sheffield, Sheffield Hallam University, and University of Plymouth — have today (September 4) published a report for the Department for Environment, Food & Rural Affairs (Defra) on their findings into efforts to increase access to Green Social Prescribing, and its effectiveness in tackling and preventing mental ill health.

Green Social Prescribing is the practice of supporting people with mental health needs to engage in nature-based activities. Referrals will typically come from GPs, community mental health teams, or social workers, but people can also self-refer. Social Prescribing Link Workers, and other trusted professionals, then connect people to community groups and agencies for practical and emotional support. There are many different types of nature-based activities and therapies, including conservation, horticulture and gardening, care farming, exercise and sports, or talking therapies in the outdoors.

Professor Ruth Garside of the European Centre for Environment and Human Health at the University of Exeter said: “Our findings are significant because it provides evidence that Green Social Prescribing is an effective way of supporting people with their mental health. But this is just the beginning and further government investment is now supporting the leadership and systems change that we know Green Social Prescribing needs to be successful. However, there must be an ongoing commitment from policymakers to understand the needs of communities and enable more diverse people to connect with nature, alongside investment in those organisations that provide nature-based activities.”

In total, 8,339 people with mental health needs took part in nature-based activities at seven Green Social Prescribing Project Test and Learn pilots across England. Compared to many other social prescribing initiatives the project reached a broader range of people, including children and young people aged under 18, ethnic minority populations (21-percent), and people from socio-economically deprived areas (57-percent).

Prior to accessing nature-based activities participants’ happiness, anxiety, life satisfaction, and feeling that their life was worthwhile was worse than national averages. After taking part in the project wellbeing had improved, and typically happiness and anxiety was in line with the national average. Levels of life satisfaction and feeling that life was worthwhile had also improved significantly.

Participants in Green Social Prescribing said:

“After the group I feel joyful, happy, calm. I have a sense of achievement and I feel my wellbeing increasing. I look forward to attending.”

“It works better than medication for me. It works better than CBT for me. Most of my stuff is related to trauma, so NICE guidelines don’t recommend medication for borderline personality disorder. I have my counselling and that is really valuable, but this is on a par with that.”

With an average cost of £507 per participant, researchers also found Green Social Prescribing to be a cost-effective method of supporting people across a wide spectrum of mental health needs. That’s when compared to other interventions, such as Cognitive Behavioural Therapy (CBT), behavioural activation, and early intervention for psychosis and collaborative care for depression.

Marion Steiner is a GP in Bristol and part of the Bristol, North Somerset and South Gloucestershire Test and Learn Pilot Site project board. She said: “Connecting with nature is a lifelong resource with proven benefits for mental and physical health. It can cut through generations of adverse life events. But many of the patients I treat can’t currently access nature in this way due to a range of personal, social, and cultural barriers. That’s why Green Social Prescribing is so important. This project has the potential to reduce a range of prescribing and treatment costs for the NHS, as well as addressing many health needs and lowering the risk of several diseases, from diabetes to depression.”

Dr Annette Haywood, Head of Public Health Section Sheffield Centre for Health and Related Research (SCHARR) and Principal Investigator of the study said: “I’m thrilled to have led on this national evaluation of Green Social Prescribing. There is already a wealth of evidence to show the positive impact that nature and outdoor activities can have on mental and physical health. The findings of this report add to this evidence-base, demonstrating that nature-based activities are a relatively cost-effective way to support people with a variety of mental health needs.”

Funding for the project was provided by HM Treasury’s Shared Outcomes Fund and various central government departments and external agencies. Partners included: Department of Health and Social Care, Department for Environment, Food and Rural Affairs, Natural England, NHS England, NHS Improvement, Public Health England, Sport England, Department for Levelling Up, Housing & Communities and the National Academy for Social Prescribing.

“Our research provides one explanation for why, in a world full of allergens, one person may be more likely to develop an allergic response than another,” said senior and corresponding author Caroline Sokol, MD, PhD, an attending physician in the Allergy and Clinical Immunology Unit at MGH, and assistant professor of medicine at Harvard Medical School. “By establishing a pathway that controls allergen responsiveness, we have identified a new cellular and molecular circuit that can be targeted to treat and prevent allergic responses including itching. Our preclinical data suggests this may be a translatable approach for humans.”

When it comes to detecting bacteria and viruses, the immune system is front and foremost at detecting pathogens and initiating long-lived immune responses against them. However, for allergens, the immune system takes a backseat to the sensory nervous system. In people who haven’t been exposed to allergens before, their sensory nerves react directly to these allergens, causing itchiness and triggering local immune cells to start an allergic reaction. In those with chronic allergies, the immune system can affect these sensory nerves, leading to persistent itchiness.

Previous research from Sokol and colleagues showed that the skin’s sensory nervous system — specifically the neurons that lead to itch — directly detect allergens with protease activity, an enzyme-driven process shared by many allergens. When thinking about why some people are more likely to develop allergies and chronic itch symptoms than others, the researchers hypothesized that innate immune cells might be able to establish a “threshold” in sensory neurons for allergen reactivity, and that the activity of these cells might define which people are more likely to develop allergies.

The researchers performed different cellular analyses and genetic sequencing to try and identify the involved mechanisms. They found that a poorly understood specific immune cell type in the skin, that they called GD3 cells, produce a molecule called IL-3 in response to environmental triggers that include the microbes that normally live on the skin. IL-3 acts directly on a subset of itch-inducing sensory neurons to prime their responsiveness to even low levels of protease allergens from common sources like house dust mites, environmental molds and mosquitos. IL-3 makes sensory nerves more reactive to allergens by priming them without directly causing itchiness. The researchers found that this process involves a signaling pathway that boosts the production of certain molecules, leading to the start of an allergic reaction.

Then, they performed additional experiments in mouse models and found removal of IL-3 or GD3 cells, as well as blocking its downstream signaling pathways, made the mice resistant to the itch and immune-activating ability of allergens.

Since the type of immune cells in the mouse model is similar to that of humans, the authors conclude these findings may explain the pathway’s role in human allergies.

“Our data suggest that this pathway is also present in humans, which raises the possibility that by targeting the IL-3-mediated signaling pathway, we can generate novel therapeutics for preventing an allergy,” said Sokol. “Even more importantly, if we can determine the specific factors that activate GD3 cells and create this IL-3-mediated circuit, we might be able to intervene in those factors and not only understand allergic sensitization but prevent it.”

Disclosures: Sokol is a paid consultant for Bayer and Merck and receives sponsored research support from GSK. Aderhold is a current employee of Werewolf Therapeutics. McAlpine is a paid consultant of Granite Bio. Woolf is a founder of Nocion Therapeutics, QurAlis and BlackBox Bio, and is on the scientific advisory board of Lundbeck Pharma, Axonis and Tafalgie Therapeutics. Villani has a financial interest in 10X Genomics, a company that designs and manufactures gene sequencing technology for use in research, and such technology is being used in this research.

Funding: This work was supported by grant no. T32HL116275 and a National Eczema Association Catalyst Research grant, National Institutes of Health (NIH) grants K99/R00 HL151750, R01 HL158534, R01 AG082185 and the Cure Alzheimer’s Fund, grant nos. R35 HL135752, NIH R35 NS105076-01 and R01 AT011447, grant nos. DP2CA247831, R01AI15116, AAAAI Foundation and D.Y.M. Leung/JACI Editors Faculty Development Award, Food Allergy Science Initiative, Massachusetts General Hospital Howard Goodman Scholarship, and the Broad Institute Next Generation Scholar and Massachusetts General Hospital Transformative Scholar Award. Sokol receives extra sponsored research support from GlaxoSmithKline.

While ketamine is a safe medication when used with medical supervision, it does have a little-known complication: it may be very harmful to a developing fetus. It should not be used during pregnancy.

But a new study suggests that ketamine prescribers aren’t paying enough attention to this risk and should do more to make sure that patients receiving ketamine aren’t pregnant and are aware of the need to use contraception while undergoing a course of treatment over multiple months.

The new article in the Journal of Clinical Psychiatry was written by researchers from the University of Michigan’s academic medical center, Michigan Medicine. It reports the results of a survey and document review conducted of ketamine clinics nationwide, and a review of records from the ketamine clinic for depression at U-M Health.

In all, they found a wide variation in policies, practices and warnings about ketamine use related to pregnancy and reproduction. This is despite the fact that the 119 clinics that answered the survey report treating a total of more than 7,000 patients with ketamine per month, and estimate that a third of patients they serve are female and pre-menopausal.

Key findings

More than 75% of responding clinics said they have a formal pregnancy screening process, but only 20% actually require a pregnancy test at least once prior to or during treatment.

More than 90% of clinics said they note that pregnancy is a contraindication to ketamine treatment in their informed consent documents and/or conversations. But less than half of clinics reported discussing specific potential risks with patients.

The researchers also looked at informed consent documents on the websites of 70 other ketamine clinics. In all, 39% did not include language about pregnancy in their documents, and those that did were generally vague.

When it came to contraception counseling, only 26% of the clinics that answered the survey said they discuss the potential need for contraception with ketamine patients. Less than 15% of the clinics specifically recommend or require contraception use during treatment.

This is especially striking, the authors say, because more than 80% of clinics reported prescribing long-term maintenance ketamine, with nearly 70% of these saying their patients receive care for more than six months and many saying patients receive ketamine for a year or more.

The review of records from 24 patients treated with ketamine at U-M’s clinic in the past showed all had taken a pregnancy test before beginning treatment and weekly during treatment, and but only half had documentation in their records that they were using contraception.

Inspiration for the study

Lead author Rachel Pacilio, M.D., a psychiatrist who recently joined Michigan Medicine as a clinical assistant professor after completing her residency at U-M Health, said the idea for the study came to her during a rotation in the perinatal psychiatry clinic.

Patients who were pregnant or had recently given birth asked her about ketamine as an option for their treatment-resistant depression. They had heard of the potential positive impact of the drug when given intravenously as an off-label use of a common anesthetic, or as an intranasal spray of esketamine that’s marketed as Spravato and approved by the U.S. Food and Drug Administration.

“There was little guidance available to prescribers other than the general recommendation to avoid ketamine in patients who are pregnant, because of the unknown potential impact on a fetus or a breastfeeding newborn,” says Pacilio. “That sparked our interest in surveying clinics to see how they were handling this during their intake processes, initial treatment courses, and during the maintenance therapy phase. As far as we know, this is the first time this has been looked into.”

Variation in oversight

Clinics offering intravenous ketamine require specialized staff and post-administration monitoring for each session. And the FDA specifically requires least two hours of in-person observation after dosing of intranasal Spravato to ensure safety and monitor for complications.

By contrast, other formulations of ketamine can be administered outside the clinical setting with minimal oversight. Some clinics surveyed reported prescribing sublingual ketamine for at-home use.

The new study did not include online, direct-to-consumer ketamine providers that offer treatment exclusively via telehealth consultations. It is unknown how these companies address reproductive and other safety concerns despite their growing popularity among patients.

“These data suggest that a large population of patients could be pregnant, or could become pregnant, while receiving ketamine treatment via multiple routes of administration. This risk increases with the duration of therapy which can last weeks for the initial course and a year or more for maintenance,” said Pacilio. “Many patients do not know that they’re pregnant in the first weeks, and animal studies of ketamine are very concerning for potential harm to the fetus during this time.”

She noted that while many psychotropic medications have been studied extensively and found to be safe for use in pregnancy, including a variety of antidepressants, antipsychotics and other psychiatric drugs, there is no data to support the use of ketamine for psychiatric illness in pregnancy.

Pacilio pointed out that the FDA’s risk mitigation program for Spravato, the nasal form of ketamine, does not include any provisions about pregnancy. A warning issued by the FDA last fall about the risks of compounded forms of ketamine available online also does not mention precautions about pregnancy.

“The variability in practice that we see among clinics in the community in this study is stark,” said Pacilio. “The field is really in need of standardization around reproductive counseling, pregnancy testing and the recommendation for contraception during ketamine treatment.”

If someone becomes pregnant while undergoing ketamine treatment, and has to stop receiving the drug for the remainder of the pregnancy, they are at risk for a depression relapse that could continue after the baby is born. Perinatal and postpartum depression are major risk factors for a range of issues in both the birthing parent and the infant.

Need for standard guidance

After sharing their findings about U-M patients in the new study with leaders of the U-M Health ketamine clinic, Pacilio said that the clinic began recommending the use of highly-reliable forms of contraception to patients who could become pregnant while receiving ketamine treatment.

Small standalone community clinics offering ketamine therapy may not have the same resources that a large clinic like U-M’s does, so standard guidance could especially benefit them.

Interventions including improved patient education with an emphasis on the requirement for pregnancy prevention for the duration ketamine treatment during the informed consent process, routine pregnancy testing before and during treatment for appropriate patients, and effective contraceptive counseling are needed. Many of these could be easily implemented and have the potential to positively impact public health.

“Ketamine is a really effective, potentially lifesaving, treatment for the right patients, but not everyone is a good candidate for it,” she said. “As psychiatrists, we need to ensure this treatment is being delivered in a way that benefits patients while preventing harm.”

In a commentary in the journal about the U-M team’s findings, psychiatrist and journal editor Marlene Freeman, M.D., wrote that based on the new findings, “It is imperative that best practices for women of reproductive age for the use of ketamine and esketamine are determined and utilized.” She added that this is especially important in light of the changing landscape of abortion-related laws.

Freeman also noted that those who have used ketamine in any form during pregnancy, as well as other psychotropic medications, can join the National Pregnancy Registry for Psychiatric Medications during pregnancy and help provide much-needed information on the impacts of these medications.

In addition to Pacilio, the study’s authors include Jamarie Geller, M.D., M.A., a psychiatry fellow at U-M, and faculty members Juan F. Lopez, M.D.; Sagar V. Parikh, M.D. and Paresh D. Patel, M.D., Ph.D.

The study was funded by U-M Department of Psychiatry.

There is an increasing need to build more complex, yet nuanced, models of human biology and behavior, particularly as they relate to the development of mental health symptoms. Despite the importance of this problem, most work still considers the brain and environment in isolation or as univariate and linear interactions.

May I. Conley, MS, MPhil, PhD candidate, Yale University, Department of Psychology, co-lead author of the study says, “For a long time, developmental scientists have faced the challenge of testing theories that, in many ways, are hiding in plain sight. From the neighborhood to the family, we recognize youth’s experiences in their environments and neurobiology both influence emotional and behavioral development. Yet, we haven’t had methods that capture the complexity of this interaction precisely.”

To address this, the investigators turned to manifold learning, a promising class of algorithms for uncovering latent structure from high-dimensional biomedical data like functional magnetic resonance imaging (fMRI). They developed the exogenous PHATE (E-PHATE) algorithm to model brain-environment interactions. Using the Adolescent Brain and Cognitive Development (ABCD) dataset, supported by the National institutes of Health and other federal partners, they used E-PHATE embeddings of participants’ brain activation during emotional and cognitive processing to predict individual differences in cognition and emotional and behavioral symptoms, both cross-sectionally and longitudinally.

One of the most noteworthy findings of the study was the effect of combining additional environmental variables into the exogenous view of E-PHATE. Researchers saw a greater correlation of brain activity with mental health symptoms through modeling either the neighborhood or familial environments in E-PHATE, but by combining those metrics along with others, the model kept improving its representation. This was specific to adding environmental information, though, rather than an effect of the number of variables (which was tested with additional analyses). This finding reinforces the need to consider the multiple environments youth navigate in conjunction with how their brain takes in information from those environments.

Erica L. Busch, MS, MPhil, PhD candidate, Yale University, Department of Psychology, first author of the study, continues, “I was excited to see that the principles of modeling neuroimaging data I’d been developing for basic science questions could be quickly adapted for clinical applications and yielded such striking results and mechanistic insights. It also underscored how fruitful interdisciplinary collaborations can be; my fellow graduate student May Conley and her advisor Dr. Baskin-Sommers are experts in biopsychosocial models of mental health symptoms and combined with my computational experience, we each played key roles in defining the question and approaches of this project.”

The work highlights the clinical applications of new machine learning and signal processing approaches. Specifically, it underscores the significance and complexity of the relationship between adolescent brains and environments as they relate to emotional and behavioral symptoms. The investigators present a general-purpose method with broad applications in both clinical and non-clinical domains.

Editor-in-Chief of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Cameron S. Carter, MD, University of California Irvine, comments, “Decades of developmental work suggests that both neurobiology and environmental context shape the development of mental health symptoms. This study demonstrates the suitability of more computational methods, like manifold learning, for modeling complex multimodal developmental data, and they have great potential to enhance research on the neurobiology of emotional and behavioral symptoms in adolescents.”

The current study is novel along three main dimensions:

1. By characterizing both neural and environmental data as multivariate measurements.
2. By considering the interaction between them as nonlinear and lower-dimensional (i.e., existing along a latent manifold, like most real-world data does).
3. By allowing for simultaneous hypothesis- and data-driven discovery of a meaningful representation of these signals.

Senior author Arielle Baskin-Sommers, PhD, Yale University, Department of Psychology, concludes, “It is important that, as a field, we improve our ability to capture the complex transactions between the person and their environment. However, to estimate these transactions, new methods are needed to handle multiple types of data and estimate their interactions within individuals. The method produced from this interdisciplinary collaboration is one example of how we can estimate these complex transactions.”

Researchers have warned that the current system is failing many young adults as they transition from children’s to adult’s services — suddenly finding themselves unable to access treatment because services do not link up effectively.

More than 750 people from across the country — including commissioners, healthcare professionals working in primary care, and people with lived experience of ADHD — completed the MAP National Survey, which highlights challenges that GPs face when prescribing ADHD medication.

ADHD affects up to seven per cent of children and up to five per cent of adults, with symptoms including patterns of hyperactivity, impulsivity and/or inattention which interfere with functioning in daily life. Failure to treat ADHD and gaps in treatment, especially as young people become adults, can have severe impacts for patients and families, increasing the risk of mental health crises and difficulties with work, education, and relationships. This failure also places additional pressure on those working in health services.

The survey found variations in “shared care” agreements between GPs, mental health specialists and patients — which need to be in place for GPs to be able to prescribe ADHD medications. This was a particular problem when young people move to adult mental health services, suggesting the current system lets down adolescents at a critical time in their lives. Current NICE guidelines recommend GPs prescribe medication for adult ADHD patients under a shared care agreement with adult mental health services.

However, the survey found that such agreements are not always easy to set up, with evidence suggesting that GPs may not feel sufficiently supported to prescribe in this way. Indeed, if appropriate support is not in place, some GPs may not prescribe ADHD medication due to concerns around insurance and liability. This can be a particular problem for patients with a private diagnosis of ADHD, and leaves GPs unable to provide effective care, and many patients without access to the medication they need.

Furthermore, more than 40 per cent of survey respondents reported waiting times of two years or more for an appointment with adult mental health services. This leaves GPs with the responsibility for providing care, but without the support they need to offer the best care for their patients at a crucial time in their lives. This can include removing access to medication, despite the treatment having been successful during childhood. Issues with access to treatment for ADHD are also worst for some underserved groups, such as young women, and young people leaving care, which is increasing health inequalities.

The survey results come just as NHS England has announced the establishment of a taskforce and a major review of ADHD services. As stated by NHS England: “People with ADHD deserve a caring and effective service from the NHS and wider society. We know there is more to do, but we do not underestimate the complexity and challenges in realising this ambition.”

Dr Anna Price, Senior Research Fellow at the University of Exeter, said: “Our findings highlight the need for a coordinated approach to address problems that lead to a postcode lottery for patients trying to access treatment for ADHD. GPs and other primary care professionals really need better support so that they can provide shared care prescribing of ADHD medication in line with UK guidelines.

“We know that failing to treat ADHD can have a huge impact. Turning 18 is often a crucial and sensitive time in life, and our research shows that lack of treatment at this time can be particularly damaging for young people who are learning to self-manage their health needs, at the same time as perhaps sitting important exams, leaving home for the first time, and embarking on careers or university study.

“We welcome the establishment of the NHS England taskforce and is a much-needed step towards better outcomes for people with ADHD.”

University of Exeter experts have recently established a Science of ADHD and Neurodevelopment collaboration, working together with people who are experts by experience, and healthcare providers. The collaboration aims to develop solutions, such as curated digital interventions and standardised shared care agreement templates, to help people with ADHD to thrive.

The study found that Global South cities have just 70% of the “cooling capacity” provided by urban greenery in the Global North.

With temperatures rising, combined with the “urban heat island” effects that make cities hotter than rural areas, heat-related illness and death in cities are becoming more common.

Urban green spaces can help reduce this risk, cooling down outdoor environments and providing vital refuges.

The research — led by an international team including Nanjing, Exeter, Aarhus and North Carolina State universities — finds there is “vast potential” to enhance urban cooling in the Global South and reduce inequality.

“Urban greenery is a really effective way of tackling what can be fatal effects of extreme heat and humidity,” said Professor Tim Lenton, of the Global Systems Institute at the University of Exeter.

“Currently, the people dying due to climate change are often in the slums of cities in the Global South, such as the hottest parts of India.

“Our analysis suggests green spaces can cool the surface temperature in the average city by about 3°C during warm seasons — a vital difference during extreme heat.”

The cooling effect of urban green spaces, especially urban forests, is caused by shading and transpirational cooling (evaporation of water).

The new study used satellite data on the world’s 500 largest cities to assess “cooling capacity” — the extent to which urban green spaces cool down a city’s surface temperatures.

All of the top ten cities for cooling capacity are in the USA: with Charlotte and Raleigh-Durham first, followed by Kansas and Baltimore. Many US cities have low population density — leading to issues of urban “sprawl” — but this brings benefits in terms of green spaces and resulting cooling.

Mogadishu in Somalia is the city with the lowest cooling capacity, followed by Sana’a in Yemen and Rosario in Argentina. Chicago is fourth-lowest — the only US city on the list with cooling capacity below 1°C.

‘Cooling benefit’

The Global South — which includes Africa, Latin America and much of Asia — contains the areas most at risk from extreme heat.

A previous study found that current climate policies will leave more than a fifth of humanity exposed to dangerously hot temperatures by 2100, with the largest at-risk populations in India and Nigeria.

The new study assessed population density and location to estimate the “cooling benefit” received by the average citizen — as green areas are often found in the richer parts of a city.

Professor Chi Xu, of Nanjing University, said: “As well as Global South cities lagging behind in terms of cooling capacity, the cooling benefit for an average resident is 2.2°C — compared to 3.4°C for a city dweller in the Global North.

“The differences are mostly due to quantity of vegetation, but efficiency of cooling is also better in the Global North — possibly due to management of green spaces and different tree species.”

Professor Jens-Christian Svenning, of the Center for Ecological Dynamics in a Novel Biosphere (ECONOVO) at Aarhus University, said: “The good news is that this nature-based solution to cooling can be substantially improved across the Global South, helping to tackle future heat stress for billions of people.”

Professor Rob Dunn, of North Carolina State University, said: “It won’t be easy to regreen cities. It can be expensive in the short-term. Yet, it will be key to making cities liveable in the immediate future. Also key will be working to prevent the loss of green space in those cities that have it, or at least that have a little.

“Changes could include ground-level green spaces and vertical and rooftop gardens, or even forests, to help protect city people from extreme heat.”

Dr. Kasahara and his collaborators have investigated the dynamics of face recognition using motor-visual synchrony — the coordination between a person’s physical movements and the visual feedback they receive from those movements. They found that whether we influence the movement of our self-image or not, levels of identification with our face remain consistent. Therefore, our sense of agency, or subjective feelings of control, do not impact our level of identification with our self-image. Their results have been published in Scientific Reports.

The effect of agency on perceptions of identity

With psychological experiments using displays and cameras, the scientists investigated where the “self-identification boundary” is and what impacts this boundary. Participants were seated and asked to look at screens showing their faces gradually changing. At some point, the participants could notice a change in their facial identity and were asked to press a button when they felt that the image on the screen was no longer them. The experiment was done in both directions: the image changing from self to other and other to self.

“It’s like watching your face in a mirror as you move it and you identify yourself, but your face slowly changes up to a point and you realize this is no longer you,” Dr. Kasahara explained.

The researchers examined how three movement conditions affect the facial boundary: synchronous, asynchronous, and static. They hypothesized that if the motions are synchronized, participants would identify with the images to a greater extent. Surprisingly, they found that whether movements were synchronized or not, their facial identity boundaries were similar. Additionally, participants were more likely to identify with static images of themselves than images with their faces moving.

Interestingly, the direction of morphing — whether from self to other or other to self — influenced how participants perceived their own facial boundaries: participants were more likely to identify with their facial images when these images morphed from self to other rather than from other to self. Overall, the results suggest that a sense of agency of facial movements does not significantly impact our ability to judge our facial identity.

“Consider the example of deepfakes, which are essentially a form of asynchronous movement. When I remain still but the visual representation moves, it creates an asynchronous situation. Even in these deepfake scenarios, we can still experience a feeling of identity connection with ourselves,” Dr. Kasahara explained. “This suggests that even when we see a fake or manipulated version of our image, for example, someone else using our face, we might still identify with that face. Our findings raise important questions about our perception of self and identity in the digital age.”

How does identity impact perceptions of control?

What about the other way around? How does our sense of identity impact our sense of agency? Dr. Kasahara recently published a paper in collaboration with Professor of Psychology at Rikkyo University, Dr. Wen Wen, who specializes in research on our sense of agency. They investigated how recognizing oneself through facial features might affect how people perceive control over their own movements.

During experiments, participants observed either their own face or another person’s face on a screen and could interact and control the facial and head movements. They were asked to observe the screen for about 20 seconds while moving their faces and changing their facial expressions. The motion of the face was controlled either only by their own facial and head motion or by an average of the participant’s and the experimenter’s motion (full control vs. partial control). Thereafter, they were asked “how much did you feel that this face looks like you?” and “how much control did you feel over this presented face?”

Again, the main findings were intriguing: participants reported a higher sense of agency over the “other face” rather than the “self-face.” Additionally, controlling someone else’s face resulted in more variety of facial movements than controlling one’s own face.

“We gave the participants a different face, but they could control the facial movements of this face — similar to deepfake technology, where AI can transfer movement to other objects. This AI technology allows us to go beyond the conventional experience of simply looking into a mirror, enabling us to disentangle and investigate the relationship between facial movements and visual identity,” Dr. Kasahara stated.

“Based on previous research, one might expect that if I see my own face, I will feel more control over it. Conversely, if it’s not my face, I might expect to feel less control because it’s someone else’s face. That’s the intuitive expectation. However, the results are the opposite — when people see their own face, they report a lower sense of agency. Conversely, when they see another person’s face, they’re more likely to feel a sense of agency.” These surprising results challenge what we thought we knew about how we see ourselves in images.

Dr. Kasahara emphasized that the acceptance of technology in society plays a crucial role in technological advancements and human evolution: “The relationship between technology and human evolution is cyclical; we evolve together. But concerns about certain computer technology may lead to restrictions. My goal is to help foster acceptance within society and update our understanding of “the self” in relation to human-computer integration technology.”

The findings, reported Sept. 1 at the European Society of Cardiology meeting and published in the Journal of the American College of Cardiology, provide inconclusive data about whether atrial fibrillation screening lowers stroke rates. The COVID pandemic led to an early halt of the study before fully enrolling, so it did not have enough participants to establish definitive results about stroke.

“Atrial fibrillation is often undiagnosed and can increase the risk of ischemic stroke, which is largely reversible by oral anticoagulation,” said lead author Renato Lopes, M.D., Ph.D., a professor of medicine and member of the Duke Clinical Research institute.

“We still need definitive evidence that diagnosis of atrial fibrillation through systematic screening can lead to subsequent treatment with oral anticoagulation and therefore, lower stroke risk,” Lopes said.

The study enrolled approximately 12,000 patients in the U.S. who were at least 70 years old with no history of atrial fibrillation. Roughly half the patients were randomly assigned to receive a long-term (14 days) continuous monitoring device, and the other half usual care.

Over a median of 15 months of follow-up, the study reported a 52% increase in the number of cases of atrial fibrillation diagnosed among the device-wearers compared to those in usual care. There was no increase in rates of hospitalization for bleeding, and no significant reduction in the rate of hospitalizations for all stroke compared with usual care.

The study was originally designed to enroll 52,000 patients, which would have given it the power to determine whether screening reduces the numbers of strokes. A large study population is needed because strokes occur in a subset of patients with atrial fibrillation.

“Despite the inconclusive results, we have a lot of lessons learned that might inform future studies” Lopes said. He said the study’s design, which enabled patients to be enrolled and screened online in a virtual format with self-applied patch devices in their homes with only remote support, could be duplicated in future studies.

In addition to Lopes, study authors include Steven J. Atlas, Alan S. Go, teven A. Lubitz, David D. McManus, Rowena J. Dolor, Ranee Chatterjee, Michael B. Rothberg, David R. Rushlow, Lori A. Crosson, Ronald S. Aronson, Michael Patlakh, Dianne Gallup, Donna J. Mills, Emily C. O’Brien, and Daniel E. Singer.

The study received funding support from the Bristol-Myers Squibb/Pfizer Alliance.

The study, published Aug. 30 in the journal Science Advances, offers renewed promise when it comes to discovering new drugs.

“The hope is we can speed up the timeline of drug discovery from years to months,” said Alex Thorman, PhD, co-first author and a postdoctoral fellow in the Department of Environmental and Public Health Sciences in the College of Medicine.

Researchers combined two approaches for screening potential new drugs. First, they used a database from the Library of Integrated Network-based Cellular Signatures (LINCS) to screen tens of thousands of small molecules with potential therapeutic effects simultaneously. Then they combined the search with targeted docking simulations used to model the interaction between small molecules and their protein targets to find compounds of interest. That sped up the timing of the work from months to minutes — taking weeks of work required for initial screening down to an afternoon.

Thorman said this faster screening method for compounds that could become drugs accelerates the drug research process. But it’s not only speed that is crucial.

He added that this newer approach is more efficient at identifying potentially effective compounds.

“And the accuracy will only improve, hopefully offering new hope to many people who have diseases with no known cure, including those with cancer,” Thorman said.

It can also create more targeted treatment options in precision medicine, an innovative approach to tailoring disease prevention and treatment that takes into account differences in people’s genes, environments and lifestyles.

“An accelerated drug discovery process also could be a game changer in the ability to respond to public health crises, such as the COVID-19 pandemic,” said Thorman. “The timeline for developing effective drugs could be expedited.”

The other co-first authors were Jim Reigle, PhD, a postdoctoral fellow at Cincinnati Children’s Hospital, and Somchai Chutipongtanate, PhD, an associate professor in the Department of Environmental and Public Health Sciences in the College of Medicine.

The corresponding authors of the study were Jarek Meller, PhD, a professor of biostatistics, health informatics and data sciences in the College of Medicine, and Andrew Herr, PhD, a professor of immunobiology in the Department of Pediatrics in the College of Medicine.

Other co-investigators included Mario Medvedovic, PhD, professor and director of the Center for Biostatistics and Bioinformatics Services in the College of Medicine, and David Hildeman, PhD, professor of immunobiology in the College of Medicine. Both Herr and Hildeman have faculty research labs at Cincinnati Children’s Hospital.

This research was funded in part by grants from the National Institutes of Health, a Department of Veterans Affairs merit award, a UC Cancer Center Pilot Project Award and a Cincinnati Children’s Hospital Innovation Fund award.

Those involved in the research are also co-inventors on three U.S. patents that are related to their work and have been filed by Cincinnati Children’s Hospital.

Now researchers from The Rockefeller University have found another rare mutation that leaves its carriers much more likely to become ill with TB — but, curiously, not with other infectious diseases. This finding, recently published in Nature, may upend long held assumptions about the immune system.

It’s long been known that an acquired deficiency of a pro-inflammatory cytokine called TNF is linked to an increased risk of developing TB. The current study, led by Rockefeller’s Stéphanie Boisson-Dupuis and Jean-Laurent Casanova, revealed a genetic cause of TNF deficiency, as well as the underlying mechanism: a lack of TNF incapacitates a specific immune process in the lungs, leading to severe — but surprisingly targeted — illness.

The findings suggest that TNF, long considered a key galvanizer of the immune response, might actually play a much narrower role — a discovery with far-reaching clinical implications.

“The past 40 years of scientific literature have attributed a wide variety of pro-inflammatory functions to TNF,” says Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases. “But beyond protecting the lungs against TB, it may have a limited role in inflammation and immunity.”

Rare risk

Casanova’s lab has been studying the genetic causes of TB for more than two decades through field work in several countries and a wide network of collaborating physicians across the world. They maintain an ever-growing database of whole-exome sequences from a global pool of patients — more than 25,000 people to date. Of those, some 2,000 have had TB.

Over the years they’ve identified several rare genetic mutations that render some people vulnerable to TB. For example, mutations in a gene called CYBB can disable an immune mechanism called the respiratory burst, which produces chemicals called reactive oxygen species (ROS). Despite its pulmonary-sounding name, the respiratory burst takes place in immune cells throughout the body.

ROS help pathogen-consuming white blood cells called phagocytes (from the Greek for “eating”) to destroy the invaders they’ve devoured. If ROS aren’t produced, those pathogens can thrive unchecked, leading to debilitating complications. As a result, carriers of this CYBB mutation become vulnerable to not just TB but to a wide variety of infectious diseases.

For the current study, the team suspected that a similar inborn error of immunity may lay behind the severe, recurring TB infections experienced by two people in Colombia — a 28-year-old woman and her 32-year-old cousin — who had been repeatedly hospitalized with significant lung conditions. In each cycle, they initially responded well to anti-TB antibiotics, but within a year, they were sick again.

Puzzlingly, however, their long-term health records showed that their immune systems functioned normally, and that they were otherwise healthy.

A telling deficiency

To find out why they were particularly prone to getting TB, the researchers performed whole-exome sequencing on the two, as well as a genetic analysis of their respective parents and relatives.

The two were the only members of their extended family with a mutation in the TNF gene, which encodes for proteins linked to the regulation of a variety of biological processes. Short for “tumor necrosis factor,” increased TNF production is also associated with a variety of conditions, including septic shock, cancer, rheumatoid arthritis, and cachexia, which causes dangerous weight loss.

The protein is largely secreted by a type of phagocyte called a macrophage, which relies on the ROS molecules generated by the respiratory burst to finish off pathogens they’ve consumed.

In these two patients, the TNF gene failed to function, preventing the respiratory burst from occurring, and thus the creation of ROS molecules. As a result, the patients’ alveolar macrophages, located in their lungs, were overrun with Mtb.

“We knew that the respiratory burst was important for protecting people against various types of mycobacteria, but now we know that TNF is actually regulating the process,” says Boisson-Dupuis. “And when it’s missing in alveolar macrophages, people will be susceptible to airborne TB.”

She adds, “It’s very surprising that the people we studied are adults who have never been sick with other infectious diseases, despite being repeatedly exposed to their microbes. They are apparently selectively at risk for TB.”

Treatment potential

The discovery also solves a long-standing mystery about why TNF inhibitors, which are used to treat autoimmune and inflammatory diseases, raise the chances of contracting TB. Without TNF, a key part of the defense against it is defunct.

The findings may lead to a radical reassessment of TNF’s role in immune function — and new treatment possibilities. “TNF is required for immunity against Mtb, but it seems to be redundant for immunity against many other pathogens,” Casanova says. “So the question is, what other pro-inflammatory cytokines are doing the jobs we thought TNF was doing? If we can discover that, we may be able to block these cytokines rather than TNF to treat diseases where inflammation plays a role.”

Mindfulness refers to the ability of an individual to focus attention on the present, in a way that is open, curious and not judgmental. Essentially, the ability to be fully in the moment.

“There’s a lot of discussion about the benefits of mindfulness, but it poses two challenges when you’re going through periods of stress,” says Tom Zagenczyk, co-author of a paper on the work and a professor of management in North Carolina State University’s Poole College of Management. “First, it’s hard to be mindful when you’re experiencing stress. Second, if it’s a truly difficult time, you don’t necessarily want to dwell too much on the experience you’re going through.

“Because hope is inherently forward looking, while mindfulness is about appreciating your current circumstances, we wanted to see how each of these two mindsets influenced people’s well-being and professional attitudes during difficult times,” Zagenczyk says. “The COVID pandemic presented us with an unfortunate, but useful, opportunity to explore this topic. And we chose to focus on the performing arts since that sector was particularly hard hit by the pandemic.”

For the study, researchers recruited 247 professional musicians from the organization MusiCares to take two surveys, one month apart. The first survey was given in September 2021. In addition to collecting broad demographic data, study participants were asked about their thoughts and experiences at the beginning of the pandemic — March to August 2020. They were also asked questions aimed at capturing how hopeful and mindful they were from September 2020 through March 2021.

The second survey was given in October 2021 and asked study participants questions aimed at capturing work engagement, work tensions, how positive their emotions were, and the extent to which they were experiencing distress.

The researchers then used statistical techniques to identify relationships between hope, mindfulness, and outcomes related to their personal well-being and attitudes toward work.

“Fundamentally, our findings tell us that hope was associated with people being happy, and mindfulness was not,” says Kristin Scott, study co-author and a professor of management at Clemson University. “And when people are hopeful — and happy — they experience less distress, are more engaged with their work, and feel less tension related to their professional lives.”

“Being mindful can be tremendously valuable — there are certainly advantages to living in the moment,” says Sharon Sheridan, study co-author and an assistant professor of management at Clemson. “But it’s important to maintain a hopeful outlook — particularly during periods of prolonged stress. People should be hopeful while being mindful — hold on to the idea that there’s a light at the end of the tunnel.”

While the study focused on musicians during an extreme set of circumstances, the researchers think there is a takeaway message that is relevant across industry sectors.

“Whenever we have high levels of job stress, it’s important to be hopeful and forward looking,” says Emily Ferrise, study co-author and a Ph.D. student at Clemson. “And to the extent possible, there is real value for any organization to incorporate hope and forward thinking into their corporate culture — through job conditions, organizational communications, etc.”

“Every work sector experiences periods of high stress,” says Zagenczyk. “And every company should be invested in having happy employees who are engaged with their work.”

“Improvements in MI management and data from observational studies have led physicians to question whether continuing beta-blockers after 1 year post-MI is needed since unnecessary treatment may result in side effects.^2-5 We conducted the ABYSS trial to provide conclusive randomised data on the effects of beta-blocker interruption vs. continuation on cardiovascular events and quality of life, but we were unable to show safety preservation in terms of clinical events nor any benefit on quality of life with beta-blocker interruption,” said Principal Investigator, Professor Johanne Silvain of the Sorbonne University, Paris, France.

The open-label, non-inferiority, randomised ABYSS trial, conducted by the ACTION Group, included patients with a prior MI taking long-term beta-blockers, with a left ventricular ejection fraction of at least 40% and no cardiovascular events in the previous 6 months. Participants were randomised (1:1) to interrupting or continuing their β-blocker medication.

The primary endpoint was a composite of death, non-fatal MI, non-fatal stroke or hospitalisation for cardiovascular reasons at the longest follow-up (minimum, 1 year), according to an analysis of non-inferiority (defined as a between-group absolute difference of <3 percentage points for the upper boundary of the two-sided 95% confidence interval [CI]). The main secondary endpoint was the change in quality of life as measured by the European Quality of Life-5 Dimensions questionnaire.

In total 3,698 patients were randomised from 49 sites in France. The mean age was 64 years and 17% were female. The median time between last MI and randomisation was 2.9 years (interquartile range 1.2-6.4 years).

Over median follow-up of 3 years, interruption of long-term beta-blocker treatment was not shown to be non-inferior to beta-blocker continuation. A primary-outcome event occurred in 23.8% of patients in the interruption group and in 21.1% in the continuation group (risk difference 2.8 percentage points; 95% CI <0.1-5.5), with a hazard ratio of 1.16 (95% CI 1.01-1.33; p=0.44 for non-inferiority).

Death occurred in 4.1% in the interruption group and 4.0% in the continuation group, while MI occurred in 2.5% and 2.4%, respectively. Of note, hospitalisation for cardiovascular causes occurred in 18.9% in the interruption group and 16.6% in the continuation group. Beta-blocker interruption was also associated with increases in systolic and diastolic blood pressure and heart rate at 6 months (all p<0.001 vs. beta-blocker continuation) and during the study follow up. Beta-blocker interruption did not improve the patients’ quality of life.

Summing up the evidence from the ABYSS trial, Professor Silvain concluded: “Differences between the groups with respect to hospitalisation for cardiovascular reasons and the negative effect on blood pressure levels, together with the absence of quality-of-life improvement do not support interruption of a chronic beta-blocker treatment in post-MI patients. These results must be put into context with recent findings from the open-label REDUCE-MI⁶ trial and ongoing trials to provide additional evidence on the optimal use of beta-blockers after MI.”

1 ‘Beta blocker interruption in patients with prior myocardial infarction: results of the ABYSS trial and effect on blood pressure and heart rate control’ will be discussed during Hot Line 1 on Friday 30 August in room London.

2 Holt A, Blanche P, Zareini B, et al. Effect of long-term beta-blocker treatment following myocardial infarction among stable, optimally treated patients without heart failure in the reperfusion era: a Danish, nationwide cohort study. Eur Heart J. 2021;42:907-914.

3 Park CS, Yang H-M, Ki Y-J, et al. Left ventricular ejection fraction 1 year after acute myocardial infarction identifies the benefits of the long-term use of beta-blockers: analysis of data from the KAMIR-NIH Registry. Circ Cardiovasc Interv. 2021;14:e010159.

4 Puymirat E, Riant E, Aissaoui N, et al. β Blockers and mortality after myocardial infarction in patients without heart failure: multicentre prospective cohort study. BMJ. 2016;354:i4801.

5 Kim J, Kang D, Park H, et al. Long-term β-blocker therapy and clinical outcomes after acute myocardial infarction in patients without heart failure: nationwide cohort study. Eur Heart J. 2020;41:3521-3529.

6 Yndigegn T, Lindahl B, Mars K, et al. Beta-blockers after myocardial infarction and preserved ejection fraction. N Engl J Med. 2024;390:1372-1381.

Despite decades of widespread treatment with the antibiotic vancomycin, vancomycin resistance among the bacterium S. aureus is extremely uncommon — only 16 such cases have reported in the U.S. to date. Vancomycin resistance mutations enable bacteria to grow in the presence of vancomycin, but they do so at a cost. Vancomycin-resistant S. aureus (VRSA) strains grow more slowly and will often lose their resistance mutations if vancomycin is not present. The reason behind vancomycin’s durability and the potential for VRSA strains to further adapt have not been adequately explored.

In this study, researchers took four VRSA strains and grew them in the presence and absence of vancomycin to see how the strains would evolve. They found that strains grown in the presence of vancomycin developed additional mutations in the ddl gene, which has previously been associated with vancomycin dependence. These mutations enabled VRSA strains to grow faster when vancomycin was present. Unlike the original strains, which quickly lost vancomycin resistance, the evolved strains maintained resistance through several generations, even when vancomycin was no longer present.

The study shows that durability of vancomycin susceptibility to date should not be taken for granted. The trade-off that often comes with vancomycin resistance can be overcome if the bacteria is allowed to grow in the presence of vancomycin. As antibiotic resistance continues to grow as a public health threat, studies like this underscores the importance of developing new antibiotics.

The authors add: “The superbug MRSA has been held off by the antibiotic vancomycin for decades. A new study shows we will not be able to count on vancomycin forever.”

Patients experiencing atrial fibrillation — a potentially dangerous medical condition in which the upper chambers of the heart beat irregularly — will often be prescribed blood thinners such as apixaban or warfarin to prevent a stroke. However, these treatment recommendations are based on results from randomized controlled trials, and it is unknown if they are applicable to populations of patients who were not included in the trial or present only in very low numbers.

In the new study, researchers used routinely collected health data from patients in the United Kingdom to attempt to emulate a previous randomized controlled trial that compared the effectiveness of apixaban and warfarin. They attempted to emulate the patient eligibility, selection and analysis approaches as the previous trial. They found that patients prescribed apixaban had similar outcomes to patients prescribed warfarin, but unlike the previous trial, they did not find that apixaban was superior. The researchers observed the differences in results may have been linked to higher quality of warfarin control, sub-optimal dosing of apixaban, and differences in the ethnicity of patients and use of concomitant medications compared with the clinical trial population.

Overall, the study established that using an existing randomized controlled trial (the reference trial) as a guide for the design of observational analysis of real patient data is an effective and valid way to estimate the treatment effects and risks of blood thinners given to patients with atrial fibrillation. The methods developed in this study can be used to investigate the effects of these medications in patient groups that are excluded from or underrepresented in these clinical trials, such as the elderly, those with multiple conditions and people with a higher risk of bleeding. This method can also help medical researchers to understand whether results from randomized controlled trials are transferable to “real-world” practices, and provides a framework that can be adapted to investigate treatment effects for other conditions.

The authors add, “Our study aimed to emulate a reference trial in oral anticoagulants in patients with atrial fibrillation using routinely collected UK healthcare data. Reference-trial informed design provides a framework for the study of treatment effects in patient groups excluded from or under-represented in trials.”

Since the 1970s, gaps in economic and social wellbeing between Americans living in different regions have grown. Some researchers hypothesize that areas with reduced economic and social well-being would see higher rates of violent crime. For instance, impoverished areas with lower tax bases might receive less police protection, or a lack of job opportunities may lead to greater involvement in criminal enterprises, in which violence can be an effective tool.

However, few studies have systematically examined potential links between geographic economic disparities and geographic disparities in violent crime rates. To address this gap, Boylan analyzed data from the National Center for Health Statistics, comparing homicide rates between the US’s 741 commuting zones across both urban and rural areas — distinct geographic areas within which most residents live and work, with few commuting into another zone.

Boylan found that, since the 1970s, disparities in US homicide rates between US commuting zones have steadily decreased, even while economic and social inequalities increased.

One potential explanation for these findings, as Boylan notes, is that since the 1970s, geographic disparities in policing, incarceration, and the share of the population that is African American has also decreased across the US. He suggests that future research could examine whether any of these factors could have contributed to the decreased disparities in homicide rates.

Alternatively, Boylan suggests, the expected violence-boosting effects of worsening social and economic conditions in some areas might have been mitigated by state, county, and federal law enforcement bodies stepping in to ensure continued prosecution of violent crime, such as in instances when local police departments were disbanded in economically challenged cities.

In contrast to the homicide findings, the researcher notes, geographic disparities in US life expectancies have increased since the 1960s, likely due to state policies that include tobacco taxes and Medicaid expansions.

Dr. Boylan adds: “There is a perception that job losses in the rust belt have led to an increase in inequality in crime. However, I provide empirical evidence that inequalities across different parts of the country in crime have steadily decreased since the 1960s and that this decrease coincides with decreases in disparities in policing, incarceration, and the share of the population that is African American.”

Gender nonconformity (GNC) refers to variations in gender expression from societal and cultural gender norms. In childhood, GNC can manifest itself in several ways, including play behavior, peer relationships, clothing, and body language. Childhood GNC does not directly indicate developing gender dysphoria (GD) later in life, although the phenomena are linked. Recently, studies have begun to establish a high co-occurrence of GNC, GD and autism spectrum disorder. However, most of this work has been carried out in clinical populations with existing diagnoses, which may lead to an overestimation of the associations between GNC and autistic traits and behavioral difficulties in a non-clinical population.

In the new study, researchers analyzed data on 718 children enrolled in the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy (SELMA) study for which there were data on play behavior and behavioral outcomes. GNC play behavior was determined using the Preschool Activities Inventory, which includes 12 “feminine” and 12 “masculine” toys, play activities and child characteristics.

In both sexes, higher levels of gender nonconforming play was associated with increased behavioral difficulties. Higher masculine play behavior scores were associated with hyperactivity and inattention in both sexes. Higher feminine play scores in boys were associated with peer relationship problems, while higher masculine play scores in girls were associated with increased likelihood of autistic traits and behavioral difficulties.

The study involves a sample of children of only one age in a single country, and cannot be used to draw any conclusions as to causation. However, the authors conclude that gender nonconformity may be associated with behavioral challenges and difficulties in both sexes, even in children without any diagnoses.

The authors add: “The results showed that children who played more with toys traditionally considered for the opposite gender had more autistic traits and behavioral problems. At the same time it is very important to keep in mind that just because a girl decides to play rougher or a boy plays with dolls, it does not mean that there will be a link to behavioral difficulties or autistic traits in this child.”

But scientists have learned that their story is much more complicated than initially believed — a number of these drugs are in fact targeting a complex composed of one receptor and one associated protein. Now, a new study in Science Advances introduces a novel approach to mapping the interactions between 215 such receptors and the three proteins that they form complexes with. The findings dramatically expand understanding of these interactions and their therapeutic potential.

“On the technical side, we can now study these receptors at unprecedented scale,” says first author Ilana Kotliar, a former graduate student in Rockefeller’s Laboratory of Chemical Biology and Signal Transduction, headed by Thomas P. Sakmar. “And on the biological side, we now know that the phenomenon of these protein-receptor interactions is much more widespread than originally thought, opening the door to future investigations.”

Uncharted territory

This family of receptors are known as GPCRs, or G protein-coupled receptors. Their accessory proteins are known as RAMPs, short for receptor activity-modifying proteins. RAMPs help transport GPCRs to the cell surface and can vastly alter how these receptors transmit signals by changing the receptor’s shape or influencing its location. Because GPCRs seldom exist in a vacuum, identifying a GPCR without accounting for how RAMPs might influence it is a bit like knowing the menu of a restaurant without checking its hours, address or delivery options.

“You could have two cells in the body in which the same drug is targeting the same receptor — but the drug only works in one cell,” says Sakmar, the Richard M. and Isabel P. Furlaud Professor. “The difference is that one of the cells has a RAMP that brings its GPCR to the surface, where that the drug can interact with it. That’s why RAMPs are so important.”

Knowing this, Sakmar and colleagues were determined to develop a technique that would allow researchers to parse out each RAMP’s effect on every GPCR. Such a comprehensive map of GPCR-RAMP interactions would supercharge drug development, with the added benefit of possibly explaining why some promising GPCR drugs mysteriously haven’t panned out.

They hoped that such a map would also contribute to basic biology by revealing which natural ligands several so-called “orphan” GPCRs interact with. “We still don’t know what activates many GPCRs in the human body,” Kotliar says. “Screenings may have missed those matches in the past because they weren’t looking for a GPCR-RAMP complex.”

But wading through every GPCR-RAMP interaction was a daunting task. With three known RAMPs and almost 800 GPCRs, searching through every possible combination was impractical, if not impossible. In 2017 Emily Lorenzen, then a graduate student in Sakmar’s lab, began a collaboration with scientists at the Science for Life Laboratory in Sweden and Sweden’s Human Protein Atlas Project to create an assay capable of screening for GPCR-RAMP interactions.

Hundreds of experiments at once

The team started by coupling antibodies from the Human Protein Atlas to magnetic beads, each pre-colored with one of 500 different dyes. These beads were then incubated with a liquid mixture of engineered cells expressing various combinations of RAMPs and GPCRs. This setup allowed researchers to simultaneously screen hundreds of potential GPCR-RAMP interactions in a single experiment. As each bead passed through a detection instrument, color coding was used to identify which GPCRs were bound to which RAMPs, enabling high throughput tracking of 215 GPCRs and their interactions with the three known RAMPs.

“A lot of this technology already existed. Our contribution was an enabling technology built upon it,” Sakmar says. “We developed a technique to test for hundreds of different complexes at once, which generates a huge amount of data, and answers many questions simultaneously.”

“Most people don’t think in multiplex terms. But that’s what we did — 500 experiments at once.”

While this work is the culmination of a team effort over a long period of time, Kotliar made herculean efforts to drag it across the finish line — shuttling samples and scarce reagents back and forth from Sweden in rare travel windows during COVID.

It paid off. The results provide a handful of long-awaited resources for GPCR researchers and drug developers: publicly available online libraries of anti-GPCR antibodies, engineered GPCR genes and, of course, the mapped interactions. “You can now type in your favorite receptor, find out what antibodies bind to it, whether those antibodies are commercially available, and whether that receptor binds to a RAMP,” Sakmar says.

The findings increase the number of experimentally identified GPCR-RAMP interactions by an order of magnitude and lay the groundwork for techniques that could help detect combinations of GPCRs and identify harmful autoantibodies. “Ultimately, it’s a technology-oriented project,” Sakmar says. “That’s what our lab does. We work on technologies to advance drug discovery.”

Yet scientists understand little about how this essential protein does its crucial work at the molecular level. “People have been studying this protein for decades without a clear consensus on what it is doing, where it binds to the genome, and what its functions are,” says Rockefeller’s Shixin Liu. Now, a new study from Liu’s laboratory sheds light on how the protein, MeCP2, interacts with DNA and chromatin.

The findings, published in Nature Structural & Molecular Biology, provide insight into this master regulator, and could open up new avenues for Rett syndrome therapies.

A single-molecule approach

MeCP2 is a baffling protein. While it has been implicated in the regulation of thousands of genes and is thought to be central to neurodevelopment, its impacts on the genome are tricky to pin down. Insufficient amounts of wildtype MeCP2 causes Rett syndrome, but too much of the protein causes a similarly debilitating neurological disorder known as MeCP2 duplication syndrome.

Liu and colleagues leveraged the lab’s area of expertise — single-molecule observation and manipulation — to better understand how MeCP2 interacts with DNA. The team tethered a single piece of DNA between micron-sized plastic beads, each held by a laser, and then incubated the DNA with fluorescently labeled MeCP2 proteins. This setup allowed them to closely monitor the mysterious protein’s dynamic behavior.

MeCP2 is generally thought to exclusively perform its functions on DNA that is modified with methylated cytosines, but lacked a satisfactory explanation for such specificity, since the protein readily binds both methylated and unmethylated DNA. The team found that MeCP2 dynamically moves on DNA, but in a much slower manner in regards to the methylated form compared to the unmethylated one. They further showed that these different dynamics allow MeCP2 to recruit another regulatory protein more efficiently to methylated DNA sites, which may help direct MeCP2’s gene regulatory functions towards specific locations within the genome. “We found that MeCP2 slides along unmethylated DNA faster, and this difference in motion may explain how the protein differentiates between the two,” says Gabriella Chua, a graduate fellow in Liu’s lab and first author on the paper.

“That’s something we could only have discovered using a single-molecule technique.”

Liu and Chua also found that the protein shows a very strong preference for binding to nucleosomes, protein spools that are wound with our genetic material, over bare DNA. This interaction stabilizes nucleosomes in a way that may suppress gene transcription — hinting at how MeCP2 itself regulates gene expression.

New thinking about nucleosomes

The observation that a master regulator of gene expression most often interacts with this tightly wound form of DNA helps bolster a growing notion that nucleosomes are far more than inert “storage spools” of DNA, and that scientists need to begin thinking of MeCP2’s function more in the context of nucleosomes.

“Our data is one of the most definitive examples of this phenomenon to date,” Liu says. “It’s clear that MeCP2 prefers binding to nucleosomes.” In this way, MeCP2 functions as a chromatin-binding protein, contrasting the conventional view that sees it chiefly as a methyl-DNA-binding protein. In this study, the team has also narrowed in on the part of the protein that is responsible for its nucleosome-binding activity.

“Bare DNA is in the minority — nucleosomes are pervasive in our genomes,” Chua says. “Several recent studies have demonstrated that nucleosomes are not merely passive barriers to transcription, but active hotspots for gene regulation.” A particularly striking example of such nucleosome functionality is how MeCP2 interacts with it.

In future work, the team plans to expand beyond the present in vitro study to examine MeCP2 in vivo, where interactions between the protein and the nucleosome are expected to be more complex. They also intend to use the techniques described in this paper to better study the many MeCP2 mutations that cause diseases such as Rett syndrome. The hope is that a more complete understanding of the protein central to this devastating disease may one day lead to therapies. “There’s no cure for Rett, but the community of researchers studying it are determined and energized. Many found our data intriguing when we shared it with them,” Chua says. “Our findings highlight how basic research can help the clinical community better understand a disease.”

Because perceptions shape attitudes and behaviors, distrust in water quality has a negative impact on people’s health, nutrition, psychological and economic well-being — even when the water meets safety standards.

“If we think our water is unsafe, we will avoid using it,” said Sera Young, professor of anthropology and global health at Northwestern and senior author of the new study.

“When we mistrust our tap water, we buy packaged water, which is wildly expensive and hard on the environment; drink soda or other sugar-sweetened beverages, which is hard on the teeth and the waistline; and consume highly processed prepared foods or go to restaurants to avoid cooking at home, which is less healthy and more expensive,” Young said. “Individuals exposed to unsafe water also experience greater psychological stress and are at greater risk of depression.”

Young is a Morton O. Schapiro Faculty Fellow at the Institute for Policy Research, a faculty fellow at the Paula M. Trienens Institute for Sustainability and Energy, and co-lead of the Making Water Insecurity Visible Working Group at the Buffett Institute for Global Affairs.

Using nationally representative data from 148,585 adults in 141 countries from the 2019 Lloyd’s Register Foundation World Risk Poll, the authors found a high prevalence of anticipated harm from water supply, with the highest in Zambia, the lowest in Singapore and an overall mean of 52.3%.

They also identified key characteristics of those who thought they would be harmed by their drinking water. Women, city dwellers, individuals with more education, and those struggling on their current income were more likely to anticipate being harmed by their drinking water.

The researchers found that, surprisingly, higher corruption perception index scores were the strongest predictor of anticipated harm from drinking water, more so than factors like infrastructure and Gross Domestic Product.

Further, even within countries with consistent access to basic drinking water services, doubts about the safety of water were widespread. This includes the U.S. where 39% of those polled anticipated serious harm from drinking water in the short term.

“Our research highlights that it is imperative both to deliver safe drinking water and to make sure that people have confidence in their water source,” said Joshua Miller, a doctoral student at the UNC Gillings School of Global Public Health and the study’s first author.

The researchers note that it is difficult for consumers to judge the hazards and safety of their water supply because many contaminants are invisible, odorless and tasteless. Without adequate information, many are left to evaluate the safety of their water based on prior experiences, media reports, and personal values and beliefs.

“It’s also possible that people correctly judge the safety of their water,” Young said. “The good people of Flint didn’t trust their water and they were spot on.”

The co-authors suggest actions officials can take to improve public trust around drinking water, including efforts to make testing more readily available, translate test results, replace lead pipes and provide at-home water filters when contaminants are detected, as well as provide improved access to safe drinking water.

“This is the kind of work that can catalyze greater attention and political will to prioritize these services in national development plans and strategies, and get us closer to achieving universal access to safe drinking water,” said Aaron Salzberg, director of the Water Institute at the UNC Gillings School of Global Public Health.

Salzberg previously served as the special coordinator for water resources in the U.S. Department of State, where he was responsible for managing the development and implementation of U.S. foreign policy on drinking water and sanitation, water resources management and transboundary water issues.

To fight invading bacteria and viruses, the immune system must first learn their molecular structure. To do this, a cellular enzyme complex known as the immunoproteasome breaks down the intruder and presents its molecular structure to the immune cells. If an overactive immunoproteasome mistakenly attacks the body’s own structures, this can lead to immune disorders. In order to regulate this process, researchers have been searching for inhibitors of the immunoproteasome for a long time. However, it is important to ensure that the other proteasome variants in the cell — such as those required for cellular recycling and waste disposal — are not also blocked. The selectivity of the drug is crucial to avoid side effects.

The research group led by Helge Bode at the Max Planck Institute for Terrestrial Microbiology in Marburg has been working for years on designing enzyme complexes on the drawing board and using synthetic biology to create new natural substances. Potential candidates for drugs to treat immune diseases, as well as antibiotics or anti-cancer drugs, come not only from the group of peptides, but also from the group of long-chain fatty acids known as polyketides. While peptides are usually produced by non-ribosomal peptide synthetases, polyketides are produced by polyketide synthases.

Fused enzymes

Now, in collaboration with Michael Groll from the Technical University Munich and Markus Kaiser from the University of Duisburg-Essen, the team has succeeded in developing a peptide-polyketide hybrid and assembling it in just a few steps. “The XUT technology we developed uses docking sites located in thiolation domains. Since these domains are present in both non-ribosomal peptide synthetases and polyketide synthases, both types of enzymes, for peptides and for polyketides, can be fused,” explains Leonard Präve, lead author of the study.

Nature itself also produces such hybrids of non-ribosomal peptide synthetases and polyketide synthases. A particular class of substances, syrbactins, is found in bacteria that damage plants or insects, for example. By inhibiting the proteasome in these higher organisms, syrbactins cause the cell to die by ‘clogging’ its waste disposal system.

Since this effect is desirable in tumour cells, syrbactins are considered as potential cancer drugs. Although drugs based on inhibition of the proteasome already exist, there has been no specific and therefore low-side effect agent against the immunoproteasome, nor one that uses syrbactin as a starting point for drug development. “With our approach, we are able to rationally modify syrbactins in several steps to create a novel, more selective inhibitor of the human immunoproteasome,” adds Helge Bode. Although the resulting compound is not yet sufficiently selective, it is already pointing the way to how further variants can now be optimised in order to reduce the side effects. In the future, these will be generated on the computer screen and in a high-throughput process, so that the best variants can be selected for specific applications.

Rice University bioengineers report harnessing the lotus effect to develop a system for culturing cancer cell clusters that can shed light on hard-to-study tumor properties. The new zinc oxide-based culturing surface mimics the lotus leaf surface structure, providing a highly tunable platform for the high-throughput generation of three-dimensional nanoscale tumor models.

The superhydrophobic array device (SHArD) designed by Rice bioengineer Michael King and collaborators can be used to create tunable, compact, physiologically relevant models for studying the progression of cancer, including metastasis — the stage in the disease when cancerous cells travel through the bloodstream from a primary tumor site to other parts of the body.

“The study of metastasis — the leading cause of cancer deaths — poses a particular challenge in part due to the difficulty of developing accurate, high-throughput models,” said King, who is corresponding author on a study published in ACS Nano that describes the new culturing platform. “We hope this tool will unlock new knowledge about this problematic stage of the disease and help us identify ways to intervene in order to stop or prevent it from happening.”

Scientists and clinicians now rely on blood samples containing circulating tumor cells — a key marker of metastasis — to understand the properties of primary tumors as well as what causes cancer to spread. Often referred to as “liquid biopsy,” this sampling approach typically does not yield enough of a “catch” to enable in-depth, large-scale studies of metastatic processes.

“‘Safety in numbers’ unfortunately also applies to cancer cells circulating in the bloodstream,” said Alexandria Carter, a researcher in the King lab who is a co-author on the study. “Cancer cells traveling alone are more likely to succumb to shear stress destruction or immune cell attacks. However, when they travel in groups, the likelihood that they successfully reach and settle in other parts of the body increases.

“Those few lone cancer cells in a single blood draw are already rare, so isolating enough clusters for a detailed study is especially challenging. This is why SHArD is an exciting new tool for understanding primary and metastatic cancer.”

The King lab had previously succeeded in creating nanorod layers of halloysite, a naturally occurring substance whose texture promotes the adhesion of circulating tumor cells while simultaneously repelling blood cells.

“When Kalana Jayawardana joined our lab as a new postdoctoral fellow in 2018, he started to experiment with growing zinc oxide nanorod surfaces,” said King, a Cancer Prevention and Research Institute of Texas Scholar who recently joined Rice as the E.D. Butcher Chair of Bioengineering and special adviser to the provost on life science collaborations with the Texas Medical Center. “At first, we didn’t have a specific application in mind, but we were curious and hopeful that the new material would have special properties that would be useful for cancer biology.”

The project was later taken over by a doctoral student in the King lab, Maria Lopez-Cavestany, and took off in an exciting direction. Cavestany, now a Ph.D. graduate, is the first author on the study.

Once they were able to grow a stable “carpet” of zinc oxide nanotubes, the researchers added a teflonlike coating on top, in essence recreating the lotus leaf structure — nanoscale roughness combined with a hydrophobic layer that together gave rise to true superhydrophobicity, a word stemming from the Greek for “extreme fear of water.” To create SHArD, the researchers added a microwell grid with perfectly sized compartments, then tested the system to assess its performance.

“SHArD is ready to use in biomedical research,” Carter said. “Any lab with clean room access can follow our protocols and create versions of this platform that meet the exact needs of their specific research projects.”

Initially intended as a means to reliably culture primary tumor models at a higher throughput, SHArD is highly tunable and can easily be adapted to culture metastatic clusters as well. The fact that SHArD was successfully used to grow spheroidal models of primary tumors already expands the cancer modeling toolkit, making it possible to create superhydrophobic culturing devices in the absence of highly specialized equipment.

“The cluster-forming device has opened the door to new areas of research into the dangerous clusters found in the bloodstream of late-stage cancer patients,” King said.

Researchers recruited participants experiencing prolonged stress from the COVID-19 pandemic for a two-week randomized controlled trial. Half of the participants were randomly assigned to a nondeceptive placebo group and the other half to the control group that took no pills. The participants interacted with a researcher online through four virtual sessions on Zoom. Those in the nondeceptive placebo group received information on the placebo effect and were sent placebo pills in the mail along with and instructions on taking the pills.

The study, published in Applied Psychology: Health and Well-Being, found that the nondeceptive group showed a significant decrease in stress, anxiety and depression in just two weeks compared to the no-treatment control group. Participants also reported that the nondeceptive placebos were easy to use, not burdensome and appropriate for the situation.

“Exposure to long-term stress can impair a person’s ability to manage emotions and cause significant mental health problems long-term, so we’re excited to see that an intervention that takes minimal effort can still lead to significant benefits,” said Jason Moser, co-author of the study and professor in MSU’s Department of Psychology. “This minimal burden makes nondeceptive placebos an attractive intervention for those with significant stress, anxiety and depression.”

The researchers are particularly hopeful in the ability to remotely administer the nondeceptive placebos by health care providers.

“This ability to administer nondeceptive placebos remotely increases scalability potential dramatically,” said Darwin Guevarra, co-author of the study and postdoctoral scholar at the University of California, San Francisco, “Remotely administered nondeceptive placebos have the potential to help individuals struggling with mental health concerns who otherwise would not have access to traditional mental health services.”

“As pharmacies close, more and more Americans are left without easy access to medications, with disproportionate consequences on certain communities. We found that patients in counties with higher social vulnerabilities and fewer primary care providers were up to 40% more likely to reside in a region with a pharmacy desert,” said Timothy Pawlik, MD, senior author of the study and holder of the Urban Meyer III and Shelley Meyer Chair for Cancer Research at the OSUCCC — James. Pawlik also serves as surgeon-in-chief at The Ohio State University Wexner Medical Center and as chair of the Department of Surgery in the Ohio State College of Medicine.

The U.S. Centers for Disease Control (CDC) defines social vulnerability as “potential negative effects on communities caused by external stresses on human health.”

“These findings highlight how disparities compound the lack of access to basic health care and how it can lead to many people not taking their prescribed medications and having worse health outcomes, especially for chronic conditions like diabetes and hypertension,” Pawlik added.

Study results were published today in JAMA Network Open.

Methods and Results

Researchers reviewed data on communities located less than 10 miles from the nearest retail pharmacy from the publicly available TelePharm Map. Counties were noted as having a high pharmacy desert density if the number of pharmacy deserts per 1,000 residents was in the 75th percentile. Social vulnerability index (SVI) and healthcare provider data were obtained from the CDC’s Agency for Toxic Substances and Disease Registry and the Area Health Resource File databases, respectively. The researchers used statistical methods to analyze the relationships between these factors.

The study found almost 46% of the 3,143 counties had at least one pharmacy desert. Counties with a high density of pharmacy deserts had higher social vulnerability and fewer primary care providers. People in these high-density pharmacy desert areas were more likely to face difficulties accessing medications and healthcare services.

Collaborators in this study include Giovanni Catalano, MD, Muhammad Muntazir Mehdi Khan, MBBS, and Odysseas P. Chatzipanagiotou, MD.

Led by Ludwig Lausanne’s Ping-Chih Ho and Alessio Bevilacqua and published in the current issue of Science Immunology, the study identifies PPARβ/δ, a master regulator of gene expression, as that essential molecular switch. Ho, Bevilacqua and their colleagues also show that the switch’s dysfunction compromises T cell “memory” of previously encountered viruses as well as the induction of anticancer immune responses in mice.

“Our findings suggest that we might be able to engage this switch pharmacologically to improve the efficacy of cancer immunotherapies,” said Ho.

When killer (or CD8+) T cells, which kill sick and cancerous cells, are activated by their target antigen, they switch on metabolic pathways that most other healthy cells only use when starved of oxygen. This type of metabolism — involving a metabolic process known as aerobic glycolysis — supports multiple processes essential to the killer T cell’s ability to proliferate and destroy its target cells.

Most killer T cells die off after they’ve cleared an infection. A few, however, transform into central memory CD8+ T cells (Tcms) that linger in the circulation to establish what we call immunity: the ability to mount a swift and lethal response to the same pathogen if it is ever encountered again. To achieve this transformation, T cells switch off aerobic glycolysis and otherwise adapt their metabolism to persist over the long term in tissues or in the circulation. How precisely they do this was until now unknown.

Aware that PPARβ/δ activates many of the metabolic processes characteristic of Tcms, Ho, Bevilacqua and their colleagues hypothesized it might play a key role in Tcm formation. They examined immunologic gene expression data collected from yellow fever vaccine recipients long after vaccination and, as expected, saw that the PPARβ/δ was produced abundantly in their Tcms.

Their studies in mice revealed that PPARβ/δ is activated in T cells not in the peak phase of the immune response to viral infection but as that response winds down. Further, CD8+ T cells were unable to make the metabolic switch required to become circulating Tcms if they failed to express PPARβ/δ. Disrupting its expression impaired survival of such Tcms and resident memory T cells in the intestines following infection.

The researchers show that T cell exposure to interleukin-15 — an immune factor important for Tcm formation — and their expression of a protein named TCF1 engages the PPARβ/δ pathway. TCF1 is already known to be critical to the rapid expansion of Tcms when they encounter their target pathogen. The researchers show in this study that it is also important to the maintenance of TCMs.

As it happens, TCF1 expression is a hallmark of a subset of CD8+ T cells — progenitor-exhausted T cells — that are found in tumors. These progenitor-exhausted T cells follow one of two paths: they either become completely lethargic, “terminally exhausted” T cells; or, given the appropriate stimulus, proliferate to produce “effector” CD8+ T cells that kill cancer cells. Checkpoint blockade immunotherapies, like anti-PD-1 antibodies, can provide such stimulus.

The observation that TCF1 modulates the PPARβ/δ pathway in T cells raised the possibility that it might also be essential to the formation and maintenance of progenitor-exhausted T cells. The researchers showed that this is indeed the case. Deleting the PPARβ/δ gene from T cells led to the loss of progenitor-exhausted T cells in a mouse model of melanoma. They also demonstrate that the PPARβ/δ pathway curtails the tendency of progenitor-exhausted T cells to stagger toward terminal exhaustion.

To assess the therapeutic potential of their findings, Ho, Bevilacqua and their colleagues exposed T cells to a molecule that stimulates PPARβ/δ activity and used the treated cells against a mouse model of melanoma. These cells delayed the growth of melanoma tumors in mice more efficiently than their untreated counterparts and bore biochemical hallmarks of progenitor exhausted T cells primed to generate cancer-killing descendants.

“Based on these findings,” said Bevilacqua, “we suggest that targeting PPARβ/δ signaling may be a promising approach to improve T cell-mediated anti-tumor immunity.

How exactly this might be achieved in people is a subject for further study that will doubtless be pursued by the Ho laboratory.

This study was supported by Ludwig Cancer Research, the Swiss National Science Foundation, the European Research Council, the Swiss Cancer Foundation, the Cancer Research Institute, Helmut Horten Stiftung, the Melanoma Research Alliance, the Taiwan Ministry of Science and Technology, the NYU Abu Dhabi Research Institute Award and Academia Sinica.

Ping-Chih Ho is a member of the Lausanne Branch of the Ludwig Institute for Cancer Research and a full professor at the University of Lausanne.

Dr. Pumpki Lei Su, an assistant professor of speech, language, and hearing in the School of Behavioral and Brain Sciences, is co-lead author on two recent articles in which researchers examined the sounds babies make. The results suggest that children in their first year are more active than previously thought in their acquisition of speech.

“We observed in these studies that infant vocalizations are not produced randomly; they form a pattern, producing three categories of sounds in clusters,” said Su, who also directs the Language Interaction and Language Acquisition in Children Lab (LILAC Lab) at the Callier Center for Communication Disorders. “The home recordings we analyzed included times when adults were interacting with their child and when children were on their own, showing that children explore their vocal capabilities with or without language input from an adult.”

One study, published May 29 in PLOS ONE, focused on typically developing infants, and the other, published Feb. 25 in the Journal of Autism and Developmental Disorders, focused on infants who later received a confirmed diagnosis of autism. The researchers documented how children “play” vocally, learning what actions produce certain sounds and then repeating that process.

Within the past 40 to 50 years, scientists have realized that vocalizations before a child’s first word are meaningful precursors for speech and can be broken into sequential stages of cooing, vocal play and babbling. Su’s team studied a dataset of all-day home recordings from more than 300 children amassed by the Marcus Autism Center, a subsidiary of Children’s Healthcare of Atlanta, and coded by senior author Dr. D. Kimbrough Oller’s team at The University of Memphis.

“Parents tell us that sometimes a baby will just scream or make low-frequency sounds for a really long period. But it’s never been studied empirically,” Su said. “With access to a huge dataset from hundreds of children during the first 12 months of their lives, we set out to quantitatively document how babies explore and cluster patterns as they practice different sound categories.”

Sound types are characterized by pitch and wave frequency as squeals, growls or vowellike sounds. The PLOS ONE study used more than 15,000 recordings from 130 typically developing children in the dataset. Infants showed significant clustering patterns: 40% of recordings showed significantly more squeals than expected by chance, and 39% showed clustered growls. Clustering was common at every age, with the highest rates occurring after 5 months of age.

“Of the 130 infants, 87% showed at least one age at which their recordings showed significant squeal clustering and at least one age with significant growl clustering,” Su said. “There was not a single infant who, on evaluation of all the available recordings, showed neither significant squeal nor growl clustering.”

Su said the study represents the first large-scale empirical study investigating the nonrandom occurrence of the three main sound types in infancy.

In the Journal of Autism and Developmental Disorders article, Su and her colleagues demonstrated that this exploration behavior also occurs during the first year in children who are later diagnosed with autism spectrum disorder.

“Whether or not a child is eventually diagnosed with autism, they are clustering sounds within one vocal category at a time,” Su said. “While one cannot rule out the possibility that some patterns may be mimicry, these are not just imitations; they are doing this with and without the presence of a parent, even in the first month of life. This process of learning to produce sounds is more endogenous, more spontaneous than previously understood.

“We tend to think babies are passive recipients of input. And certainly, parents are their best teachers. But at the same time, they’re doing a lot of things on their own.”

Su has received a three-year grant from the National Institute on Deafness and Other Communication Disorders (NIDCD) to study parents’ use of “parentese” — or baby talk — with autistic children. Parentese is an exaggerated style of speech often containing high-pitched elongated words and singsong diction.

Parentese is portrayed in the literature as a type of optimal input for typically developing children, who tend to pay better attention and respond to it more than they do to normal speech. It also helps children learn to segment words. But is it also ideal for autistic children?

“One hypothesis of why parentese works is that it encourages social interaction by being very animated,” Su said. “Autistic children have differences in social communication and responses to sensory stimuli. Would they also find parentese engaging? Could it be too loud or extreme? This new grant will allow me to examine whether parentese facilitates word learning for autistic children compared to a more standard adult-directed register.”

Other researchers who contributed to both articles include co-lead author Dr. Hyunjoo Yoo of The University of Alabama; Dr. Edina Bene from The University of Memphis; Dr. Helen Long of Case Western Reserve University; and Dr. Gordon Ramsay from the Emory University School of Medicine. Additional researchers from the Marcus Autism Center contributed to the Journal of Autism and Developmental Disorders study.

The research was funded by grants from the NIDCD (R01DC015108) and the National Institute of Mental Health (P50MH100029), both components of the National Institutes of Health.

Muscles and nerves are long-lasting, high-performance organs whose cellular components are subject to constant wear and tear. The protein BAG3 plays a critical role in the elimination of damaged components, identifying these and ensuring that they are enclosed by cellular membranes to form an “autophagosome.” Autophagosomes are like a garbage bag in which cellular waste is collected for later shredding and recycling. The research team led by Professor Jörg Höhfeld of the University of Bonn Institute of Cell Biology has shown that strength training activates BAG3 in the muscles. This has important ramifications for cellular waste disposal because BAG3 has to be activated to efficiently bind damaged cell components and promote membrane envelopment. An active elimination or clearing system is essential for the long-term preservation of muscle tissues. “Impairment of the BAG3 system does indeed cause swiftly progressing muscle weakness in children as well as heart failure — one of the most common causes of death in industrialized Western nations,” Professor Höhfeld explains.

Important implications for sports training and physical therapy

The study was conducted with significant involvement by sports physiologists of German Sport University Cologne and the University of Hildesheim. Professor Sebastian Gehlert of Hildesheim emphasizes how important the findings are: “We now know what intensity level of strength training it takes to activate the BAG3 system, so we can optimize training programs for top athletes and help physical therapy patients build muscle better.” Professor Gehlert also makes use of these findings to support members of the German Olympic team.

Necessary for the muscles … and more

The BAG3 system is not only active in the muscles. Mutations in BAG3 can lead to a nerve disease known as Charcot-Marie-Tooth syndrome (named after the discovering scientist). The disease cause nerve fibers in the arms and legs to die off, leaving the individual unable to move his or her hands or feet. By studying cells from sufferers, the research team has now shown that certain manifestations of the syndrome cause faulty regulation of BAG3 elimination processes. The findings demonstrate the far-reaching significance of this system for tissue preservation.

Unexpected regulation pointing the way to new therapies

In analyzing BAG3 activation more closely, the researchers were surprised at what they observed. “Many cell proteins are activated by the attachment of phosphate groups in a process known as phosphorylation. With BAG3, however, the process is reversed,” explains Professor Jörg Höhfeld, also a member of the Transdisciplinary Research Area (TRA) Life and Health at the University of Bonn, “BAG3 is phosphorylated in resting muscles, and the phosphate groups are removed during activation.” At this point, phosphatases become the main focus of interest — the enzymes that remove the phosphate groups. To identify the phosphatases that activate BAG3, Höhfeld is collaborating with chemist and cell biologist Professor Maja Köhn of the University of Freiburg. “Identifying the phosphatases involved is a key step,” she relates, “so we can pursue the development of substances potentially able to influence BAG3 activation in the body.” The research may open up new therapeutic possibilities for muscle weakness, heart failure and nerve diseases.

Relevant for space travel

Work on the BAG3 system is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) through a research unit headed by Prof. Höhfeld. In addition, Höhfeld receives funds from the German Space Agency as the research is of interest for purposes of manned space missions. Professor Höhfeld points out: “BAG3 is activated under mechanical force. But what happens if mechanical stimulation does not take place? In astronauts living in a weightless environment, for example, or immobilized intensive care patients on ventilation?” In such cases, the lack of mechanical stimulation rapidly leads to muscle atrophy, the cause of which Höhfeld ascribes at least in part to the non-activation of BAG3. Drugs developed to activate BAG3 might help in such situations, he believes, which is why Höhfeld’s team is preparing experiments to be conducted on board of the International Space Station (ISS). BAG3 research thus could in fact help us reach Mars someday.

Institutions involved and funding secured

The University of Bonn’s partners in this study are the University of Freiburg, German Sport University, Forschungszentrum Jülich, the University of Antwerp and the University of Hildesheim. The work is co-funded by the German Research Foundation and the German Space Agency, part of the German Aerospace Center.

It is a major risk factor for cirrhosis and liver cancer. And because treatment options are limited, MASH is the second leading cause for liver transplants in the United States after cirrhosis caused by chronic hepatitis C infection.

A better understanding of the pathological processes that drive MASH is critical to creating effective treatments. In a new paper published August 19, 2024 in PNAS, a team of scientists from Sanford Burnham Prebys, the University of California San Diego School of Medicine and elsewhere, describe the complex interplay between diseased liver cells and macrophages — a type of white blood cell whose jobs include killing and removing harmful cells and pathogens and helping to spur normal healing.

Debanjan Dhar, PhD, associate professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys, is senior author of the study. David Brenner, MD, president and CEO of Sanford Burnham Prebys, and Christopher Glass, MD, PhD, professor of cellular and molecular medicine at UC San Diego, are corresponding authors. Souradipta Ganguly, PhD, a postdoctoral research fellow at UC San Diego and Sanford Burnham Prebys, is first author.

The researchers found that the heterogeneous mix of macrophages involved with MASH was different, depending on whether the disease was progressing or regressing. More importantly, they identified specific macrophage subpopulations that are critical for resolving MASH and liver fibrosis in which accumulating scar tissue impairs the organ’s ability to function or repair itself. These fibrotic bands restrict blood flow, imperiling the entire organ.

“In MASH, Kupffer cells (a type of macrophage that resides in the liver) are lost and replaced by four distinct macrophage subpopulations. When the disease is in regression — that is, symptoms or severity are decreasing — two lipid associated macrophage subpopulations are dominant and express TREM2, a cell receptor that regulates cell survival, proliferation and anti-inflammatory responses,” said Brenner.

“MASH regression occurs in the presence if TREM2+ macrophages. They not only restrict the progression of MASH-fibrosis, but effectively slow it and reduce inflammation. The absence of TREM2+ macrophages allows the disease to progress.”

In early and moderate stages, MASH often produces no tell-tale symptoms, which is part of the why it has reached epidemic proportions in the U.S. The American Liver Foundation estimates 80 to 100 million Americans have fatty liver disease which, undiagnosed and untreated, progresses to nonalcoholic steatohepatitis, MASH, cirrhosis, liver cancer and death, often in combination with other conditions, such as obesity.

An estimated 1.5% to 6.5% of U.S. adults have MASH. afflicted by the condition, and roughly 24% of adults have metabolic dysfunction-associated steatotic fatty liver disease, the starting point for MASH, cirrhosis and worse.

“Our findings suggest that lipid associated macrophages that express TREM2 and TREM2 are required both for the emergence of more liquid associated macrophages and for their reparative functions,” said Dhar.

“Effective degradation of scar tissue as a protective mechanism is mediated by TREM2, and the absence of TREM2+ macrophages not only disrupts the liver’s ability to remove fibrotic tissue, but it also harms the entire immune response and healing process.”

Going forward, the scientists say a TREM2 agonist — a drug or substance that mimics the function of TREM2 — might be beneficial for MASH/fibrosis therapy and help spur MASH and fibrosis regression in patients also undergoing lifestyle modification, weight loss or bariatric surgery.

“There is only one approved treatment for MASH, and it was only approved earlier this year,” said Glass. “Any opportunities to expand clinical options that benefit patients need to be thoroughly pursued because liver disease in this country — and around the world — is only getting worse.”

Additional authors on the study include Sara Brin Rosenthal, Kei Ishizuka, Theresa V. Rohm, Naser Khader, Sebastiano Archilei, Jerrold M. Olefsky, Ariel E. Feldstein, Tatiana Kisseleva and Rohit Loomba, all at UC San Diego; Ty D. Troutman, UC San Diego and Cincinnati Children’s Hospital Medical Center, and German Aleman Muench, Yasuyo Sano and Pejman Soroosh, Janssen Research & Development, San Diego.

This study was supported by National Institutes of Health grants to D.D. (R01DK137061, R01DK133930), Altman Clinical and Translational Research Institute (ACTRI — KL2TR001444) and the San Diego Digestive Diseases Research Center (NIH DK120515). It was partially supported by the ACTRI (NIH UL1TR001442). T.K. was supported by NIH grants DK099205, AA028550, DK101737, AA011999, DK120515, AA029019, DK091183; C.K.G by NIH grants DK091183 and HL147835. T.D.T. was supported by NIH grants P30DK063491, T32DK007044, P30DK078392, the American Association for the Study of Liver Diseases (PNC23-216751) and the Center for Inflammation and Tolerance through the Cincinnati Children’s Research Foundation. R.L. received funding support from NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515), NHLBI (P01HL147835), the John C. Martin Foundation (RP124). J.M.O was supported by the Diabetes Research Center (P30DK063491) and Horton JPI MRA: Obesity and its metabolic complications (20175015). A.E.F was supported by the NIH grant R01DK113592. T.V.R was supported by grants from the Swiss National Science Foundation (P2BSP3_200177) and the Larry L. Hillblom Foundation (2023-D-012-FEL).

Since the first recording in July 1924, human electroencephalography (EEG) has been integral to our understanding of brain function and dysfunction: most significantly in the clinical diagnosis of epilepsy, where the analysis of the EEG signal meant that a condition previously seen as a personality disorder was quickly redefined as a disorder of brain activity.

Now, a century on, more than 500 experts from around the globe, have been asked to reflect on the impact of this groundbreaking methodology, as well as on the challenges and priorities for the future.

A survey, led by University of Leeds academics, saw respondents — with 6,685 years of collective experience — presented with possible future developments for EEG, ranging from those deemed ‘critical to progress’ to the ‘highly improbable,’ and asked to estimate how long it might be before they were achieved. The results are published today (22 August 2024) in the journal Nature Human Behaviour.

Futuristic innovations

The list features an array of fascinating, futuristic innovations that experts believe could be achieved within a generation. This includes using EEG to enhance cognitive performance; early detection of learning disabilities; widespread use as a lie detector; and use as a primary communication tool for those with severe motor disabilities and locked-in syndrome.

Real-time, reliable diagnosis of brain abnormalities such as seizures or tumours is believed to be just 10-14 years away, while the probability of reading the content of dreams and long-term memories is judged to be more than 50 years away by some experts, but dismissed by many as closer to science fiction than reality.

It may be surprising to many that, according to the survey published today (22 August) in the journal Nature Human Behaviour, within a generation we could all be carrying around our own, personal, portable, EEG.

The paper’s co-author, Dominik Welke, Research Fellow at the University of Leeds, said: “They could really become something like a smartphone: where almost everybody has access to them and can use them daily — ideally improving their life by providing meaningful insight into physiological factors.”

He added: “One such positive, potential future use of EEG technology could be vigilance control for drivers or pilots. These work-safety systems could assist the user in identifying if they were falling asleep, then wake them up or tell the co-pilot they need to take over.”

The hardware involved in recording EEG is relatively basic, remaining unchanged — in principle — since it was first used by psychiatrist Hans Berger, in Germany, on July 6, 1924. What has drastically changed since then is the analysis of — and what we can do with — the now digitally-recorded data.

Consisting of just electrodes and an amplifier, EEG systems are becoming increasingly cheap to produce, as well as more portable and user-friendly. Coupled with its non-invasive nature, there is little to prevent it from becoming more accessible to a wider audience.

Reducing health inequalities

While the prospect of EEG technology being widely used in gaming and VR — predicted to be only around 20 years away — will thrill gamers, the truly exciting possibility for scientists and clinicians is that this increasing accessibility will allow them to engage with communities traditionally excluded from EEG research, crucially, in low-income countries that cannot afford more complex imaging technology.

Advances in AI-driven automation are also expected to improve and speed up analysis of complicated data.

Dr Welke said: “Looking ahead to the future: from the hardware side, it’s comparatively cheap and easy to produce, and from the analysis and software side, with these new computing technologies, all the puzzle pieces are there to really roll out EEG to a very large user base.

“As opposed to other methods out there — such as MRI, or implanted devices — EEG has the potential to make neuroimaging available to all the people in the world.”

The paper’s lead author, Faisal Mushtaq, Professor of Cognitive Science and the Director of the Centre for Immersive Technologies at the University of Leeds, said: “Nearly all the data we currently have on the human brain comes from a very small segment of the world’s population.

“There is a growing recognition that this is hampering our ability to generalise findings and improve global brain health.

“EEG stands out as the most cost-effective and logistically feasible neuroimaging tool for worldwide use across diverse settings. This would help build a neuroscience that is inclusive and representative of the global population.

He added: “Our partners at the Global Brain Consortium are laying the foundations for increasing reach in this way and I expect this will unlock new opportunities for groundbreaking discoveries on the mechanisms of brain function.”

Ethical questions

Alongside the optimism that emerging technologies are opening exciting new possibilities for EEG, the experts consulted also sounded a note of caution, with concerns that ranged from a lack of adherence to agreed standards and protocols to ethical questions created by novel commercial applications and the lure of ‘neuroenhancement’.

Dr Welke said: “I’m sure some of the multi-national tech companies might be very interested in rolling out EEG or other neuroimaging technology, just to get more information on their users that hints at their preferences and emotions 24 hours a day. But should it be used in this way?

“There are obvious concerns around cognitive freedom and mental privacy. This feeds back into the importance of ‘responsibility’ — the fact that new ways of using a technology are also likely to raise new ethical questions.”

Another objective of the survey was to identify the priorities of the EEG community for guiding future efforts. Participants rated how important major developments and advancements in various domains of EEG research would be to their work.

Professor Mushtaq said: “I think that EEG, when combined with technologies such as AI and virtual reality, could radically transform the ways in which we interact with machines, and in doing so, play an extremely important role in science and society over the next 100 years.

“But to ensure this, the neuroscience community — from academic, clinical and industry settings — must commit to promoting robust, ethical, inclusive, and sustainable practices that will help realise its enormous potential.”

The work was conducted by more than 90 authors, ranging from early career researchers to eminent figures in the field, collectively known as the EEG100 consortium.

It started out as a partnership between #EEGManyLabs — an international network of researchers from more than 30 countries assessing the replicability of the results of some of the most important and influential EEG experiments of psychological phenomena — and the Global Brain Consortium, a diverse network of brain researchers, clinicians and institutions committed to achieving improved and more equitable health outcomes worldwide.

The paper’s last author, Pedro Antonio Valdés-Sosa, Director of China Cuba Laboratory for Neurotechnology at the University of Electronic Science and Technology of China/Cuban Neuroscience Center, said: “In several countries, including Cuba, we have demonstrated that EEG can mass-screen some nervous system disorders at a population level.

“This technology is especially appropriate when resources are limited, as they are in disengaged groups worldwide.

“There are hurdles to overcome to employ EEG at a global scale, but by doing so, we can hopefully improve millions more lives.”

Dr Sadhana Sharma, Head of Bioscience for Health Strategy at the Biotechnology and Biological Sciences Research Council (BBSRC) — which funded the paper’s lead authors — said: “EEG technology has the potential to transform our day-to-day activities and how we diagnose and treat neurological conditions in the future, ensuring that insights into brain health are accessible to diverse populations worldwide.

“As we embrace developments in bioscience, our focus remains on fostering interdisciplinary collaborations that drive ethical, equitable and impactful advancements in brain science on a global scale.”

Although the exact molecule they identified in the worms has not yet been studied in humans, the new work helps scientists better understand the complex crosstalk between the gut and the brain. It also may shed light on why fasting — not eating for set periods of time — has benefits that are independent from the number of calories a person eats. The new study was published in Nature Communicationson August 11, 2024.

“We’ve found for the first time that fasting is conveying information to the brain beyond just caloric withdrawal,” says Scripps Research Professor of Neuroscience Supriya Srinivasan, PhD, the senior author of the new study. “These findings make me wonder whether there are molecules made in the guts of other animals, including mammals, that explain some of the health outcomes associated with fasting.”

Researchers have long known that the brain controls the production and breakdown of fats in humans, other mammals and model organisms such as C. elegans. In 2017, Srinivasan’s group identified FLP-7, a brain hormone that triggers fat burning in the roundworm’s gut. However, C. elegans do not have sensory nerves in their intestines, so scientists have struggled to pin down the reverse communication pathway: How does the gut signal the brain?

“We knew that altering the metabolic state of the gut could change the properties of neurons in the brain, but it was very mysterious how this actually happened,” says Srinivasan.

In the new work, Srinivasan and her colleagues removed more than 100 signaling molecules from C. elegans intestines, one at a time, and measured their impact on the brain’s production of FLP-7. They found one molecule that had a large effect on FLP-7: a form of insulin known as INS-7. In humans, insulin is most known as the hormone produced by the pancreas that control blood sugar levels. But this insulin molecule was instead being made by gut cells and also impacting fat metabolism via the brain.

“When we first found that this was an insulin, we thought it was paradoxical,” recalls Srinivasan. “Insulin is so well studied in mammals, and there was no precedent for an insulin molecule having this role.”

However, when the group probed how INS-7 was impacting FLP-7-producing brain cells, they found that it was not activating insulin receptors — as all previously discovered insulin molecules do — but by blocking the insulin receptor. In turn, this blockade set off a cascade of other molecular events that eventually made the brain cells stop producing FLP-7.

“INS-7 is basically a signal coming from the intestines that tells the brain not to burn any more fat stores right now because there’s no food coming in,” explains Srinivasan.

Studies have previously shown that periods of fasting can influence the body in a variety of ways, but the mechanisms of those changes have been unclear. The new study points toward one way that an empty gut can signal the brain, which could potentially lead to a variety of health impacts beyond fat.

The new results, Srinivasan says, help explain how the brain and digestive system communicate in both directions to control metabolism based on the availability of food. More research is needed to uncover which specific pathways are involved in new gut-to-brain signals in mammals. Compounds that mimic gut hormones — such as semaglutide, commonly known under brand names such as Ozempic, Wegovy and Rybelus — have recently emerged as popular ways to control obesity and diabetes, so new gut peptides could add to this drug class. Srinivasan is also planning experiments to probe how C. elegans gut cells are triggered to produce INS-7 during fasting and which types of brain cells are affected by the molecule.

This work was supported by funding from the National Institutes of Health (R01 DK124706 and R01 AG056648).

“Even in very young children, we found academic readiness was starting to lag behind healthy children their age,” said corresponding author Heather Conklin, PhD, St. Jude Department of Psychology and Biobehavioral Sciences member and Section of Neuropsychology chief. “They were gradually falling behind their same-age peers in academic fundamentals, such as learning their letters, numbers and colors.”

Previous research has focused on school-aged children, but this is one of the first studies to examine academic readiness after brain tumor treatment in infants and young children (less than 3 years old). The scientists uncovered the gap in readiness skills by following a group of 70 patients who had been treated for brain tumors over time. Six months after diagnosis and annually for five years, “we found an increasing gap between these young patients treated for brain tumors and their typically developing peers because their academic readiness skills were not developing as fast,” Conklin said.

Even though the scientists observed gaps between the children’s abilities as they aged, it was present early and had predictive power. “Early academic readiness was predictive of long-term reading and math outcomes,” Conklin said. “The effect isn’t temporary. These children don’t just catch up naturally.”

Intervening early may protect academic readiness and achievement

While presenting a challenge, the findings also offer a strategy to address this problem: early intervention. Since the difference in academic readiness arises early after treatment, intervening then, as opposed to in elementary school (when most conventional interventions begin), may improve outcomes.

“We now know that we don’t need to wait until patients are struggling with math and reading; we can intervene earlier,” Conklin said. “We showed that the variability we’re seeing early on predicts longer-term academic skills, which highly suggests earlier interventions will be beneficial and make a real difference.”

Early interventions need to be informed by what increases vulnerability to or protects against the academic readiness gap to succeed. The researchers looked at the factors involved, such as treatment type and demographics, and found only one characteristic mattered.

Socioeconomic status protects and suggests early interventions may work

“The only clinical or demographic factor we found that predicted academic readiness was socioeconomic status,” Conklin said. “Being from a family of higher socioeconomic status had a protective effect on children’s academic readiness.”

The finding that higher socioeconomic status is partially protective suggests that investing in resources to replace lost early enrichment experiences can mitigate the readiness gap. By increasing access to those replacement opportunities, more children could be protected.

“We know that being away from their home environment, caregivers, daycare, play dates, parks and early intervention services during these critical developmental years is probably having a negative impact on very young patients,” Conklin said. “Our results suggest that families can make play meaningful, and by making little changes in how they interact with their child, with the support of their medical team and receiving appropriate resources, they may be able to make a difference in their child’s cognitive and academic outcomes.”

Authors and funding

The study’s first author is Melanie Somekh, formerly of St. Jude. The study’s other authors are Michelle Swain, Queensland Children’s Hospital; Lana Harder, Children’s Medical Center Dallas; Bonnie Carlson-Green, Children’s Minnesota; Joanna Wallace, Lucile Packard Children’s Hospital Stanford; Ryan Kaner, Rady Children’s Hospital San Diego; Jeanelle S Ali, The Children’s Hospital of Eastern Ontario and Jason Ashford, Jennifer Harman, Catherine Billups, Arzu Onar-Thomas, Thomas Merchant and Amar Gajjar, all of St. Jude.

The study was supported by grants from the National Cancer Institute (St. Jude Cancer Center Support [CORE] Grant (P30 CA21765)) and ALSAC, the fundraising and awareness organization of St. Jude.

Distal myopathy with rimmed vacuoles, or GNE myopathy, is a very rare disease in which muscle atrophy and degeneration occurs in the distal limbs (such as fingers and ankles). Symptoms typically begin from the teens to the early 30s. It gradually leads to a profound loss of motor control. This can greatly affect one’s quality of life as they slowly lose muscle strength, without any approved treatments available.

“Despite there being a demand from patients, developing a treatment to slow down symptom progression has been difficult due to the rarity of the disease,” remarks Masashi Aoki, a professor from Tohoku University, “For example, there are approximately 400 people with GNE myopathy in all of Japan.” A treatment for a population this size is considered an “ultra orphan drug” — because it is not profitable for pharmaceutical companies to develop treatment for such a small group. As a result, these patients are “orphaned” and left without any help.

Despite these hurdles, a team of researchers stepped in to develop a treatment. Patients with GNE myopathy have reduced functioning of an enzyme that produces sialic acid, so patients were given a drug containing aceneuramic acid (a type of sialic acid) to supplement this deficit.

Researchers conducted investigator-initiated phase I and phase II/III studies, and an efficacy confirmation study sponsored by Nobelpharma Co., Ltd. These studies demonstrated the treatment effects of an ultra-orphan drug, “Aceneuramic Acid (Acenobel®) Extended Release Tablets 500mg” for GNE myopathy.

In the current study, 19 patients with GNE myopathy completed a 72-week treatment plan without major adverse effects. These patients originally participated in a 48-week double-blind treatment study to compare the drug to a placebo, and treatment was extended to 72 weeks for this trial. The safety and efficacy of the treatment was confirmed in the current study, leading to Nobelpharma Co., Ltd. obtaining official manufacturing and marketing approval from the Ministry of Health, Labour and Welfare in Japan (March 2024). This approval is great news for patients, who finally have a safe, viable treatment option.

The research team plans to continue monitoring the efficacy of the treatment over even longer periods of time.

The results of the extension study were published online on June 5, 2024 in the Journal of Neurology, Neurosurgery, and Psychiatry.

In a study published today in the Journal of Allergy and Clinical Immunology, a research team from the school of biomedical engineering (SBME) has identified a specific cascade of events that lead to allergies and asthma. In doing so, they have opened many new avenues for exploring potential preventions and treatments.

“Our research finally shows how the gut bacteria and antibiotics shape a newborn’s immune system to make them more prone to allergies,” said senior author Dr. Kelly McNagny (he/him), professor in the SBME and the department of medical genetics. “When you see something like this, it really changes the way you think about chronic disease. This is a well-sculpted pathway that can have lasting consequences on susceptibility to chronic disease as an adult.”

Allergies are a result of the immune system reacting too strongly to harmless substances like pollen or pet dander, and a leading cause for emergency room visits in kids. Normally, the immune system protects us from harmful invaders like bacteria, viruses and parasites. In the case of allergies, it mistakes something harmless for a threat — in this case, parasites — and triggers a response that causes symptoms like sneezing, itching or swelling.

The stage for our immune system’s development is set very early in life. Research over the past two decades has pointed toward microbes in the infant gut playing a key role. Babies often receive antibiotics shortly after birth to combat infections, and these can diminish certain bacteria. Some of those bacteria produce a compound called butyrate, which is key to halting the processes uncovered in this research.

Dr. McNagny’s lab had previously shown that infants with fewer butyrate-producing bacteria become particularly susceptible to allergies. They had also shown that this could be mitigated or even reversed by providing butyrate as a supplement in early life.

Now, by studying the process in mice, they have discovered how this works.

Mice with depleted gut bacteria who received no butyrate supplement developed twice as many of a certain type of immune cell called ILC2s. These cells, discovered less than 15 years ago, have quickly become prime suspects in allergy development. The researchers showed that ILC2s produce molecules that ‘flip a switch’ on white blood cells to make them produce an abundance of certain kinds of antibodies. These antibodies then coat cells as a defence against foreign invaders, giving the allergic person an immune system that is ready to attack at the slightest provocation.

Every cell, molecule and antibody described along this cascade increases dramatically in number without butyrate to dampen them.

Butyrate must be given during a narrow window after birth — a few months for humans, a few weeks for mice — in order to prevent the proliferation of ILC2s and all that follows. If that opportunity is missed and ILC2s multiply, then the remaining steps are assured and remain with somebody for life.

Now that researchers know what those other steps are, they have many more potential targets for halting the cascade, even after the supplementation window has closed.

“We can now detect when a patient is on the verge of developing lifelong allergies, simply by the increase in ILC2s,” said Ahmed Kabil (he/him), the study’s first author and a PhD candidate in the SBME. “And we can potentially target those cell types instead of relying on supplementation with butyrate, which only works early in life.”

As Dr. McNagny and study co-lead Dr. Michael Hughes point out, treating people’s allergies with antihistamines and inhalers relieves the symptoms but does not cure the disease. To achieve more lasting progress, researchers must target the cells and mechanisms that build this hypersensitive immune system. Until now, there hadn’t been a selective way to do that.

With this new understanding, patients can look forward to more effective, long-term solutions that address the root of the problem, paving the way for a future where allergies are managed more effectively, or perhaps avoided altogether.

Not that experts haven’t tried.

Sleep analysis, also known as polysomnography, is used to diagnose sleep disorders by recording multiple types of data, including brain (electroencephalogram or EEG) and heart (electrocardiogram or ECG). Typically, patients are hooked up to dozens of sensors and wires in a clinic, tracking brain, eye, muscle, breathing, and heart activity while sleeping. Not exactly Zzz-inducing.

But what if you could perform the same test at home, just as accurately and in real time?

For the first time, computer science researchers at the University of Southern California have developed an approach that matches the performance of expert-scored polysomnography using just a single-lead echocardiogram. The software, which is open-source, allows anyone with basic coding experience to create their own low-cost, DIY sleep-tracking device.

“Researchers have been trying for decades to find simpler and cheaper methods to monitor sleep‚ especially without the awkward cap,” said lead author Adam Jones, who recently earned his PhD from USC. “But so far, the poor performance, even in ideal conditions, has led to the conclusion that it won’t be possible and that measuring brain activity is necessary. Our research shows that this assumption is no longer true.”

The model, which assesses sleep stages at the highest level, also significantly outperformed other EEG-less models, said the researchers, including commercial sleep-tracking devices. “We wanted to develop a system that addresses the limitations of current methods and the need for more accessibility and affordability in sleep analysis,” said Jones.

The study, published June 2024 in the journal Computers in Biology and Medicine, was co-authored by Laurent Itti, a professor of computer science and Jones’ advisor, and Jones’ longtime collaborator, Bhavin R. Sheth, a USC alumnus and electrical engineer at the University of Houston.

Could the heart be leading the band?

Sleep, a key cognitive decline predictor, becomes shorter and more fragmented with age — a finding validated by both previous studies and the researchers’ neural network. But this decline happens earlier than you might expect. A recent study in Neurology found that people who have more interrupted sleep in their 30s and 40s are more than twice as likely to have memory problems a decade later.

Chronic poor sleep can also contribute to the accumulation of beta-amyloid plaques, a hallmark of Alzheimer’s disease.

“It’s a little scary,” said Jones, who admits he was formerly in the “sleep when I’m dead” camp before embarking on this research as a hobby project in 2010. “That’s why I want these interventions to come quickly and to make them accessible to as many people as possible. This software could help tease apart what’s happening when we sleep every night.”

The researchers trained their model on a large, diverse dataset of 4,000 recordings from subjects ranging from 5 to 90 years old, using only heart data and a deep-learning neural network. Through trial and error, spanning hundreds of iterations, they found that the automated ECG-only network could score sleep just as well as the “gold standard” polysomnography. It successfully categorized sleep into all five stages, including rapid eye movement (REM), which is essential for memory consolidation and emotional stability, and non-REM sleep, including deep sleep, which is crucial for physical and mental restoration.

In addition to simplifying a typically expensive and cumbersome process, this insight highlights a deeper connection between the heart and the brain than previously understood. It also underscores the role of the autonomic nervous system, which links the brain and heart.

“The heart and the brain are connected in ways that are not well-understood, and this research aims to bridge that gap,” said Jones. “There is a lot of evidence in my paper that, in fact, the heart may be leading the band, as it were.”

The work could also help improve sleep studies in remote populations, helping to shed light on the origins and functions of sleep.

In a follow-up paper currently being prepared, Jones aims to explore further what the network focuses on in the ECG data. “I think there is a lot of information hidden in the heart that we don’t know about yet,” he said.

The researchers will present their results at the fall meeting of the American Chemical Society (ACS).

AI’s vast number of uses has made it almost ubiquitous in today’s technological landscape. However, many AI models are black boxes, meaning it’s not clear exactly what steps are taken to produce a result. And when that result is something like a potential drug molecule, not understanding the steps might stir up skepticism with scientists and the public alike. “As scientists, we like justification,” explains Rebecca Davis, a chemistry professor at the University of Manitoba. “If we can come up with models that help provide some insight into how AI makes its decisions, it could potentially make scientists more comfortable with these methodologies.”

One way to provide that justification is with XAI. These machine learning algorithms can help us see behind the scenes of AI decision making. Though XAI can be applied in a variety of contexts, Davis’ research focuses on applying it to AI models for drug discovery, such as those used to predict new antibiotic candidates. Considering that thousands of candidate molecules can be screened and rejected to approve just one new drug — and antibiotic resistance is a continuous threat to the efficacy of existing drugs — accurate and efficient prediction models are critical. “I want to use XAI to better understand what information we need to teach computers chemistry,” says Hunter Sturm, a graduate student in chemistry in Davis’ lab who’s presenting the work at the meeting.

The researchers started their work by feeding databases of known drug molecules into an AI model that would predict whether a compound would have a biological effect. Then, they used an XAI model developed by collaborator Pascal Friederich at Germany’s Karlsruhe Institute of Technology to examine the specific parts of the drug molecules that led to the model’s prediction. This helped explain why a particular molecule had activity or not, according to the model, and that helped Davis and Sturm understand what an AI model might deem important and how it creates categories once it has examined many different compounds.

The researchers realized that XAI can see things that humans might have missed; it can consider far more variables and data points at once than a human brain. For example, when screening a set of penicillin molecules, the XAI found something interesting. “Many chemists think of penicillin’s core as the critical site for antibiotic activity,” says Davis. “But that’s not what the XAI saw.” Instead, it identified structures attached to that core as the critical factor in its classification, not the core itself. “This might be why some penicillin derivatives with that core show poor biological activity,” explains Davis.

In addition to identifying important molecular structures, the researchers hope to use XAI to improve predictive AI models. “XAI shows us what computer algorithms define as important for antibiotic activity,” explains Sturm. “We can then use this information to train an AI model on what it’s supposed to be looking for,” Davis adds.

Next, the team will partner with a microbiology lab to synthesize and test some of the compounds the improved AI models predict would work as antibiotics. Ultimately, they hope XAI will help chemists create better, or perhaps entirely different, antibiotic compounds, which could help stem the tide of antibiotic-resistant pathogens.

“AI causes a lot of distrust and uncertainty in people. But if we can ask AI to explain what it’s doing, there’s a greater likelihood that this technology will be accepted,” says Davis.

Sturm adds that he thinks AI applications in chemistry and drug discovery represent the future of the field. “Someone needs to lay the foundation. That’s what I hope I’m doing.”

The research was funded by the University of Manitoba, the Canadian Institutes of Health Research and the Digital Research Alliance of Canada.

The study examined genes that cause inborn errors of metabolism (disorders of the processes that cells use to convert food to energy) and inborn errors of immunity (disorders that affect immune system function). These rare and complex diseases are not fully understood.

“There had previously been only a small number of genes that were on both lists of diseases, but we found that many more have overlap,” said Andrew Patterson, PhD, who led the study as a postdoctoral fellow working with Jeffrey Rathmell, PhD, at Vanderbilt University Medical Center. “Our study showed that a large number of genes associated with inborn errors of metabolism can also potentially affect T cell function when they are mutated.”

The findings suggest that patients with an inborn error of metabolism may also have immune defects that could impact their care, and conversely that metabolic defects may contribute to symptoms in patients with inborn errors of immunity.

“There’s a lot more that will have to be learned, but these connections might point to different therapies,” said Rathmell, Cornelius Vanderbilt Professor of Immunobiology and director of the Vanderbilt Center for Immunobiology. “Rather than different categories, these diseases are part of a continuum; there’s a gray zone between them and a potential new class of inborn errors of immunometabolism that intersects the two.”

Patterson and the research team used a gene-editing CRISPR approach to screen the inborn errors of metabolism genes for immune defects and the inborn errors of immunity genes for metabolic defects. They further analyzed one example from each set — one metabolic gene that had an immune defect; one immunity gene that had a metabolic defect — to more carefully examine the mechanistic impact.

Overall, Rathmell’s team is interested in discovering how metabolic pathways regulate T cell function, with the goal of developing targeted therapies for immune-mediated disorders.

“What we’ve done is lay the foundation for further investigation,” Patterson said. “The two examples we studied in detail point to new biology and new mechanisms, and there are hundreds of other genes we identified to analyze for their roles in T cell function.”

The findings are available on the Functional ImmunoGenomices reSource (FIGS) website for other researchers to use.

“If you’re trying to understand the connections between metabolism and immunity, this is a great place to start,” Rathmell said.

Patterson recently joined the faculty of the University of Louisville as an assistant professor of Biochemistry and Molecular Genetics. Vanderbilt collaborators Vivian Gama, PhD, associate professor of Cell and Developmental Biology, and Janet Markle, PhD, assistant professor of Pathology, Microbiology and Immunology, were important contributors to the study.

In a study just published in Parkinsonism and Related Disorders, a team of researchers from the University of Florida and the Fixel Institute for Neurological Diseases shows that video assessment can help detect early Parkinsonism in an individual by comparing the movement of the left and right sides of their body. The approach, researchers say, exploits the fact that Parkinson’s disease usually starts asymmetrically, meaning one side is more affected than the other in early stages of the disease.

Researchers applied machine learning to analyze videos of individuals performing simple movements with their hands and legs that are commonly used by neurologists. The team looked for subtle differences between healthy individuals and those with early Parkinson’s disease. Their approach achieved 86% accuracy in distinguishing between the two groups.

“The technique is non-invasive, uses standard video recordings, and could potentially help in detecting signs of Parkinsonism earlier, improving treatment outcomes and patient management,” said lead author Deigo Guarin, an assistant professor of applied physiology and kinesiology at UF.

The two students met during a summer engineering program and quickly bonded over their shared aspirations in sports and ophthalmology. This friendship led them to Dr. Andrew G. Lee, Chair of the Department of Ophthalmology at the Blanton Eye Institute, Houston Methodist Hospital. Under Lee’s mentorship, Memon and Panzo immersed themselves in a novel project aimed at refining the skills of NFL officials through neuro-ophthalmologic training.

Their efforts have already produced results, with two significant articles published and more to come. The first study, featured in the Journal of Neuro-Ophthalmology, presents a specially designed curriculum on neuro-ophthalmologic principles tailored for NFL officials. The results were promising, showing a statistically significant improvement in officials’ knowledge after training. This suggests a positive reception and willingness among NFL officials to incorporate these principles into their decision-making processes on the field.

The second manuscript, published in Vision, provides a comprehensive overview of existing research on neuro-ophthalmology and its application in NFL officiating. The study offers innovative recommendations on how officials can use 2D game data to create 3D simulations, thereby enhancing their training and on-field performance. In addition, the team has created weekly quiz questions that test officials’ understanding of neuro-ophthalmology principles in relation to game play.

A memorable highlight was watching the Houston Texans clinch a 21-16 victory over the Arizona Cardinals in November 2023, all while analyzing the practical application of neuro-ophthalmologic training by NFL officials during the game.

The innovative initiative showcases the versatility and interdisciplinary skills of ENMED students. It also demonstrates the potential for medical principles to improve sports officiating. Memon and Panzo have set a new standard for integrating medical and engineering knowledge in sports, offering a promising future where science and athletics can collaborate to ensure precision and fairness.

The team would like to acknowledge Walt Anderson, former NFL SVP of Officiating Training and Development, for his invaluable insights and support on this project. Anderson currently serves as the NFL Rules and Officiating Analyst.

These compounds are essential in the pharmaceutical industry but have been challenging to synthesize with the required stereochemical accuracy. The innovative reagent t-BuSF uses strain-release reactivity to achieve a level of efficiency and selectivity previously unattainable, paving the way for more effective drug development and broader applications in medical research.

“Sulfur-based compounds, including those developed using the new methods, are known to have favorable physiochemical properties that make them ideal candidates for drug development,” said Justin M. Lopchuk, Ph.D., lead author and associate member of the Drug Discovery Department at Moffitt. “The ability to synthesize these compounds rapidly and stereochemical control open new possibilities for designing targeted therapies that combat cancer cells more effectively while minimizing side effects.”

By leveraging the unique properties of the t-BuSF reagent, researchers were able to explore previously inaccessible chemical space within the sulfur family, particularly in the S(IV) and S(VI) oxidation states. This advancement has resulted in the creation of over 70 new chemical compounds, many of which have immediate applications in medicinal chemistry and the development of new pharmaceutical agents.

Lopchuk adds that this research has already been used to significantly improve the scalable synthesis of DFV890, an investigational compound from Novartis currently in clinical trials at Moffitt and other locations for myeloid diseases.

The new battery, which is 0.1 millimeters long and 0.002 millimeters thick — roughly the thickness of a human hair — can capture oxygen from air and use it to oxidize zinc, creating a current with a potential of up to 1 volt. That is enough to power a small circuit, sensor, or actuator, the researchers showed.

“We think this is going to be very enabling for robotics,” says Michael Strano, the Carbon P. Dubbs Professor of Chemical Engineering at MIT and the senior author of the study. “We’re building robotic functions onto the battery and starting to put these components together into devices.”

Ge Zhang PhD ’22 and Sungyun Yang, an MIT graduate student, are the lead author of the paper, which appears in Science Robotics.

Powered by batteries

For several years, Strano’s lab has been working on tiny robots that can sense and respond to stimuli in their environment. One of the major challenges in developing such tiny robots is making sure that they have enough power.

Other researchers have shown that they can power microscale devices using solar power, but the limitation to that approach is that the robots must have a laser or another light source pointed at them at all times. Such devices are known as “marionettes” because they are controlled by an external power source. Putting a power source such as a battery inside these tiny devices could free them to roam much farther.

“The marionette systems don’t really need a battery because they’re getting all the energy they need from outside,” Strano says. “But if you want a small robot to be able to get into spaces that you couldn’t access otherwise, it needs to have a greater level of autonomy. A battery is essential for something that’s not going to be tethered to the outside world.”

To create robots that could become more autonomous, Strano’s lab decided to use a type of battery known as a zinc-air battery. These batteries, which have a longer lifespan than many other types of batteries due to their high energy density, are often used in hearing aids.

The battery that they designed consists of a zinc electrode connected to a platinum electrode, embedded into a strip of a polymer called SU-8, which is commonly used for microelectronics. When these electrodes interact with oxygen molecules from the air, the zinc becomes oxidized and releases electrons that flow to the platinum electrode, creating a current.

In this study, the researchers showed that this battery could provide enough energy to power an actuator — in this case, a robotic arm that can be raised and lowered. The battery could also power a memristor, an electrical component that can store memories of events by changing its electrical resistance, and a clock circuit, which allows robotic devices to keep track of time.

The battery also provides enough power to run two different types of sensors that change their electrical resistance when they encounter chemicals in the environment. One of the sensors is made from atomically thin molybdenum disulfide and the other from carbon nanotubes.

“We’re making the basic building blocks in order to build up functions at the cellular level,” Strano says.

Robotic swarms

In this study, the researchers used a wire to connect their battery to an external device, but in future work they plan to build robots in which the battery is incorporated into a device.

“This is going to form the core of a lot of our robotic efforts,” Strano says. “You can build a robot around an energy source, sort of like you can build an electric car around the battery.”

One of those efforts revolves around designing tiny robots that could be injected into the human body, where they could seek out a target site and then release a drug such as insulin. For use in the human body, the researchers envision that the devices would be made of biocompatible materials that would break apart once they were no longer needed.

The researchers are also working on increasing the voltage of the battery, which may enable additional applications.

The research was funded by the U.S. Army Research Office, the U.S. Department of Energy, the National Science Foundation, and a MathWorks Engineering Fellowship.

The percentage of people who get a new dementia diagnosis each year varies a lot across regions of the U.S., the study finds.

And the differences between regions of the country are even larger for people on the young end of the dementia-risk age range, ages 66 to 74, and for those who are Black or Hispanic.

In fact, the same person would have as much as twice the chance of getting a dementia diagnosis in some areas of the U.S. as in others, the study shows. The findings suggest that the chance of being diagnosed may be more about the health system than about individual factors that affect dementia risk.

A formal diagnosis is required for access to advanced new tests and treatments for dementia. Many of them aim to slow down the progression of dementia in its earliest stages, called mild cognitive impairment or mild Alzheimer’s disease.

The new study focuses on regional differences in “diagnostic intensity” of dementia — the kind of difference that exists even after all kinds of dementia risk factors and regional differences in population and health care are taken into account.

Performed by a team based at the University of Michigan, it’s published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

“These findings go beyond demographic and population-level differences in risk, and indicate that there are health system-level differences that could be targeted and remediated,” said Julie Bynum, M.D., M.P.H., the U-M Health geriatrician and health care researcher who led the study.

“The message is clear: from place to place the likelihood of getting your dementia diagnosed varies, and that may happen because of everything from practice norms for health care providers to individual patients’ knowledge and care-seeking behavior,” said Bynum, a professor of internal medicine at the U-M Medical School. “But the good news is, these are things we can act on once we know where to look.”

Bynum and her colleagues at U-M and the Dartmouth College Geisel School of Medicine did the study using data from the records of 4.8 million people who were covered by traditional Medicare and over the age of 66 in 2019.

They note that while nearly 7 million Americans currently have a diagnosis of dementia, millions more likely have symptoms but no formal diagnosis.

Insurance coverage for new biomarker tests, brain imaging scans and dementia-slowing medications depends on diagnosis. But even for those who don’t qualify for these, a confirmed diagnosis can be important for accessing specialized care and support for patients and their family members or friends who act as caregivers.

Going beyond risk factors: More about the study

Researchers have already found many factors that are linked to an individual’s higher risk of developing Alzheimer’s disease and other forms of dementia. These include years of high blood pressure, high cholesterol and tobacco or alcohol use, to lower levels of formal education, sleep and social interaction.

But the new study shows for the first time that the differences in diagnosis by region aren’t explained by differences in the dementia risk level of different populations.

It looked at diagnoses within each of 306 hospital referral regions developed for the Dartmouth Atlas of Health Care and used in many studies. Each HRR includes at least one hospital capable of doing advanced heart surgery and brain surgery; the researchers chose to use these regions because dementia diagnosis and advanced treatment also requires specialized services.

In all, 143,029 of the people in the total population used in the study were newly diagnosed with Alzheimer’s or another form of dementia in 2019. The rest of the 356,656 people who had that diagnosis in this population had been diagnosed before 2019.

That means that overall, about 7% of people covered by traditional Medicare have a dementia diagnosis at any given time, and 3% of this population is diagnosed each year, with an average age at diagnosis of about 83 years.

The researchers then calculated the regional rates of new diagnoses and total diagnosed individuals as of 2019 for each HRR. The prevalence of diagnosed dementia ranged from as low as 4% to as high as 14% depending on HRR, and the rate of new dementia diagnoses in 2019 ranged from 1.7% to 5.4%.

They then looked at rates for three age groups — 66 to 74, 75 to 84 and 85 and over — and for people identified as white, Black or Hispanic. They also included data about the percentage of the population in each HRR that had less than a high school education, that smoked, and that had obesity or diabetes — all risk factors for dementia.

They also incorporated information about the general intensity of all kinds of chronic disease diagnosis in each HRR.

By taking all these factors into account, the researchers were able to calculate a predicted rate of diagnosis for new and total Alzheimer’s and dementia cases for each HRR, and for individuals in each HRR. This is what they called diagnostic intensity.

Compared to the national average, people residing areas of the lowest-intensity are 28% less likely to be diagnosed, whereas those residing in areas of the highest-intensity are 36% more likely to be diagnosed.

The general concentration of diagnosed dementia cases was highest in the southern U.S., similar to the “stroke belt” of high risk for stroke and cardiovascular disease.

But the South was no longer a uniform hotbed of dementia diagnosis once the researchers adjusted for the other factors.

Implications for regional change

Bynum explains that the findings could reflect variations in clinical practices — for example, how often people are screened by their primary care physicians for early signs of dementia, or the availability of specialists to make a confirmed diagnosis.

Variation could also stem from cultural or personal differences in how likely a person is to seek care of any kind, to schedule an appointment specifically because of memory concerns, or to mention problems with memory or thinking proactively to a health care provider without being prompted during an existing appointment.

While the researchers can’t say for certain if the variation reflects underdiagnosis or overdiagnosis, they do say that the areas with lower-than-expected diagnosis rates for dementia could use the new findings to look at what barriers might stand in the way of someone getting diagnosed.

“The goal these days should be to identify people with cognitive issues earlier, yet our data show the younger age group of Medicare participants is the one with the most variation,” Bynum said. “For communities and health systems, this should be a call to action for spreading knowledge and increasing efforts to make services available to people. And for individuals, the message is that you may need to advocate for yourself to get what you need, including cognitive checks.”

She adds that Medicare covers a cognitive screening during each enrollee’s annual wellness visit.

She also notes that the recent launch of Medicare’s GUIDE model for dementia care may offer a path to improving care. The model incentivizes clinical practices to coordinate dementia care better and offer around-the-clock access to a trained provider.

In addition to Bynum, the study’s authors are Slim Benloucif and Jonathan Martindale of the U-M Department of Internal Medicine, A. James O’Malley of Dartmouth College and Matthew A. Davis, Ph.D., of the U-M School of Nursing and the U-M Medical School’s Department of Learning Health Sciences.

Bynum and Davis are members of the U-M Institute for Healthcare Policy and Innovation, and leaders of the Center to Accelerate Population Research in Alzheimer’s or CAPRA.

The study was funded by the National Institute on Aging of the National Institutes of Health (P01AG019783).

Full details about the diagnostic intensity rate and other data for each HRR will be available on the CAPRA website and at https://michmed.org/38XeZ .

In a new study published Aug. 15 in Science, Yale researchers identified how brain cells begin to coalesce into this wired network in early development before experience has a chance to shape the brain. It turns out that very early development follows the same rules as later development — cells that fire together wire together. But rather than experience being the driving force, it’s spontaneous cellular activity.

“One of the fundamental questions we are pursuing is how the brain gets wired during development,” said Michael Crair, co-senior author of the study and the William Ziegler III Professor of Neuroscience at Yale School of Medicine. “What are the rules and mechanisms that govern brain wiring? These findings help answer that question.”

For the study, researchers focused on mouse retinal ganglion cells, which project from the retina to a region of the brain called the superior colliculus where they connect to downstream target neurons. The researchers simultaneously measured the activity of a single retinal ganglion cell, the anatomical changes that occurred in that cell during development, and the activity of surrounding cells in awake neonatal mice whose eyes had not yet opened. This technically complex experiment was made possible by advanced microscopy techniques and fluorescent proteins that indicate cell activity and anatomical changes.

Previous research has shown that before sensory experience can take place — for instance, when humans are in the womb or, in the days before young mice open their eyes — spontaneously generated neuronal activity correlates and forms waves. In the new study, researchers found that when the activity of a single retinal ganglion cell was highly synchronized with waves of spontaneous activity in surrounding cells, the single cell’s axon — the part of the cell that connects to other cells — grew new branches. When the activity was poorly synchronized, axon branches were instead eliminated.

“That tells us that when these cells fire together, associations are strengthened,” said Liang Liang, co-senior author of the study and an assistant professor of neuroscience at Yale School of Medicine. “The branching of axons allows more connections to be made between the retinal ganglion cell and the neurons sharing the synchronized activity in the superior colliculus circuit.”

This finding follows what’s known as “Hebb’s rule,” an idea put forward by psychologist Donald Hebb in 1949; at that time Hebb proposed that when one cell repeatedly causes another cell to fire, the connections between the two are strengthened.

“Hebb’s rule is applied quite a lot in psychology to explain the brain basis of learning,” said Crair, who is also the vice provost for research and a professor of ophthalmology and visual science. “Here we show that it also applies during early brain development with subcellular precision.”

In the new study, the researchers were also able to determine where on the cell branch formation was most likely to occur, a pattern that was disrupted when the researchers disturbed synchronization between the cell and the spontaneous waves.

Spontaneous activity occurs during development in several other neural circuits, including in the spinal cord, hippocampus, and cochlea. While the specific pattern of cellular activity would be different in each of those areas, similar rules may govern how cellular wiring takes place in those circuits, said Crair.

Going forward, the researchers will explore whether these patterns of axon branching persist after a mouse’s eyes open and what happens to the downstream connected neuron when a new axon branch forms.

“The Crair and Liang labs will continue to combine our expertise in brain development and single-cell imaging to examine how the assembly and refinement of brain circuits is guided by precise patterns of neural activity at different developmental stages,” said Liang.

The research was supported in part by the Kavli Institute of Neuroscience at Yale School of Medicine.

Beyond the biggest sources of each dietary category — cheese for saturated fat and soft drinks for added sugar — the study identifies a longer list of popular sources that helps explain why it’s so hard to limit fat and sugar to the recommended 10% of daily calories. With that overconsumption of unexpected sources like chicken and ketchup, for example, comes a risk for a variety of ailments, such as cardiovascular disease, diabetes and cancer.

The analysis of data on over 35,000 U.S. adults is part of a project aimed at developing a research tool that can streamline assessment of these dietary downsides. But the work also may open consumers’ eyes to the unexpected sources of fat and sugar that add up over the course of a day — and perhaps convince shoppers to read labels to see where these hidden sources are, researchers say.

“Chicken breast is promoted as a lower saturated fat food, but it still has a little bit of saturated fat. But it is helpful to know how foods with smaller amounts also slowly add saturated fat in a stealthy way into the diet,” said first author Christopher Taylor, professor and director of medical dietetics in the School of Health and Rehabilitation Sciences at The Ohio State University.

“Being able to meet less than 10% is to identify the big contributors, but also to be able to see where saturated fat and added sugar may still exist in other food choices. It doesn’t make them poor choices — it’s about being aware of how the morning latte may be contributing.”

And then there’s the abundance of added sugar, which raises a public health policy concern, said lead author Susan Schembre, associate professor of oncology at Georgetown University’s Lombardi Comprehensive Cancer Center.

“It’s everywhere. It’s in so many unexpected foods, and often in surprising amounts,” she said.

The study was published recently in the journal Nutrients.

Researchers analyzed data from 36,378 U.S. adults aged 19 and older who had participated from 2005 to 2018 in the National Health and Nutrition Examination Survey. The survey collects 24-hour dietary recalls from each participant — detailing not just what, but when, all food and drinks were consumed over the previous two days.

Overall, the top sources of saturated fat were cheese, pizza, ice cream and eggs. Leading sources of added sugar were soft drinks, tea, fruit drinks, and cakes and pies. Based on the USDA “What We Eat in America” food list, other categories contributing to saturated fat intake include cold cuts, cream substitutes, fried potatoes and whole milk. Categories with added sugar include tomato-based condiments, cereal bars, energy drinks and yeast breads.

The research team also examined differences in the top sources of saturated fat and added sugar in a range of race/ethnicity subpopulations and age groups, an important detail when assessing diets to develop more personalized health interventions, Schembre said.

“Before you understand what you can intervene on, you have to know what people are consuming,” she said.

The team is creating an app for targeted assessment of “nutrients of concern,” and demonstrated that this analytic method produced a representative list of foods behind most saturated fat and added sugar intake. NHANES data is key to understanding nutrition in the United States, but for disease interventions, getting at the problem food and drink sources of fat, added sugar and, still to come, sodium, is more efficient and effective.

Unsurprisingly, the results of this analysis showed that overall, saturated fat constituted at least 12% of a day’s calories, and added sugar consumption ranged from 14% to 16% of calories. Generally, dietary recommendations focus on avoiding the major contributors, like pizza and ice cream — which is what makes this longer list valuable and, for some, eye-opening, Taylor said.

“There are the foods that are higher in saturated fat and added sugar that are consumed frequently, and they get targeted, but there’s also that smaller cumulative effect of things that are generally perceived as healthy, but they’re all contributing just a little bit,” he said. “And then when you top it off with some of those higher sources, it ends up taking you over the threshold for that 10% of the day’s calories.

“We’re trying to hit the sweet spot of capturing the big front-seat items, but also understanding those things that are stealthy contributors.”

This research was supported by the National Cancer Institute.

Additional co-authors were Peter Madril of Ohio State; Cynthia Thompson, Kelli Richardson and Edward Bedrick of the University of Arizona; Genevieve Dunton of the University of Southern California; Michelle Jospe of Georgetown Lombardi Comprehensive Cancer Center; and Rick Weiss of Viocare Inc.

In the study, 241 participants with severe brain injury who do not respond when given a simple instruction were assessed with functional MRI (fMRI), electroencephalography (EEG), or both tests. During these tests, participants heard instructions, such as “imagine opening and closing your hand” followed, 15-30 seconds later by “stop imagining opening and closing your hand.” The fMRI and EEG brain responses showed that 60 (25 percent) of participants repeatedly followed this instruction covertly over minutes. According to the authors of the study, published August 15 in the New England Journal of Medicine, patients who demonstrate this phenomenon, called cognitive motor dissociation, understand language, remember instructions and can sustain attention, even though they appear unresponsive. For these patients, cognitive (i.e., thinking) abilities exceed, and are therefore dissociated from, motor abilities.

“Some patients with severe brain injury do not appear to be processing their external world. However, when they are assessed with advanced techniques such as task-based fMRI and EEG, we can detect brain activity that suggests otherwise,” said lead study author Yelena Bodien, PhD, an investigator for the Spaulding-Harvard Traumatic Brain Injury Model Systems and Massachusetts General Hospital’s Center for Neurotechnology and Neurorecovery. “These results bring up critical ethical, clinical, and scientific questions — such as how can we harness that unseen cognitive capacity to establish a system of communication and promote further recovery?”

Following a significant brain injury, individuals may have a disorder of consciousness, which can include coma, a vegetative state or minimally conscious state. Since the first study demonstrating cognitive motor dissociation in individuals with disorders of consciousness was published nearly two decades ago, centers around the world have found that this condition occurs in approximately 15 to 20 percent of unresponsive patients. However, the current study suggests it could be present in 25 percent of patients, or even more. Cognitive motor dissociation was most common in participants assessed with fMRI and EEG, suggesting that multiple tests, using different approaches, may be required to ensure consciousness is not missed.

This study included participant data from six different sites spanning the United States, United Kingdom, and Europe collected over approximately 15 years. Each site developed and rigorously tested their methods for detecting cognitive motor dissociation to minimize the possibility that a positive result was obtained spuriously. Some sites recruited participants from the intensive care unit just days after they sustained a severe brain injury, often from a trauma such as a car accident, a stroke or cardiac arrest. Other sites included participants who were months to years after their injury or illness and were living in nursing facilities or at home.

In addition to studying the 241 participants who did not respond to simple instructions, the research included 112 participants who did respond to simple instructions at the bedside. This latter group would be expected to perform well on the fMRI and EEG tests, but, in 62 percent of those participants, researchers did not detect brain responses suggesting they were covertly following instructions. The authors note that this finding may reflect the complexity of the fMRI and EEG tasks and underscores the high-level of thinking skills required to perform them.

Just knowing that somebody is cognitively aware and more capable than is immediately apparent, can alter their clinical care substantially. “Families have told us that once a positive test result revealing cognitive motor dissociation is shared with the patients’ clinical team, it can change the way that the team interacts with their loved one,” Bodien said. “Suddenly, the team is paying more attention to subtle behavioral signs that could be under volitional control, or speaking to the patient, or playing music in the room. On the other hand, failing to detect cognitive motor dissociation can have serious consequences, including premature withdrawal of life support, missed signs of awareness, and lack of access to intensive rehabilitation.”

“We find that this kind of sharp dissociation of retained cognitive capabilities and no behavioral evidence of them is not uncommon. I think we now have an ethical obligation to engage with these patients, to try to help them connect to the world,” said senior study author Nicholas Schiff, MD, the Jerold B. Katz Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine and administrative lead of the consortium. “What we need here is what we in our consortium have been trying to get started for twenty years: a sustained effort to benefit patients who have disorders of consciousness with systematic medical research, technology development, and better clinical infrastructure.

One limitation of the study was that the testing was not standardized; each of the study sites tested patients in their own way, creating variability within the data. In addition, many participants were enrolled because family members heard about the study and reached out to researchers. This recruitment approach limits the researchers’ ability to determine the global prevalence of cognitive motor dissociation. There are no professional guidelines that stipulate how cognitive motor dissociation should be assessed and most centers are unable to provide this testing; clinical translation will need to be a focal point for future research.

“To continue our progress in this field, we need to validate our tools and to develop approaches for systematically and pragmatically assessing unresponsive patients so that the testing is more accessible,” said Bodien. “The Emerging Consciousness Program at Mass General Hospital offers these evaluations clinically, however elsewhere, a patient may have to enroll in a research study to get tested. We know that cognitive motor dissociation is not uncommon, but resources and infrastructure are required to optimize detection of this condition and provide adequate support to patients and their families.”

The researchers added that the findings may spur research of specific interventions to foster effective communication, including brain-computer interfaces.

However, this was not the case when people’s friends overtly derogated others. The real benefits of venting, the researchers conclude, are the strengthening of bonds that might pay off in the future — and the improved health and happiness enjoyed by people who are well liked by their friends.

“Since the 1950s, we’ve known the Freudian catharsis explanation for venting is wrong. It can feel good to vent, but venting doesn’t reliably decrease anger and sometimes even amplifies anger,” said lead author Jaimie Krems, an associate professor of psychology at UCLA. “We didn’t have a good explanation for what venting does for us. So we tested a novel alliance view of venting — that under certain parameters, venting can make the people we vent to support us over the people we vent about.”

Most research on close relationships has focused on romantic partnerships. Yet, especially for younger people, friendship plays some of the roles that have traditionally been found in romantic relationships; the U.S. surgeon general has also talked about the “loneliness epidemic.” There is a need to better understand friendship, researchers say, including how people might ‘compete’ to make their friends like them better than other friends.

“As much as people readily admit that we compete for romantic partners’ finite time and affection, people seem less willing to admit to competing for friends,” Krems said. “But if being relatively better liked means getting better support from friends, then we should expect some friend competition, whether or not we like that it exists.”

In a paper published in Evolution and Human Behavior, Krems and colleagues at Oklahoma State University and Hamilton College asked participants to listen to a friend vent or gossip about or derogate a mutual friend. Although the vignettes varied across experiments, those venting typically began by telling participants, “I’m so frustrated and hurt right now…” before venting about a mutual friend canceling on them at the last minute.

In the derogation condition, this same complaint was prefaced with: “I’m so frustrated and angry right now…” In other conditions, the participant heard the speaker gossip about having dinner with the mutual friend or vent about the speaker’s car problems.

After reading the vignette, participants rated their feelings about the speaker and the target on an 11-point sliding scale. Participants who heard people vent about a friend canceling on them liked the speaker better than the target. This was not the case when speakers derogated the target for the same behavior, shared neutral gossip about targets or vented about their car troubles.

In another experiment, participants heard their friends vent about or derogate the target and were asked to divide a pot of lottery tickets between the speaker and target. Participants gave more tickets to the speaker than to the target, but only in the venting — not the derogation — condition.

However, venting backfired in an additional experiment. When researchers hinted the person venting was secretly rivalrous with the targeted friend, participants no longer liked that person better than the target.

The results show that venting makes the speaker more likable only when listeners do not perceive the speaker as having any aggressive intent toward the target. This suggests venting might be an effective tool of competition for listeners’ affections precisely because it isn’t readily recognized as such.

The benefits of being relatively better liked by one’s friends can include being given preferential treatment, as in the ticket example above, but could also have less tangible effects. For example, friends are associated with improved economic mobility, health, well-being and longevity.

The researchers emphasize that none of this competition has to be conscious, and some other scholars have suggested that such tactics might work best if we’re fooling ourselves that we’re not competing. If we don’t think we’re doing it to be aggressive, others might be less likely to realize we’re engaging in what might be an act of aggression.

The researchers also emphasize the ways in which venting can fail, such as when those venting are perceived as aggressive, choose the wrong thing to vent about or the wrong person to vent to. That venting works at all suggests, they say, that people can be deeply — if not consciously — strategic about what they vent about and to whom.

“People are so lonely right now, and that puts even greater pressure on us as researchers to be honest about how friendship works,” Krems said. “As much as we want it to be all unicorns and rainbows, sometimes it’s more like a koala: cuddly but also vicious.”

Specifically, electronic and mobile health interventions can help people achieve:

• 1329 more steps / day
• 55 minutes more moderate-to-vigorous exercise / week
• 45 minutes more overall physical activity / week
• 7 hours less sedentary behaviour / week
• 103 fewer calories consumed / day
• 20% more fruits and vegetables consumed / day
• 5.5 grams less saturated fat consumed / day
• 1.9 kilograms of weight loss over 12 weeks
• Improved sleep quality
• Less severe insomnia.

With the global economic burden of chronic diseases estimated to exceed US $47 trillion by 2023, effective interventions are in high demand. According to the World Health Organization, one in eight people are now living with obesity; 422 million people have diabetes; and cardiovascular disease is the leading cause of death worldwide.

Lead researcher, UniSA’s Dr Ben Singh, says people’s health behaviours must change if we are to reduce the incidence of chronic disease.

“With the rise of preventable chronic diseases like obesity, cardiovascular disease, and type 2 diabetes, finding mechanisms that can help reduce people’s risk is important,” Dr Singh says.

“Our study found that digital and mobile health interventions can have a positive effect on people’s health and wellbeing, not only helping them to increase their physical activity and reduce sedentary behaviour, but also improving their diet and quality of sleep.

“Given the wide accessibility and popularity of health apps, their capability to tailor information and deliver timely reminders and prompts, and scalability to diverse populations, they could be a very effective intervention to promote better health.

“Making positive changes to your health and wellbeing can be a challenge — it’s always easier to add kilos to your waistline, than it is to reduce them — but by incorporating digital tools into your everyday life, you’re more likely to achieve positive outcomes.”

The research identified consistent findings across different age groups, health behaviours, interventions, and health populations, indicating that digital health apps could help underpin broader public health campaigns. While researchers recommend further investigation to better understand impacts among specific groups of people, at top line, digital health apps appear to be a win-win for all.

Stem cell therapy has been heralded as a new way to treat many diseases, ranging from multiple sclerosis, Alzheimer’s and glaucoma to Type 1 diabetes. The anticipated advances have yet to materialize in part because it has proved much more difficult than originally thought to control the types of cells that develop from stem cells.

“The great strength of stem cells is their ability to adapt to the body, replicate and transform themselves into other kinds of cells, whether these are brain cells, heart muscle cells, bone cells or other cell types,” explained Allen Ehrlicher, an associate professor in McGill’s Department of Bioengineeringand the Canada Research Chair in Biological Mechanics. “But that is also one of the biggest challenges of working with them.”

Recently, a team of McGill researchers discovered that by stretching, bending and flattening the nuclei of stem cells to differing degrees, they could generate precisely targeted cells that they could direct to become either bone or fat cells.

The first applications of this discovery are likely to involve bone regeneration, possibly relating to dental or cranio-facial repair, or treatments for bone traumas or osteoporosis, according to Ehrlicher, the senior author on the study, who led the research team.

He cautions, however, that it is likely to take a decade or two before this new understanding of how to differentiate stem cells translates into clinical treatments. Ongoing testing and manipulation of stem cells will help this discovery be incorporated into medical treatments.

The next steps in the research will involve determining how the molecular mechanisms underlying the different cells allow them to be stretched into cells that can become either fat or bone and then translating this knowledge into 3D fibre cultures.

Fingerprints are one of the best-recognised examples of pattern formation by epithelial cells. The primary cells in the epithelium are the keratinocytes, and they are known to form patterns at the microscopic and macroscopic levels. While factors affecting this pattern formation have been reported, the exact mechanisms underlying the process are still not fully understood.

A team of researchers, led by Associate Professor Ken Natsuga at the Faculty of Medicine, Hokkaido University, have revealed that cell-cell adhesion governs pattern formation in keratinocytes. Their findings were published in the journal Life Science Alliance.

“In this study, we used an immortalized keratinocyte cell line, called HaCaT, which retains all the properties of normal keratinocytes,” Natsuga explained. “In order to ensure that our findings were accurate, we established single-cell cultures from this cell line.”

The team observed pattern formation in both the original heterogeneous cell line, as well as in single-cell-derived cultures. During culturing, the keratinocytes moved randomly and spontaneously formed high- and low-density regions, leading to pattern formation.

The pattern formation was markedly influenced by starvation. When the culture medium was renewed, patterns were obscured, but reappeared as the nutrients in the culture medium were consumed by the keratinocytes.

The team then examined the gene expression in the keratinocytes, which revealed that cell adhesion proteins and keratinocyte differentiation proteins were upregulated in high-density regions. “As cell adhesion is necessary for the development of high-cell-density regions, we specifically investigated the expression of adherens junction (AJ) molecules such as E-cadherin and actin,” Natsuga elaborated. “We found that these molecules were localized at the intercellular junctions of high-density regions.”

The authors then used a mathematical model to confirm that, under spatially uniform density and stress, strong cell adhesion leads to the formation of density patterns. They were also able to demonstrate that the keratinocyte patterns influenced cell proliferation and differentiation, and that serum starvation influences epidermal stratification (a type of differentiation) in skin cells from mice.

“Our study presents a novel and robust model of cell-cell adhesion-induced patterning (CAIP),” concludes Natsuga. “We have deepened our mechanistic insight into cellular organization and its consequences for cell fate decisions and epithelial stratification.” The team demonstrated that epithelial cell-cell adhesion is essential and sufficient for patterning. Future work will focus on adding more variables to the model to understand other processes that occur concurrently during development.

Standard risk ALL has an excellent prognosis, with remission rates over 90%. However, around 15% of patients who achieve remission later experience a relapse. Previous studies examining genomic alterations to predict relapse risk have primarily focused on high-risk ALL subgroups. SR B-ALL represents a larger group of patients and accounts for approximately half of children with ALL that relapse. This study is one of the first to systematically examine genetic factors on a large scale that influence relapse risk in SR B-ALL.

“ALL, as the most common childhood cancer, is a great success story with over 90% of children cured. But there remains a population of children whose disease is not fully cured, and we’ve not completely understood why that’s the case,” said co-senior author, Charles Mullighan, MBBS (Hons), MSc, MD, St. Jude Comprehensive Cancer Center Deputy Director and Department of Pathology member. “This study focused on that group of poorly understood cases, where we know less about the features that influence the risk of treatment not working and the disease coming back.”

Identifying genetic variations that modulate risk

Genomic profiling identifies specific genetic alterations associated with cancer susceptibility, relapse risk and how tumors respond to therapeutics. These studies allow scientists and clinicians to predict how patients are likely to respond to therapy, providing insights that shape the treatment of childhood ALL. Results from this collaborative study demonstrate the importance of genomic profiling in accurately determining patient risk in B-ALL, in conjunction with traditional criteria.

“We are planning to reduce conventional therapies in the future for children with ALL because we know that many patients can be cured with less therapy,” explained co-senior author, Mignon Loh, MD, leader of Seattle Children’s Cancer and Blood Disorders Center, COG ALL Committee chair emeritus, Seattle Children’s Ben Towne Center for Childhood Cancer Research director, and head of Seattle Children’s Division of Pediatric Hematology, Oncology, Bone Marrow Transplant and Cellular Therapy. “We want to make sure we accurately identify those children, and because of the special design of the study, this project allowed us to do just that.”

The scientists conducted genome and transcriptome sequencing on both SR B-ALL samples that relapsed and samples that remained in complete remission in a one:two ratio. They found that ALL subtypes, genetic alterations and patterns of aneuploidy (extra or missing chromosomes) were associated with the risk of relapse and time to relapse. Some B-ALL subtypes, such as hyperdiploid and ETV6::RUNX1 ALL, had a low frequency of relapse, but others including PAX5-altered, TCF3/4::HLF, ETV6::RUNX1-like and BCR::ABL1-like were associated with an increased risk of relapse. Notably, the specific type of genetic changes within those B-ALL subtypes further influenced the risk of relapse. This work demonstrated that genetic variations and cancer subtypes influence relapse risk in SR B-ALL, and patients classified as standard-risk can have tumors with high-risk features.

“Whole genome sequencing was important to accurately and comprehensively identify these changes, and they could not all have been identified without it,” explained Mullighan. “Children with SR ALL should have their tumor cell genome sequenced upon their initial diagnosis to identify if their tumor cells have these high-risk features, so that their initial therapy intensity can be increased.”

“Beyond conventional therapies, this information could also be used to develop and explore novel, personalized treatment strategies,” added Loh.

Since the genetic code was first deciphered in the 1960s, our genes seemed like an open book. By reading and decoding our chromosomes as linear strings of letters, like sentences in a novel, we can identify the genes in our genome and learn why changes in a gene’s code affect health.

This linear rule of life was thought to govern all forms of life — from humans down to bacteria.

But a new study by Columbia researchers shows that bacteria break that rule and can create free-floating and ephemeral genes, raising the possibility that similar genes exist outside of our own genome.

“What this discovery upends is the notion that the chromosome has the complete set of instructions that cells use to produce proteins,” says Samuel Sternberg, associate professor of biochemistry & molecular biology at the Vagelos College of Physicians and Surgeons, who led the research with Stephen Tang, an MD/PhD student at the medical school.

“We now know that, at least in bacteria, there can be other instructions not preserved in the genome that are nonetheless essential for cell survival.”

“Astonishing” and “alien biology”

The scientific reaction had already made news a few months ago when the paper first appeared as a preprint. In a Nature News article, scientists called the discovery “alien biology,” “astonishing,” and “shocking.”

“It repeatedly left us in disbelief,” Tang says, “and we went from doubt to amazement as the mechanism gradually came into view.”

Bacteria and their viruses have been locked in battle for eons, as viruses try to inject their DNA into the bacterial genome and bacteria devise cunning methods (e.g. CRISPR) to defend themselves. Many bacterial defense mechanisms remain unexplored but could lead to new genome editing tools.

The bacterial defense system Sternberg and Tang picked to explore is an odd one: The system involves a piece of RNA with unknown function and a reverse transcriptase, an enzyme that synthesizes DNA from an RNA template. The most common defense systems in bacteria cut or degrade incoming viral DNA, “so we were puzzled by the idea of defending the genome by DNA synthesis,” Tang says.

Free-floating genes

To learn how the odd defense works, Tang first created a new technique to identify the DNA produced by the reverse transcriptase. The DNA he found was long but repetitive, containing multiple copies of a short sequence within the defense system’s RNA molecule.

He then realized that this portion of the RNA molecule folds into a loop, and the reverse transcriptase travels numerous times around the loop to create the repetitive DNA. “It’s like you were intending to photocopy a book, but the copier just started churning out the same page over and over again,” Sternberg says.

The researchers originally thought something might be wrong with their experiments, or that the enzyme was making a mistake and the DNA it created was meaningless.

“This is when Stephen did some ingenious digging and found that the DNA molecule is a fully functioning, free-floating, transient gene,” Sternberg says.

The protein coded by this gene, the researchers found, is a critical part of the bacteria’s antiviral defense system. Viral infection triggers production of the protein (dubbed Neo by the researchers), which prevents the virus from replicating and infecting neighboring cells.

Extrachromosomal genes in humans?

If similar genes are found freely floating around in cells of higher organisms, “that would really be a game-changing discovery,” Sternberg says. “There might be genes, or DNA sequences, that don’t reside in any of the 23 human chromosomes. Maybe they’re only made in certain environments, in certain developmental or genetic contexts, and yet provide critical coding information that we rely on for our normal physiology.”

The lab is now using Tang’s methods to look for human extrachromosomal genes produced by reverse transcriptases.

Thousands of reverse transcriptase genes exist in the human genome and many have still undiscovered functions. “There is a significant gap to be filled that might reveal some more interesting biology,” Sternberg says.

Gene-editing wellspring

Though gene therapies that take advantage of CRISPR editing are in clinical trials (and one was approved last year for sickle cell), CRISPR is not the perfect technology.

New techniques that combine CRISPR with a reverse transcriptase are giving genome engineers more power. “The reverse transcriptase gives you the ability to write in new information at sites that CRISPR cuts, which CRISPR alone cannot do,” Tang says, “but everyone uses the same reverse transcriptase that was discovered decades ago.”

The reverse transcriptase that creates Neo has certain properties that may make it a better option for genome editing in the lab and for creating new gene therapies. And more mysterious reverse transcriptases exist in bacteria that are waiting to be explored.

“We think bacteria may have a treasure trove of reverse transcriptases that could be opportune starting points for new technologies once we understand how they work,” Sternberg says.

Now, researchers at the Broad Institute of MIT and Harvard have developed a machine-learning approach that promises to speed up AAV engineering for gene therapy. The tool helps researchers engineer the protein shells of AAVs, called capsids, to have multiple desirable traits, such as the ability to deliver cargo to a specific organ but not others or to work in multiple species. Other methods only look for capsids that have one trait at a time.

The team used their approach to design capsids for a commonly used type of AAV called AAV9 that more efficiently targeted the liver and could be easily manufactured. They found that about 90 percent of the capsids predicted by their machine learning models successfully delivered their cargo to human liver cells and met five other key criteria. They also found that their machine learning model correctly predicted the behavior of the proteins in macaque monkeys even though it was trained only on mouse and human cell data. This finding suggests that the new method could help scientists more quickly design AAVs that work across species, which is essential for translating gene therapies to humans.

The findings, which appeared recently in Nature Communications, come from the lab of Ben Deverman, institute scientist and director of vector engineering at the Stanley Center for Psychiatric Research at the Broad. Fatma-Elzahraa Eid, a senior machine learning scientist in Deverman’s group, was the first author on the study.

“This was a really unique approach,” Deverman said. “It highlights the importance of wet lab biologists working with machine learning scientists early to design experiments that generate machine learning enabling data rather than as an afterthought.”

Group leader Ken Chan, graduate student Albert Chen, research associate Isabelle Tobey, and scientific advisor Alina Chan, all in Deverman’s lab, also contributed significantly to the study.

Make way for machines

Traditional approaches for designing AAVs involve generating large libraries containing millions of capsid protein variants and then testing them in cells and animals in several rounds of selection. This process can be costly and time-consuming, and generally results in researchers identifying only a handful of capsids that have a specific trait. This makes it challenging to find capsids that meet multiple criteria.

Other groups have used machine learning to expedite large-scale analysis, but most methods optimized proteins for one function at the expense of another.

Deverman and Eid realized that datasets based on existing large AAV libraries weren’t well suited for training machine learning models. “Instead of just taking data and giving it to machine learning scientists we thought, ‘What do we need to train machine learning models better?'” Eid said. “Figuring that out was really instrumental.”

They first used an initial round of machine learning modeling to generate a new moderately sized library, called Fit4Function, that contained capsids that were predicted to package gene cargo well. The team screened the library in human cells and mice to find capsids that had specific functions important for gene therapy in each species. They then used that data to build multiple machine learning models that could each predict a certain function from a capsid’s amino acid sequence. Finally, they used the models in combination to create “multifunction” libraries of AAVs optimized for multiple traits at once.

The future of protein design

As proof of concept, Eid and other researchers in Deverman’s lab combined six models to design a library of capsids that had multiple desired functions, including manufacturability and the ability to target the liver across human cells and mice. Almost 90 percent of these proteins displayed all of the desired functions simultaneously.

The researchers also found that the model — trained only on data from mice and human cells — correctly predicted how AAVs distributed to different organs of macaques, suggesting that these AAVs do this through a mechanism that translates across species. That could mean that in the future, gene therapy researchers could more quickly identify capsids with multiple desirable properties for human use.

In the future, Eid and Deverman say their models could help other groups create gene therapies that either target or specifically avoid the liver. They also hope that other labs will use their approach to generate models and libraries of their own that, together, could form a machine-learning atlas: a resource that could predict the performance of AAV capsids across dozens of traits to accelerate gene therapy development.

The study, published in the journal Physiology & Behavior, shows that cutting calories by 20% did not significantly reduce the distance that mice voluntarily chose to run each day.

The researchers set out to understand what happens to mice when the amount of food available to them is reduced. The findings, they hoped, would be relevant to wild animals that do not always get as much food as they want on a given day, and also to humans, whose doctors often prescribe dieting.

It is somewhat difficult to obtain accurate data on the amount of voluntary exercise that humans engage in. Though it is easy to categorize what people recognize as voluntary exercise, like a trip to the gym, there is much gray area that’s hard to quantify, such as walking to a cafeteria to purchase lunch instead of eating a meal from a nearby lunch box.

Tracking what lab mice choose to do is much easier, and lab mice generally like to run on wheels for many hours per day. In this study, researchers saw the mice chose to run at similar levels, regardless of how much they ate.

“Voluntary exercise was remarkably resistant to reducing the amount of food by 20% and even by 40%,” said UCR biologist and corresponding study author Theodore Garland, Jr. “They just kept running.”

The researchers spent three weeks getting a baseline level of running activity for the mice, then a week with calories reduced by 20%, and another week at minus 40%. This experiment was done both with regular mice as well as “high runner” mice bred to enjoy running.

Though the high runners reduced their total distance slightly with 40% calorie restriction, the distance was only an 11% reduction. As they started out running three times farther per day than normal mice, the reduction is considered slight. “They’re still running at extremely high levels,” Garland said. The regular mice did not reduce their daily distance, even at 40% calorie reduction.

Because running gives a “runners high,” in part by increasing dopamine and cannabinoid levels in the brain, the researchers believe the mice were motivated to keep going even with less food. “Wheel running is a self-rewarding behavior,” Garland said.

In addition, the researchers were surprised to find that body mass was not significantly affected by the 20% reduction in calories in either the regular or high-runner mice. Although there was some drop in body mass with a 40% reduction, it was not as high as predicted.

“People often lose about 4% of their body mass when they’re dieting. That’s in the same range as these mice,” Garland said.

This study contributes to our understanding of why some people like to exercise and others don’t. In the future, the researchers are planning additional studies to understand why both the amount of voluntary exercise and body mass are so resistant to calorie restriction.

“There has to be some type of compensation going on if your food goes down by 40% and your weight doesn’t go down very much,” Garland said. “Maybe that’s reducing other types of activities, or becoming metabolically more efficient, which we didn’t yet measure.”

As habitat destruction causes food shortages for wild animals, this type of information could be instrumental for people trying to preserve species. And for the many people interested in improving their health, the implications could be similarly significant.

“We don’t want people on diets to say, ‘I don’t have enough energy, so I’ll make up for it by not exercising.’ That would be counterproductive, and now we know, it doesn’t have to be this way,” Garland said.

Researchers found the protein, which they named PKZILLA-1, while studying how a type of algae called Prymnesium parvum makes its toxin, which is responsible for massive fish kills.

“This is the Mount Everest of proteins,” said Bradley Moore, a marine chemist with joint appointments at Scripps Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences and senior author of a new study detailing the findings. “This expands our sense of what biology is capable of.”

PKZILLA-1 is 25% larger than titin, the previous record holder, which is found in human muscles and can reach 1 micron in length (0.0001 centimeter or 0.00004 inch).

Published today in Science and funded by the National Institutes of Health and the National Science Foundation, the study shows that this giant protein and another super-sized but not record-breaking protein — PKZILLA-2 — are key to producing prymnesin — the big, complex molecule that is the algae’s toxin. In addition to identifying the massive proteins behind prymnesin, the study also uncovered unusually large genes that provide Prymnesium parvum with the blueprint for making the proteins.

Finding the genes that undergird the production of the prymnesin toxin could improve monitoring efforts for harmful algal blooms from this species by facilitating water testing that looks for the genes rather than the toxins themselves.

“Monitoring for the genes instead of the toxin could allow us to catch blooms before they start instead of only being able to identify them once the toxins are circulating,” said Timothy Fallon, a postdoctoral researcher in Moore’s lab at Scripps and co-first author of the paper.

Discovering the PKZILLA-1 and PKZILLA-2 proteins also lays bare the alga’s elaborate cellular assembly line for building the toxins, which have unique and complex chemical structures. This improved understanding of how these toxins are made could prove useful for scientists trying to synthesize new compounds for medical or industrial applications.

“Understanding how nature has evolved its chemical wizardry gives us as scientific practitioners the ability to apply those insights to creating useful products, whether it’s a new anti-cancer drug or a new fabric,” said Moore.

Prymnesium parvum, commonly known as golden algae, is an aquatic single-celled organism found all over the world in both fresh and saltwater. Blooms of golden algae are associated with fish die offs due to its toxin prymnesin, which damages the gills of fish and other water breathing animals. In 2022, a golden algae bloom killed 500-1,000 tons of fish in the Oder River adjoining Poland and Germany. The microorganism can cause havoc in aquaculture systems in places ranging from Texas to Scandinavia.

Prymnesin belongs to a group of toxins called polyketide polyethers that includes brevetoxin B, a major red tide toxin that regularly impacts Florida, and ciguatoxin, which contaminates reef fish across the South Pacific and Caribbean. These toxins are among the largest and most intricate chemicals in all of biology, and researchers have struggled for decades to figure out exactly how microorganisms produce such large, complex molecules.

Beginning in 2019, Moore, Fallon and Vikram Shende, a postdoctoral researcher in Moore’s lab at Scripps and co-first author of the paper, began trying to figure out how golden algae make their toxin prymnesin on a biochemical and genetic level.

The study authors began by sequencing the golden alga’s genome and looking for the genes involved in producing prymnesin. Traditional methods of searching the genome didn’t yield results, so the team pivoted to alternate methods of genetic sleuthing that were more adept at finding super long genes.

“We were able to locate the genes, and it turned out that to make giant toxic molecules this alga uses giant genes,” said Shende.

With the PKZILLA-1 and PKZILLA-2 genes located, the team needed to investigate what the genes made to tie them to the production of the toxin. Fallon said the team was able to read the genes’ coding regions like sheet music and translate them into the sequence of amino acids that formed the protein.

When the researchers completed this assembly of the PKZILLA proteins they were astonished at their size. The PKZILLA-1 protein tallied a record-breaking mass of 4.7 megadaltons, while PKZILLA-2 was also extremely large at 3.2 megadaltons. Titin, the previous record-holder, can be up to 3.7 megadaltons — about 90-times larger than a typical protein.

After additional tests showed that golden algae actually produce these giant proteins in life, the team sought to find out if the proteins were involved in making the toxin prymnesin. The PKZILLA proteins are technically enzymes, meaning they kick off chemical reactions, and the team played out the lengthy sequence of 239 chemical reactions entailed by the two enzymes with pens and notepads.

“The end result matched perfectly with the structure of prymnesin,” said Shende.

Following the cascade of reactions that golden algae uses to make its toxin revealed previously unknown strategies for making chemicals in nature, said Moore. “The hope is that we can use this knowledge of how nature makes these complex chemicals to open up new chemical possibilities in the lab for the medicines and materials of tomorrow,” he added.

Finding the genes behind the prymnesin toxin could allow for more cost effective monitoring for golden algae blooms. Such monitoring could use tests to detect the PKZILLA genes in the environment akin to the PCR tests that became familiar during the COVID-19 pandemic. Improved monitoring could boost preparedness and allow for more detailed study of the conditions that make blooms more likely to occur.

Fallon said the PKZILLA genes the team discovered are the first genes ever causally linked to the production of any marine toxin in the polyether group that prymnesin is part of.

Next, the researchers hope to apply the non-standard screening techniques they used to find the PKZILLA genes to other species that produce polyether toxins. If they can find the genes behind other polyether toxins, such as ciguatoxin which may affect up to 500,000 people annually, it would open up the same genetic monitoring possibilities for a suite of other toxic algal blooms with significant global impacts.

In addition to Fallon, Moore and Shende from Scripps, David Gonzalez and Igor Wierzbikci of UC San Diego along with Amanda Pendleton, Nathan Watervoort, Robert Auber and Jennifer Wisecaver of Purdue University co-authored the study.

“Our research has the potential to improve the success of stem-cell transplants and expand their use,” explained Ulrich Steidl, M.D., Ph.D., professor and chair of cell biology, interim director of the Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, and the Edward P. Evans Endowed Professor for Myelodysplastic Syndromes at Einstein, and deputy director of the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center (MECCC).

Dr. Steidl, Einstein’s Britta Will, Ph.D., and Xin Gao, Ph.D., a former Einstein postdoctoral fellow, now at the University of Wisconsin in Madison, are co-corresponding authors on the paper.

Mobilizing Stem Cells

Stem-cell transplants treat diseases in which an individual’s hematopoietic (blood-forming) stem cells (HSCs) have become cancerous (as in in leukemia or myelodysplastic syndromes) or too few in number (as in bone marrow failure and severe autoimmune disorders). The therapy involves infusing healthy HSCs obtained from donors into patients. To harvest those HSCs, donors are given a drug that causes HSCs to mobilize, or escape, from their normal homes in the bone marrow and enter the blood, where HSCs can be separated from other blood cells and then transplanted. However, drugs used to mobilize HSCs often don’t liberate enough of them for the transplant to be effective.

“It’s normal for a tiny fraction of HSCs to exit the bone marrow and enter the blood stream, but what controls this mobilization isn’t well understood,” said Dr. Will, associate professor of oncology and of medicine, and the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research at Einstein, and the co-leader of the Stem Cell and Cancer Biology research program at MECCC. “Our research represents a fundamental advance in our understanding, and points to a new way to improve HSC mobilization for clinical use.”

Tracking Trogocytosis

The researchers suspected that variations in proteins on the surface of HSCs might influence their propensity to exit the bone marrow. In studies involving HSCs isolated from mice, they observed that a large subset of HSCs display surface proteins normally associated with macrophages, a type of immune cell. Moreover, HSCs with these surface proteins largely stayed in the bone marrow, while those without the markers readily exited the marrow when drugs for boosting HSCs mobilization were given.

After mixing HSCs with macrophages, the researchers discovered that some HSCs engaged in trogocytosis, a mechanism whereby one cell type extracts membrane fractions of another cell type and incorporates them into their own membranes. Those HSCs expressing high levels of the protein c-Kit on their surface were able to carry out trogocytosis, causing their membranes to be augmented with macrophage proteins — and making them far more likely than other HSCs to stay in the bone marrow. The findings suggest that impairing c-Kit would prevent trogocytosis, leading to more HSCs being mobilized and made available for transplantation.

“Trogocytosis plays a role in regulating immune responses and other cellular systems, but this is the first time anyone has seen stem cells engage in the process. We are still seeking the exact mechanism for how HSCs regulate trogocytosis,” said Dr. Gao, assistant professor of pathology and laboratory medicine at the University of Wisconsin-Madison, Madison, WI.

The researchers intend to continue their investigation into this process: “Our ongoing efforts will look for other functions of trogocytosis in HSCs, including potential roles in blood regeneration, eliminating defective stem cells and in hematologic malignancies,” added Dr. Will.

The study originated in the laboratory of the late Paul S. Frenette, M.D., a pioneer in hematopoietic stem cell research and founding director of the Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine Research at Einstein. Other key contributors include Randall S. Carpenter, Ph.D., and Philip E. Boulais, Ph.D., both postdoctoral scientists at Einstein.

The Science paper is titled, “Regulation of the hematopoietic stem cell pool by c-Kit-associated trogocytosis.” Additional authors are Huihui Li, Ph.D., and Maria Maryanovich, Ph.D., both at Einstein, Christopher R. Marlein, Ph.D., at Einstein and FUJIFILM Diosynth Biotechnologies, Wilton, England, and Dachuan Zhang, Ph.D., at Einstein and Shanghai Jiao Tong University School of Medicine, Shanghai, China, Matthew Smith at the University of Wisconsin-Madison, and David J. Chung, M.D., Ph.D., at Memorial Sloan Kettering Cancer Center, New York, NY.

The study was funded by grants from the National Institutes of Health (U01DK116312, R01DK056638, R01DK112976, R01HL069438, DK10513, CA230756, R01HL157948 and R35CA253127).

“Previous publications from our lab have mainly focused on neuronal protection,” said Li-Huei Tsai, Picower Professor in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences at MIT and senior author of the new study in Nature Communications. Tsai also lead’s MIT’s Aging Brain Initiative. “But this study shows that it’s not just the gray matter, but also the white matter that’s protected by this method.”

This year Cognito Therapeutics, the spin-off company that licensed MIT’s sensory stimulation technology, published phase II human trial results in the Journal of Alzheimer’s Disease indicating that 40Hz light and sound stimulation significantly slowed the loss of myelin in volunteers with Alzheimer’s. Also this year Tsai’s lab published a study showing that gamma sensory stimulation helped mice withstand neurological effects of chemotherapy medicines, including by preserving myelin. In the new study, members of Tsai’s lab led by former postdoc Daniela Rodrigues Amorim used a common mouse model of myelin loss — a diet with the chemical cuprizone — to explore how sensory stimulation preserves myelination.

Amorim and Tsai’s team found that 40Hz light and sound not only preserved myelination in the brains of cuprizone-exposed mice, it also appeared to protect oligodendrocytes (the cells that myelinate neural axons), sustain the electrical performance of neurons, and preserve a key marker of axon structural integrity. When the team looked into the molecular underpinnings of these benefits, they found clear signs of specific mechanisms including preservation of neural circuit connections called synapses; a reduction in a cause of oligodendrocyte death called “ferroptosis;” reduced inflammation; and an increase in the ability of microglia brain cells to clean up myelin damage so that new myelin could be restored.

“Gamma stimulation promotes a healthy environment,” said Amorim who is now a Marie Curie Fellow at the University of Galway in Ireland. “There are several ways we are seeing different effects.”

The findings suggest that gamma sensory stimulation may help not only Alzheimer’s disease patients but also people battling other diseases involving myelin loss, such as multiple sclerosis, the authors wrote in the study.

Maintaining myelin

To conduct the study, Tsai and Amorim’s team fed some male mice a diet with cuprizone and gave other male mice a normal diet for six weeks. Halfway into that period, when cuprizone is known to begin causing its most acute effects on myelination, they exposed some mice from each group to gamma sensory stimulation for the remaining three weeks. In this way they had four groups: completely unaffected mice, mice that received no cuprizone but did get gamma stimulation, mice that received cuprizone and constant (but not 40Hz) light and sound as a control, and mice that received cuprizone and also gamma stimulation.

After the six weeks elapsed, the scientists measured signs of myelination throughout the brains of the mice in each group. Mice that weren’t fed cuprizone maintained healthy levels, as expected. Mice that were fed cuprizone and didn’t receive 40Hz gamma sensory stimulation showed drastic levels of myelin loss. Cuprizone-fed mice that received 40Hz stimulation retained significantly more myelin, rivaling the health of mice never fed cuprizone by some, but not all, measures.

The researchers also looked at numbers of oligodendrocytes to see if they survived better with sensory stimulation. Several measures revealed that in mice fed cuprizone, oligodendrocytes in the corpus callosum region of the brain (a key point for the transit of neural signals because it connects the brain’s hemispheres) were markedly reduced. But in mice fed cuprizone and also treated with gamma stimulation, the number of cells were much closer to healthy levels.

Electrophysiological tests among neural axons in the corpus callosum showed that gamma sensory stimulation was associated with improved electrical performance in cuprizone-fed mice who received gamma stimulation compared to cuprizone-fed mice left untreated by 40Hz stimulation. And when researchers looked in the anterior cingulate cortex region of the brain, they saw that MAP2, a protein that signals the structural integrity of axons, was much better preserved in mice that received cuprizone and gamma stimulation compared to cuprizone-fed mice who did not.

Molecular mechanisms

A key goal of the study was to identify possible ways in which 40Hz sensory stimulation may protect myelin.

To find out, the researchers conducted a sweeping assessment of protein expression in each mouse group and identified which proteins were differentially expressed based on cuprizone diet and exposure to gamma frequency stimulation. The analysis revealed distinct sets of effects between the cuprizone mice exposed to control stimulation and cuprizone-plus-gamma mice.

A highlight of one set of effects was the increase in MAP2 in gamma-treated cuprizone-fed mice. A highlight of another set was that cuprizone mice who received control stimulation showed a substantial deficit in expression of proteins associated with synapses. The gamma-treated cuprizone-fed mice did not show any significant loss, mirroring results in a 2019 Alzheimer’s 40Hz study that showed synaptic preservation. This result is important, the researchers wrote, because neural circuit activity, which depends on maintaining synapses, is associated with preserving myelin. They confirmed the protein expression results by looking directly at brain tissues.

Another set of protein expression results hinted at another important mechanism: ferroptosis. This phenomenon, in which errant metabolism of iron leads to a lethal buildup of reactive oxygen species in cells, is a known problem for oligodendrocytes in the cuprizone mouse model. Among the signs was an increase in cuprizone-fed, control stimulation mice in expression of the protein HMGB1, which is a marker of ferroptosis-associated damage that triggers an inflammatory response. Gamma stimulation, however, reduced levels of HMGB1.

Looking more deeply at the cellular and molecular response to cuprizone demyelination and the effects of gamma stimulation, the team assessed gene expression using single-cell RNA sequencing technology. They found that astrocytes and microglia became very inflammatory in cuprizone-control mice but gamma stimulation calmed that response. Fewer cells became inflammatory and direct observations of tissue showed that microglia became more proficient at clearing away myelin debris, a key step in effecting repairs.

The team also learned more about how oligodendrocytes in cuprizone-fed mice exposed to 40Hz sensory stimulation managed to survive better. Expression of protective proteins such as HSP70 increased and as did expression of GPX4, a master regulator of processes that constrain ferroptosis.

In addition to Amorim and Tsai, the paper’s other authors are Lorenzo Bozzelli, TaeHyun Kim, Liwang Liu, Oliver Gibson, Cheng-Yi Yang, Mitch Murdock, Fabiola Galiana-Meléndez, Brooke Schatz, Alexis Davison, Md Rezaul Islam, Dong Shin Park, Ravikiran M. Raju, Fatema Abdurrob, Alissa J. Nelson, Jian Min Ren, Vicky Yang and Matthew P. Stokes.

Fundacion Bancaria la Caixa, The JPB Foundation, The Picower Institute for Learning and Memory, the Carol and Gene Ludwig Family Foundation, Lester A. Gimpelson, Eduardo Eurnekian, The Dolby Family, Kathy and Miguel Octavio, the Marc Haas Foundation, Ben Lenail and Laurie Yoler, and the National Institutes of Health provided funding for the study.

Chronic wounds are open wounds that heal slowly, if they heal at all. For example, sores that occur in some patients with diabetes are chronic wounds. These wounds are particularly problematic because they often recur after treatment and significantly increase the risk of amputation and death.

One of the challenges associated with chronic wounds is that existing treatment options are extremely expensive, which can create additional problems for patients.

“Our goal here was to develop a far less expensive technology that accelerates healing in patients with chronic wounds,” says Amay Bandodkar, co-corresponding author of the work and an assistant professor of electrical and computer engineering at North Carolina State University. “We also wanted to make sure that the technology is easy enough for people to use at home, rather than something that patients can only receive in clinical settings.”

“This project is part of a bigger DARPA project to accelerate wound healing with personalized wound dressings,” says Sam Sia, co-corresponding author of the work and professor of biomedical engineering at Columbia University. “This collaborative project shows that these lightweight bandages, which can provide electrical stimulation simply by adding water, healed wounds faster than the control, at a similar rate as bulkier and more expensive wound treatment.”

Specifically, the research team developed water-powered, electronics-free dressings (WPEDs), which are disposable wound dressings that have electrodes on one side and a small, biocompatible battery on the other. The dressing is applied to a patient so that the electrodes come into contact with the wound. A drop of water is then applied to the battery, activating it. Once activated, the bandage produces an electric field for several hours.

“That electric field is critical, because it’s well established that electric fields accelerate healing in chronic wounds,” says Rajaram Kaveti, co-first author of the study and a post-doctoral researcher at NC State.

The electrodes are designed in a way that allows them to bend with the bandage and conform to the surface of the chronic wounds, which are often deep and irregularly shaped.

“This ability to conform is critical, because we want the electric field to be directed from the periphery of the wound toward the wound’s center,” says Kaveti. “In order to focus the electric field effectively, you want electrodes to be in contact with the patient at both the periphery and center of the wound itself. And since these wounds can be asymmetrical and deep, you need to have electrodes that can conform to a wide variety of surface features.”

“We tested the wound dressings in diabetic mice, which are a commonly used model for human wound healing,” says Maggie Jakus, co-first author of the study and a graduate student at Columbia. “We found that the electrical stimulation from the device sped up the rate of wound closure, promoted new blood vessel formation, and reduced inflammation, all of which point to overall improved wound healing.”

Specifically, the researchers found that mice who received treatment with WPEDs healed about 30% faster than mice who received conventional bandages.

“But it is equally important that these bandages can be produced at relatively low cost — we’re talking about a couple of dollars per dressing in overhead costs.” says Bandodkar.

“Diabetic foot ulceration is a serious problem that can lead to lower extremity amputations,” says Aristidis Veves, a co-author of the study and professor of surgery at Beth Israel Deaconess Center. “There is urgent need for new therapeutic approaches, as the last one that was approved by the Food and Drug Administration was developed more than 25 years ago. My team is very lucky to participate in this project that investigates innovative and efficient new techniques that have the potential to revolutionize the management of diabetic foot ulcers.”

In addition, the WPEDs can be applied quickly and easily. And once applied, patients can move around and take part in daily activities. This functionality means that patients can receive treatment at home and are more likely to comply with treatment. In other words, patients are less likely to skip treatment sessions or take shortcuts, since they aren’t required to come to a clinic or remain immobile for hours.

“Next steps for us include additional work to fine-tune our ability to reduce fluctuations in the electric field and extend the duration of the field. We are also moving forward with additional testing that will get us closer to clinical trials and — ultimately — practical use that can help people,” says Bandodkar.

The paper, “Water-powered, electronics-free dressings that electrically stimulate wounds for rapid wound closure,” will be published Aug. 7 in the open-access journal Science Advances. The paper’s co-authors include Henry Chen, an undergraduate in the joint biomedical engineering department at NC State and UNC; Bhavya Jain, Navya Mishra, Nivesh Sharma and Baha Erim Uzuno?lu, Ph.D. students at NC State; Darragh Kennedy and Elizabeth Caso of Columbia; Georgios Theocharidis and Brandon Sumpio of Beth Israel Deaconess Medical Center; Won Bae Han of Korea University and the Georgia Institute of Technology; Tae-Min Jang of Korea University; and Suk-Won Hwang of Korea University and the Korea Institute of Science and Technology.

This work was done with support from the Defense Advanced Research Projects Agency under grant D20AC00004 and from the Center for Advanced Self-Powered Systems of Integrated Sensors and Technologies at NC State, which is funded by National Science Foundation grant 1160483. Bandodkar and Kaveti are inventors on a patent application related to this work.

A team of scientists created a new method to 3D print vascular networks that consist of interconnected blood vessels possessing a distinct “shell” of smooth muscle cells and endothelial cells surrounding a hollow “core” through which fluid can flow, embedded inside a human cardiac tissue. This vascular architecture closely mimics that of naturally occurring blood vessels and represents significant progress toward being able to manufacture implantable human organs. The achievement is published in Advanced Materials.

“In prior work, we developed a new 3D bioprinting method, known as “sacrificial writing in functional tissue” (SWIFT), for patterning hollow channels within a living cellular matrix. Here, building on this method, we introduce coaxial SWIFT (co-SWIFT) that recapitulates the multilayer architecture found in native blood vessels, making it easier to form an interconnected endothelium and more robust to withstand the internal pressure of blood flow,” said first author Paul Stankey, a graduate student at SEAS in the lab of co-senior author and Wyss Core Faculty member Jennifer Lewis, Sc.D.

The key innovation developed by the team was a unique core-shell nozzle with two independently controllable fluid channels for the “inks” that make up the printed vessels: a collagen-based shell ink and a gelatin-based core ink. The interior core chamber of the nozzle extends slightly beyond the shell chamber so that the nozzle can fully puncture a previously printed vessel to create interconnected branching networks for sufficient oxygenation of human tissues and organs via perfusion. The size of the vessels can be varied during printing by changing either the printing speed or the ink flow rates.

To confirm the new co-SWIFT method worked, the team first printed their multilayer vessels into a transparent granular hydrogel matrix. Next, they printed vessels into a recently created matrix called uPOROS composed of a porous collagen-based material that replicates the dense, fibrous structure of living muscle tissue. They were able to successfully print branching vascular networks in both of these cell-free matrices. After these biomimetic vessels were printed, the matrix was heated, which caused collagen in the matrix and shell ink to crosslink, and the sacrificial gelatin core ink to melt, enabling its easy removal and resulting in an open, perfusable vasculature.

Moving into even more biologically relevant materials, the team repeated the printing process using a shell ink that was infused with smooth muscle cells (SMCs), which comprise the outer layer of human blood vessels. After melting out the gelatin core ink, they then perfused endothelial cells (ECs), which form the inner layer of human blood vessels, into their vasculature. After seven days of perfusion, both the SMCs and the ECs were alive and functioning as vessel walls — there was a three-fold decrease in the permeability of the vessels compared to those without ECs.

Finally, they were ready to test their method inside living human tissue. They constructed hundreds of thousands of cardiac organ building blocks (OBBs) — tiny spheres of beating human heart cells, which are compressed into a dense cellular matrix. Next, using co-SWIFT, they printed a biomimetic vessel network into the cardiac tissue. Finally, they removed the sacrificial core ink and seeded the inner surface of their SMC-laden vessels with ECs via perfusion and evaluated their performance.

Not only did these printed biomimetic vessels display the characteristic double-layer structure of human blood vessels, but after five days of perfusion with a blood-mimicking fluid, the cardiac OBBs started to beat synchronously — indicative of healthy and functional heart tissue. The tissues also responded to common cardiac drugs — isoproterenol caused them to beat faster, and blebbistatin stopped them from beating. The team even 3D-printed a model of the branching vasculature of a real patient’s left coronary artery into OBBs, demonstrating its potential for personalized medicine.

“We were able to successfully 3D-print a model of the vasculature of the left coronary artery based on data from a real patient, which demonstrates the potential utility of co-SWIFT for creating patient-specific, vascularized human organs,” said Lewis, who is also the Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS.

In future work, Lewis’ team plans to generate self-assembled networks of capillaries and integrate them with their 3D-printed blood vessel networks to more fully replicate the structure of human blood vessels on the microscale and enhance the function of lab-grown tissues.

“To say that engineering functional living human tissues in the lab is difficult is an understatement. I’m proud of the determination and creativity this team showed in proving that they could indeed build better blood vessels within living, beating human cardiac tissues. I look forward to their continued success on their quest to one day implant lab-grown tissue into patients,” said Wyss Founding Director Donald Ingber, M.D., Ph.D. Ingber is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital and Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS.

Additional authors of the paper include Katharina Kroll, Alexander Ainscough, Daniel Reynolds, Alexander Elamine, Ben Fichtenkort, and Sebastien Uzel. This work was supported by the Vannevar Bush Faculty Fellowship Program sponsored by the Basic Research Office of the Assistant Secretary of Defense for Research and Engineering through the Office of Naval Research Grant N00014-21-1-2958 and the National Science Foundation through CELL-MET ERC (#EEC-1647837).

To help protect drivers and machine operators from the dangers of drifting off, engineers at the University of California, Berkeley, have created prototype earbuds that can detect the signs of drowsiness in the brain.

The earbuds detect brain waves in the same way as an electroencephalogram (EEG), a test that doctors use to measure electrical activity in the brain. While most EEGs detect brain waves using a series of electrodes attached to the head, the earbuds do so using built-in electrodes that are designed to make contact with the ear canal.

The electrical signals detected by the ear buds are smaller than those picked up by a traditional EEG. However, in a new study, the researchers show that their Ear EEG platform is sensitive enough to detect alpha waves, a pattern of brain activity that increases when you close your eyes or start to fall asleep.

“I was inspired when I bought my first pair of Apple’s AirPods in 2017. I immediately thought, ‘What an amazing platform for neural recording,'” said study senior author Rikky Muller, an associate professor of electrical engineering and computer sciences at UC Berkeley. “We believe that this technology has many potential uses, and that classifying drowsiness is a good indicator that the technology can be used to classify sleep and even diagnose sleep disorders.”

Using an earbud as an EEG electrode poses a variety of practical challenges. In order to obtain an accurate EEG, electrodes need to make good contact with the skin. This is relatively easy to achieve in traditional EEGs, which use flat metal electrodes stuck to the scalp. However, it is much trickier to design an earbud that will fit snugly — and comfortably — in a wide variety of ear sizes and shapes.

When Muller’s team started working on the project, other groups developing Ear EEG platforms were either using wet electrode gels to ensure a good seal between the earbud and the ear canal, or creating custom-molded earpieces for each individual user. She and her team wanted to design a model that was dry and user generic, so that anyone could stick them in their ears and get reliable readings.

“My personal goal was to try to make a device that could be used every day by someone who would really benefit from it,” said Ryan Kaveh, a UC Berkeley postdoctoral scholar and co-first author of the study. “In order to do that, I knew that it would have to be reusable, fit a variety of people, and [be] easy to manufacture.”

Kaveh co-led the study with graduate student Carolyn Schwendeman and collaborated with Ana Arias’s lab at UC Berkeley to design the final earpiece in three sizes: small, medium and large. The earpiece incorporates multiple electrodes in a cantilevered design that applies gentle outward pressure to the ear canal and uses flexible electronics to ensure a comfortable fit. The signals are read out through a custom, low-power, wireless electronic interface.

In a 2020 paper, the researchers showed that these earpieces can detect a number of physiological signals, including eye blinks, alpha brain waves and the auditory steady-state response, which is the brain’s response to hearing a steady pitch. In the new study, they improved the earpiece design and incorporated machine learning to demonstrate how the earpieces could be used in a real-world application.

As part of the experiment, they asked nine volunteers to wear the earpieces while doing a series of boring tasks in a darkened room. Every so often, the volunteers were asked to rate their level of drowsiness, and their response times were measured.

“We found that even when the signal quality from the earpieces seemed worse, we could still classify the onset of drowsiness with the same level of accuracy as much more complicated, bulky systems,” Kaveh said. The earpieces also retain their accuracy when categorizing drowsiness in brand-new users, a characteristic of devices that could work ‘out of the box’.

Muller, who developed the Ear EEG with the support of the Bakar Fellowship and the Bakar Prize, is continuing to refine the design and explore other potential applications of the device, which can also record signals beyond EEG, such as heart beats, eye movements and jaw clenches.

“Wireless earbuds are something we already wear all the time,” Muller said. “That’s what makes Ear EEG such a compelling approach to wearables. It doesn’t require anything extra.”

This study was supported in part by the Ford University Research Program and a Bakar Spark Award.

With a goal of understanding and addressing immunotherapy’s limitations, researchers at Washington University School of Medicine in St Louis have found that the immune system can be its own worst enemy in the fight against cancer. In a new study in mice, a subset of immune cells — type 1 regulatory T cells, or Tr1 cells — did its normal job of preventing the immune system from overreacting but did so while inadvertently restraining immunotherapy’s cancer-fighting power.

“Tr1 cells were found to be a heretofore unrecognized obstacle to immunotherapy’s effectiveness against cancer,” said senior author Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor in the Department of Pathology & Immunology, and director of the Bursky Center for Human Immunology & Immunotherapy at Washington University School of Medicine. “By removing or circumventing that barrier in mice, we successfully reenergized the immune system’s cancer-fighting cells and uncovered an opportunity to expand the benefits of immunotherapy for more cancer patients.”

The study is available in Nature.

Cancer vaccines represent a new approach to personalize cancer immunotherapy. Aimed at the mutant proteins specific to a patient’s tumor, such vaccines induce killer T cells to attack tumor cells while leaving healthy cells unharmed. Schreiber’s group previously showed that more effective vaccines also activate helper T cells, another immune cell type, that recruit and expand additional killer T cells to destroy the tumors. But when they tried to add increased amounts of the helper T cell target to supercharge the vaccine they found they generated a different type of T cell that inhibited rather than promoted tumor rejection.

“We tested the hypothesis that by increasing helper T cell activation we would induce enhanced elimination of the sarcoma tumors in mice,” said first author Hussein Sultan, PhD, an instructor in pathology & immunology. So he injected groups of tumor bearing mice with vaccines that activated killer T cells equally while triggering a different degree of helper T cell activation.

Much to the researchers’ surprise in this latest study, the vaccine meant to hyperactivate helper T cells produced the opposite effect and inhibited tumor rejection.

“We thought that more helper T cell activation would optimize elimination of the sarcoma tumors in mice,” Sultan said. “Instead, we found that vaccines containing high doses of helper T cell targets induced inhibitory Tr1 cells that completely blocked tumor elimination. We know that Tr1 cells normally control an overactive immune system, but this is the first time they have been shown to dampen its fight against cancer.”

Tr1 cells normally put the brakes on the immune system to prevent it from attacking the body’s healthy cells. But their role in cancer has not been seriously explored. Looking through previously published data, the researchers found that tumors from patients who had responded poorly to immunotherapy had more Tr1 cells compared with tumors of patients who had responded well. The number of Tr1 cells also increased in mice as tumors grew bigger, rendering the mice insensitive to immunotherapy.

To bypass the inhibiting cells, the researchers treated the vaccinated mice with a drug that enhances killer T cells’ fighting power. The drug, developed by biotechnology startup Asher Biotherapeutics, carries modifications in the immune-boosting protein called interleukin 2 (IL-2) that specifically revs up killer T cells and reduces the toxicity of unmodified IL-2 treatments. The additional boost from the drug overcame Tr1 cells’ inhibition and rendered the immunotherapy more effective.

“We are committed to personalizing immunotherapy and broadening its effectiveness,” said Schreiber. “Decades of researching basic tumor immunology have expanded our understanding of how to trigger the immune system to achieve the most robust antitumor response. This new study adds to our understanding of how to improve immunotherapy to benefit more people.”

As co-founder of Asher Biotherapeutics — which provided the mouse version of the modified IL-2 drugs — Schreiber is indirectly involved in the company’s clinical trials testing the human version of the drug as a monotherapy in cancer patients. If successful, the drug has the potential to be tested in combination with cancer treatment vaccines.

DEEs affect 1 in 590 children and involve more than 825 genes. Current testing methods can clinically identify the root cause, or etiology, of approximately 50% of individuals’ DEEs, which guides clinicians and families to appropriate care and support. However, the remaining half of all patients remain unsolved.

“About half of the patients with DEE will get a diagnosis, and half of them won’t,” said co-corresponding author Heather Mefford, MD, PhD, St. Jude Center for Pediatric Neurological Disease Research and Department of Cell & Molecular Biology.

When a child is diagnosed with DEE, linking the encephalopathy to a specific gene can allow the clinician to provide appropriate treatment or control over the symptoms of the disorder. This knowledge is also invaluable to the family.

“The half who do not receive diagnosis not only won’t be able to get gene-specific recommendations in their therapy, they won’t be able to link with family organizations that can connect them with other families with children that also have mutations in that gene,” explained Mefford.

The value of identifying rare genetic links to DEE

Addressing the genetic root causes for DEEs has been a long-term goal for Mefford, who was instrumental in raising the number of diagnosable cases to 50%, up from approximately 5% just a decade ago.

Today, 80% of identifiable DEEs can be explained by 27 genes. To tackle the remaining unsolved cases, the numerous rare occurrences of the disorder must be identified, a challenge that co-first author and St. Jude Graduate School of Biomedical Sciences student Christy LaFlamme embraced.

“One way we can get at the remaining 50% is by exploring what traditional tests don’t look at,” said LaFlamme. “Current tests don’t look at noncoding space that regulates gene expression. A lot of these disorders are due to losing expression of epilepsy genes.”

DNA methylation fingerprint offers solution

Mefford is exploring epigenetics, the changes in gene expression that may or may not involve DNA alterations, as a potential solution. One such epigenetic change involves a process vital to gene expression called DNA methylation. This process is akin to a chef leaving notes beside a recipe instructing the reader to skip or repeat a step.

“For some genetic disorders, everyone with a mutation in the same gene has a methylation profile across their genome that puts them in a category with all the others with the same genetic disorder,” said Mefford. This methylation landscape is called an “episignature” and is akin to a DEE fingerprint.

While episignatures allowed the researchers to broadly identify DEE-causing variants, taking a closer look at the individual methylation instances, referred to as rare methylation analysis, presented another opportunity. “The underlying cause of the disease ends up manifesting into an episignature that can serve as a marker for that gene,” explained LaFlamme. “With rare methylation events, their analysis can point directly to the cause of the disease.”

New technologies aid in rare methylation detection

Exploring these rare methylation events across the genome using long-read DNA sequencing pointed the researchers toward DNA regions that are not commonly assessed, offering an answer to the cause of these cases.

This one-two punch allowed the researchers to identify the causative and candidate etiologies of DEEs in 2% of previously unidentified cases. This represents another significant step in identifying rare instances of DEEs and another tool to aid in diagnosing children with DEE.

Mefford is determined to continue chipping away in earnest. Her placement within the St. Jude Pediatric Translational Neuroscience Initiative means the so-called “N of few,” the rarer occurrences of neurological disorders like DEE, can continue to be tackled.

“We are still dedicated to trying to solve the remaining cases. We’ve always leveraged new technologies, such as next-generation sequencing 10 years ago and now methylation analysis and long-read sequencing,” said Mefford. “We’re always looking for technologies that will give us new information to try and solve those cases.”

NanoSTING Therapeutic HIGHLIGHTS

• NanoSTING, a nasal spray, can prevent multiple respiratory viruses by activating the immune system and preventing infection from viruses. It can also protect against SARS-CoV-2 reinfection.
• A single intranasal dose of the NanoSTING has proven effective against strains of SARS-CoV-2 and the flu virus.
• NanoSTING is complementary to vaccines and enables cells to be in a heightened state of alert to prevent attack from respiratory viruses.

NanoSTING-NS Pan-coronavirus Vaccine HIGHLIGHTS

• UH researchers have developed NanoSTING-SN, a nasal vaccine that prevents transmission to the unvaccinated and fights multiple COVID variants.
• NanoSTING-SN provides the exciting potential towards a universal coronavirus vaccine and may end the cycle of onward transmission and viral evolution in immunocompromised people.
• Intramuscular vaccines prevent disease but are less efficient in preventing infections. NanoSTING-SN can provide improved protection against transmission for COVID variants and related sarbecoviruses.

NanoSTING

NanoSTING is a special formula that uses tiny fat droplets to deliver an immune-boosting ingredient called cGAMP. This formula helps the body’s cells stay on high alert to prevent attack from respiratory viruses.

“Using multiple models, the team demonstrated that a single treatment with NanoSTING not only protects against pathogenic strains of SARS-CoV-2 but also prevents transmission of highly transmissible variants like the Omicron variants,” reports Varadarajan. “Delivery of NanoSTING to the nose ensures that the immune system is activated in the nasal compartment and this in turn prevents infection from viruses.”

As the recent COVID19 pandemic illustrated, the development of off-the-shelf treatments that counteract respiratory viruses is a largely unsolved problem with a huge impact on human lives.

“Our results showed that intranasal delivery of NanoSTING, is capable of eliciting beneficial type I and type III interferon responses that are associated with immune protection and antiviral benefit,” reports first author and postdoctoral associate, Ankita Leekha.

The authors further show that NanoSTING can protect against both Tamiflu sensitive and resistant strains of influenza, underscoring its potential as a broad-spectrum therapeutic.

“The ability to activate the innate immune system presents an attractive route to armoring humans against multiple respiratory viruses, viral variants and also minimizing transmission to vulnerable people,” said Leekha. “The advantage of NanoSTING is that only one dose is required unlike the antivirals like Tamiflu that require 10 doses.”

The mechanism of action of NanoSTING is complementary to vaccines, monoclonal antibodies and antivirals, the authors noted.

Nano STING-SN

Despite the successful implementation of multiple vaccines against SARS-CoV-2, these vaccines need constant updates due to viral evolution, plus the current generation of vaccines only offers limited protection against transmission of SARS-CoV-2.

Enter NanoSTING-SN, a multi-antigen, intranasal vaccine, that eliminates virus replication in both the lungs and the nostrils and has the ability to protect against multiple coronaviruses and variants.

“Using multiple preclinical models, the team demonstrated that the vaccine candidate protects the primary host from disease when challenged with highly pathogenic variants. Significantly, the vaccine also prevents transmission of highly transmissible variants like the Omicron variants to vaccine-naïve hosts,” reports Varadarajan.

The authors further show that the nasal vaccine was 100% effective at preventing transmission of the Omicron VOCs to unvaccinated hosts.

“The ability to protect against multiple coronaviruses and variants provides the exciting potential towards a universal coronavirus vaccine,” said Leekha. “The ability to prevent infections and transmission might finally end this cycle of onward transmission and viral evolution in immunocompromised people.”

The research was conducted by a collaborative team at UH including Xinli Liu, College of Pharmacy and Vallabh E. Das, College of Optometry along with Brett L. Hurst of Utah State University and consultation from AuraVax Therapeutics, a spinoff from Varadarajan’s Single Cell Lab at UH, which is developing NanoSTING.

Funding for the studies was provided by NIH (R01GM143243), Owens Foundation, and AuraVax Therapeutics.

“Over that embryonic period [up to eight weeks from conception], triploidy had rarely been reported in mammals outside of women,” said Mandi de Mestre, professor of equine medicine at Cornell University. “The study tells us that over the first six weeks of gestation, this will likely be the primary cause of pregnancy loss following natural conception.”

de Mestre is the corresponding author of “Naturally Occurring Horse Model of Miscarriage Reveals Temporal Relationship Between Chromosomal Aberration Type and Point of Lethality,” published in the Proceedings of the National Academy of Sciences.

Human miscarriages occur in 10-20% of pregnancies and are commonly associated with chromosomal errors, but there have been no suitable animal models that truly duplicate the features of the condition. The new research findings will help veterinarians better understand the causes of pregnancy loss in horses and identifies horses as an excellent model for studying human miscarriage.

“We were able to study the impact of chromosome errors across the entire pregnancy in the horse,” de Mestre said. “We found that triploidy is only associated with losses in early pregnancy.”

In the study, de Mestre’s laboratory at Cornell, and earlier at The Royal Veterinary College, London, received 256 fetus and placenta samples from veterinarians who treated horses with failed pregnancies over a period of 10 years. Using the samples, the researchers were able to investigate the prevalence of different types of chromosomal copy number errors associated with pregnancy loss. They found that chromosomal errors occurred in 57.9% of pregnancy losses up to day 55 of gestation, in 57.2% of losses between days 56 and 110 and in only 1.4% of losses between days 111 and the end of pregnancy. Aneuploidy (loss or gain of a single whole chromosome) was mainly associated with miscarriages in the first 10 weeks of pregnancy, while deletions or duplications of only part of a chromosome were found in miscarriages after 110 days. These findings turned out to be remarkably similar to those observed in a number of large studies in women, according to the paper.

Horses are a good model for studying human pregnancies because they have a similar gestation period — 11 months compared to nine months in women — and the embryo develops at a similar rate in the early stages. In addition, horse chromosomes have a very similar genetic content to human chromosomes, which makes them particularly relevant for the study of chromosome errors.

Reasons for miscarriage in women in very early pregnancy have been difficult to determine because most fetuses during this period are lost at home, leaving scientists without material — and data — to study. The study’s findings provide insight into the frequency of chromosome errors over the equivalent period of the first six weeks of human gestation.

Because of the value of horses and the emotional attachment their owners have to them, horses receive a high level of care, with routine tracking of pregnancies, which then provide extensive data for research.

Other animal models, such as mice, are not comparable to human pregnancies. Mice have a gestation period of about three weeks, and natural pregnancy losses in mice are low.

In terms of equine health, the study provides new details about common chromosomal abnormalities that will likely change the clinical management of pregnancies. For example, if a clinician determines that a horse has a major chromosomal error, they may no longer choose to extend that pregnancy by administering hormones, a common practice in pregnant mares. The study will also point researchers toward the development of new diagnostic tests for chromosome abnormalities in horse fetuses and investigating molecular mechanisms that lead to these abnormalities.

“This research has provided a foundation for understanding the genetic causes of pregnancy loss in horses, often referred to as pregnancy loss of unknown cause,” said Shebl Salem, a postdoctoral researcher in de Mestre’s Equine Pregnancy Lab and a co-first author of the study.

Other co-first authors include Jessica Lawson of the Royal Veterinary College in London, United Kingdom; and Donald Miller, de Mestre lab manager.

The study was partly funded by the Horserace Betting Levy Board and Thoroughbred Breeders Association.

“We were interested in the culinary pairing of yogurt and honey, which is common in the Mediterranean diet, and how it impacts the gastrointestinal microbiome,” said Hannah Holscher, associate professor in the Department of Food Science and Human Nutrition, part of the College of Agricultural, Consumer and Environmental Sciences at Illinois. She is a co-author of the two studies, which are both published in The Journal of Nutrition.

Greek yogurt and other yogurts contain probiotic strains such as Bifidobacterium animalis in addition to conventional yogurt starter cultures. Consumption of certain probiotics can promote digestive health and regular bowel movements, and it can have a positive effect on mood and cognition.

“The enzymes in our mouth, stomach, and intestines help with digestion and facilitate nutrient absorption, but they also reduce the viability of microbes. That’s great when it’s pathogens but not necessarily when it comes to beneficial bacteria,” Holscher said. “We wanted to see if honey could help probiotic bacteria survive in the gut.”

In the first study, the researchers conducted a laboratory experiment where they tested the effect of four different kinds of honey (alfalfa, buckwheat, clover, and orange blossom) on the viability of B. animalis in yogurt through simulated digestion processes. They grew microbes in petri dishes with solutions that mimicked the composition of saliva, stomach acid, intestinal bile, and enzymes.

For the saliva and stomach fluids, there were no differences in B. animalis survival between any of the honey varietals and control treatments of yogurt mixed with sugar or water. However, yogurt with honey — particularly the clover varietal — helped support the survival of probiotics in the intestinal phase of digestion.

Next, the researchers wanted to test their findings in a clinical study. They recruited 66 healthy adults and asked them to consume two different items for two weeks each — yogurt with clover honey and pasteurized, heat-treated yogurt. The participants provided stool samples and information about their bowel movements. They also filled out questionnaires and completed tasks evaluating their mood, cognition, and overall well-being.

“Our findings showed that pairing honey with yogurt supported the survival of the yogurt’s probiotic bacteria in the gut, so the lab study results did translate to real-world application in humans,” Holscher stated.

However, there were no changes in intestinal transit time, bowel movement frequency, or any of the mood and cognition measures. Holscher said this is likely because the participants already were healthy adults with regular bowel movements, so there wasn’t a lot of room for improvement.

The researchers also conducted a smaller follow-up study with 36 participants who consumed a third food item, yogurt with sugar. When the researchers compared the results of all three conditions, the combination of yogurt with honey preserved the most probiotics, but there were no effects on the health measures.

“We found that one tablespoon of honey in a serving of yogurt helps support probiotic survival. However, we have to keep in mind that honey is an added sugar, and most Americans need to be cognizant of the amount of sugar in their diet to maintain a healthy body weight,” she stated. “But adding a little bit of honey to unsweetened yogurt is a nice culinary pairing to incorporate into your menu rotation.”

You can also add toppings to make a yogurt parfait and support gut health and the microbiome by getting more fiber in your diet. For example, you can add berries and seeds, or nuts, and drizzle a bit of honey on top, Holscher suggested.

At the Vanderbilt University Institute of Imaging Science (VUIIS), scientists are focusing on a previously understudied part of the brain and spinal cord — white matter. Their discoveries could lead to treatments that restore nerve activity through the targeted delivery of electromagnetic stimuli or drugs.

As in the brain, the spinal cord is made up nerve cell bodies (gray matter), which process sensation and control voluntary movement, and axons (white matter), fibers that connect nerve cells and which project to the rest of the body.

In a recent paper published in the Proceedings of the National Academy of Sciences, Anirban Sengupta, PhD, John Gore, PhD, and their colleagues report the detection of signals from white matter in the spinal cord in response to a stimulus that are as robust as gray matter signals.

“In the spinal cord, the white matter signal is quite large and detectable, unlike in the brain, where it has less amplitude than the gray matter (signal),” said Sengupta, research instructor in Radiology and Radiological Sciences at Vanderbilt University Medical Center.

“This may be due to the larger volume of white matter in the spinal cord compared to the brain,” he added. Alternatively, the signal could represent “an intrinsic demand” in metabolism within the white matter, reflecting its critical role in supporting gray matter.

For several years, Gore, who directs the VUIIS, and his colleagues have used functional magnetic resonance imaging (fMRI) to detect blood oxygenation-level dependent (BOLD) signals, a key marker of nervous system activity, in white matter.

Last year they reported that when people who are having their brains scanned by fMRI perform a task, like wiggling their fingers, BOLD signals increase in white matter throughout the brain.

The current study monitored changes in BOLD signals in the white matter of the spinal cord at rest and in response to a vibrotactile stimulus applied to the fingers in an animal model. In response to stimulation, white matter activity was higher in “tracts” of ascending fibers that carry the signal from the spine to the brain.

This result is consistent with white matter’s known neurobiological function, the researchers noted. White matter contains non-neuronal glial cells that do not produce electrical impulses, but which regulate blood flow and neurotransmitters, the signaling molecules that transmit signals between nerve cells.

Much remains to be learned about the function of white matter in the spinal cord. But the findings from this research may help in improved understanding of diseases that affect white matter in the spinal cord, including multiple sclerosis, Sengupta said.

“We will be able to see how activity in the white matter changes in different stages of the disease,” he said. Researchers also may be able to monitor the effectiveness of therapeutic interventions, including neuromodulation, in promoting recovery following spinal cord injury.

Sengupta, the paper’s corresponding author, earned his doctorate at the Indian Institute of Technology in New Delhi in 2018, and joined the Vanderbilt faculty in 2024 after completing a postdoctoral fellowship at VUIIS.

Gore is University Distinguished Professor of Radiology and Radiological Sciences, Biomedical Engineering, Molecular Physiology and Biophysics, and Physics and Astronomy. Other VUIIS co-authors were Arabinda Mishra, Feng Wang, PhD, and Li Min Chen, MD, PhD.

The study was supported by National Institutes of Health grants R01NS092961 and R01NS113832.

The research is published Aug. 2 in Science Advances.

The compound targets gram-positive bacteria, which can cause drug-resistant staph infections, toxic shock syndrome and other illnesses that can turn deadly. It was developed through a collaboration between the labs of Scott Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology, and Michael Caparon, PhD, a professor of molecular microbiology, and Fredrik Almqvist, a professor of chemistry at the University of Umeå in Sweden.

A new type of antimicrobial would be good news for clinicians seeking effective treatments against pathogens that are becoming more resistant to currently available drugs, and thus much more dangerous.

“All of the gram-positive bacteria that we’ve tested have been susceptible to that compound. That includes enterococci, staphylococci, streptococci, C. difficile, which are the major pathogenic bacteria types,” said Caparon, the co-senior author. “The compounds have broad-spectrum activity against numerous bacteria.”

It’s based on a type of molecule called ring-fused 2-pyridone. Initially, Caparon and Hultgren had asked Almqvist to develop a compound that might prevent bacterial films from attaching to the surface of urethral catheters, a common cause of hospital-associated urinary tract infections. Discovering that the resulting compound had infection-fighting properties against multiple types of bacteria was a happy accident.

The team named their new family of compounds GmPcides (for gram-positive-icide). In past work, the authors showed that GmPcides can wipe out bacteria strains in petri dish experiments. In this latest study, they decided to test it on necrotizing soft-tissue infections, which are fast-spreading infections usually involving multiple types of gram-positive bacteria, for which Caparon already had a working mouse model. The best known of these, necrotizing fasciitis or “flesh-eating disease,” can quickly damage tissue severely enough to require limb amputation to control its spread. About 20% of patients with flesh-eating disease die.

This study focused on one pathogen, Streptococcus pyogenes, which is responsible for 500,000 deaths every year globally, including flesh-eating disease. Mice infected with S. pyogenes and treated with a GmPcide fared better than did untreated animals in almost every metric. They had less weight loss, the ulcers characteristic of the infection were smaller, and they fought off the infection faster.

The compound appeared to reduce the virulence of the bacteria and, remarkably, speed up post-infection healing of the damaged areas of the skin.

It is not clear how GmPcides accomplish all of this, but microscopic examination revealed that the treatment appears to have a significant effect on bacterial cell membranes, which are the outer wrapping of the microbes.

“One of the jobs of a membrane is to exclude material from the outside,” Caparon said. “We know that within five to ten minutes of treatment with GmPcide, the membranes start to become permeable and allow things that normally should be excluded to enter into the bacteria, which suggests that those membranes have been damaged.”

This can disrupt the bacteria’s own functions, including those that cause damage to their host, and make the bacteria less effective at combating the host’s immune response to infections.

In addition to their antibacterial effectiveness, GmPcides appear to be less likely to lead to drug-resistant strains. Experiments designed to create resistant bacteria found very few cells able to withstand treatment and thus pass on their advantages to the next generation of bacteria.

Caparon explained that there is a long way to go before GmPcides are likely to find their way into local pharmacies. Caparon, Hultgren and Almqvist have patented the compound used in the study and licensed it to a company, QureTech Bio, in which they have an ownership stake, with the expectation that they will be able to collaborate with a company that has the capacity to manage the pharmaceutical development and clinical trials to potentially bring GmPcides to market.

Hultgren said that the kind of collaborative science that created GmPcides is what is needed to treat intractable problems like antimicrobial resistance.

“Bacterial infections of every type are an important health problem, and they are increasingly becoming multi-drug resistant and thus harder to treat,” he said. “Interdisciplinary science facilitates the integration of different fields of study that can lead to synergistic new ideas that have the potential to help patients.”

Respiratory viruses, typically causing mild illness, can have more serious consequences, as shown during the Covid-19 pandemic, including severe cases requiring hospitalization and the chronic sequelae of “long Covid.” These conditions often result in the destruction of large areas of the lungs, particularly the alveoli responsible for gas exchanges. Ineffective repair of these structures can lead to ARDS or a permanent reduction in the lungs’ ability to oxygenate blood, causing chronic fatigue and exercise intolerance.

While the role of macrophages during the acute phase of respiratory viral infections is well known, their function in the post-inflammatory period has been largely unexplored. A study by the GIGA Institute at the University of Liège reveals that atypical macrophages, characterized by specific markers and transiently recruited during the early recovery phase, play a beneficial role in regenerating pulmonary alveoli.

Led by Dr. Coraline Radermecker and Prof. Thomas Marichal from the Immunophysiology Laboratory, the study was conducted by Dr. Cecilia Ruscitti and benefited from the ULiège’s advanced technological platforms, including flow cytometry, fluorescence microscopy, and single-cell RNA sequencing. “Our findings provide a novel and crucial mechanism for alveolar repair by these atypical macrophages,” explains Coraline Radermecker. “We have detailed their characteristics, origin, location in the damaged lung, the signals they require to function, and their role in tissue regeneration, specifically acting on type 2 alveolar epithelial cells, the progenitors of alveolar cells.” The scientific community had overlooked these macrophages because they express a marker previously thought to be specific for another immune cell population, the neutrophils, and because they appear only briefly during the repair phase before disappearing.

“Our study highlights the reparative role of these macrophages, countering the prevailing idea that macrophages following respiratory viral infections are pathogenic,” adds Thomas Marichal. “By targeting the amplification of these macrophages or stimulating their repair functions, we could develop therapies to improve alveolar regeneration and reduce complications from serious respiratory infections and ARDS.”

To illustrate, consider the lungs as a garden damaged by a storm (viral infection). These newly discovered macrophages act like specialized gardeners who clear debris and plant new seeds, enabling the garden to regrow and regain its vitality.

This scientific breakthrough underscores the importance of research at the University of Liège and opens new avenues for treating respiratory diseases.

Long COVID, also known as Post-COVID-19 condition, is generally defined as symptoms persisting for three months or more after acute COVID-19. The condition can affect and damage many organ systems, leading to severe and long-term impaired function and a broad range of symptoms, including fatigue, cognitive impairment — often referred to as ‘brain fog’ — breathlessness and pain.

Long COVID can affect almost anyone, including all age groups and children. It is more prevalent in females and those of lower socioeconomic status, and the reasons for such differences are under study. The researchers found that while some people gradually get better from long COVID, in others the condition can persist for years. Many people who developed long COVID before the advent of vaccines are still unwell.

“Long COVID is a devastating disease with a profound human toll and socioeconomic impact,” said Janko Nikolich, MD, PhD, senior author of the paper, director of the Aegis Consortium at the U of A Health Sciences, professor and head of the Department of Immunobiology at the U of A College of Medicine — Tucson, and BIO5 Institute member. “By studying it in detail, we hope to both understand the mechanisms and to find targets for therapy against this, but potentially also other infection-associated complex chronic conditions such as myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia.”

If a person has been fully vaccinated and is up to date with their boosters, their risk of long COVID is much lower. However, 3%-5% of people worldwide still develop long COVID after an acute COVID-19 infection. According to the Centers for Disease Control and Prevention, long COVID affects an estimated 4%-10% of the U.S. adult population and 1 in 10 adults who had COVID develop long COVID.

The review study also found that a wide range of biological mechanisms are involved, including persistence of the original virus in the body, disruption of the normal immune response, and microscopic blood clotting, even in some people who had only mild initial infections.

There are no proven treatments for long COVID yet, and current management of the condition focuses on ways to relieve symptoms or provide rehabilitation. Researchers say there is a dire need to develop and test biomarkers such as blood tests to diagnose and monitor long COVID and to find therapies that address root causes of the disease.

People can lower their risk of developing long COVID by avoiding infection — wearing a close-fitting mask in crowded indoor spaces, for example — taking antivirals promptly if they do catch COVID-19, avoiding strenuous exercise during such infections, and ensuring they are up to date with COVID vaccines and boosters.

“Long COVID is a dismal condition but there are grounds for cautious optimism,” said Trisha Greenhalgh, lead author of the study and professor at Oxford’s Nuffield Department of Primary Care Health Sciences. “Various mechanism-based treatments are being tested in research trials. If proven effective, these would allow us to target particular subgroups of people with precision therapies. Treatments aside, it is becoming increasingly clear that long COVID places an enormous social and economic burden on individuals, families and society. In particular, we need to find better ways to treat and support the ‘long-haulers’ — people who have been unwell for two years or more and whose lives have often been turned upside down.”

The full paper, “Long COVID: a clinical update,” is published in The Lancet.