While some people with lung diseases receive transplants, donor organs remain in short supply. As an alternative, medications and other treatments can be used to manage symptoms, but no cure is available for disorders such as chronic obstructive pulmonary disease and cystic fibrosis. Researchers continue to seek better medications, often relying on testing in rodents. But these animal models may only partially capture the complexities of pulmonary diseases in humans, and they might not accurately predict the safety and efficacy of new drugs. Meanwhile, bioengineers are exploring the production of lung tissue in the lab, either as a more accurate model to study human lungs or as a potential material to use in implants. One technique involves 3D printing structures that mimic human tissue, but designing a suitable bioink to support cell growth remains challenging. So, Ashok Raichur and colleagues set out to overcome this obstacle.

The team began with mucin, a mucus component that hasn’t been widely explored for bioprinting. Segments of this antibacterial polymer’s molecular structure resemble epidermal growth factor, a protein that promotes cell attachment and growth. Raichur and colleagues reacted mucin with methacrylic anhydride to form methacrylated mucin (MuMA), which they then mixed with lung cells. Hyaluronic acid — a natural polymer found in connective and other tissues — was added to increase the bioink’s viscosity and enhance cell growth and adhesion to MuMA. After the ink was printed in test patterns including round and square grids, it was exposed to blue light to crosslink the MuMA molecules. The crosslink bonds stabilized the printed structure in the form of a porous gel that readily absorbed water to support cell survival.

The researchers found that the interconnected pores in the gel facilitated diffusion of nutrients and oxygen, encouraging cell growth and formation of lung tissue. The printed structures were nontoxic and slowly biodegraded under physiological conditions, making them potentially suitable as implants in which the printed scaffold would gradually be replaced by newly grown lung tissue. The bioink could also be used to make 3D models of lungs to study lung disease processes and evaluate potential treatments.

The authors acknowledge funding from the Government of India’s Department of Science and Technology.

“Physical activity during leisure time and as transportation is becoming increasingly important now that many jobs and domestic activities are becoming more sedentary,” says lead author of the study Adam Viktorisson, researcher at Sahlgrenska Academy at the University of Gothenburg, Sweden.

Twenty years follow-up

The research study covers 3,614 people from the region of Västra Götaland, 269 of whom suffered a stroke in the twenty years spanned by the study. Three months after the stroke, 120 of these had died or were dependent on help to carry out activities of daily living.

Physical activity data was gathered from surveys. Some participants were also given a pedometer to wear. Physical activity during leisure time or for transportation showed a link to the objective measurements from the pedometers, while physical activity at work did not.

Occupational physical activity did not protect

The health benefits of physical activity are well known, but earlier studies tend to mainly focus on physical activity during leisure time. Research in recent years has shown that physical activity at work can instead have negative health impacts, increasing the risk of cardiovascular disease.

“How and when we carry out physical activity seems to play a crucial role in determining its health benefits. In our study leisure time and transport related physical activities were associated with a lower risk of stroke, whereas activities during work time or in the household were not” Adam Viktorisson points out.

“Physically demanding jobs are often linked to stress, little opportunity for recovery, air pollution and generally poorer socioeconomic conditions, which can counteract the positive effects of physical activity.”

Promote public health

The study used data from the INTERGENE cohort at the University of Gothenburg. Study participants were surveyed and data was collected from 2001 to 2004, encompassing both clinical data and questionnaire data. The researchers hope that these results will bring greater awareness and lead to changes in public health policy to encourage physical activity in society.”Encouraging people to be physically active in their daily lives, for example by walking, cycling and doing other types of exercise, can be an important strategy in reducing the number of strokes and improving the prognosis of people who suffer a stroke,” says Adam Viktorisson.

The study, led by Pankaj Arora, M.D., and Naman Shetty, M.D., examined data from 35,206 participants in the UK Biobank. The researchers investigated the clinical correlates of TTR levels, differences in TTR levels based on genetic variations and the association of TTR levels with health outcomes.

Arora and his team found that lower TTR levels are significantly associated with an increased risk of heart failure and all-cause mortality. Specifically, individuals with low TTR levels had a 17 percent higher risk of heart failure and an 18 percent higher risk of death from any cause compared to those with higher TTR levels. These findings were even more pronounced in individuals carrying the V142I TTR gene variant, which is known to destabilize the TTR protein.

The study revealed that TTR levels were lower in females compared to males and were influenced by several health factors. Higher systolic and diastolic blood pressure, total cholesterol, albumin levels, triglyceride levels, and creatinine levels were associated with increased TTR levels. Higher C-reactive protein levels were linked to lower TTR levels. Notably, carriers of the V142I TTR gene variant had significantly lower TTR levels compared to non-carriers, highlighting a genetic influence on this protein.

“Our research highlights the critical role of TTR levels in predicting heart disease risk,” Arora said. “By understanding the factors that influence TTR levels, we can better identify individuals at high risk and develop targeted interventions to prevent adverse outcomes.”

“These findings underscore the potential benefits of incorporating TTR level measurements in screening programs, especially for individuals with genetic predispositions,” Shetty said.

Arora, the senior author and a cardiologist at the UAB Cardiovascular Institute, says the implications of this study are far-reaching. It suggests that monitoring of TTR levels could be a valuable tool in managing heart disease risk, particularly for those with known genetic variations like the V142I TTR variant. Low TTR levels raise the pre-test probability of a positive genetic test, specifically for detecting the V142I variant, which typically takes time to process.

“This information can be used to counsel family members while they await the results of genetic testing,” Arora said. “This research marks a significant step forward in the quest to understand and mitigate the risks associated with cardiac amyloidosis and other heart-related conditions.”

The device records what the team calls Autonomic Neurography (ANG), neural activity from the human vagus and carotid sinus nerves as well as other autonomic nerves found in the skin and muscle of the neck. The vagus nerve is a “superhighway” of the involuntary nervous system, with tendrils extending from the base of the skull through the torso and abdomen to influence digestion, heart rate and the immune system. The vagus nerve plays a pivotal role in the body’s inflammatory response to injury or infection, and has been a focus for research into deadly conditions like sepsis, a leading cause of emergency room deaths affecting at least 1.7 million adults in the U.S. each year according to the National Institute of General Medical Sciences, and post-traumatic stress disorder, which affects about 3.5% of the population according to the National Institute of Mental Health.

To offer medical professionals a real-time, clinically proven tool for detecting levels of activity in the involuntary nervous system, an early warning sign of a body under stress, the researchers designed a flexible, adhesive-integrated electrode array (as reported in a 2022 Scientific Reports paper). The current study, published July 29, 2024 in Nature Communications Biology, used this approach with the aim of detecting deep neural activity in a simulated clinical hyperinflammatory model.

“We are encouraged by our results. The device is poised to provide an early diagnostic marker of pathogen infection, or inflammation from a pathological process,” said the study’s senior author Imanuel Lerman, head of the Lerman Lab of UC San Diego’s Qualcomm Institute, School of Medicine, and Jacobs School of Engineering, as well as the VA Center of Excellence for Stress and Mental Health. Lerman is the founder of InflammaSense Inc., the company that licenses the device’s technology. “Based on the study results, we are now deploying the device at the intensive care units of the Jacobs Medical Center at UC San Diego Health. The device will detect early involuntary neural signaling indicative of impending sepsis.”

Troy Bu, a Ph.D. candidate in the Jacobs School’s Department of Electrical and Computer Engineering, is the study’s first author.

Real-Time in the Emergency Room

To replace surgically implanted microelectrodes to monitor or activate the vagus nerve, the new device leverages a powerful technique called “magnetoneurography” to more accurately detect cervical nerve firing non-invasively in real-time. The device detects the magnetic fields arising from activity in the vagus and carotid sinus nerves, which “pulse” to warn the involuntary nervous system of a threat.

Researchers tested the device in nine adult human subjects. Patients had their blood drawn and their plasma tested for baseline levels of inflammation-triggering proteins called cytokines. Next, they were injected with bacteria-sourced toxins called lipopolysaccharides, inducing a temporary hyperinflammatory state in the body that mimicked the inflammation associated with a blood infection.

Inside a magnetically shielded room at the UC San Diego Qualcomm Institute Magnetoencephalography Center, researchers placed sensors from their device at points of the vagus nerve beneath the right ear and over the right carotid artery, where both the vagus nerve and carotid sinus nerve are found. The device monitored heart rate and the magnetic fields arising from nerve activity.

Within half an hour of the patients’ injection with lipopolysaccharides, the device detected changes in their nerve activity below the right ear. Researchers confirmed the rise in nerve activity and the release of inflammatory proteins through blood samples. They also recorded changes in heart rate throughout, as well as a noticeable link between nerve firing at both sites and changes in a particular inflammatory cytokine called tumor necrosis alpha, or TNF-α and the anti-inflammatory cytokine called IL-10.

TNF-α is a herald of sorts; patients with high levels are at a higher risk of entering septic shock, a deadly condition where the body’s inflammatory response overshoots the mark and causes devastating system-wide effects that can ultimately result in death.

Elevated levels of IL-10, on the other hand, can indicate patients at risk of immunoparalysis, a condition that occurs during sepsis when immune cells are unable to fight off either foreign or resident microbes, or resident viruses that can lead to uncontrolled infection and death.

“With sepsis, every minute counts and early treatments save lives,” said Bu. “Early sepsis detection is critical as, every hour sepsis is not treated, the likelihood of death increases by up to seven percent. Our technology can provide doctors with an early warning sign of hyperimmune or immunoparalysis response in sepsis. Doctors can then provide the correct treatment as quickly as possible.”

As in the 2022 study, researchers again found that patients separated into groups with distinct responses to the stress of the injection. Some patients showed higher peaks in the presence of inflammatory proteins and stronger side effects, while others’ peaks were lower.

With this technology, doctors may be able to identify subgroups of patients at higher risk of a hyperactive immune response and immunoparalysis, both of which contribute to sepsis-related complications and mortality. The device may also be used to determine whether treatments are reducing inflammation in the body, to better understand the nervous system and inflammation in people experiencing PTSD and other mental health conditions, and to tailor the dosage of therapies that target individual patients’ nervous systems.

This study was a collaboration between UC San Diego, Sandia National Laboratories, the University of Wisconsin-Madison, the VA Center for Stress and Mental Health, Quspin Laboratory, Stanford University and InflammaSense Inc.

Funding was provided by the Biomedical Advanced Research and Development Authority (BARDA) and the David and Janice Katz Neural Sensor Research Fund in Memory of Allen E. Wolf.

In a paper published July 25 in a special 50^th anniversary issue of the peer-reviewed journal Cell, the authors surveyed hundreds of studies that have emerged over the years looking at the causes underpinning types 1 (T1D) and 2 (T2D) diabetes and new treatments for the disease. They examine the role that genes, environmental factors, and social determinants of health play and diabetes’ effect on cardiovascular and kidney disease.

What they found shows there are many advances in treatments that could stem the tide of a disease that has struck millions of people around the globe and continues to grow. In addition, some of these advances could be used to treat other disorders. But there are still challenges ahead.

“As the prevalence of diabetes continues to grow around the world, it is important to understand the latest advancements in research so that clinicians can provide the best care to their patients, and patients can make informed choices that support improved health outcomes,” said lead author Dr. E. Dale Abel, chair of the UCLA Department of Medicine. “This is an educational resource that integrates the latest research and trends in diabetes management, which may have implications for clinical practice as the diabetic patient population continues to grow.

“This review will be the go-to reference for physicians and researchers, providing a state-of-the-art update of where the field is currently, and where it is headed,” Abel added.

Most people are affected by type 2 diabetes, for which inadequate diet and obesity are important underlying causes. Type 1 diabetes accounts for fewer than 5% of all cases. As of 2021 about 529 million people around the world were diagnosed with diabetes, representing about 6.1% of the global population, or about one in 16 people. Prevalence in some regions is as high as 12.3%. Type 2 diabetes comprises about 96% of cases, with more than half due to obesity. Some 1.31 billion people are projected to have the disease by 2050, with prevalence rising as high as 16.8% in North Africa and the Middle East and 11.3% in Latin America and the Caribbean, the researchers write.

Genetics, the central nervous system, and the interplay between various organs as well as social and environmental factors such as food insecurity and air pollution play a role in development of diabetes.

But some recent discoveries represent significant strides toward managing and perhaps even reversing the disease. For instance, a 2019 study found that a 14-day course of the antibody teplizumab delayed the progression of type 1 diabetes from stage 1 to stage 3 by 24 months. A follow-up analysis in 2021 showed that the delay could be up to 32.5 months.

Based on these results, the U.S. Food and Drug Administration approved teplizumab as the first disease-modifying therapy for type 1 diabetes, the researchers write.

Advances in insulins with optimized pharmacokinetics, algorithm-driven subcutaneous insulin pumps, continuous glucose monitoring, and improved tools for self-management have significantly improved the quality of life and outcomes for people with stage 3 type 1 diabetes.

In addition, stem cells could replace insulin-producing cells that are lost in type 1 diabetes, Abel said.

For type 2 diabetes, three classes of glucose-lowering medicines that were introduced in the last 20 years — GLP1RAs (glucagon like peptide-1 receptor agonists), DPP-4 inhibitors, and SGLT-2 inhibitors — have enabled people to control their glucose levels without gaining weight and with a low risk of developing hypoglycemia. Personalized and precision medicine approaches are being explored to target the molecular mechanisms behind diabetes. However, they must demonstrate that benefits are clinically superior to standard care and are cost-effective. Also, it remains to be seen if precision approaches can be implemented in all settings worldwide, including those with few resources.

Combinations of GLP1Ras and with molecules that target other receptors such as GIP have shown even greater efficacy in treating diabetes. Recent trials have also shown that they are very effective in treating obesity, certain types of heart failure and even sleep apnea, in part because of their potency to induce weight loss and reduce inflammation. Clinical trials are now underway to test their efficacy in treating other disorders such as Alzheimer’s disease, Abel said.

“Advances in therapy now raise the hope of preventing or curing T1D and treating T2D in ways that not only improve metabolic homeostasis, but also concretely reduce the risk and progression of cardio-renal disease,” the researchers write. “Finally, as we understand and develop tools for discerning the underlying heterogeneity leading to diabetes and its complications, the stage will be set for targeting therapies and prevention strategies to optimize their impact, in ways that will be broadly applicable across diverse populations and availability of health care resources.”

Additional co-authors are Anna Gloyn of Stanford University, Carmella Evans-Molina of Indiana University, Joshua Joseph of The Ohio State University, Shivani Misra of Imperial College London, Utpal Pajvani of Columbia University, Judith Simcox of University of Wisconsin-Madison, Katalin Susztak of University of Pennsylvania, and Daniel Drucker of University of Toronto.

The research programs of study authors have been funded by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK127236, U01DK127786, U01DK127382, R01 DK127308, R01DK133881, UC4 DK104166, P30 DK097512, UM1 DK126185, U01DK123743, U24DK098085, P30DK11607406, R01DK132403, AHRQ R01HS028822, DK103818, DK119767, R01DK133479), National Heart, Lung and Blood Institute (RO1DK125079, R61HL141783), American Heart Association (20SFRN35120123, 23SFRNCCS1052486, 23SFRNPCS1067039, 24FIM1266846), U.S. Department of Veterans Affairs Merit Award (I01BX001733), Wellcome Trust (095101, 200837), Wellcome Trust Career Development Award (223024/Z/21/Z), Glenn Foundation, American Federation for Aging Research (A22068); Hatch Grant (WIS04000-1024796); JDRF (JDRF201309442); Canadian Institutes of Health Research (154321), a BBDC-Novo Nordisk Chair in Incretin Biology, and Sinai Health-Novo Nordisk Fund in Regulatory Peptides.

“Liver fibrosis is the critical feature that creates chronic liver disease and liver cancer. If we can keep fibrosis in check then we can meaningfully impact liver disease,” said Tamer Sallam, MD, corresponding author of the study and vice chair and associate professor in the department of medicine at the David Geffen School of Medicine at UCLA.

“For decades we have believed that targeting inflammation is one of the most important ways to reduce MAFLD. But this new research indicates that inflammation, while still important, may not be the main driver of fibrosis.”

The study, published in the Journal of Clinical Investigation, looked specifically at a protein called lipopolysaccharide binding protein (LBP), which is involved in the body’s immune response, and how LBP functions in mice. Findings showed that mice without LBP in their liver cells had lower levels of liver inflammation and better liver function but no change in fibrosis.

In addition to mouse models, the researchers also studied genetic analyses from large human datasets and human tissue samples from MAFLD patients at different stages in the disease, to examine the consequence of loss of LBP function. The evidence combined showed that the LBP does not alter scar tissue markers.

Sallam indicated a need to further explore how LBP influences inflammation and whether other factors can offer a more potent reduction in inflammation and have an impact on reducing fibrosis.

“Reducing scar burden is one of the holy grails in the treatment of advanced liver diseases,” Sallam said. “These results suggest that certain ways of targeting inflammation may not be a viable option and that more directed therapies against other pathways could help us better target fibrosis and improve outcomes for patients.”

A new study suggests that getting at a patient’s eye level when talking with them about their diagnosis or care can really make a difference. Sitting or crouching at a hospitalized patient’s bedside was associated with more trust, satisfaction and even better clinical outcomes than standing, according to the new review of evidence.

The study’s authors, from the University of Michigan and VA Ann Arbor Healthcare System, note that most of the studies on this topic varied with their interventions and outcomes, and were found to have high risk of bias. Their findings are published in a systematic review in the Journal of General Internal Medicine.

So, the researchers sat down and figured out how to study the issue as part of their own larger evaluation of how different non-verbal factors impact care, perceptions and outcomes.

Until their new study ends, they say their systematic review should prompt clinicians and hospital administrators to encourage more sitting at the bedside.

Something as simple as making folding chairs and stools available in or near patient rooms could help — and in fact, the VA Ann Arbor has installed folding chairs in many hospital rooms at the Lieutenant Colonel Charles S. Kettles VA Medical Center.

Nathan Houchens, M.D., the U-M Medical School faculty member and VA hospitalist who worked with U-M medical students to review the evidence on this topic, says they focused on physician posture because of the power dynamics and hierarchy of hospital-based care.

An attending or resident physician can shift that relationship with a patient by getting down to eye level instead of standing over them, he notes.

He credits the idea for the study to two former medical students, who have now graduated and gone on to further medical training elsewhere: Rita Palanjian, M.D. and Mariam Nasrallah, M.D.

“It turns out that only 14 studies met criteria for evaluation in our systematic review of the impacts of moving to eye level, and only two of them were rigorous experiments,” said Houchens. “Also, the studies measured many different things, from length of the patient encounter and patient impressions of empathy and compassion, to hospitals’ overall patient evaluation scores as measured by standardized surveys like the federal HCAHPS survey.”

In general, he said, the data paint the picture that patients prefer clinicians who are sitting or at eye level, although this wasn’t universally true. And many studies acknowledged that even when physicians were assigned to sit with their patients, they didn’t always do so — especially if dedicated seating was not available.

Houchens knows from supervising U-M medical students and residents at the VA that clinicians may be worried that sitting down will prolong the interaction when they have other patients and duties to get to. But the evidence the team reviewed suggests this is not the case.

He notes that other factors, such as concerns about infection transmission, can also make it harder to consistently get to eye level.

“We hope our work will bring more recognition to the significance of sitting and the general conclusion that patients appreciate it,” says Houchens. Making seating available, encouraging physicians to get at eye level, and senior physicians making a point to sit as role models for their students and residents, could help too.

A recently launched VA/U-M study, funded by the Agency for Healthcare Research and Quality and called the M-Wellness Laboratory study, includes physician posture as part of a bundle of interventions aimed at making hospital environments more conducive to healing and forming bonds between patient and provider.

In addition to encouraging providers to sit by their patients’ bedsides, the intervention also includes encouraging warm greetings as providers enter patient rooms and posing questions to patients about their priorities and backgrounds during conversations.

The researchers will look for any differences in hospital length of stay, readmissions, patient satisfaction scores, and other measures between the units where the bundle of interventions is being rolled out, and those where it is not yet.

In addition to Houchens and the two former students, the authors of the systematic review are U-M and VA hospitalist Ashwin Gupta, M.D., Whitney Townsend of the U-M Taubman Health Sciences Library, VA chief of medicine and U-M professor Sanjay Saint, M.D., M.P.H., and Jason Engle, M.P.H. Saint and Engle are part of the VA Center for Clinical Management Research, and Saint is a member of the U-M Institute for Healthcare Policy and Innovation.

Houchens, Gupta, and Saint are faculty in the Division of Hospital Medicine of the Department of Internal Medicine at Michigan Medicine, U-M’s academic medical center.

The newly published study was funded by U-M and VA resources. The newly launched study is funded by AHRQ grant HS28963-01.

The researchers employed cultures of neurons and microglia, derived from either mouse models or human stem cells, and used cutting-edge imaging technology to demonstrate that microglia establish contact with neurons through tunnelling nanotubes (TNTs) to alleviate them from toxic protein accumulations. Additionally, the microglia transfer healthy mitochondria, the powerhouses of the cells, to affected neurons, which significantly reduces oxidative stress, restores vital functions and ultimately rescues these nerve cells.

Live imaging of tunnelling nanotubes

Using live cell imaging microscopy, the scientists observed the formation of connections between neurons and microglia.

“Further research is needed to understand the formation and function of TNTs in detail, but it was thrilling to observe that microglia play an active role in maintaining neuronal health and supporting neurons in times of need,” details Dr Hannah Scheiblich, first author of the article who worked with Prof. Heneka at the University Hospital Bonn and the German Center for Neurodegenerative Diseases.

Microglia rescue neurons through protein removal and mitochondria donation

In co-cultures of neurons and microglia, the team further observed that when toxic proteins accumulate within neurons, the number of TNTs connecting the two cell types increased and that these nanotubes contained alpha-synuclein and tau particles. The pathological proteins were transferred from neurons to microglia, not vice versa, where they were degraded over time. The results not only showed that microglia can effectively alleviate neurons from toxic protein burdens but that they also transfer mitochondria toward affected neurons via the same TNTs.

Mitochondria are important component of cells and when they don’t function properly, it can lead to energy deficits and oxidative stress. Both alpha-synuclein and tau can impair mitochondrial activity, contributing to the dysfunction and death of neurons in neurodegenerative diseases. Remarkably, when microglia transferred healthy mitochondria to affected neurons, the scientists noticed that it restored energy production and reduced oxidative damage, effectively preserving neuronal functioning and survival.

Altogether, these findings suggest that, by clearing protein aggregates from neurons and transferring functional mitochondria, microglial TNTs directly support neuronal health and can mitigate the progression of neurodegeneration.

Exploring the impact of genetic mutations

Next, the researchers investigated whether known genetic mutations associated with neurodegenerative diseases influenced the formation of tunnelling nanotubes and the TNT-based rescue mechanisms. They observed that mutations on the LRRK2 and Trem2 genes, respectively linked to Parkinson’s disease and frontotemporal dementia, either reduced aggregate removal or compromised the delivery of functional mitochondria. Additionally, alterations linked to Parkinson’s in gene Rac1 could also affect TNT formation and functionality.

These results indicate new ways by which known genetic mutations may be contributing to neurodegenerative diseases. By disrupting TNT-mediated neuroprotective mechanisms, these genetic variants prevent microglia from supporting neurons effectively. Targeting these genes may provide an avenue to enhance TNT formation and activate transfer via these nanotubes, which may in turn help mitigate the progression of certain neurodegenerative diseases.

An international collaboration for promising results

This research work was conducted with several key collaborators including Dr Daniele Bano, Prof. Donato Di Monte, and Prof. Eike Latz from the German Center for Neurodegenerative Diseases, Dr Ádám Dénes from the Institute of Experimental Medicine in Budapest, Dr Ronald Melki from the François Jacob Institute of biology in Paris and Prof. Hans-Christian Pape from the University of Münster. Thanks to this team effort and the jointly generated data set, the results open promising avenues when it comes to understanding the brain and its associated diseases.

“This study has not only deepened our understanding of intercellular communication through tunnelling nanotubes,” concludes Prof. Michael Heneka. “It has challenged the conventional view of microglia as contributors to neuroinflammation, highlighted a novel neuroprotective mechanism and offered insights into potential therapeutic strategies for neurodegenerative conditions linked to alpha-synuclein and tau pathology.”

Now, the same research group has applied the therapeutic strategy to damaged human cartilage cells. In the new study, the treatment activated the gene expression necessary to regenerate cartilage within just four hours. And, after only three days, the human cells produced protein components needed for cartilage regeneration.

The researchers also found that, as the molecular motion increased, the treatment’s effectiveness also increased. In other words, the molecules’ “dancing” motions were crucial for triggering the cartilage growth process.

The study was published today (July 26) in the Journal of the American Chemical Society.

“When we first observed therapeutic effects of dancing molecules, we did not see any reason why it should only apply to the spinal cord,” said Northwestern’s Samuel I. Stupp, who led the study. “Now, we observe the effects in two cell types that are completely disconnected from one another — cartilage cells in our joints and neurons in our brain and spinal cord. This makes me more confident that we might have discovered a universal phenomenon. It could apply to many other tissues.”

An expert in regenerative nanomedicine, Stupp is Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern, where he is founding director of the Simpson Querrey Institute for BioNanotechnology and its affiliated center, the Center for Regenerative Nanomedicine. Stupp has appointments in the McCormick School of Engineering, Weinberg College of Arts and Sciences and Feinberg School of Medicine. Shelby Yuan, a graduate student in the Stupp laboratory, was primary author of the study.

Big problem, few solutions

As of 2019, nearly 530 million people around the globe were living with osteoarthritis, according to the World Health Organization. A degenerative disease in which tissues in joints break down over time, osteoarthritis is a common health problem and leading cause of disability.

In patients with severe osteoarthritis, cartilage can wear so thin that joints essentially transform into bone on bone — without a cushion between. Not only is this incredibly painful, patients’ joints also can no longer properly function. At that point, the only effective treatment is a joint replacement surgery, which is expensive and invasive.

“Current treatments aim to slow disease progression or postpone inevitable joint replacement,” Stupp said. “There are no regenerative options because humans do not have an inherent capacity to regenerate cartilage in adulthood.”

What are ‘dancing molecules’?

Stupp and his team posited that “dancing molecules” might encourage the stubborn tissue to regenerate. Previously invented in Stupp’s laboratory, dancing molecules are assemblies that form synthetic nanofibers comprising tens to hundreds of thousands of molecules with potent signals for cells. By tuning their collective motions through their chemical structure, Stupp discovered the moving molecules could rapidly find and properly engage with cellular receptors, which also are in constant motion and extremely crowded on cell membranes.

Once inside the body, the nanofibers mimic the extracellular matrix of the surrounding tissue. By matching the matrix’s structure, mimicking the motion of biological molecules and incorporating bioactive signals for the receptors, the synthetic materials are able to communicate with cells.

“Cellular receptors constantly move around,” Stupp said. “By making our molecules move, ‘dance’ or even leap temporarily out of these structures, known as supramolecular polymers, they are able to connect more effectively with receptors.”

Motion matters

In the new study, Stupp and his team looked to the receptors for a specific protein critical for cartilage formation and maintenance. To target this receptor, the team developed a new circular peptide that mimics the bioactive signal of the protein, which is called transforming growth factor beta-1 (TGFb-1).

Then, the researchers incorporated this peptide into two different molecules that interact to form supramolecular polymers in water, each with the same ability to mimic TGFb-1. The researchers designed one supramolecular polymer with a special structure that enabled its molecules to move more freely within the large assemblies. The other supramolecular polymer, however, restricted molecular movement.

“We wanted to modify the structure in order to compare two systems that differ in the extent of their motion,” Stupp said. “The intensity of supramolecular motion in one is much greater than the motion in the other one.”

Although both polymers mimicked the signal to activate the TGFb-1 receptor, the polymer with rapidly moving molecules was much more effective. In some ways, they were even more effective than the protein that activates the TGFb-1 receptor in nature.

“After three days, the human cells exposed to the long assemblies of more mobile molecules produced greater amounts of the protein components necessary for cartilage regeneration,” Stupp said. “For the production of one of the components in cartilage matrix, known as collagen II, the dancing molecules containing the cyclic peptide that activates the TGF-beta1 receptor were even more effective than the natural protein that has this function in biological systems.”

What’s next?

Stupp’s team is currently testing these systems in animal studies and adding additional signals to create highly bioactive therapies.

“With the success of the study in human cartilage cells, we predict that cartilage regeneration will be greatly enhanced when used in highly translational pre-clinical models,” Stupp said. “It should develop into a novel bioactive material for regeneration of cartilage tissue in joints.”

Stupp’s lab is also testing the ability of dancing molecules to regenerate bone — and already has promising early results, which likely will be published later this year. Simultaneously, he is testing the molecules in human organoids to accelerate the process of discovering and optimizing therapeutic materials.

Stupp’s team also continues to build its case to the Food and Drug Administration, aiming to gain approval for clinical trials to test the therapy for spinal cord repair.

“We are beginning to see the tremendous breadth of conditions that this fundamental discovery on ‘dancing molecules’ could apply to,” Stupp said. “Controlling supramolecular motion through chemical design appears to be a powerful tool to increase efficacy for a range of regenerative therapies.”

For the first time, researchers at Tulane National Primate Research Center found that a cancer drug significantly reduced levels of SIV, the nonhuman primate equivalent of HIV, in the brain by targeting and depleting certain immune cells that harbor the virus.

Published in the journal Brain, this discovery marks a significant step toward eliminating HIV from hard-to-reach reservoirs where the virus evades otherwise effective treatment.

“This research is an important step in tackling brain-related issues caused by HIV, which still affect people even when they are on effective HIV medication,” said lead study author Woong-Ki Kim, PhD, associate director for research at Tulane National Primate Research Center. “By specifically targeting the infected cells in the brain, we may be able to clear the virus from these hidden areas, which has been a major challenge in HIV treatment.”

Antiretroviral therapy (ART) is an essential component of successful HIV treatment, maintaining the virus at undetectable levels in the blood and transforming HIV from a terminal illness into a manageable condition. However, ART does not completely eradicate HIV, necessitating lifelong treatment. The virus persists in “viral reservoirs” in the brain, liver, and lymph nodes, where it remains out of reach of ART.

The brain has been a particularly challenging area for treatment due to the blood-brain barrier — a protective membrane that shields it from harmful substances but also blocks treatments, allowing the virus to persist. In addition, cells in the brain known as macrophages are extremely long-lived, making them difficult to eradicate once they become infected.

Infection of macrophages is thought to contribute to neurocognitive dysfunction, experienced by nearly half of those living with HIV. Eradicating the virus from the brain is critical for comprehensive HIV treatment and could significantly improve the quality of life for those with HIV-related neurocognitive problems.

Researchers focused on macrophages, a type of white blood cell that harbors HIV in the brain. By using a small molecule inhibitor to block a receptor that increases in HIV-infected macrophages, the team successfully reduced the viral load in the brain. This approach essentially cleared the virus from brain tissue, providing a potential new treatment avenue for HIV.

The small molecule inhibitor used, BLZ945, has previously been studied for therapeutic use in amyotrophic lateral sclerosis (ALS) and brain cancer, but never before in the context of clearing HIV from the brain.

The study, which took place at the Tulane National Primate Research Center, utilized three groups to model human HIV infection and treatment: an untreated control group, and two groups treated with either a low or high dose of the small molecule inhibitor for 30 days. The high-dose treatment lead to a notable reduction in cells expressing HIV receptor sites, as well as a 95-99% decrease in viral DNA loads in the brain .

In addition to reducing viral loads, the treatment did not significantly impact microglia, the brain’s resident immune cells, which are essential for maintaining a healthy neuroimmune environment. It also did not show signs of liver toxicity at the doses tested.

The next step for the research team is to test this therapy in conjunction with ART to assess its efficacy in a combined treatment approach. This could pave the way for more comprehensive strategies to eradicate HIV from the body entirely.

This research was funded by the National Institutes of Health, including grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke, and was supported with resources from the Tulane National Primate Research Center base grant of the National Institutes of Health, P51 OD011104.

The study, recently published in Nature Communications, demonstrates the effectiveness of their novel gene therapy technology in improving muscle tissue and overall strength in mice models with Duchenne muscular dystrophy.

Duchenne muscular dystrophy is a genetic disorder caused by mutations in the DMD gene, resulting in a lack of the protein dystrophin. This deficiency leads to progressive muscle weakness and loss of muscle tissue over time. Patients with the disease experience impaired mobility, heart and lung problems, and ultimately a shortened life expectancy.

“Current gene therapy for Duchenne muscular dystrophy utilizes a truncated version of dystrophin,” said Renzhi Han, PhD, senior author of the study and professor of pediatrics at the IU School of Medicine. “Unfortunately, this option doesn’t fully protect the muscles because it lacks many important functional domains of full-length dystrophin.”

While the U.S. Food and Drug Administration recently approved a micro-dystrophin gene therapy for Duchenne muscular dystrophy, Han said the therapeutic outcomes have been less satisfactory than expected.

Building on their experience using adeno-associated virus methods to deliver extra-large therapeutic genes into cells, Han and his team at the Herman B Wells Center for Pediatric Research developed a triple-adeno-associated virus vector system to deliver a complete version of the dystrophin protein into the muscles.

“We optimized and tested our new three-vector system to make sure it produced and assembled the full-length dystrophin protein effectively,” Han said. “Our data confirmed we successfully restored full-length dystrophin in both the skeletal and heart muscles of mice with DMD, leading to significant improvements in their muscle health, strength and function.”

Han has filed a provisional patent application for his triple-adeno-associated virus vector system and is collaborating with the IU Innovation and Commercialization Office to advance the treatment toward market availability. He is also seeking additional funding so patients with Duchenne muscular dystrophy have access to promising new treatment options.

“I believe this new gene therapy approach offers significant advantages to patients compared to what they currently have available, and I’m eager to get it into further clinical development,” he said.

Other IU School of Medicine study authors include Yuan Zhou, Chen Zhang, Weidong Xiao and Roland W. Herzog.

A new study in the Journal of the American Heart Association, led by Lindsay Rosman, PhD,assistant professor of medicine in the division of cardiology at the University of North Carolina School of Medicine, is the first to show that wearable devices, such as smart watches, can significantly amplify anxiety and increase healthcare use in patients with Afib.

The study included 172 patients from UNC Health with a prior diagnosis of Afib who completed a survey and had their information linked to electronic health records. About half of the study sample had a wearable device and their data was compared to individuals without a wearable device. Rosman and her team found that patients with Afib who use wearables are more likely to be preoccupied with their heart symptoms, report concerns about their AFib treatment, and use healthcare resources compared to Afib patients without these devices. Providers and healthcare clinics were also impacted, as wearable users were more likely to call the clinic and send messages to their healthcare providers than individuals who did not have a device.

Also, 1 in 5 AFib patients who used wearables in this study experienced intense fear and anxiety in response to irregular rhythm notifications from their device. And a similar proportion (20%) routinely contacted their doctors when ECG results were abnormal or indicative of possible AFib. But it’s unclear if they actually needed to see a doctor, due to the alerts from their devices. It’s also unclear if the reported anxiety contributed to the worsening of symptoms, although anxiety has been a well-documented contributing factor to various conditions, including AFib.

“Given the significant increase in use of wearable devices in this patient group (and the population in general),” said Rosman, “we believe prospective studies and randomized trials are needed to understand the net effects of wearables — including their alerts — on patients’ healthcare use and psychological well-being, as well as the downstream effects on providers, hospitals, and health systems.”

AD is a devastating neurodegenerative disorder affecting millions of people worldwide. Accumulation of Aβ — peptides consisting of 36 to 43 amino acids — is an early critical hallmark of the disease. Recent clinical trials demonstrating a slowing of cognitive and functional decline in individuals with AD who are treated with anti-Aβ antibodies reinforce the important role of Aβ in the disease process. Despite the key cellular effects of Aβ and its essential role in AD, the traditional assumption that neurons are the primary source of toxic Aβ in the brain has remained untested.

In the study, Rajani and Busche showed that non-neuronal brain cells called oligodendrocytes produce Aβ. They further demonstrated that selectively suppressing Aβ production in oligodendrocytes in an AD mouse model is sufficient to rescue abnormal neuronal hyperactivity. The results provide evidence for a critical role of oligodendrocyte-derived Aβ for early neuronal dysfunction in AD. Collectively, the findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.

According to the authors, the functional rescue is remarkable given the relatively modest reduction in plaque load that results from blocking oligodendrocyte Aβ production, while blocking neuronal Aβ production leads to a near elimination of plaques — another hallmark of the disease. This small contribution of oligodendrocytes to plaque load could suggest that a main effect of oligodendrocyte-derived Aβ is to promote neuronal dysfunction.

Together with the data showing an increased number of Aβ-producing oligodendrocytes in deeper cortical layers of the brains of individuals with AD, these results indicate that oligodendrocyte-derived Aβ plays a pivotal role in the early impairment of neuronal circuits in AD, which has important implications for how the disease progresses and is treated. The increased number of oligodendrocytes in human AD brains also raises the intriguing possibility that these cells could potentially offset reduced Aβ production due to neuronal loss as the disease progresses.

The authors add, “Our study challenges the long-held belief that neurons are the exclusive source of amyloid beta in the brain, one of the key toxic proteins that builds up in Alzheimer’s Disease. In fact, we show that oligodendrocytes, the myelinating cells of the central nervous system, can also produce significant amounts of amyloid beta which impairs neuronal function, and suggests that targeting these cells may be a promising new strategy to treat Alzheimer’s Disease.”

Ferroptosis is triggered by the iron-mediated production of reactive oxygen species (ROS) and subsequent lipid peroxidation, which plays a crucial role in shrinking cancerous tumors. This is the first time that Par-4, already known for killing cancer cells through apoptosis — a form of programmed cell death — has been shown to promote ferroptosis in glioblastoma cells.

The tumor suppressor protein Par-4 is widely expressed across species, but is often reduced, mutated, or inactivated in the presence of various cancers. In the study “Tumor suppressor Par-4 activates autophagy-dependent ferroptosis,” recently published in the journal Communications Biology, the researchers identified that Par-4 plays an unanticipated role in promoting ferroptosis-mediated cancer regression. They demonstrated that Par-4 triggers the activation of ferritinophagy (autophagic degradation of ferritin) through the nuclear receptor co-activator 4 (NCOA4). This activation is necessary for the accumulation of the labile iron pool, the production of ROS, and the subsequent lipid peroxidation, all of which lead to ferroptosis.

Ferroptosis plays a key role in various health issues, such as cancer, heart disease, brain damage, kidney failure, lung injury, and diseases like Parkinson’s, Huntington’s, and Alzheimer’s. The identification of Par-4 as a key player in ferroptosis is essential, as it is involved in the main processes and signals that make this alternative cell death pathway, ferroptosis, occur. Many types of cancer cells don’t respond to today’s treatments or have developed resistance to existing drugs therapies.

This research was a collaborative effort between Associate Professor Mazin Magzoub’s lab at NYU Abu Dhabi and Professor Vivek M. Rangnekar from the University of Kentucky, who discovered Par-4 in 1993.

“Our team’s discovery that Par-4 triggers ferroptosis is a breakthrough in the field of cancer treatment development,” said Galadari, who is the Senior Vice Provost for Research and Managing Director of the Research Institute at NYU Abu Dhabi. “Developing methods to activate alternative cell death pathways presents new opportunities for the creation of more potent and effective therapies for glioblastoma and other deadly and debilitating diseases.”

“Investing in research at institutions such as NYUAD is instrumental in transforming the UAE into a knowledge-based economy that attracts local, regional, and global talent — a symbiotic relationship that creates opportunities, knowledge, and wealth,” Galadari added.

When it comes to muscles and muscle disorders, the importance of a discovery like this cannot be overstated.

The muscle of muscles

The very core function of life — breathing — is controlled by your skeletal muscles, as is regulation of whole-body metabolism and every movement you make:

In context

Skeletal muscles are formed during embryonic development by the fusion of hundreds of specialized cells called myoblasts. Adult skeletal muscles maintain regenerative capacity, which is attributed to the presence of muscle stem cells, named satellite cells.

After injury, satellite cells undergo several rounds of proliferation followed by their differentiation into myoblasts. These myoblasts once again fuse with each other and to injured myofibers to accomplish muscle regeneration.

In many muscular disorders, this intrinsic capacity of muscles to regenerate is diminished resulting in the loss of muscle mass and function.

The science

UH researchers found that Inositol-requiring enzyme 1, a key signaling protein, is essential for myoblast fusion during muscle formation and growth.

“During muscle regeneration, IRE1 augments the activity of X-box binding protein 1 which in turn stimulates the gene expression of multiple transmembrane proteins required for myoblast fusion,” reports Ashok Kumar, Else and Philip Hargrove Endowed Professor of pharmacy in the Department of Pharmacological and Pharmaceutical Sciences at the UH College of Pharmacy, in EMBO Reports.

According to researchers, increasing the levels of IRE1 or XBP1 in muscle stem cells outside the body, followed by their injection in patients’ muscle tissues will improve muscle repair and reduce the severity of disease.

“We also found that augmenting the levels of IRE1α or XBP1 in myoblasts leads to the formation of myotubes (muscle cells) having an increased diameter,” said Kumar.

That increase in diameter can be significant.

“Size is very important for muscle. Muscle grows only in size, not in number,” said Aniket Joshi, a graduate student in Kumar’s lab and first author on the article. “Muscular people have larger muscle cells. Larger muscles generally work better- can lift more weight, run and walk faster, and improve overall metabolism of the body and prevent various diseases, such as type II diabetes.”

Flexing their muscles

This new research is not the first flex for Kumar’s team. In 2021, research from Kumar’s lab published in the ELife journal described the role of the IRE1α/XBP1 signaling axis in regeneration of healthy skeletal muscle after acute injury and in models of Duchenne Muscular Dystrophy. In this study, they found that IRE1α/XBP1 signaling axis also plays an important cell autonomous role in satellite cells.

Along with Kumar and Joshi, post-doctoral fellow Meiricris Tomaz da Silva and research assistant professor, Anirban Roy conducted the research in Kumar’s lab. Other authors on the article from the University of Houston include Micah Castillo, Preethi Gunaratne, Mingfu Wu, Yu Liu, and a former post-doctoral fellow in Kumar’s lab Tatiana E. Koike along with Takao Iwawaki of Kanazawa Medical University, Japan.

RSV causes a significant disease burden in the global population, with an estimated 33.1 million cases each year, and is the leading cause of infant bronchiolitis and viral pneumonia. It is also particularly problematic for children and elderly people, with treatment options limited and relatively ineffective.

Working with human airway epithelial cells, the team of scientists has discovered that RSV suppresses a key biological pathway in our cells (called “the JAK/STAT pathway”) and prevents key “immune system igniters” from moving into the nuclei of cells. These igniters are ordinarily activated by interferon-alpha, our own natural antiviral.

Nigel Stevenson, Assistant Professor of Virology Immunology in Trinity’s School of Biochemistry and Immunology, is the senior author of the research article that has just been published in leading journal Frontiers in Immunology. Nigel, who is based in the Trinity Biomedical Sciences Institute (TBSI), said:

“Interferon-alpha, which activates signals in our cells through the JAK/STAT pathway, is responsible for kick-starting hundreds of antiviral genes into action, which then target the virus in a number of different ways. So when RSV prevents interferon from communicating to these genes the virus slams the brakes on our immune response, which can result in the virus taking hold and quite quickly causing very serious medical issues.

“Our discovery is an exciting revelation because it identifies the JAK/STAT pathway as a prime target for therapeutic immune restoration. And this new knowledge is very valuable to drug designers, as they need to fully understand how a virus evades our immune system before they can successfully create a therapeutic to turn the tide.

“We predict such a therapeutic could make a significant impact in treating RSV and even clear an RSV infection, which would represent a much-needed solution for both children and the elderly, who are very vulnerable to this dangerous virus.”

“The way A-beta behaves in a variety of environments, including the human brain, is elusive,” said Brian Sun, an electrical systems and engineering alumnus of Washington University in St. Louis who is now an MD/PhD student in the School of Medicine.

“There’s an understanding of growth and decay that isn’t fully fleshed out,” he added.

That’s going to change, thanks to research recently published by Sun with colleagues in Associate Professor Matthew Lew’s lab at the Preston M. Green Department of Electrical and Systems Engineering (ESE) in WashU’s McKelvey School of Engineering. .

In first of its kind work, Sun and colleagues were able to make measurements of amyloid fibril beta-sheet assemblies, the underlying girders of the protein conglomeration, while they were changing. Previous high-resolution microscopy studies have only gotten static shots.

“We wanted to look specifically at dynamics of the underlying structure of A-beta that could be responsible for the changes we’re seeing, not just changes in the overall shape,” Sun said.

Lew uses Lego as an analogy, noting that current imaging technology shows you the full Lego building but not any look at how each individual brick is organized.

“The individual proteins are always changing in response to their environment,” Lew said. “It is like having certain Lego bricks causing other bricks to change their shape. The changing architecture of the proteins and the assembled aggregates together leads to the complexity of neurogenerative disease.”

The Lew lab has developed a new type of imaging tech that allows them to see the orientation and other minute details in nanostructures of biological systems that were previously invisible. Their technique — single-molecule orientation-localization microscopy (SMOLM) — uses the flashes of light from chemical probes to visualize the sheets of peptides underlying Aβ42, one kind of A-beta peptide.

Using SMOLM lets them look at individual orientation of the underlying beta-sheets to see the relationship between their organization and how that relates to the overall structure of the amyloid protein.

Multiple ways to remodel

Aβ42 is constantly changing, and step one is to try to find a method to the madness, a model or pattern of action to predict the protein’s behavior.

Now that the Lew lab can make these measurements, they made some intuitive observations and found some surprises hidden in the amyloid-beta architecture.

As can be expected, stable Aβ42 structures tend to retain stable underlying beta-sheetsgrowing structures have underlying beta-sheets that become more defined and rigid as the growth continues. Decaying structures exhibit increasingly disordered and less rigid beta-sheets. But they also found more than one way that Aβ42 can renovate.

“There are multiple different ways for Aβ42 structures to remain stable, or grow and decay,” Sun said.

The researchers also discovered that Aβ42 can grow and decay in ways that defy expectations. For example, Aβ42 can grow and decay in ways that preserve the underlying structure; sometimes there’s growth where the peptides just pile on, but the underlying beta-sheet orientations don’t change. In other cases, Aβ42 undergoes “stable decay,” where the opposite happens i.e. peptides leave, but beta-sheet structure remains. Finally, Aβ42’s beta-sheets sometimes reorganize and change orientations without immediate accompanying changes to the overall shape. These nano-structural reorganizations can predispose to future large-scale remodeling.

“Because SMOLM can track Aβ42’s underlying organization and not just its shape, we can see different kinds of subtypes of remodeling that aren’t visible to diffraction-limited, non-orientation imaging modalities,” Sun said.

If it all sounds a bit vague, keep in mind this is the first pass at even looking at these constantly shifting nanoscale structures. There were no previous works to compare notes, which makes it all the more notable that Sun crafted this work while juggling COVID-19 lockdown restrictions and his undergrad course load at WashU, which he completed in three years. It paves the way for him and others to start really getting a handle on amyloid architecture.

He’ll likely end up chasing more of these questions during the graduate phase of his MD/PhD training, where he plans to design nanoscale imaging systems and sensors that could reveal hidden mechanisms of difficult-to-treat diseases.

Sun credits WashU ESE department and the Lew lab for the rigorous training that made this study and academic trajectory possible, as well as WashU’s MSTP for supporting his continued research post-graduation. “I’m really glad I went through this journey,” he said.

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R35GM124858.

Her latest research examines the health records and health care use of youth, individuals under age 21, who likely have been involved or whose families have been involved in the justice system. The challenge was identifying youth who have been impacted by mass incarceration, as most health care systems don’t routinely ask about incarceration. Families may not disclose that information due to stigma, fear of child protective services involvement, or judgment.

“There are few, if any, large community-level studies about the health of youth affected by incarceration, or their family’s incarceration, using medical records,” explains Boch, an assistant professor at the University of Cincinnati College of Nursing. “Despite a lot of youth and families affected by incarceration, gaps remain in understanding its prevalence and consequences. There are numerous reasons for this, some include a lack of provider awareness, lack of curriculum in provider training, lack of funding for this research and lack of routine sensitive screening for exposure.”

Boch and her research team searched the electronic medical records for justice-related keywords such as “prison,” “jail,” “sentenced,” “probation,” “parole,” and others, to determine the impact of incarceration. The researchers used data from Cincinnati Children’s Hospital collected over an 11-year period.

Their study, published in Academic Pediatrics, found that of the more than 1.7 million records reviewed, 38,263 (or 2.2%) of youth seen between January 2009 and December 2020 likely had a parent incarcerated or faced some type of confinement as a juvenile. This small percentage was also responsible for a disproportionate number of physical and mental health diagnoses and health care visits at Cincinnati Children’s. They were compared against a socio demographically matched sample without a justice keyword and the total sample population of youth.

Nearly 63.3% of all behavioral health inpatient admissions, 23.7% of all hospitalization inpatient days and 45.5% of all foster care visits were attributed to the 2.2% of youth who had documented probable personal or family justice system involvement. The findings complement another study led by Boch, published in 2021 using data from Nationwide Children’s Hospital in Columbus, Ohio.

Youth with a justice keyword in their record had 1.5 to 16.2 times the prevalence of various physical and mental health disorder groupings studied compared to matched youth who didn’t have a justice keyword but do have similar socioeconomic backgrounds. They also had 428.2 more physical health diagnoses and 269.2 more mental health diagnoses per 100 youth than the matched youth.

According to the study, youth with a justice keyword made up a large proportion of all of those who were diagnosed with health disorders or conditions at Cincinnati Children’s from 2009-2020. This includes 42.9% of all schizophrenia spectrum and other psychotic disorders, 42.1% of all bipolar and related disorders, 38.3% of all suicide and self-injury disorders, 24.5% of all trauma and stress related disorders, 44.9% of all shaken baby syndrome cases, 13.9% of all infectious diseases, 12.5% of speech language disorders and 12.8% of all youth pregnancies.

Nationally, about 7% of U.S. youth have had a parent incarcerated. Findings at Cincinnati Children’s and Nationwide Children’s Hospital in Columbus grossly underestimate the number of youth affected by incarceration or confinement, says Boch.

“Our data reflects families who disclosed and health providers who documented,” says Boch. “Families who refrain from disclosing or whose information is not documented were not represented which is a key limitation. This study is an attempt to uncover the size of the impact of mass incarceration on youth health in Cincinnati. Our health care systems and correctional systems clearly overlap and impact the lives of children.

“Replication of these findings in other communities would strengthen the growing justification for decarceration efforts and other reforms, especially if we want all U.S. children and families to thrive,” says Boch. “We will continue to have health care disparities and lead the world with poor health outcomes if we continue to lead in incarceration.”

Other co-authors of the study include Joshua Lambert, PhD, University of Cincinnati; Christopher Wilderman, PhD, Duke University; and Judith Dexheimer, PhD; Robert Kahn, MD; and Sarah Beal, PhD, all of the University of Cincinnati and Cincinnati Children’s.

The research study of Cincinnati youth was supported by Boch’s awards, including the Agency for Healthcare Research and Quality and Patient Centered Outcomes Research Institute (AHRQ/PCORI) K12 PEDSnet Scholars Learning Health Systems Career Development Program, internal funding from the University of Cincinnati College of Nursing Dean’s New Investigator Award, internal funding from the Cincinnati Children’s Hospital Medical Center James M. Anderson Center for Health Systems Excellence, and the NIH/NIMHD Loan Repayment Award for Clinician Scientists from Disadvantaged Backgrounds.

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University of Illinois Urbana-Champaign chemical and biomolecular engineering professor Simon Rogers and graduate student Krutarth Kamani specialize in determining how soft materials yield to stress and have shown how solid and liquid physical states can exist together in the same material. This area is of high interest due to its importance to industrial, environmental and biomedical applications.

Along the way, the team identified a communication breakdown among the scientists who work in this area, causing a bottleneck between a theoretical understanding of soft material behavior and real-world applications.

When soft materials — natural or synthetic — deform under pressure, they eventually reach a critical point where they either return to their original form or undergo permanent deformation, like stretching or breaking a piece of elastic. This process is known as yielding. A gradual yielding transition is termed ductile behavior, while an abrupt one is referred to as brittle behavior, the researchers said.

“At a recent conference, we realized that all of us who study soft materials from all over Europe and North America couldn’t agree what the connection is between brittle and ductile behavior nor how to define it.”

In the study, published in the Proceedings of the National Academy of Sciences, instead of viewing soft material behavior as one or the other — brittle or ductile — Rogers’ team considers a spectrum of yielding behaviors. This allowed the team to build a continuum model, which led to them uncovering the brittility factor. This factor is critical in determining how and why soft materials fail.

Essentially, brittility affects how a material deforms permanently under stress. The team’s model indicates that the higher the brittility factor, the less a soft material will deform permanently before yielding.

As in the team’s past studies, the model was developed and tested using data from numerous experiments that subjected various soft materials to stress while measuring the individual strain responses using a device called a rheometer.

“We didn’t expect this study to explain as much as it does,” said Rogers, who is also an affiliate at the Beckman Institute for Advanced Science and Technology at the U. of. I. “What we ended up with was a way to bring a whole bunch of soft material behaviors together under the same physics umbrella. Previously, they’d been studied independently or maybe all been applied simultaneously, but never thought of as being physically or mathematically connected.”

This finding will allow researchers to explain precisely why some materials are more resistant to rapid yielding than others, a question that has eluded researchers for decades.

“This single parameter amazingly connects so many puzzling observations researchers have come across over the years,” Kamani said.

“This work marks the point at which we are approaching the crest of the hill in understanding soft materials behavior,” Rogers said. “We’ve always felt like each step takes us higher, but with no end in sight. Now we can see the top of the hill, and we are closer to the top and free to move forward in whatever direction we would like.”

The National Science Foundation supported this research.

Many people think of their brains as being intrinsically synced to the human-made clocks on their electronic devices, counting time in very specific, minute-by-minute increments. But the study, published this month in the latest issue of the peer-reviewed Cell Press journal Current Biology, showed that our brains don’t work that way.

By analyzing changes in brain activity patterns, the research team found that we perceive the passage of time based on the number of experiences we have — not some kind of internal clock. What’s more, increasing speed or output during an activity appears to affect how our brains perceive time.

“We tell time in our own experience by things we do, things that happen to us,” said James Hyman, a UNLV associate professor of psychology and the study’s senior author. “When we’re still and we’re bored, time goes very slowly because we’re not doing anything or nothing is happening. On the contrary, when a lot of events happen, each one of those activities is advancing our brains forward. And if this is how our brains objectively tell time, then the more that we do and the more that happens to us, the faster time goes.”

Methodology and Findings

The findings are based on analysis of activity in the anterior cingulate cortex (ACC), a portion of the brain important for monitoring activity and tracking experiences. To do this, rodents were tasked with using their noses to respond to a prompt 200 times.

Scientists already knew that brain patterns are similar, but slightly different, each time you do a repetitive motion, so they set out to answer: Is it possible to detect whether these slight differences in brain pattern changes correspond with doing the first versus 200th motion in series? And does the amount of time it takes to complete a series of motions impact brain wave activity?

By comparing pattern changes throughout the course of the task, researchers observed that there are indeed detectable changes in brain activity that occur as one moves from the beginning to middle to end of carrying out a task. And regardless of how slowly or quickly the animals moved, the brain patterns followed the same path. The patterns were consistent when researchers applied a machine learning-based mathematical model to predict the flow of brain activity, bolstering evidence that it’s experiences — not time, or a prescribed number of minutes, as you would measure it on a clock — that produce changes in our neurons’ activity patterns.

Hyman drove home the crux of the findings by sharing an anecdote of two factory workers tasked with making 100 widgets during their shift, with one worker completing the task in 30 minutes and the other in 90 minutes.

“The length of time it took to complete the task didn’t impact the brain patterns. The brain is not a clock; it acts like a counter,” Hyman explained. “Our brains register a vibe, a feeling about time. …And what that means for our workers making widgets is that you can tell the difference between making widget No. 85 and widget No. 60, but not necessarily between No. 85 and No. 88.”

But exactly “how” does the brain count? Researchers discovered that as the brain progresses through a task involving a series of motions, various small groups of firing cells begin to collaborate — essentially passing off the task to a different group of neurons every few repetitions, similar to runners passing the baton in a relay race.

“So, the cells are working together and over time randomly align to get the job done: one cell will take a few tasks and then another takes a few tasks,” Hyman said. “The cells are tracking motions and, thus, chunks of activities and time over the course of the task.”

And the study’s findings about our brains’ perception of time applies to activities-based actions other than physical motions too.

“This is the part of the brain we use for tracking something like a conversation through dinner,” Hyman said. “Think of the flow of conversation and you can recall things earlier and later in the dinner. But to pick apart one sentence from the next in your memory, it’s impossible. But you know you talked about one topic at the start, another topic during dessert, and another at the end.”

By observing the rodents who worked quickly, scientists also concluded that keeping up a good pace helps influence time perception: “The more we do, the faster time moves. They say that time flies when you’re having fun. As opposed to having fun, maybe it should be ‘time flies when you’re doing a lot’.”

Takeaways

While there’s already a wealth of information on brain processes over very short time scales of less than a second, Hyman said that the UNLV study is groundbreaking in its examination of brain patterns and perception of time over a span of just a few minutes to hours — “which is how we live much of our life: one hour at a time. “

“This is among the first studies looking at behavioral time scales in this particular part of the brain called the ACC, which we know is so important for our behavior and our emotions,” Hyman said.

The ACC is implicated in most psychiatric and neurodegenerative disorders, and is a concentration area for mood disorders, PTSD, addiction, and anxiety. ACC function is also central to various dementias including Alzheimer’s disease, which is characterized by distortions in time. The ACC has long been linked to helping humans with sequencing events or tasks such as following recipes, and the research team speculates that their findings about time perception might fall within this realm.

While the findings are a breakthrough, more research is needed. Still, Hyman said, the preliminary findings posit some potentially helpful tidbits about time perception and its likely connection to memory processes for everyday citizens’ daily lives. For example, researchers speculate that it could lend insights for navigating things like school assignments or even breakups.

“If we want to remember something, we may want to slow down by studying in short bouts and take time before engaging in the next activity. Give yourself quiet times to not move,” Hyman said. “Conversely, if you want to move on from something quickly, get involved in an activity right away.”

Hyman said there’s also a huge relationship between the ACC, emotion, and cognition. Thinking of the brain as a physical entity that one can take ownership over might help us control our subjective experiences.

“When things move faster, we tend to think it’s more fun — or sometimes overwhelming. But we don’t need to think of it as being a purely psychological experience, as fun or overwhelming; rather, if you view it as a physical process, it can be helpful,” he said. “If it’s overwhelming, slow down or if you’re bored, add activities. People already do this, but it’s empowering to know it’s a way to work your own mental health, since our brains are working like this already.”

The study, one of the largest of its kind, utilized data from MVP, a longitudinal study of U.S. Veterans, with over 29% of the participants being of non-European ancestry. Researchers identified 13,672 specific regions in DNA that are associated with one or more traits, such as physical characteristics or health conditions. These regions, known as genetic risk areas, can influence the likelihood of a person having certain traits or developing certain diseases.

“Understanding the genetic factors underlying health disparities is crucial for developing targeted interventions and treatments that can benefit all people, regardless of their background,” said the study’s corresponding author, Scott Damrauer, MD, an associate professor of Genetics at Penn and vascular surgeon at the Crescenz VA. “By uncovering these genetic insights across diverse populations, we are taking significant steps towards a more personalized and inclusive approach to healthcare.”

Specifically, the study discovered population-specific signals, such as the rs72725854 variant at the PCAT2 locus associated with prostate cancer risk, predominantly observed in African-American men. It also revealed a novel gout risk variant, rs35965584, in the African-American population group, alongside the known variant rs2231142.

The study showed that the genetics of most traits are similar between groups of diverse people, but, certain groups do have their own distinct genetic features. They were able to find these differences more accurately, especially in African-American and mixed ancestry groups, thanks to improvements in how they analyze DNA, like fine mapping, which allows researchers to identify the exact genetic changes responsible for a particular trait or condition. The findings highlight the importance of including diverse genetic backgrounds in understanding the genetic causes of health disparities.

“Our work demonstrates overwhelmingly more similarities than differences in genetic associations between groups,” said first author Anurag Verma, PhD, an assistant professor of Translational Medicine and Human Genetics and VA MVP researcher. “However, the unique genetic variations identified in diverse populations provide critical insights into health disparities and have significant implications for precision medicine.”

“Biobanks like the MVP serve as a pivotal resource for generating new genetic association resources and insights. The findings from this inclusive and diverse study lay the foundation for future genetic research that will, first and foremost, help us better care for our nations Veterans — as well as their families, caregivers, survivors, and other non-Veterans. This was only possible due to the altruism and the diversity of participating Veterans,” said VA’s MVP Program Director, Sumitra Muralidhar, PhD.

The study was funded by the U.S. Department of Veterans Affairs’ Office of Research and Development.

Opioids are the gold standard of chronic pain treatment, but they come with a host of negative side effects including constipation, addiction potential and respiratory depression that can lead to death. This study, published in Scientific Reports, offers a potential new way to treat acute and chronic pain by reducing the amount of opioid needed for pain relief while also lowering its addiction potential.

“We have been investigating the role of Heat shock protein 90 in regulating opioid signaling in the spinal cord for some time,” said John Streicher, PhD, member of the Comprehensive Center for Pain & Addiction at UArizona Health Sciences and a professor in the College of Medicine — Tucson’s Department of Pharmacology. “This study provides proof of principle that Hsp90 isoform inhibitors are effective at improving opioid pain relief and reducing side effects. This is the critical link that makes our work translationally relevant, giving us a clear path forward to develop a new drug that could benefit millions of people who live with chronic pain.”

Heat shock protein 90 is a chaperone protein that helps other proteins function, including those that promote tumor growth. It has been studied primarily in the context of cancer. Streicher is leading in a long-term effort to investigate its role in opioid receptor activation and pain relief.

Streicher’s prior research showed that Heat shock protein 90 acted upon opioid receptors in the brain differently than in the spinal cord. Inhibiting Hsp90 in the brain blocked the analgesic properties of morphine, meaning the opioid lost its ability to reduce the sensation of pain. But inhibiting Hsp90 in the spinal cord amplified the pain-relieving effects of morphine.

Building on that research, the team tested nonselective Hsp90 inhibitors in mouse models and saw a twofold-to-fourfold increase in the potency of pain relief provided by morphine. At the same time, tolerance was reduced and established tolerance was reversed. Tolerance is a condition where the body gets used to a medication so that more medication or a different medication is needed to achieve the same response.

Early cancer-focused studies, however, found that nonselective Hsp90 inhibitors can cause serious side effects, including macular degeneration. Streicher’s solution was to target individual isoforms of Hsp90, of which there are four.

“Isoforms are different versions of the same thing, like trim packages on a car,” Streicher said. “They are all slightly different and have similar roles, but not identical roles. So these four Hsp90 isoforms are four proteins that we can target individually.”

By using selective inhibitors to target each isoform, they were able to identify and isolate the isoforms that are active in the spinal cord from Hsp90-alpha, the one that is active in the brain. Recent reports have linked Hsp90-alpha with the serious side effect of retinal degeneration.

“We took isoform-selected inhibitors that we got from our collaborator, Brian Blagg, PhD, at the University of Notre Dame, and gave them to mice systemically via IV injection,” Streicher said. “We found that you can give these isoform-selective inhibitors by a translatable route and get the benefits. Pain relief goes up and side effects go down, and presumably we’re going to avoid some of those nasty side effects of the nonselective Hsp90 inhibitors.”

The findings suggest that selective Hsp90 inhibitors could be used as part of a dose-reduction plan in conjunction with opioid therapy prescribed by a physician for chronic pain. The goal is for doctors to be able to prescribe lower amounts of opioids that provide patients with the same pain-relieving benefits and fewer negative side effects.

“What I’m envisioning is you’d be given a pill that is a combination therapy of an opioid with one of these isoform inhibitors,” Streicher said. “The addition of that Hsp90 inhibitor would make the opioid better — it would increase the effectiveness of the pain relief and decrease the side effects.”

Streicher and his team are working to optimize the selective Hsp90 inhibitors to produce a stable drug that can be taken orally.

“Dr. Streicher’s research is an excellent example of the innovative, translational science that is needed to transform health care for pain and addiction,” said Todd Vanderah, PhD, director of the Comprehensive Center for Pain & Addiction, Regents Professor and head of the Department of Pharmacology. “This study is an important step toward developing a novel evidence-based therapy that will provide better treatment options with fewer disruptive side effects, empowering people with chronic pain to thrive.”

The research team included four co-first authors: David Duron, PhD, JD, former doctoral candidate in the Streicher Lab; Parthasaradhireddy Tanguturi, PhD, researcher/scientist in the Department of Pharmacology; former doctoral candidate Christopher Campbell, PhD; and Kerry Chou, former undergraduate student at the UArizona College of Nursing. Other co-authors included Paul Bejarano, and former doctoral candidates Katherin Gabriel, PhD, and Jessica Bowden, DVM, PhD, all of the Department of Pharmacology; Sanket Mishra, PhD, Christopher Brackett, PhD, and Brian Blagg, PhD, of the Department of Chemistry and Biochemistry at the University of Notre Dame’s College of Science; and Deborah Barlow and Karen Houseknecht, PhD, of the Department of Biomedical Sciences at the University of New England’s College of Osteopathic Medicine.

That’s the key finding of a new paper by UC Davis MIND Institute researcher Sally Ozonoff and the Baby Siblings Research Consortium. The consortium is a collection of more than 20 research groups at universities worldwide.

Ozonoff is a distinguished professor in the Department of Psychiatry and Behavioral Sciences. She has studied the recurrence of autism in families for decades.

The new study is based on a large, diverse group of families at research sites across the United States, Canada, and the United Kingdom. It confirms the same research group’s 2011 findings about the likelihood of autism in siblings.

The new research was published this week in Pediatrics.

Increasing autism rates prompt new study

“The rate of autism diagnosis in the general community has been steadily increasing since our previous paper was published,” Ozonoff explained.

The latest estimates from the Centers for Disease Control and Prevention show that about 1 in 36 children has autism. In 2011, the estimate was 1 in 68.

Ozonoff noted that there have also been changes in autism diagnostic criteria over the past decade. In addition, there is a growing awareness of autism in girls.

“So, it was important to understand if these had any impact on the likelihood of autism recurrence within a family,” she said.

The 2011 paper found a recurrence rate of 18.7%, while the new paper found a rate of 20.2% — a small but not significant increase.

“This should reassure providers who are counseling families and monitoring development. It should also help families plan for and support future children,” Ozonoff said.

A larger, more diverse study

The new study included data from 1,605 infants at 18 research sites. All infants had an older autistic sibling.

“This study was much larger than the first and included more racially diverse participants,” Ozonoff said. The original study included 664 children.

Researchers followed the children from as early as 6 months of age for up to seven visits. Trained clinicians assessed the children for autism at age 3 using the Autism Diagnostic Observation Schedule (ADOS-2), a well-validated tool. The data were gathered from 2010 to 2019.

Sex of first autistic child, multiple autistic siblings key factors

Researchers found that the sex of the first autistic child influenced the likelihood that autism would recur within a family.

“If a family’s first autistic child was a girl, they were 50% more likely to have another child with autism than if their first autistic child was a boy,” Ozonoff said. “This points to genetic differences that increase recurrence likelihood in families who have an autistic daughter.”

The researchers also found that a child with multiple autistic siblings has a higher chance of autism (37%) than a child with only one sibling on the spectrum (21%).

The sex of the infant was also associated with the likelihood of familial recurrence. If the later-born infant was a boy, they were almost twice as likely as a girl to be diagnosed themselves.

“The familial recurrence rate if the new baby was a boy was 25%, whereas it was 13% if the new baby was a girl,” Ozonoff explained. “This is in line with the fact that boys are diagnosed with autism about four times as often as girls in general.”

Race, maternal education level influence recurrence

The researchers found that race and the mother’s education level were likely factors as well. In non-white families, the recurrence rate was 25%. In white families, the recurrence rate was about 18%. In families where the mother had a high school education or less, recurrence was 32%. With some college, the rate was 25.5%, and with a college degree the rate was 19.7%. When the mother had a graduate degree, it dropped to 16.9%.

“These findings are new — and critical to replicate,” Ozonoff explained. “They do mirror the recent CDC findings that autism is more prevalent in children of historically underrepresented groups.” She noted that this reversed a longtime trend of lower prevalence in those groups.

Most importantly, said Ozonoff, if these findings are replicated, they may indicate that there are social determinants of health that may lead to higher rates of autism in families. She emphasized that this study was not designed to answer those critical questions, and more research is needed.

Tracking outcomes

Unlike the first study, the researchers also tracked families who dropped out of the three-year study to see if their outcomes differed from those who did. “We wondered whether families who stayed in the study may have had children who were more affected — making them more worried about their development,” she explained.

That could have biased the estimates of recurrence to be higher than they really were. The current study showed that was not the case.

“So, now we have two large, independent studies that report familial recurrence in the same range,” Ozonoff said. “This reinforces how important it is that providers closely monitor the siblings of autistic children for delays in social development or communication. This is especially true in families who have reduced access to care, because early diagnosis and intervention are critical.”

Additional Information:

Study co-authors included Gregory Young and Rebecca Schmidt of UC Davis; Jessica Bradshaw of the University of South Carolina, Tony Charman of Kings College London; Katarzyna Chawarska of Yale University, Jana M. Iverson of Boston University; Cheryl Klaiman of Emory University; Rebecca Landa of Johns Hopkins University; Nicole McDonald of UCLA; Daniel Messinger of the University of Miami; Carol Wilkinson of Harvard University, and Lonnie Zwaigenbaum of the University of Alberta.

The study, appearing today in the Journal of Clinical Investigation, focused on two proteins called melanocortin 3 and melanocortin 4 found primarily on the surface of neurons in the brain that play a central role in regulating feeding behavior and maintaining the body’s energy balance.

Melanocortin 3 and melanocortin 4 impact everything from sensing long-term energy stores to processing signals from the gut regarding short-term fullness, or satiety, said U-M physiologist Roger Cone, who led the study.

The class of drugs known as GLP-1 agonists, which includes semaglutides (e.g., Ozempic) and tirzepatides (e.g., Mounjaro), have received substantial attention recently for their effectiveness in treating not only type 2 diabetes, but also obesity, heart disease and potentially addiction. They work by mimicking a natural hormone that the gut produces when it is full, triggering the brain to reduce feeding behavior.

“So the obvious question for us was: How do these GLP-1 drugs, which work by manipulating satiety signals, function when we prime the melanocortin system?” said Cone, professor of molecular and integrative physiology at the U-M Medical School and director of the U-M Life Sciences Institute where his lab is located.

Working in mouse models, Cone and his colleagues tested the effects of several hormones that reduce food intake. They compared the results in normal mice with mice that genetically lacked the MC3R protein, in mice that were given chemicals to block the activity of MC3R, and in mice that were given a drug to increase the activity of MC4R. (Because MC3R is a natural negative regulator of MC4R, meaning it decreases the activity of MC4R, blocking MC3R and increasing MC4R activity has similar effects.)

In all cases, Naima Dahir, first author of the study and a postdoctoral research fellow in Cone’s lab, and colleagues found that adjusting the melanocortin system — either by inhibiting MC3R or increasing MC4R activity — made the mice more sensitive to GLP-1 drugs and other hormones that affect feeding behavior. The mice that were given a GLP-1 drug in combination with an MC4R agonist or MC3R antagonist showed up to five times more weight loss and reduced feeding than mice receiving only the GLP-1 drugs.

“We found that activating the central melanocortin system hypersensitizes animals to the effects of not just GLP-1s, but to every anti-feeding hormone we tested,” Cone said.

The researchers also measured activity in parts of the brain thought to trigger nausea in response to GLP-1 drugs and observed no increased activation when GLP-1 drugs were combined with alterations to the melanocortin system. In contrast, priming of the melanocortin neurons significantly increased GLP-1 drug activation of neurons in hypothalamic feeding centers in the brain.

The findings indicate that pairing the existing GLP-1 drugs with an MC4R agonist could increase sensitivity to the desired effects of the drugs by up to fivefold, without increasing unwanted side effects.Ultimately, this approach could enable patients who are sensitive to the side effects to take a lower dose, or could improve the results in patients who have not responded to the existing drug dosages. Further drug development and clinical testing are needed before this can occur.

While this research has been conducted only in mouse models, Cone is optimistic that the results will translate well to humans.

“The melanocortin system is highly conserved in humans,” he said. “Everything we’ve observed in the mouse over the past decades studying these proteins has also been found in humans, so I suspect that these results would also be translatable to patients.”

This research was funded by the National Institutes of Health and Courage Therapeutics.

And the neurological source of creativity — what’s going on in our brains when we think outside the box — is similarly elusive.

But now, a research team led by a University of Utah Health researcher and based in Baylor College of Medicine has used a precise method of brain imaging to unveil how different parts of the brain work together in order to produce creative thought.

Their findings published in BRAIN on June 18.

The new results could ultimately help lead to interventions that spark creative thought or aid people who have mental illnesses that disrupt these regions of the brain.

Outside the bo

Higher cognitive processes like creativity are especially hard to study. “Unlike motor function or vision, they’re not dependent on one specific location in the brain,” says Ben Shofty, MD, PhD, assistant professor of neurosurgery in the Spencer Fox Eccles School of Medicine and senior author on the paper. “There’s not a creativity cortex.”

But there’s evidence that creativity is a distinct brain function. Localized brain injury caused by stroke can lead to changes in creative ability — both positive and negative. That discovery suggests that narrowing down the neurological basis of creativity is possible.

Shofty suspected that creative thought might rely strongly on parts of the brain that are also activated during meditation, daydreaming, and other internally focused types of thinking. This network of brain cells is the default mode network (DMN), so called because it’s associated with the “default” patterns of thought that happen in the absence of specific mental tasks. “Unlike most of the functions that we have in the brain, it’s not goal-directed,” Shofty says. “It’s a network that basically operates all the time and maintains our spontaneous stream of consciousness.”

The DMN is spread out across many dispersed brain regions, making it more difficult to track its activity in real time. The researchers had to use an advanced method of brain activity imaging to understand what the network was doing moment-to-moment during creative thought. In a strategy most commonly used to pinpoint the location of seizures in patients with severe epilepsy, tiny electrodes are implanted in the brain to precisely track the electrical activity of multiple brain regions.

Participants in the study were already undergoing this kind of seizure monitoring, which meant that the research team could also use the electrodes to measure brain activity during creative thinking. This provided a much more detailed picture of the neural basis of creativity than researchers had been able to capture before. “We could see what’s happening within the first few milliseconds of attempting to perform creative thinking,”Shofty says.

Two steps toward originality

The researchers saw that during a creative thinking task in which participants were asked to list novel uses for an everyday item, like a chair or a cup, the DMN lit up with activity first. Then, its activity synchronized with other regions in the brain, including ones involved in complex problem-solving and decision-making. Shofty believes this means that creative ideas originate in the DMN before being evaluated by other regions.

What’s more, the researchers were able to show that parts of the network are required specifically for creative thought. When the researchers used the electrodes to temporarily dampen the activity of particular regions of the DMN, people brainstormed uses for the items they saw that were less creative. Their other brain functions, like mind wandering, remained perfectly normal.

Eleonora Bartoli, PhD, assistant professor of neurosurgery at Baylor College of Medicine and co-first author on the paper, explains that this result shows that creativity isn’t just associated with the network but fundamentally depends on it. “We moved beyond correlational evidence by using direct brain stimulation,” she says. “Our findings highlight the causal role of the DMN in creative thinking.”

The activity of the network is changed in several disorders, such as ruminative depression, in which the DMN is more active than normal, possibly related to increased dwelling on negative internally directed thoughts. Shofty says that a better understanding of how the network operates normally may lead to better treatments for people with such conditions.

By characterizing the brain regions involved in creative thought, Shofty hopes to ultimately inspire interventions that can help spark creativity. “Eventually, the goal would be to understand what happens to the network in such a way that we can potentially drive it toward being more creative.”

The team say this new approach could reduce the need for invasive and costly diagnostic tests while improving treatment outcomes early when interventions such as lifestyle changes or new medicines may have a chance to work best.

Dementia poses a significant global healthcare challenge, affecting over 55 million people worldwide at an estimated annual cost of $820 billion. The number of cases is expected to almost treble over the next 50 years.

The main cause of dementia is Alzheimer’s disease, which accounts for 60-80% of cases. Early detection is crucial as this is when treatments are likely to be most effective, yet early dementia diagnosis and prognosis may not be accurate without the use of invasive or expensive tests such as positron emission tomography (PET) scans or lumbar puncture, which are not available in all memory clinics. As a result, up to a third of patients may be misdiagnosed and others diagnosed too late for treatment to be effective.

A team led by scientists from the Department of Psychology at the University of Cambridge has developed a machine learning model able to predict whether and how fast an individual with mild memory and thinking problems will progress to developing Alzheimer’s disease. In research published today in eClinical Medicine, they show that it is more accurate than current clinical diagnostic tools.

To build their model, the researchers used routinely-collected, non-invasive, and low-cost patient data — cognitive tests and structural MRI scans showing grey matter atrophy — from over 400 individuals who were part of a research cohort in the USA.

They then tested the model using real-world patient data from a further 600 participants from the US cohort and — importantly — longitudinal data from 900 people from memory clinics in the UK and Singapore.

The algorithm was able to distinguish between people with stable mild cognitive impairment and those who progressed to Alzheimer’s disease within a three-year period. It was able to correctly identify individuals who went on to develop Alzheimer’s in 82% of cases and correctly identify those who didn’t in 81% of cases from cognitive tests and an MRI scan alone.

The algorithm was around three times more accurate at predicting the progression to Alzheimer’s than the current standard of care; that is, standard clinical markers (such as grey matter atrophy or cognitive scores) or clinical diagnosis. This shows that the model could significantly reduce misdiagnosis.

The model also allowed the researchers to stratify people with Alzheimer’s disease using data from each person’s first visit at the memory clinic into three groups: those whose symptoms would remain stable (around 50% of participants), those who would progress to Alzheimer’s slowly (around 35%) and those who would progress more rapidly (the remaining 15%). These predictions were validated when looking at follow-up data over 6 years. This is important as it could help identify those people at an early enough stage that they may benefit from new treatments, while also identifying those people who need close monitoring as their condition is likely to deteriorate rapidly.

Importantly, those 50% of people who have symptoms such as memory loss but remain stable, would be better directed to a different clinical pathway as their symptoms may be due to other causes rather than dementia, such as anxiety or depression.

Senior author Professor Zoe Kourtzi from the Department of Psychology at the University of Cambridge said: “We’ve created a tool which, despite using only data from cognitive tests and MRI scans, is much more sensitive than current approaches at predicting whether someone will progress from mild symptoms to Alzheimer’s — and if so, whether this progress will be fast or slow.

“This has the potential to significantly improve patient wellbeing, showing us which people need closest care, while removing the anxiety for those patients we predict will remain stable. At a time of intense pressure on healthcare resources, this will also help remove the need for unnecessary invasive and costly diagnostic tests.”

While the researchers tested the algorithm on data from a research cohort, it was validated using independent data that included almost 900 individuals who attended memory clinics in the UK and Singapore. In the UK, patients were recruited through the Quantiative MRI in NHS Memory Clinics Study (QMIN-MC) led by study co-author Dr Timothy Rittman at Cambridge University Hospitals NHS Trust and Cambridgeshire and Peterborough NHS Foundation Trusts (CPFT).

The researchers say this shows it should be applicable in a real-world patient, clinical setting.

Dr Ben Underwood, Honorary Consultant Psychiatrist at CPFT and assistant professor at the Department of Psychiatry, University of Cambridge, said: “Memory problems are common as we get older. In clinic I see how uncertainty about whether these might be the first signs of dementia can cause a lot of worry for people and their families, as well as being frustrating for doctors who would much prefer to give definitive answers. The fact that we might be able to reduce this uncertainty with information we already have is exciting and is likely to become even more important as new treatments emerge.”

Professor Kourtzi said: “AI models are only as good as the data they are trained on. To make sure ours has the potential to be adopted in a healthcare setting, we trained and tested it on routinely-collected data not just from research cohorts, but from patients in actual memory clinics. This shows it will be generalisable to a real-world setting.”

The team now hope to extend their model to other forms of dementia, such as vascular dementia and frontotemporal dementia, and using different types of data, such as markers from blood tests.

Professor Kourtzi added: “If we’re going to tackle the growing health challenge presented by dementia, we will need better tools for identifying and intervening at the earliest possible stage. Our vision is to scale up our AI tool to help clinicians assign the right person at the right time to the right diagnostic and treatment pathway. Our tool can help match the right patients to clinical trials, accelerating new drug discovery for disease modifying treatments.”

The study was funded by Wellcome, the Royal Society, Alzheimer’s Research UK, the Alzheimer’s Drug Discovery Foundation Diagnostics Accelerator, the Alan Turing Institute, and the National Institute for Health Research Cambridge Biomedical Research Centre.

The study, in fruit flies and mice, also identified ways to block this process, which could have implications for treating or preventing the muscle wasting sometimes associated with inflammatory diseases, including bacterial infections, Alzheimer’s disease and long COVID.

The study is published July 12 in the journal Science Immunology.

“We are interested in understanding the very deep muscle fatigue that is associated with some common illnesses,” said senior author Aaron Johnson, PhD, an associate professor of developmental biology. “Our study suggests that when we get sick, messenger proteins from the brain travel through the bloodstream and reduce energy levels in skeletal muscle. This is more than a lack of motivation to move because we don’t feel well. These processes reduce energy levels in skeletal muscle, decreasing the capacity to move and function normally.”

To investigate the effects of brain inflammation on muscle function, the researchers modeled three different types of diseases — an E. coli bacterial infection, a SARS-CoV-2 viral infection and Alzheimer’s. When the brain is exposed to inflammatory proteins characteristic of these diseases, damaging chemicals called reactive oxygen species build up. The reactive oxygen species cause brain cells to produce an immune-related molecule called interleukin-6 (IL-6), which travels throughout the body via the bloodstream. The researchers found that IL-6 in mice — and the corresponding protein in fruit flies — reduced energy production in muscles’ mitochondria, the energy factories of cells.

“Flies and mice that had COVID-associated proteins in the brain showed reduced motor function — the flies didn’t climb as well as they should have, and the mice didn’t run as well or as much as control mice,” Johnson said. “We saw similar effects on muscle function when the brain was exposed to bacterial-associated proteins and the Alzheimer’s protein amyloid beta. We also see evidence that this effect can become chronic. Even if an infection is cleared quickly, the reduced muscle performance remains many days longer in our experiments.”

Johnson, along with collaborators at the University of Florida and first author Shuo Yang, PhD — who did this work as a postdoctoral researcher in Johnson’s lab — make the case that the same processes are likely relevant in people. The bacterial brain infection meningitis is known to increase IL-6 levels and can be associated with muscle issues in some patients, for instance. Among COVID-19 patients, inflammatory SARS-CoV-2 proteins have been found in the brain during autopsy, and many long COVID patients report extreme fatigue and muscle weakness even long after the initial infection has cleared. Patients with Alzheimer’s disease also show increased levels of IL-6 in the blood as well as muscle weakness.

The study pinpoints potential targets for preventing or treating muscle weakness related to brain inflammation. The researchers found that IL-6 activates what is called the JAK-STAT pathway in muscle, and this is what causes the reduced energy production of mitochondria. Several therapeutics already approved by the Food and Drug Administration for other diseases can block this pathway. JAK inhibitors as well as several monoclonal antibodies against IL-6 are approved to treat various types of arthritis and manage other inflammatory conditions.

“We’re not sure why the brain produces a protein signal that is so damaging to muscle function across so many different disease categories,” Johnson said. “If we want to speculate about possible reasons this process has stayed with us over the course of human evolution, despite the damage it does, it could be a way for the brain to reallocate resources to itself as it fights off disease. We need more research to better understand this process and its consequences throughout the body.

“In the meantime, we hope our study encourages more clinical research into this pathway and whether existing treatments that block various parts of it can help the many patients who experience this type of debilitating muscle fatigue,” he said.

“Recent advances in surgical neuromodulation have enabled long-term continuous monitoring of brain activity in OCD patients during their everyday lives,” said Dr. Nicole Provenza, an assistant professor at Baylor College of Medicine and McNair Scholar. “We used this novel opportunity to identify key neural signatures that can act as predictors of clinical state in twelve individuals with treatment-resistant OCD who were receiving DBS therapy.”

DBS is emerging as an effective treatment for severe, treatment-resistant OCD

OCD is a common and debilitating mental health condition that affects 2-3% of the population worldwide. About two million people in the US suffer from OCD. In severe cases, patients spend an extraordinary amount of time performing repetitive, seemingly senseless compulsions and perseverating on intrusive thoughts. OCD has a huge toll on the well-being and quality of life of patients and their caregivers and can interfere with the ability to maintain employment and relationships. While psychotherapy and medications are effective in a majority of the affected individuals, approximately 20-40% of individuals with severe OCD are resistant to these conventional treatments.

Since the early 2000s, DBS therapy has been used to modulate neural activity in specific regions of the brain linked to OCD symptoms. Many patients who qualify for this therapy have not received sufficient benefit from conventional therapies. In this treatment-resistant population, roughly two-thirds of patients show significant improvement in OCD symptoms after DBS.

Much like how pacemaker devices regulate electrical activity in the heart, DBS devices regulate electrical activity in the brain. DBS devices carry electrical impulses from the generator, typically implanted in the upper chest, via a pair of thin leads (wires) to specific target regions in the brain. Precise tuning of the stimulation parameters allows the electrical pulses to restore a dysfunctional brain circuit to a healthy state.

DBS is an FDA-approved procedure commonly used to treat movement disorders such as essential tremors and Parkinson’s disease and is increasingly being used to treat severe OCD.

“We have seen remarkable progress in the field of DBS research, a technology that has been used for decades to treat movement disorders,” said Dr. John Ngai, Director of the Brain Research Through Advancing Innovative Neurotechnologies® Initiative (The BRAIN Initiative®) at the National Institutes of Health, which provided partial funding for this study. “The advance reported here represents just one on a growing list of success stories where the BRAIN Initiative has helped develop a new generation of DBS technologies, bringing treatments for conditions like OCD closer to the clinic.”

Need for a clinical biomarker to monitor OCD patient’s response to DBS

Defining the correct dose is oftentimes more difficult for psychiatric disorders like OCD than for movement disorders. “In patients with movement disorders, it is more obvious when stimulation delivery and tuning is correct because abnormal movements such as tremors or stiffness decrease right away,” said Dr. Sheth, professor and Vice Chair of Research in the Department of Neurosurgery at Baylor College of Medicine, director of the Gordon and Mary Cain Pediatric Neurology Research Foundation Laboratories, and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. “However, it is much more difficult to achieve this level of precise DBS programming for OCD and other psychiatric disorders because there is a long delay between stimulation initiation and symptom improvement. It is difficult to know what particular adjustment led to a particular change months later. Our goal in undertaking this study was therefore to find a reliable neural biomarker to guide us during DBS management, and to remotely monitor changes in our patients’ symptoms. This is particularly important because several of our patients travel long distances from around the country or world to get DBS treatment, which for OCD is currently offered only in very few specialized centers.”

Targeting the root of the OCD problem

To identify an optimal target for developing a biomarker, the team focused on one of the most characteristic behaviors in OCD — the tendency for pathological avoidance. Individuals with OCD often suffer from difficult-to-control avoidance of potential harm or distress. In trying to avoid such perceived threats in daily life, they are often plagued by intrusive internal thoughts and irrational fears (obsessions), which lead to rigid routines and repetitive behaviors (compulsions).

The team’s goal was to understand how low-frequency brain oscillations in the theta (4-8 Hz) to alpha (8-12 Hz) range, which have been found by a large body of scientific literature to play a prominent role in cognitive processes, were altered in individuals with severe, treatment-resistant OCD. To do so, they took advantage of a novel feature of modern DBS devices — the ability to not only deliver stimulation but also record brain activity.

Usually, studies that monitor brain activity patterns are designed to be brief episodes that are conducted as participants perform a specific cognitive task. However, this study is unique because the researchers were able to use the DBS system to continuously monitor brain activity patterns in the background of everyday activities. This feature of the study brought the research into the natural lives of the study participants rather than confining it to unnatural laboratory settings.

Recordings started upon implantation of the DBS system. Because stimulation is typically initiated days to weeks later, the team was able to measure neural activity patterns in the severely symptomatic state. Interestingly, they found that 9 Hz (theta-alpha border) ventral striatum neural activity demonstrated a prominent circadian rhythm that fluctuated over the 24-hour cycle.

“Before DBS, we saw an extremely predictable and periodic neural activity pattern in all participants,” said Dr. Goodman, professor and D. C. and Irene Ellwood Chair in Psychiatry in theMenninger Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine. “However, after DBS activation, as individuals began responding and improving symptomatically, we saw a breakdown in this predictable pattern. This is a very interesting phenomenon and we have a theory to explain it. Individuals with OCD have a limited repertoire of responses to any given situation. They often perform the same rituals repeatedly and seldom vary their routines or engage in new activities, which may result in high predictability of activity in this brain region. However, after DBS activation, their behavioral repertoire is expanded; they might respond more flexibly to situations and not be just driven by a strong desire to avoid OCD triggers. This expanded repertoire may be a reflection of the more diverse brain activity pattern. Thus, we think this loss of a highly predictable neural activity indicates that the participants engaged in fewer repetitive and compulsive OCD behaviors.”

“In summary, we have identified a neurophysiological biomarker that can serve as a reliable indicator of improvements in mood and behaviors in OCD patients after DBS treatment. We anticipate these findings to transform how patients are monitored throughout DBS therapy,” added Dr. Sheth, who is also a McNair Scholar and Cullen Foundation Endowed Chair at Baylor College of Medicine.

“Incorporating this information into a clinician-facing dashboard, for example, could help guide therapy delivery, thus demystifying the process of DBS programming for OCD and making the therapy more accessible to a greater number of clinicians and patients. Moreover, we are excited by the potential possibility that such similar neural activity signatures may underlie other neuropsychiatric disorders and could serve as biomarkers to diagnose, predict, and monitor those conditions,” Dr. Provenza concluded.

Led by Natashya Falcone and co-first authors Tess Grett Mathes and Mahsa Monirizad, the research team delved into the realm of self-assembling peptide-based hydrogels, renowned for their versatility in mimicking extracellular matrices (ECMs) of diverse microenvironments.

AD presents an intricate challenge in neurodegenerative research. Traditional two-dimensional (2D) models have limitations in capturing the complexity of the disease. Through their innovative approach, the team developed a multi-component hydrogel scaffold, named Col-HAMA-FF, designed to mimic the amyloid-beta (β) containing microenvironment associated with AD.

The study’s findings, published in a recent issue of Acta Biomaterialia, illuminate the formation of β-sheet structures within the hydrogel matrix, mimicking the nanostructures of amyloid-β proteins. By culturing healthy neuronal progenitor cells (NPCs) within this amyloid-mimicking environment and comparing results to those in a natural-mimicking matrix, the researchers observed elevated levels of neuroinflammation and apoptosis markers. This suggests a significant impact of amyloid-like structures on NPC phenotypes and behaviors.

Dr. Ali Khademhosseini, the study’s corresponding author, expressed excitement about the implications of their findings: “This foundational work provides a promising scaffold for future investigations into AD mechanisms and drug testing. By bridging the gap between 3D hydrogel models and the complex reality of AD pathological nanostructures, we aim to understand this interaction on healthy neuronal cells so that we can accelerate the development of effective therapeutic strategies.”

The study represents a crucial step towards unraveling the mysteries of the b-amyloid-like environment which can be found in AD and marks a milestone in the quest for innovative solutions to combat neurodegenerative disorders.

The study, published in Nature Materials and in collaboration with the University of Padua and the Veneto Institute of Molecular Medicine (VIMM), uses innovative biotechnologies to measure the mechanical forces exerted by the embryo during its development.

These forces are crucial in the formation of organs and anatomical systems, such as the formation of the neural tube, which gives rise to the central nervous system.

Congenital spinal cord malformations affect around one in 2,000 newborns in Europe each year.

Although these malformations have been studied for decades, they cannot be fully explained through molecular and genetic studies alone.

As a result, researchers are now looking at the physical and mechanical forces in tissues during embryo development. However, this can be challenging as the embryonic spinal cord is tiny — too small to be seen with the naked eye — and extremely delicate. Force measuring devices therefore need to be similarly small and soft to avoid disrupting normal growth.

To overcome these difficulties, researchers 3D printed tiny force sensors (about 0.1mm wide) directly inside the developing nervous system of chicken embryos.

These force sensors begin as a liquid applied directly to the developing embryos. When exposed to a strong laser, the liquid transforms into a spring-like solid. This solid attaches to the growing spinal cord of the embryos and gets deformed by the mechanical forces produced by the embryo’s cells.

This enabled them to measure the minute forces — about a tenth of the weight of a human eyelash — that embryos must generate to form the spinal cord.

For normal embryonic development, these forces must be greater than the opposing negative forces.

Quantifying the forces would allow researchers to explore drugs capable of sufficiently increasing positive forces or decreasing negative ones, in order to help prevent congenital malformations such as spina bifida.

Such drugs could also complement the benefits of folic acid intake — a well-established strategy for preventing developmental problems before and during pregnancy.

Lead author, Marie Sklowdowska Curie postdoctoral fellow, Dr Eirini Maniou (UCL Great Ormond Street Institute of Child Health and University of Padua), said: “Thanks to the use of novel biomaterials and advanced microscopy, this study promises a step change in the field of embryonic mechanics and lays the foundation for a unified understanding of development.

“Our work paves the way for identifying new preventative and therapeutic strategies for central nervous system malformations.”

The research group also demonstrated that the same technology could be applied to human stem cells, as they develop into spinal cord cells.

In the future, this would allow for comparisons between the stem cells of healthy donors and patients with spina bifida, with the goal of understanding why some people develop the condition.

Co-senior author, Dr Gabriel Galea (UCL Great Ormond Street Institute of Child Health), said: “This technology is very versatile and widely applicable to many research fields, and we hope it will be quickly adopted and applied by other groups to address fundamental questions.”

Co-senior author, Professor Nicola Elvassore (University of Padua and VIMM), added: “This discovery not only allows us to better understand the mechanical forces at play during embryonic development but also offers new perspectives for intervening and preventing conditions like spina bifida.

“The ability to quantify embryonic forces with such precision represents a significant step forward in biomedical research.”

The work — which the researchers said has implications for responsibly designing online content viewing platforms and algorithms, as well as helping users better recognize extreme content — is available online and will be published in the October issue of the International Journal of Human-Computer Studies.

“Anyone who has used YouTube or similar websites will know that these platforms automatically play the next video, without waiting for us to initiate it,” said senior investigator S. Shyam Sundar, Evan Pugh University Professor and the James P. Jimirro Professor of Media Effects at the Penn State Bellisario College of Communications. “We often hear about people going down rabbit holes of extreme content online, because these platforms automatically transition from mainstream to extreme content, in order to maintain audience interest.”

For example, a search for jogging may recommend increasingly extreme content, moving from jogging to running, then marathons to ultramarathons of 50 to 100 miles. The same can be said for any topic, the researchers said, including those that already lend themselves to polarization, such as politics.

“People tend to blame the autoplay feature — when one video ends, another plays automatically — for the rabbit hole perception, but we’ve yet to unpack the psychological effect of autoplay in the context of online viewing,” said lead author Cheng “Chris” Chen, assistant professor of communication design at Elon University who earned her doctorate in mass communications from Penn State. “Prior studies have pointed out that being stuck in a rabbit hole is a complex experience, which could also be influenced by one’s prior media consumption experience.”

To understand how autoplay and prior media consumption may work together to influence a user’s perception of falling down the rabbit hole of extreme content, the researchers designed an experimental video platform dubbed VIDNATION. The platform had 12 versions, each with video combinations of consistently non-extreme content or increasingly extreme content under three different autoplay modes: the ability to toggle autoplay on or off, autoplay without the option to turn it off and manually clicking the next video to play.

The researchers recruited 394 online participants and randomly assigned them to different VIDNATION versions. After receiving a tour of the interface, the users watched four one-minute-long videos of either non-extreme or increasingly extreme content with varying levels of control.

Participants completed a questionnaire before using VIDNATION, documenting how much and what type of content they typically watched. They also completed a questionnaire after exiting the platform, indicating the control they felt, the extremity they perceived in the content and whether they believed they had gone down a rabbit hole.

“We found that altering aspects of online media technology can have an effect on people’s perceptions of what they are consuming,” said Sundar, who is co-director the Media Effects Research Laboratory and director of the Center for Socially Responsible Artificial Intelligence at Penn State. “It is important to provide a reasonable level of control to users, so that they can decide for themselves whether or not they want to continue watching mainstream content that veers toward extreme material.”

The researchers pointed to the concept of “interpassivity,” or the idea that a user can allow technology — such as enabling the autoplay feature — to make decisions on their behalf, as key to triggering a sense of control in them.

“Autoplay is not just a passive experience; it offers both automation and interactivity,” Chen said. “Rabbit hole perception is not only influenced by algorithms and browsing history but also by how users engage with autoplay. Our study shows that when users have control over the action of autoplay, their engagement with autoplay — toggling it on or off — can increase or decrease their perception of falling into a rabbit hole.”

Once a user toggled autoplay on, the researchers found that they felt more conscious of their media experience and were more likely to see the rabbit hole. However, the feeling of control also made them less conscious of the fact that the content violated their expectations, making them less likely to perceive a rabbit hole.

For those who reported lower amounts of online viewing prior to the experiment, the passive viewing experience of autoplayed videos without any manual control led to an increased perception of falling down the rabbit hole even when the videos consisted of non-extreme content.

The researchers said these results can be used to promote more mindful use of online platforms and inform more responsible platform designs.

“Often, people go down rabbit holes without realizing that they are exposed to fringe, extreme content,” Sundar said. “The more novel the next video, the more likely that a person would continue watching, even if the material is sensational. They may mistake it to be mainstream opinion. We want to identify and promote interface designs that enable people, especially heavy users, to be thoughtful consumers who realize that what they are watching — beyond a point — is not mainstream content, so they can adjust their views and behaviors based on that understanding.”

Other co-authors include Jingshi Kang, a doctoral student at Fudan University who was a visiting scholar at Penn State in 2023, and Pejman Sajjadi, user experience researcher at Meta in California, who was a postdoctoral scholar at Penn State.

The human brain is remarkably adept at adjusting what we hear based on contexts, like our current environment or priorities, but it’s still unknown how exactly the brain helps us detect, filter and react to sounds.

Now, biologists at the University of Maryland are a step closer to solving that mystery. Using an animal model, the researchers found that the orbitofrontal cortex (OFC), a brain region associated with decision-making but not typically linked to hearing, plays a central role in helping the auditory cortex (a primary hearing center of the brain) adapt to changing contexts or situations. The team’s findings were published in the journal Current Biology on July 11, 2024.

“Our hearing doesn’t just depend on the sounds around us. It also relies heavily on what we’re doing and what’s important to us at that moment,” explained UMD Biology Assistant Professor Melissa Caras, the paper’s senior author. “Understanding the neural mechanisms responsible for these adjustments can also lead to a better understanding of and potential treatments for neurodevelopmental disorders like autism, dyslexia or schizophrenia — conditions where sensory regulation goes awry.”

To closely examine the brain circuitry involved in the hearing process, the researchers turned to gerbils, small mammals whose basic hearing system is similar to that of humans. The animals were exposed to sound patterns in two different contexts. In one context, the animals listened to sounds passively without needing to do anything. In the other, the animals had to perform a specific action in response to the sounds they heard. By recording and manipulating the brain activity of the animals, the team discovered that the OFC helped the animals switch between passive and active listening.

“In short, the OFC sends signals to the auditory cortex when it’s time to pay closer attention to sounds,” Caras said. “It’s not certain whether the signals are sent directly or indirectly via an intermediary brain region, but we do know that activity in the OFC is essential to how the gerbils behaved in our experiments.”

When the OFC was silenced, the animals’ auditory cortex did not switch between passive and active listening, impairing their ability to pay attention to and react to a behaviorally relevant sound.

“In terms of a more human-oriented analogy, it would be as if I told you to suddenly pay attention to your refrigerator humming in the background,” Caras explained. “If your OFC was silenced and unable to send a signal to your auditory cortex, you might have difficulty doing so because the ability to rapidly alter your sound perception would be impaired.”

While this study was conducted in animals, Caras says the findings may have notable implications for human health and well-being. The ability to quickly shift attention to important sounds is essential for many day-to-day activities including communicating with others and navigating busy or dangerous environments.

“We’re just beginning to understand how the brain fine tunes hearing sensitivity in response to sudden shifts in behavioral contexts. We plan to explore exactly how the OFC communicates with the auditory cortex and see whether it’s possible to strengthen the connection and improve hearing ability,” Caras said. “This work is paving the way for researchers and health care professionals to develop better strategies for improving hearing in both healthy individuals and those with sensory impairments.”

This research was supported by the National Institutes of Health (Award Nos. R00DC016046 and R01DC020742).

Now, however, in a study published recently in the Journal of Clinical Immunology, researchers from Tokyo Medical and Dental University (TMDU) and Kagoshima University have identified a previously undocumented manifestation among patients with 18q del syndrome: late-onset combined immunodeficiency (LOCID), affecting both B and T cells. This novel finding underscores the critical importance of routinely assessing the functionality of both B and T cells in individuals with 18q del syndrome.

Elaborating further on this novel finding, Professor Kanegane says, “In this study, we came across two patients with chromosome 18q del syndrome presenting with LOCID, which, to the best of our knowledge, has not yet been reported in patients with the syndrome.”

Patient 1 was a 29-year-old man diagnosed with 18q del syndrome. Despite initially having few infections, he developed Pneumocystis pneumonia (PCP). Array-based comparative genomic hybridization (CGH) analysis showed a deletion in the 18q21.32-q22.3 chromosome region.

Patient 2 was a 48-year-old woman who had not been previously diagnosed with 18q del syndrome. However, she was diagnosed with granulomatous lymphadenitis, and a biopsy of her lymph nodes revealed a loss of 18q21.33-qter.

Both patients exhibited hypogammaglobulinemia, characterized by abnormally low levels of immunoglobulins (IgG, IgA, IgM, and IgE). Patient 1’s serum immunoglobulin levels were significantly below normal ranges. He reported IgG of 188 mg/dL (normal: 870-1,700 mg/dL), IgA of 105 mg/dL (normal: 110-410 mg/dL), IgM of 26 mg/dL (normal: 33-190 mg/dL), and IgE of <5 IU/mL (normal: 232 IU/mL). His CD4⁺ T cells had a decreased percentage of naïve T cells, accounting for only 3.58% of the total CD3⁺CD4⁺ cell population. Moreover, his T-cell receptor excision circles (TREC) levels and Ig κ-deleting recombination excision circle (KREC) levels were extremely low at 25.27 copies/105 cells (normal: > 565 copies/105 cells) and 93.36 copies/105 cells (normal: ≥ 456 copies/105 cells) respectively, indicating poor T-cell production.

Similar conditions were noted for patient 2, who reported IgG of 8 mg/dL, IgA of 9 mg/dL, IgM of 131 mg/dL, and IgE of 0.3 IU/mL. Her CD4⁺ T cells and naïve CD4⁺ T cells were depleted, with naïve T cells accounting for only 6% of the CD3⁺CD4⁺ cell population. Her TREC levels were 0 copies/10⁵ cells, and her KREC levels were 11.4 copies/10⁵ cells.

Importantly, CD4⁺ and CD8⁺ T cells failed to divide in response to phytohemagglutinin (PHA) stimulation, indicating severe functional impairment of T cells in both the patients.

Based on their immune profiles and clinical history, both of them were diagnosed with LOCID, a condition where both humoral (antibody-mediated) and cell-mediated immune responses were impaired, making them highly susceptible to infections.

This novel finding is significant, as Dr. Tomomasa, the co-authored of this study, states, “While cases involving deletion of the same region as those of the two patients presented in this study have been reported earlier, patients with 18q del syndrome developing LOCID have never been reported. We speculate that these patients simply have not yet developed LOCID or that they might not have been adequately assessed for it.”

On the basis of these results, the researchers recommend annual testing for both cellular and humoral immunity in patients with 18q del syndrome. This proactive approach can allow for the early detection of combined immune deficiencies, facilitating timely interventions and personalized treatment strategies. Ultimately, such regular monitoring can significantly improve clinical outcomes and enhance the quality of life for individuals diagnosed with 18q del syndrome.

Now, researchers at the Broad Institute of MIT and Harvard and the University of Iowa have developed a gene-editing approach that efficiently corrects the most common mutation that causes cystic fibrosis, found in 85 percent of patients. With further development, it could pave the way for treatments that are administered only once and have fewer side effects.

The new method, published today in Nature Biomedical Engineering, precisely and durably corrects the mutation in human lung cells, restoring cell function to levels similar to that of Trikafta. The approach is based on a technique called prime editing, which can make insertions, deletions, and substitutions up to hundreds of base pairs long in the genome with few unwanted byproducts. Prime editing was developed in 2019 by the lab of David Liu, who is the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad, as well as a professor at Harvard University and a Howard Hughes Medical Institute investigator.

“We are hopeful that the use of prime editing to correct the predominant cause of cystic fibrosis might lead to a one-time, permanent treatment for this serious disease,” said Liu, the senior author on the study. “Developing a strategy to efficiently correct this challenging mutation also provided a blueprint for optimizing prime editing to precisely correct other mutations that cause devastating disorders.”

Postdoctoral researcher Alex Sousa and graduate student Colin Hemez, both from Liu’s lab, were first authors on the study.

Gene repair

Cystic fibrosis is caused by mutations in the CFTR gene that impair ion channels in the cell membrane that pump chloride out of cells. There are more than 2,000 known variants of the CFTR gene, 700 of which cause disease. The most common is a three base-pair CTT deletion that causes the ion channel protein to misfold and degrade.

Correcting the CTT deletion in CFTR has long been the goal of gene-editing therapies by labs including Liu’s, but most attempts have not been efficient enough to confer a therapeutic benefit, or use approaches such as CRISPR/Cas9 nuclease editing that generate double-stranded breaks in DNA, which can generate unwanted changes in the target gene and other locations in the genome.

Prime editing, a more flexible and controlled kind of gene editing that does not require double-stranded breaks, could help address this limitation. To more efficiently correct the CFTR mutation, Liu’s team combined six different enhancements to the technology. These included improving the prime editing guide RNAs that program prime editor proteins to find their target and to make the desired edit, as well as modifying the prime editor protein itself and other changes that make the target site more accessible. In combination, these refinements corrected about 60 percent of the CTT deletions in human lung cells and about 25 percent in cells taken directly from patient lungs and grown in a dish, an increase from previous methods that corrected less than 1 percent of the mutation in cells. The new approach also generated 3.5 times fewer unwanted insertions and deletions per edit than previous methods that use the Cas9 nuclease enzyme.

Next, researchers will need to develop ways to package and deliver the prime editing machinery to the airways in mice and ultimately humans. The team is hopeful that recent developments such as lipid nanoparticles that reach the lungs in mice may help expedite translation of this approach.

A new study from Keck Medicine of USC published in The American Journal of Gastroenterology finds that transgender adults have double the prevalence of cirrhosis compared to cisgender adults (people whose gender identity matches the sex they were assigned at birth), suggesting a need for more supportive, preventive care.

“Our study reveals that cirrhosis disproportionately affects transgender individuals and highlights a pressing health issue that needs addressing,” said Brian P. Lee, MD, MAS, a hepatologist and liver transplant specialist with Keck Medicine and principal investigator of the study.

Lee and his colleagues launched the study to provide scientifically backed liver health guidance for physicians so they could offer transgender patients a higher level of care.

Besides discovering that transgender cirrhosis rates are double that of the cisgender population, the study authors also learned that the majority of transgender adults with cirrhosis (60%) have a diagnosis of anxiety and/or depression, compared to 40% of the cisgender patients with cirrhosis.

They also found that alcohol was the leading cause of cirrhosis in the transgender group, accounting for some 60% of cases while the percentage of cisgender adults with alcohol-associated cirrhosis was approximately 50%.

In other findings, transgender patients with cirrhosis also tended to be younger (a larger portion were 44 or younger), had higher rates of viral hepatitis and were five times more likely to have HIV/AIDS than their cisgender counterparts.

Possible reasons behind the disparity

Lee hypothesizes that the increased rates of depression and anxiety may be driving higher rates of alcohol use among transgender patients, which in turn, may result in greater cases of cirrhosis.

The increased rate of HIV/AIDS among transgender patients may also be a factor in that both conditions are known to be associated with liver disease progression, according to Lee.

Lack of access to quality health care could also play a role, hypothesizes Jeffrey Kahn, MD, a hepatologist and liver transplant physician with Keck Medicine and co-author of the study.

Researchers also studied the five-year outcomes among all transgender and cisgender patients with cirrhosis. Interestingly, despite the differences in the two groups, the number of possible negative outcomes of cirrhosis — liver failure, liver transplant and liver cancer, as well as death, by any cause — was the same.

“This finding suggests that the transgender community is underserved in the initial stages of liver disease, but individuals are able to secure the care they need once cirrhosis is diagnosed,” said Kahn. “Early prevention is key because if liver disease is caught in time, there is less of a chance it will progress to cirrhosis.”

To reach their conclusions, study authors culled data from a large national database, Optum Clinformatics® Data Mart Database (Optum), that contained medical claims for more than 60 million patients covered by commercial insurance or Medicare between the years of 2007-2022. They first identified all transgender and cisgender adults, and then compared the incidences of cirrhosis among each group as well as causes of the disease. Additionally, researchers tracked depression and anxiety in patients.

Lee and Kahn hope the study will spur more research and motivate health care practitioners to provide transgender patients with extra support, including liver screenings and access to mental health resources. “This population requires specific attention from clinicians and researchers alike,” said Lee.

Keck Medicine efforts to support transgender patient wellness

Keck Medicine launched the USC Gender-Affirming Care Program to provide tailored, supportive health care to the transgender population. The program provides a full range of expert, compassionate health care services for the transgender, non-binary and gender-diverse community, including everything from routine health care, such as preventive cancer screenings, yearly checkups and flu shots, to gender-affirming hormone therapy and surgery.

The program is comprised of physicians from several disciplines, including family medicine, plastic surgery, gynecology, urology and otolaryngology. Specialists in voice, occupational and physical therapy are also available to patients.

Additionally, Keck Medicine hospitals have been awarded the ‘LGBTQ+ Healthcare Equality Leader’ designation in the Human Rights Campaign Foundation’s 2024 Healthcare Equality Index (HEI) for seven times in recent years. HEI is the leading national benchmarking survey of health care facility policies and practices dedicated to the equitable treatment and inclusion of LGBTQ+ patients, visitors and employees.

The treatment, not yet studied in patients, involves the lab engineering of natural killer (NK) cells — white blood cells that destroy tumor cells — to more effectively battle hepatocellular carcinoma (HCC), one of the most treatment-resistant types of solid tumor.

Genetically modified NK-cell therapy doesn’t require personalization like chimeric antigen receptor (CAR)-expressing T-cell therapy — a relatively new, personalized form of immunotherapy. That means an NK-cell therapy could be mass produced and shelf-ready for patients, who could begin therapy without delay, their new research shows.

“To some extent all tumor cells — perhaps hepatocellular carcinoma more so — inhibit immune cells that try to kill them,” said UC San Diego School of Medicine Professor Dan Kaufman, M.D., Ph.D., lead author on the study, director of the Sanford Advanced Therapy Center at the university’s Sanford Stem Cell Institute and Moores Cancer Center member.

“This is one key reason why some immunotherapies like CAR T cells have been less successful for solid tumors than for blood cancers — the immunosuppressive tumor microenvironment.”

Kaufman and his team produced stem cell-derived NK cells in which the receptor for transforming growth factor beta (TGF-β) — a protein that impairs immune function — was disabled. HCC tumors and the liver in general contain copious amounts of the substance, which both inhibits the immune cell activity and allows cancer to proliferate.

They found that typical NK cells without the disabled receptor, like CAR T cells, were not very effective in battling the cancer. “These are pretty resistant tumors — when we put them in mice, they grow and kill the mice,” he said. The five-year survival rate for HCC in humans is less than 20 percent.

When researchers tested the modified NK cells against the cancer, however, “we got very good anti-tumor activity and significantly prolonged survival,” he noted.

“These studies demonstrate that it is crucial to block transforming growth factor beta — at least for NK cells, but I also think it’s true for CAR T cells,” Kaufman said. “If you unleash NK cells by blocking this inhibitory pathway, they should kill cancer quite nicely.”

Kaufman anticipates that his team’s discovery will manifest itself in the clinical trials of many research groups and companies — whether they’re working on CAR T-cell or NK-cell therapies, battling hepatocellular carcinoma or other challenging types of solid tumors.

“Anyone developing such therapies for solid tumors should be working to inhibit transforming growth factor beta activity to improve cancer-killing and attain effective anti-tumor activity,” he said.

Co-authors of this study include Jaya Lakshmi Thangaraj; Michael Coffey; and Edith Lopez, all of the Division of Regenerative Medicine at UC San Diego’s School of Medicine.

This work was made possible by the NIH/NCI grants U01CA217885, P30CA023100 (administrative supplement), and the Sanford Stem Cell Institute at the University of California San Diego.

The research, led by Trinity College Dublin neuroscientist Prof. Sonia Bishop and Google researcher Samy Abdel-Ghaffar while he was a PhD student in Prof. Bishop’s lab at UC Berkeley, has identified how the brain represents different categories of emotional stimuli in a way that allows for more than a simple ‘approach avoid’ dichotomy when guiding behavioural responses. The research was funded by the National Institutes of Health, USA.

Sonia Bishop, now Chair of Psychology, in Trinity’s School of Psychology and senior author of the paper explains: “It is hugely important for all species to be able to recognise and respond appropriately to emotionally salient stimuli, whether that means not eating rotten food, running from a bear, approaching an attractive person in a bar or comforting a tearful child.

“How the brain enables us to respond in a nuanced way to emotionally-charged situations and stimuli has long been of interest. But, little is known about the how the brain stores schemas or neural representations to support the nuanced behavioural choices we make in response to emotional natural stimuli.

“Neuroscience studies of motivated behaviour often focus on simple approach or avoidance behaviours — such as lever pressing for food or changing locations to avoid a shock. However, when faced with natural emotional stimuli, humans don’t simply choose between ‘approach’ or ‘avoid’. Rather they select from a complex range of suitable responses. So, for example, our ‘avoid’ response to a large bear (leave the area ASAP) is different to our ‘avoid’ response to a weak, diseased, animal (don’t get too close). Similarly our ‘approach’ response to the positive stimuli of a potential mate differs to our ‘approach’ reaction to a cute baby.

“Our research reveals that the occipital temporal cortex is tuned not only to different categories of stimuli but it also breaks down these categories based on their emotional characteristics in a way that is well suited to guide selection between alternate behaviours.”

The research team from Trinity College Dublin, University of California Berkeley, University of Texas at Austin, Google and University of Nevada Reno, analysed the brain activity of a small group of volunteers when viewing over 1,500 images depicting natural emotional scenes such as a couple hugging, an injured person in a hospital bed, a luxurious home, and an aggressive dog.

Participants were asked to categorise the images as positive, negative or neutral and to also rate the emotional intensity of the images. A second group of participants picked the behavioural responses that best matched each scene.

Using cutting-edge modelling of brain activity divided into tiny cubes (of under 3mm³) the study discovered that the occipital temporal cortex (OTC), a region at the back of the brain, is tuned to represent both the type of stimulus (single human, couple, crowd, reptile, mammal, food, object, building, landscape etc.) and the emotional characteristics of the stimulus — whether it’s negative, positive or neutral and also whether it’s high or low in emotional intensity.

Machine learning showed that these stable tuning patterns were more efficient in predicting the behaviours matched to the images by the second group of participants than could be achieved by applying machine learning directly to image features — suggesting that the OTC efficiently extracts and represents the information needed to guide behaviour.

Samy Abdel-Ghaffar, Google, commented: “For this project we used Voxel-Wise Modeling, which combines machine learning methods, large datasets and encoding models, to give us a much more fine-grained understanding of what each part of the OTC represents than traditional neuroimaging methods. This approach let us explore the intertwined representation of categorical and emotional scene features, and opened the door to novel understanding of how OTC representations predict behaviour.”

Prof. Bishop added: “These findings expand our knowledge of how the human brain represents emotional natural stimuli. In addition, the paradigm used does not involve a complex task making this approach suitable in the future, for example, to further understanding of how individuals with a range of neurological and psychiatric conditions differ in processing emotional natural stimuli.”

More about the study method:

The team used a novel large dataset of 1,620 emotional natural images and conducted functional magnetic resonance imaging with adult human volunteers, acquiring over 3,800 3D pictures of brain activity while participants viewed these images. Participants judged these images on valence (positive, negative or neutral) and arousal (or emotional intensity).

Modelling this data using small 2.4×2.4x3mm chunks or ‘voxels’ of brain activity, the researchers found that regions of occipital temporal cortex, in the back of the brain, showed differential representation of both stimulus semantic category and affective value. For example, positive high arousal faces were represented in slightly different regions to negative high arousal faces and neutral low arousal faces.

Furthermore, when a completely new set of participants were asked to select behaviours that went with each image, the top dimensions of this neural coding representational ‘space’ better predicted the behaviours selected than the top dimensions based directly on image features (for example is the stimulus animate-positive?). This suggests that the brain chooses which information is important or not important to represent and hold stable representations of sub-categories of animate and inanimate stimuli that integrate affective information and are optimally organised to support the selection of behaviours to different types of emotional natural stimuli.

The investigators used the new platform, called GeneMAP (Gene-Metabolite Association Prediction), to identify a gene necessary for mitochondrial choline transport. The resource and derived findings were published July 8 in the journal Nature Genetics.

“We sought to gain insight into a fundamental question: ‘How does genetic variation determine our “chemical individuality” — the inherited differences that make us biochemically unique?” said Eric Gamazon, PhD, associate professor of Medicine in the Division of Genetic Medicine at Vanderbilt University Medical Center. Gamazon is the senior and co-corresponding author of the study with Kivanç Birsoy, PhD, of The Rockefeller University.

Metabolic reactions play critical roles in nutrient absorption, energy production, waste disposal, and synthesis of cellular building blocks including proteins, lipids and nucleic acids. About 20% of protein-coding genes are dedicated to metabolism, including genes that code for small-molecule transporters and enzymes, Gamazon said.

Abnormalities in metabolic functions are associated with a range of disorders including neurodegenerative diseases and cancers.

“Despite decades of research, many metabolic genes still lack known molecular substrates. The challenge is in part due to the enormous structural and functional diversity of the proteins,” Gamazon said.

To discover functions for “orphan” transporters and enzymes — proteins with unknown substrates — the researchers developed the GeneMAP discovery platform. They used datasets from two independent large-scale human metabolome genome-wide/transcriptome-wide association studies and demonstrated with in silico validation that GeneMAP can identify known gene-metabolite associations and discover new ones. In addition, they showed that GeneMAP-derived metabolic networks can be used to infer the biochemical identity of uncharacterized metabolites.

To experimentally validate new gene-metabolite associations, the researchers selected their top finding (SLC25A48-choline) and performed in vitro biochemical studies. SLC25A48 is a mitochondrial transporter that did not have a defined substrate for transport. Choline is an essential nutrient used in multiple metabolic reactions and in the synthesis of cell membrane lipids.

The researchers showed that SLC25A48 is a genetic determinant of plasma choline levels. They further conducted radioactive mitochondrial choline uptake assays and isotope tracing experiments to demonstrate that loss of SLC25A48 impairs mitochondrial choline transport and synthesis of the choline downstream metabolite betaine.

They also investigated the consequences of the relationship between SLC25A48 and choline on the human medical phenome (symptoms, traits and diseases listed in electronic health records) using large-scale biobanks (UK Biobank and BioVU). They identified eight disease associations.

“What’s exciting about this study is its interdisciplinarity — the combination of genomics and metabolism to identify a long-sought mitochondrial choline transporter,” Gamazon said. “We think, given the extensive in silico validation studies in independent datasets and the proof-of-principle experimental studies, our approach can help identify the substrates of a wide range of enzymes and transporters, and ‘deorphanize’ these metabolic proteins.”

Birsoy is Chapman-Perelman Associate Professor, Head of the Laboratory of Metabolic Regulation and Genetics at The Rockefeller University, and a Searle and Pew-Stewart Scholar. Co-authors of the study include Artem Khan, Gokhan Unlu, PhD, (who completed his doctoral degree at Vanderbilt), Yuyang Liu, Ece Kilic and Timothy Kenny, PhD, at Rockefeller, and Phillip Lin at VUMC.

The research was supported by the National Institutes of Health (grants F99CA284249, F32DK127836, R01DK123323, R01HG011138, R01GM140287, R56AG068026, U24OD035523, R35HG010718), Boehringer Ingelheim Fonds PhD Fellowship, and Damon Runyon Cancer Research Foundation.

Researchers at the University of Reading and Durham University collected an enormous dataset of brain and body sizes from around 1,500 species to clarify centuries of controversy surrounding brain size evolution.

Bigger brains relative to body size are linked to intelligence, sociality, and behavioural complexity — with humans having evolved exceptionally large brains. The new research, published today (Monday, 8 July), reveals the largest animals do not have proportionally bigger brains, challenging long-held beliefs about brain evolution.

Professor Chris Venditti, lead author of the study from the University of Reading, said: “For more than a century, scientists have assumed that this relationship was linear — meaning that brain size gets proportionally bigger, the larger an animal is. We now know this is not true. The relationship between brain and body size is a curve, essentially meaning very large animals have smaller brains than expected.”

Professor Rob Barton, co-author of the study from Durham University, said: “Our results help resolve the puzzling complexity in the brain-body mass relationship. Our model has a simplicity that means previously elaborate explanations are no longer necessary — relative brain size can be studied using a single underlying model.”

Beyond the ordinary

The research reveals a simple association between brain and body size across all mammals which allowed the researchers to identify the rule-breakers — species which challenge the norm.

Among these outliers includes our own species, Homo sapiens, which has evolved more than 20 times faster than all other mammal species, resulting in the massive brains that characterise humanity today. But humans are not the only species to buck this trend.

All groups of mammals demonstrated rapid bursts of change — both towards smaller and larger brain sizes. For example, bats very rapidly reduced their brain size when they first arose, but then showed very slow rates of change in relative brain size, suggesting there may be evolutionary constraints related to the demands of flight.

There are three groups of animals that showed the most pronounced rapid change in brain size: primates, rodents, and carnivores. In these three groups, there is a tendency for relative brain size to increase in time (the “Marsh-Lartet rule”). This is not a trend universal across all mammals, as previously believed.

Dr Joanna Baker, co-author of the study also from the University of Reading, said: “Our results reveal a mystery. In the largest animals, there is something preventing brains from getting too big. Whether this is because big brains beyond a certain size are simply too costly to maintain remains to be seen. But as we also observe similar curvature in birds, the pattern seems to be a general phenomenon — what causes this ‘curious ceiling’ applies to animals with very different biology.”

Now, researchers have found an approach that could extend naloxone’s lifesaving power, even in the face of ever-more-dangerous opioids. A team of researchers from Washington University School of Medicine in St. Louis, Stanford University and the University of Florida have identified potential drugs that make naloxone more potent and longer lasting, capable of reversing the effects of opioids in mice at low doses without worsening withdrawal symptoms. The study is published July 3 in Nature.

“Naloxone is a lifesaver, but it’s not a miracle drug; it has limitations,” said co-senior author Susruta Majumdar, PhD, a professor of anesthesiology at Washington University. “Many people who overdose on opioids need more than one dose of naloxone before they are out of danger. This study is a proof of concept that we can make naloxone work better — last longer and be more potent — by giving it in combination with a molecule that influences the responses of the opioid receptor.”

Opioids such as oxycodone and fentanyl work by slipping inside a pocket on the opioid receptor, which is found primarily on neurons in the brain. The presence of opioids activates the receptor, setting off a cascade of molecular events that temporarily alters how the brain functions: reducing the perception of pain, inducing a sense of euphoria and slowing down breathing. It is this suppression of breathing that makes opioids so deadly.

The molecular compound described in the paper is a so-called negative allosteric modulator (NAM) of the opioid receptor. Allosteric modulators are a hot area of research in pharmacology, because they offer a way to influence how the body responds to drugs by fine-tuning the activity of drug receptors rather than the drugs themselves. Co-author Vipin Rangari, PhD, a postdoctoral fellow in the Majumdar lab, did the experiments to chemically characterize the compound.

Naloxone is an opioid, but unlike other opioids, its presence in the binding pocket doesn’t activate the receptor. This unique feature gives naloxone the power to reverse overdoses by displacing problematic opioids from the pocket, thereby deactivating the opioid receptor. The problem is that naloxone wears off before other opioids do. For example, naloxone works for about two hours, while fentanyl can stay in the bloodstream for eight hours. Once naloxone falls out of the binding pocket, any fentanyl molecules that are still circulating can re-attach to and re-activate the receptor, causing the overdose symptoms to return.

The research team — led by co-senior authors Majumdar; Brian K. Kobilka, PhD, a professor of molecular and cellular physiology at Stanford University; and Jay P. McLaughlin, PhD, a professor of pharmacodynamics at the University of Florida — set out to find NAMs that strengthen naloxone by helping it stay in the binding pocket longer and suppress the activation of the opioid receptor more effectively.

To do so, they screened a library of 4.5 billion molecules in the lab in search of molecules that bound to the opioid receptor with naloxone already tucked into the receptor’s pocket. Compounds representing several molecular families passed the initial screen, with one of the most promising dubbed compound 368. Further experiments in cells revealed that, in the presence of compound 368, naloxone was 7.6 times more effective at inhibiting the activation of the opioid receptor, partly because naloxone stayed in the binding pocket at least 10 times longer.

“The compound itself doesn’t bind well without naloxone,” said Evan O’Brien, PhD, the lead author on the study and a postdoctoral scholar in Kobilka’s lab at Stanford. “We think naloxone has to bind first, and then compound 368 is able to come in and cap it in place.”

Even better, compound 368 improved naloxone’s ability to counteract opioid overdoses in mice and enabled naloxone to reverse the effects of fentanyl and morphine at 1/10th the usual doses.

However, people who overdose on opioids and are revived with naloxone can experience withdrawal symptoms such as pain, chills, vomiting and irritability. In this study, while the addition of compound 368 boosted naloxone’s potency, it did not worsen the mice’s withdrawal symptoms.

“We have a long way to go, but these results are really exciting,” McLaughlin said. “Opioid withdrawal likely won’t kill you, but they’re so severe that users often resume taking opioids within a day or two to stop the symptoms. The idea that we can rescue patients from overdose with reduced withdrawal might just help a lot of people.”

Compound 368 is just one of several molecules that show potential as NAMs of the opioid receptor. The researchers have filed a patent on the NAMs, and are working on narrowing down and characterizing the most promising candidates. Majumdar estimates that it will be 10 to 15 years before a naloxone-enhancing NAM is brought to market.

“Developing a new drug is a very long process, and in the meantime new synthetic opioids are just going to keep on coming and getting more and more potent, which means more and more deadly,” Majumdar said. “Our hope is that by developing a NAM, we can preserve naloxone’s power to serve as an antidote, no matter what kind of opioids emerge in the future.”

“How far is the virus getting through?” asked Erica Spackman, Ph.D., a virologist at the U.S. Department of Agriculture (USDA) in Athens, Ga. To find out, she and her collaborators tested nearly 300 milk products from 132 processors.

The researchers found no infectious virus in the samples, Spackman and her collaborators report this week in the Journal of Virology, a journal of the American Society for Microbiology. “Milk is safe,” she said. “Just like bacterial pathogens that occur in milk, or other viruses that could occur in milk, the sanitation processes that are in place are getting rid of the pathogens.”

The milk processing pipeline includes multiple layers of protection, Spackman said. Microbiological surveillance of milk products can identify pathogens, and milk from cows with mastitis or other disease conditions does not enter the food supply. Finally, heating during the pasteurization process can destroy H5N1 and other, more common bacterial pathogens.

Bird flu primarily infects and spreads among migratory birds and can be transmitted to domestic poultry, but the virus has been detected in other animals as well. Recently, those have included cats, dogs and juvenile goats, as well as a polar bear in Alaska and elephant and fur seals in the Antarctic. However, the discovery of H5N1 on dairy farms in March was a surprise — the virus had never been found in dairy cattle before.

Soon after the discovery, diagnostic testing revealed that an infectious form of the virus was present in raw milk, suggesting the virus passes from cow to milk. That finding led the U.S. Food and Drug Administration and the USDA to investigate whether pasteurization effectively eliminated risks posed to consumers. Between April 18 and April 22, 2024, researchers used real-time PCR to analyze 297 samples of pasteurized retail milk products, including 23 types of products, collected from 17 states.

“We did a viability assay to detect live virus and went as sensitive as we could to get even the least little bit of virus, but couldn’t detect anything,” Spackman said. Using PCR, the researchers did identify viral genetic material in 20% of samples. “It looks like the virus is just totally inactivated,” she said.

Spackman said the new findings “give us reassurance that what we have been doing — pasteurization — is keeping us safe from what we don’t know about.”

The research, which could expand the toolkit available to drug developers in improving the safety profiles of medications and reducing side effects, was published in Science by organic chemists at the University of British Columbia (UBC), the Massachusetts Institute of Technology (MIT), and the University of Michigan.

“Azetidines are a particularly useful, stable form of heterocycle, but synthesizing them has been incredibly challenging,” says Dr. Corinna Schindler, Canada Research Chair in synthetic solutions for bioactive compounds at UBC and senior author on the paper.

Heterocycles play a major role in the design of modern drug families — including cancer drugs and antibiotics. Some reviews indicate 85 per cent of all biologically active chemical entities contain a heterocycle.

But many heterocycles currently used in pharmaceutical design tend to oxidize under physiological conditions. This can lead to off-target effects and challenges with the safety profiles of medications.

Azetidines — organic compounds that contain three carbon atoms and one nitrogen atom, and are liquid at room temperature — are known to be metabolically robust and don’t undergo oxidation reactions under physiological conditions.

“This is something that synthetic organic chemists have tried to achieve for a long time, and we’re hopeful this will enable researchers to develop new synthetic transformations of azetidines with more useful chemical and medical functions,” says Dr. Schindler, whose lab conducted the research at the University of Michigan with graduate student Emily Wearing and in conjunction with Dr. Heather Kulik’s lab at the Massachusetts Institute of Technology.

The team used light-driven reactions and a computational approach to the problem and for the first time were able to engage compounds called imines productively in reactions to form new azetidines.

In the study, the researchers asked 485 children between the ages of five and twelve to choose between six different foods with and without lumps, seeds and pieces of fruit in them. The foods were bread, orange juice, peanut butter, strawberry jam, yogurt and tomato soup. The researchers showed children drawings of these foods both with and without lumps, and then asked them to choose between them.

In 76 percent of the instances, six-year-olds opted for foods without lumps, the highest preference rate observed across the age groups.

“The fact that children in general are not happy with too many lumps in food is probably something many people can recognize, but this is the first time that a scientific study has linked a specific age group, namely six-year-olds, so clearly to this food preference,” says Dr. Ching Yue Chow, first author of the study.

To get answers that were as precise as possible, the researchers have used real foods to test how consistent children were in answering these questions in other studies.

Protection against dangerous foods

According to Ching Yue Chow, there may be an explanation for why children’s fear of complex texture in food peaks around the age of six.

“Food neophobia is often described as the reluctance to eat new or unfamiliar foods. It is thought to be a protective function to prevent children from eating potentially poisonous foods or other dangerous things when they start to become more independent. Studies have reported that food neophobia starts from a low baseline at weaning. It increases sharply as a child becomes more mobile and independent, reaching a peak at around 6 or 7 years old.

As such, it makes sense that this particular group in our study does not like too many lumps in food, as it is at this age that they are most cautious when it comes to food,” explains Ching Yue Chow.

The researchers also examined whether chunk size in food has anything to say. But here, they found no unequivocal answer.

“It seemed that the children generally had no problem in distinguishing different sizes of chunks when foods were in their mouths. For them, it’s mostly about the presence or absence of chunks,” says Ching Yue Chow.

However, despite there being a low point in the desire to eat food with chunks at the age of six, it gradually goes the other way in 7-12-year-olds, the study shows. And this is supported by our previous knowledge in advance of how children’s food preferences mature with age.

“As children reach school age, they may become more influenced by classmates and others within their circle to try new types of food and have more of a desire to expand their horizons. We can also see that the proportion that would like to have food with chunks in food grows in concert with their age in the study,” says Ching Yue Chow.

New dishes may need to be introduced 8-15 times

And according to the researcher, the “anti-chunk phase” that 6-year-olds have, you have to accept as a parent, although it can be frustrating when the kids don’t want to eat the food they’re served. But that can easily change once they’re past the critical age of six. You just have to keep trying — often up to 15 times, the recommendation goes:

“A lot of research on children and foods shows that repeated exposures to new dishes have a positive effect on whether they’ll bother eating them. Specifically, it is about giving children the opportunity to taste new food while there is something on the plate that they already know. Often they need to be presented with the new dish 8-15 times before they develop preference for it, but persistence pays off,” explains Ching Yue Chow.

Furthermore, it’ a good idea to avoid compulsions and rewards for children to eat their vegetables.

“Rewarding a child with an ice cream if they eat their broccoli, is a very short-term strategy. Because the moment you remove the ice cream, they don’t want to eat the healthy foods. At the same time, you shouldn’t pressure a child or try to force them to eat certain things, because you risk that they will eat the new food even less than before because they associate it with something negative,” says Ching Yue Chow.

The new research results shed more light on the food preferences of children between the ages of five and twelve, which the researcher hopes can make parents and the food industry wiser about our relationships with food.

“It is important to understand the underlying psychology of children when you, as a parent, serve them food and when you as a company develop new products to avoid children becoming unnecessarily picky. Here, I hope that our study can serve as an inspiration to parents and those who develop new food products,” concludes Ching Yue Chow.

The 6-year-olds like lumps in their food the least:

About the study:

• The research was carried out in a close collaboration between Future Consumer Lab, Department of Food Science, University of Copenhagen and the CASS Food Research Centre at Deakin University, Australia.
• The researchers behind the study are: Ching Yue Chow, Anne C. Bech, Annemarie Olsen, Russell Keast, Catherine G. Russell and Wender L.P. Bredie.
• The study involved 485 Australian children aged 5-12 years.
• The study is funded by Innovation Fund Denmark and Arla Foods.

P. aeruginosa is responsible for over 500,000 deaths per year around the world, of which over 300,000 are associated with antimicrobial resistance (AMR). People with conditions such as COPD (smoking-related lung damage), cystic fibrosis (CF), and non-CF bronchiectasis, are particularly susceptible.

How P. aeruginosa evolved from an environmental organism into a specialised human pathogen was not previously known. To investigate this, an international team led by scientists at the University of Cambridge examined DNA data from almost 10,000 samples taken from infected individuals, animals, and environments around the world. Their results are published today in Science

By mapping the data, the team was able to create phylogenetic trees — ‘family trees’ — that show how the bacteria from the samples are related to each other. Remarkably, they found that almost seven in ten infections are caused by just 21 genetic clones, or ‘branches’ of the family tree, that have rapidly evolved (by acquiring new genes from neighbouring bacteria) and then spread globally over the last 200 years. This spread occurred most likely as a result of people beginning to live in densely-populated areas, where air pollution made our lungs more susceptible to infection and where there were more opportunities for infections to spread.

These epidemic clones have an intrinsic preference for infecting particular types of patients, with some favouring CF patients and other non-CF individuals. It turns out that the bacteria can exploit a previously unknown immune defect in people with CF, allowing them to survive within macrophages. Macrophages are cells that ‘eat’ invading organisms, breaking them down and preventing the infection from spreading. But a previously-unknown flaw in the immune systems of CF patients means that once the macrophage ‘swallows’ P. aeruginosa, it is unable to get rid of it.

Having infected the lungs, these bacteria then evolve in different ways to become even more specialised for a particular lung environment. The result is that certain clones can be transmitted within CF patients and other clones within non-CF patients, but almost never between CF and non-CF patient groups.

Professor Andres Floto, Director of the UK Cystic Fibrosis Innovation Hub at the University of Cambridge and Royal Papworth Hospital NHS Foundation Trust, and senior author of the study said: “Our research on Pseudomonas has taught us new things about the biology of cystic fibrosis and revealed important ways we might be able to improve immunity against invading bacteria in this and potentially other conditions.

“From a clinical perspective, this study has revealed important information about Pseudomonas. The focus has always been on how easily this infection can spread between CF patients, but we’ve shown that it can spread with worrying ease between other patients, too. This has very important consequences for infection control in hospitals, where it’s not uncommon for an infected individual to be on an open ward with someone potentially very vulnerable.

“We are incredibly lucky at Royal Papworth Hospital where we have single rooms and have developed and evaluated a new air-handling system to reduce the amount of airborne bacteria and protect all patients.”

Dr Aaron Weimann from the Victor Phillip Dahdaleh Heart & Lung Research Institute at the University of Cambridge, and first author on the study, said: “It’s remarkable to see the speed with which these bacteria evolve and can become epidemic and how they can specialise for a particular lung environment. We really need systematic, pro-active screening of all at risk patient groups to detect and hopefully prevent the emergence of more epidemic clones.”

The research was funded by Wellcome and the UK Cystic Fibrosis Trust.

Their method involves mixing bacteria with food and drug additives from a list of compounds that the FDA classifies as “generally regarded as safe.” The researchers identified formulations that help to stabilize several different types of microbes, including yeast and bacteria, and they showed that these formulations could withstand high temperatures, radiation, and industrial processing that can damage unprotected microbes.

In an even more extreme test, some of the microbes recently returned from a trip to the International Space Station, coordinated by Space Center Houston Manager of Science and Research Phyllis Friello, and the researchers are now analyzing how well the microbes were able to withstand those conditions.

“What this project was about is stabilizing organisms for extreme conditions. We’re really thinking about a broad set of applications, whether it’s missions to space, human applications, or agricultural uses,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT, a gastroenterologist at Brigham and Women’s Hospital, and the senior author of the study.

Miguel Jimenez, a former MIT research scientist who is now an assistant professor of biomedical engineering at Boston University, is the lead author of the paper, which will appear in Nature Materials.

Surviving extreme conditions

About six years ago, with funding from NASA’s Translational Research Institute for Space Health (TRISH), Traverso’s lab began working on new approaches to make helpful bacteria such as probiotics and microbial therapeutics more resilient. As a starting point, the researchers analyzed 13commercially available probiotics and found that six of these products did not contain as many live bacteria as the label indicated.

“What we found was that, perhaps not surprisingly, there is a difference, and it can be significant,” Traverso says. “So then the next question was, given this, what can we do to help the situation?”

For their experiments, the researchers chose four different microbes to focus on: three bacteria and one yeast. These microbes are Escherichia coli Nissle 1917, a probiotic; Ensifer meliloti, a bacterium that can fix nitrogen in soil to support plant growth; Lactobacillus plantarum, a bacterium used to ferment food products; and the yeast Saccharomyces boulardii, which is also used as a probiotic.

When microbes are used for medical or agricultural applications, they are usually dried into a powder through a process called lyophilization. However, they can not normally be made into more useful forms such as a tablet or pill because this process requires exposure to an organic solvent, which can be toxic to the bacteria. The MIT team set out to find additives that could improve the microbes’ ability to survive this kind of processing.

“We developed a workflow where we can take materials from the ‘generally regarded as safe’ materials list from the FDA, and mix and match those with bacteria and ask, are there ingredients that enhance the stability of the bacteria during the lyophilization process?” Traverso says.

Their setup allows them to mix microbes with one of about 100 different ingredients and then grow them to see which survive the best when stored at room temperature for 30 days. These experiments revealed different ingredients, mostly sugars and peptides, that worked best for each species of microbe.

The researchers then picked one of the microbes, E. coli Nissle 1917, for further optimization. This probiotic has been used to treat “traveler’s diarrhea,” a condition caused by drinking water contaminated with harmful bacteria. The researchers found that if they combined caffeine or yeast extract with a sugar called melibiose, they could create a very stable formulation of E. coli Nissle 1917. This mixture, which the researchers called formulation D, allowed survival rates greater than 10 percent after the microbes were stored for six months at 37 degrees Celsius, while a commercially available formulation of E. coli Nissle 1917 lost all viability after only 11 days under those conditions.

Formulation D was also able to withstand much higher levels of ionizing radiation, up to 1,000 grays. (The typical radiation dose on Earth is about 15 micrograys per day, and in space, it’s about 200 micrograys per day.)

The researchers don’t know exactly how their formulations protect bacteria, but they hypothesize that the additives may help to stabilize the bacterial cell membranes during rehydration.

Stress tests

The researchers then showed that these microbes can not only survive harsh conditions, they also maintain their function after these exposures. After Ensifer meliloti were exposed to temperatures up to 50 degrees Celsius, the researchers found that they were still able to form symbiotic nodules on plant roots and convert nitrogen to ammonia.

They also found that their formulation of E. coli Nissle 1917 was able to inhibit the growth of Shigella flexneri, one of the leading causes of diarrhea-associated deaths in low- and middle-income countries, when the microbes were grown together in a lab dish.

Last year, several strains of these extremophile microbes were sent to the International Space Station, which Jimenez describes as “the ultimate stress test.”

“Even just the shipping on Earth to the preflight validation, and storage until flight are part of this test, with no temperature control along the way,” he says.

The samples recently returned to Earth, and Jimenez’ lab is now analyzing them. He plans to compare samples that were kept inside the ISS to others that were bolted to the outside of the station, as well as control samples that remained on Earth.

The research was funded by NASA’s Translational Research Institute for Space Health, Space Center Houston, MIT’s Department of Mechanical Engineering, and by 711 Human Performance Wing and the Defense Advanced Research Projects Agency.

Other authors of the paper include Johanna L’Heureux, Emily Kolaya, Gary Liu, Kyle Martin, Husna Ellis, Alfred Dao, Margaret Yang, Zachary Villaverde, Afeefah Khazi-Syed, Qinhao Cao, Niora Fabian, Joshua Jenkins, Nina Fitzgerald, Christina Karavasili, Benjamin Muller, and James Byrne.

Researchers led by Yasuhiro Murakawa at the RIKEN Center for Integrative Medical Sciences (IMS) and Kyoto University in Japan and IFOM ETS in Italy have discovered several rare types of helper T cells that are associated with immune disorders such as multiple sclerosis, rheumatoid arthritis, and even asthma. Published July 4 in Science, the discoveries were made possible by a newly developed technology they call ReapTEC, which identified genetic enhancers in rare T cell subtypes that are linked to specific immune disorders. The new T cell atlas is publicly available and should help in the development of new drug therapies for immune-mediated diseases.

Helper T cells are kind of white blood cell that make up a large part of the immune system. They recognize pathogens and regulate the immune response. Many immune-mediated disease are caused by abnormal T cell function. In autoimmune diseases like multiple sclerosis, they mistakenly attack parts of the body as if they were pathogens. In the case of allergies, T cells overreact to harmless substances in the environment like pollen. We know of several common T cells, but recent studies have shown that rare and specialized types of T cells exist, and they might be related to immune-mediated diseases.

Within all cells, including T cells, there are regions of DNA called “enhancers”. This DNA does not code for proteins. Instead, it codes for small pieces of RNA, and enhances the expression of other genes. Variations in T cell enhancer DNA therefore lead to differences in gene expression, and this can affect how T cells function. Some enhancers are bidirectional, which means that both strands of the DNA are used as templates for enhancer RNA. The researchers from several different laboratories at RIKEN IMS, as well as colleagues at other institutes, teamed up to develop the new ReapTEC technology and look for connections between bidirectional T cell enhancers and immune diseases.

After analyzing about a million human T cells, they found several groups of rare T cell types, accounting for less than 5% of the total. Applying ReapTEC to these cells identified almost 63,000 active bidirectional enhancers. To figure out if any of these enhancers are related to immune diseases, they turned to genome-wide association studies (GWAS), which have reported numerous genetic variants, called single-nucleotide polymorphisms, that are related to various immune diseases.

When the researchers combined the GWAS data with the results of their ReapTEC analysis, they found that genetic variants for immune-mediated diseases were often located within the bidirectional enhancer DNA of the rare T cells that they had identified. In contrast, genetic variants for neurological diseases did not show a similar pattern, meaning that the bidirectional enhancers in these rare T cells are related specifically to immune-mediated diseases.

Going even deeper into the data, the researchers were able to show that individual enhancers in certain rare T cells are related to specific immune diseases. Overall, among the 63,000 bidirectional enhancers, they were able to identify 606 that included single-nucleotide polymorphisms related to 18 immune-mediated diseases. Lastly, the researchers were able to identify some of the genes that are the targets of these disease-related enhancers. For example, when they activated an enhancer that contained a genetic variant related to inflammatory bowel disease, the resulting enhancer RNA triggered upregulation of the IL7R gene.

“In the short-term, we have developed a new genomics method that can be used by researchers around the world,” says Murakawa. “Using this method, we discovered new types of helper T cells as well as genes related to immune disorders. We hope that this knowledge will lead to a better understanding of the genetic mechanisms underlying human immune-mediated diseases.”

In the long-term, the researchers believe follow-up experiments will be able to identify new molecules that can be used to treat immune-mediated diseases.

Selective schools are government-funded schools that enrol only the highest performing students. Pupils take a standardized entrance exam, from which the best-scoring are enrolled.

Some argue that selective schools are necessary for bright pupils to reach their full academic potential. Selective schools can outperform or perform just as well as elite schools in final year exams, but without the high fees charged to parents. Hence, selective schools can offer a means for children from low socioeconomic backgrounds to receive a first-class education.

However, others argue that selective schools disproportionately benefit high socioeconomic children whose parents can afford private tutoring to prepare them for the entrance exams.

“Studies show that parents wish to enrol their children into selective schools, because they believe it will increase the chances of their children getting into a prestigious university, and securing a well-paid and high-status job,” says Melissa Tham, a research fellow at the Mitchell Institute at Victoria University, Melbourne, Australia.

To find out whether there are benefits associated with selective schools, Tham and her colleagues Shuyan Huo, and Andrew Wade tracked almost 3000 pupils from the Longitudinal Surveys of Australian Youth (LSAY), a nationally representative survey program that follows young Australians over an 11-year period. The survey started when respondents were aged 15 in 2009.

As expected, the selective schools featured in the study had a higher proportion of academically high-achieving students, as measured by mathematics and reading scores.

However, at ages 19 and 25 there was little difference between the educational and employment outcomes of children who attended selective schools versus non-selective schools. For example, the study found that while 81% of selective school students went on to secure a job or university place at 19 compared to 77.6% of pupils from non-selective schools, this difference disappeared when the students were matched on key characteristics, including socioeconomic background, gender, and geographical location.

At age 25, all outcomes between selective and non-selective school students were not significant, except general life satisfaction. Attending a selective school increased a student’s general life satisfaction score by just 0.19 points. Meanwhile, students who attended non-selective school were just as likely to go on to study at university or secure a job as their peers who attended selective schools.

“These very modest findings indicate that attending an academically selective school does not appear to pay off in large benefits for individuals,” says Andrew Wade, co-author of the study.

“We argue that academically selective schools in the government sector therefore contradicts the principles of inclusive and equitable education which underpin Australia’s school system.”

According to the authors, the findings suggest that more research is needed to determine whether selective schools offer any benefit to academically able students.

“Rather than tweak some aspects of the enrolment processes, we see greater value in conducting a thorough and critical examination of fully and partially selective schools, and scaling back selectivity if the supposed benefits are not found,” says Huo.

Young adults who have higher levels of inflammation, which is associated with obesity, physical inactivity, chronic illness, stress and smoking, may experience reduced cognitive function in midlife, a new study out of UC San Francisco has found.

Researchers previously linked higher inflammation in older adults to dementia, but this is one of the first studies to connect inflammation in early adulthood with lower cognitive abilities in midlife.

“We know from long-term studies that brain changes leading to Alzheimer’s disease and other dementias may take decades to develop,” said first author Amber Bahorik, PhD, of the UCSF Department of Psychiatry and Behavioral Sciences and the Weill Institute for Neurosciences. “We wanted to see if health and lifestyle habits in early adulthood may play a part in cognitive skills in midlife, which in turn may influence the likelihood of dementia in later life.”

In their study, publishing in Neurology on July 3, researchers found that only 10% of those with low inflammation performed poorly on testing of processing speed and memory, compared to 21% and 19%, respectively, of those with either moderate or higher levels of inflammation.

When researchers adjusted for factors like age, physical activity and total cholesterol, disparities remained in processing speed; and the researchers also found differences in executive functioning, which includes working memory, problem solving and impulse control.

The study followed 2,364 adults in the CARDIA study, which aims to identify the factors in young adulthood that lead to cardiovascular disease two-to-three decades later.

Participants were 18 to 30 years old when they entered the study and were tested four times over an 18-year period for the inflammatory marker C-reactive protein (CRP). They took the cognitive tests five years after their last CRP measurement, by which time most participants were in their forties and fifties.

About half the participants were female; a little under half were Black, and the rest were white. Some 45% had lower stable inflammation, while 16% had moderate or increasing inflammation; 39% had higher levels.

A link between inflammation and health risks

The researchers also linked higher levels of inflammation with physical inactivity, higher BMI and current smoking.

“Inflammation plays a significant role in cognitive aging and may begin in early adulthood,” said senior author Kristine Yaffe, MD, a professor of psychiatry and behavioral sciences, neurology, and epidemiology and biostatistics at UCSF. “There is likely a direct and indirect effect of inflammation on cognition.”

Yaffe is a member of the first team of experts to determine that 30% of dementia risk is preventable. Her recent research has looked at the association in midlife between fragmented sleep and lower cognition and the effects of personalized health and lifestyle changes in preventing memory loss in higher-risk older adults.

“Fortunately, there are ways to reduce inflammation — such as by increasing physical activity and quitting smoking — that might be promising paths for prevention,” Yaffe said.

The team had a professional dancer repeat short dance choreographies in front of a green screen. She was asked to express different emotions through her movements: anger, contentment, fear, happiness, neutrality, and sadness. To capture the dance movements as “data,” the scientists dived into the MPIEA’s technology pool: the dancer wore a full-body motion capture suit from XSENS®, equipped with a total of 17 highly sensitive sensors. In combination with a film camera, the dynamic body movements were measured and recorded. The researchers then extracted the objective kinematic characteristics (movement parameters) and programmed the software EMOKINE, which provides these movement parameters from data sets at the touch of a button.

Computerized Tracking for Whole-Body Movement

A total of 32 statistics from 12 movement parameters were compiled and extracted from a pilot dance dataset. The kinematic parameters recorded were, for example, speed, acceleration, or contraction of the limbs.

“We identified 12 kinematic features of emotional whole-body movements that have been discussed separately in the literature about previous research. We then extracted all of them from one same data set, and subsequently fed the features into the EMOKINE software,” reports first author Julia F. Christensen of the MPIEA.

Movement tracking has been used in many areas in recent years because the objective recording of movement parameters can provide insights into people’s intentions, feelings and state of mind. However, this research requires a theory-based methodology so meaningful conclusions can be drawn from the recorded data.

“This work shows how artistic practice, psychology, and computer science can work together in an ideal way to develop methods for studying human cognition,” says co-first author Andrés Fernández of the Max Planck Institute for Intelligent Systems in Tübingen, Germany.

The methodological framework that accompanies the software package, and which explicitly uses dance movements to study emotions, is a departure from previous research approaches, which have often used video clips of “emotional actions,” such as waving hands or walking.

“We are particularly excited about the publication of this work, which involved so many experts, for example from the Goethe University Frankfurt am Main, the University of Glasgow, and a film team from WiseWorld Ai, Portugal. It brought together disciplines from psychology, neuroscience, computer science, and empirical aesthetics, but also from dance and film,” summarizes senior author Gemma Roig, Professor of Computer Science, Computational Vision, and AI Lab at Goethe University.

The Open-Source Software Package

EMOKINE is freely available on ZENODO and GitHub and can be adapted to other motion capture systems with minor modifications. These freely available digital tools can be used to analyze the emotional expression of dancers and other groups of artists, and also everyday movements.

The researchers now hope that the EMOKINE software they have developed will be used in experimental psychology, affective neuroscience, and in computer vision — especially in AI-assisted analysis of visual media, a branch of AI that enables computers and systems to extract meaningful information from digital images, videos, and other visual inputs. EMOKINE will help scientists answer research questions about how kinematic parameters of whole-body movements convey different intentions, feelings, and states of mind to the observer.

Published in Science, Science Immunology, and Science Translation Medicine on May 16, 2024, the findings are outlined in four individual papers and build on a 2022 phase I clinical trial conducted by the nonprofit scientific research organization IAVI. The findings represent a key step forward in an immunization strategy that could protect against the virus.

“All in all, these studies show that we have a good chance at creating an effective HIV vaccine — we just need to keep iterating and build on these findings in future clinical trials,” says co-senior author of all four studies, William Schief, PhD, who is also a Scripps Research professor; vice president for antigen design and selection, Infectious Disease Research, at Moderna, Inc.; and executive director of vaccine design at IAVI’s Neutralizing Antibody Center.

The HIV vaccine strategy involves stimulating the body to produce mature broadly neutralizing antibodies (bnAbs). bnAbs are among the immune system’s key players in fighting HIV, since they can block many variants of the virus. The problem is that bnAbs produced by the human body are rare. The IAVI trial, spearheaded in part by Schief, focused on inducing the immune cells that could eventually evolve into the right bnAbs — ones that could protect host cells from multiple HIV strains. These precursor immune cells, known as B cells, were stimulated with the help of a priming immunogen — a customized molecule to “prime” the immune system and elicit responses from the correct precursor cells.

But the primer also requires additional “booster” immunogens to coax the immune system into producing not just precursor cells, but coveted VRC01-class bnAbs — a rare and specific class of antibodies known to neutralize more than 90 percent of diverse HIV strains. Boosters are also needed for the production of BG18 — another important bnAb class that binds to sugars on the HIV spike protein. That’s where the new studies come in: Researchers developed immunization regimens that could prime either VRC01 or BG18 precursors, and subsequently boost those precursors further down the path toward becoming bnAbs.

“The results contained in these papers are deeply exciting and further support the germline-targeting strategy to HIV vaccine development that IAVI and our partners are pursuing,” says Mark Feinberg, MD, PhD, president and CEO of IAVI. “We look forward to continuing our collaboration with Scripps Research and partners to advance further research building on these promising findings.”

This groundbreaking science is enabled by collaboration between scientific institutions and funding partners. Without the ongoing, critical support of the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), the Collaboration for AIDS Vaccine Discovery (CAVD), the Bill & Melinda Gates Foundation, and Moderna (the manufacturer of the mRNA used in these studies), this research would not have been possible.

Priming rare antibodies

In the first study, which focused on BG18, Scripps Research scientists collaborated with co-senior authors Shane Crotty, PhD, chief scientific officer at La Jolla Institute for Immunology, and Devin Sok, PhD, former vice president, discovery and innovation at IAVI. Using a priming immunogen, they consistently primed exceptionally rare BG18 precursors in a wild-type animal model.

To confirm they were able to prime the correct precursors, the researchers then teamed up with Andrew Ward, PhD, Scripps Research integrative structural and computational biology professor and co-senior author of the study. Using cryo-EM structural analysis, they validated that the antibodies were indeed part of the BG18 class.

“The fact that priming worked well in macaques suggests that it has a good chance of succeeding in humans,” says co-first author, Jon Steichen, PhD, an institute investigator in the Department of Immunology and Microbiology at Scripps Research.

Steichen was also co-first author on a second study, in which mice were modified to produce a low frequency of BG18 precursors. Scripps Research and IAVI scientists, along with the team of co-senior author Facundo Batista, PhD, associate director and scientific director of the Ragon Institute of MGH, MIT, and Harvard, used priming methods similar to the ones used in the first paper. However, a key difference was that this time, they also administered one of two boost immunogens using RNA technology. This resulted in boosting the primed B cells to adapt to recognize more native-like versions of HIV.

“This study showed that we can start to walk the B cells along toward bnAb development,” Steichen explains.

Supercharging the immune system into action

For the third study, Schief and his team worked with IAVI scientists, wherein they primed a mouse model with the same immunogen used in the 2022 IAVI clinical trial. This resulted in mice that produced VRC01-class precursor B cells similar to those found in people. But the researchers also designed a new booster immunogen to drive the antibody response toward becoming matured bnAbs — the next vital step in a sequential immunization series that could effectively fight HIV. The results: a “prime-boost” regimen that can drive VRC01-class B cells toward bnAb development.

“The findings demonstrate that we are able to make the antibody responses go in the right direction using this heterologous booster, which administers a different version of the vaccine than was given previously,” says Christopher Cottrell, PhD, a senior staff scientist at Scripps Research who was the first co-author on this study.

Understanding the immunology

In the fourth and final study, on which Cottrell was also a co-first author, the team worked again with Batista’s team at the Ragon Institute and used the same immunogens — but in a different mouse model where his team could control the frequency of bnAb precursors that were modified to be similar to those found in humans. This allowed the researchers to take a deeper dive into the immunology associated with HIV vaccination by examining the germinal centers — specialized microstructures in the body that protect against viral reinfection. Germinal centers provide B cells with a space to rapidly increase and mutate their antibody genes, ultimately helping the immune system fight off viral strains.

In addition, the researchers examined how germinal centers accumulate HIV mutations over time. They found that a prime-boost regimen increased precursor B-cell activity in germinal centers across different lineages, which could eventually lead to an increase in matured VRC01-class bnAbs.

What’s next

Overall, all four papers confirm that the priming step to turn on the right bnAb precursors is possible when it comes to developing an HIV vaccine. Three of those papers specifically demonstrate that it’s also possible to guide antibody precursors toward becoming bnAbs that can fight HIV.

“Taken together, the findings give us more confidence that we’re able to prime precursors from multiple bnAb targets, and they also show that we’re starting to learn the rules for how to advance precursor maturation through heterologous boosting,” Schief added.

Following these results, the researchers are advancing phase 1, experimental medicine trials for both the VRC01 and BG18 projects. Vaccines aiming to prime and boost VRC01-class antibodies are being further evaluated in two clinical trials run by IAVI, IAVI G002 and IAVI G003, and a vaccine to prime BG18-class responses is being evaluated in HVTN144. These studies use both adjuvanted protein immunizations (IAVI G001 and HVTN144) and mRNA delivery (IAVI G002 and G003).

The results of these studies will guide the critical next steps on the discovery path to an HIV vaccine.

Inflammatory cell death, knows as necroptosis, is an important regulatory tool in the body’s arsenal against disease. However, in some diseases, the process can go haywire; for example, cancer cells are able to suppress inflammatory signals and thus escape death.

“Usually treatments for cancer use pharmacological induction to kill the cells, but those chemicals tend to diffuse throughout the tissues and it’s hard to contain to a precise location. You get a lot of unwanted effects,” said study leader Kai Zhang, a professor of biochemistry at the U. of I. “We can make the cells responsive to light, and we can focus the light beam to be smaller than one cell. That is how we can use light to very precisely target a cell and turn on its death pathway.”

The researchers use a method called optogenetics to make the cells respond to light. They borrowed a light-activated gene from plants and inserted it into intestinal cell cultures, attaching it to the gene for RIPK3, a protein that regulates necroptosis.

“When activated, RIPK3 undergoes oligomerization — it forms clusters of protein complexes. Our light-sensitive proteins cluster together when exposed to blue light. So by triggering the light-sensitive proteins to come together, the RIPK3 comes together and oligomerizes, and that’s how we mimic the activation pathway,” said graduate student Teak-Jung Oh, the first author of the paper published in the Journal of Molecular Biology.

However, killing the cell itself is not the only goal. Inducing the inflammatory cell death pathway, rather than outright killing the cell mechanically or chemically, triggers the immune system to respond. The ruptured cells release chemicals called cytokines that irritate nearby cells and attract T cells, white blood cells that play an important role in how the immune system identifies and attacks threats, Zhang said.

“Certain cancer cell types create a local immunosuppressive environment, where T cells are either not recruited or, if they do come, they do not recognize it as a threat and do not infiltrate the cancerous area. But by opening up some cancer cells through necroptosis, we hope to modulate this immune suppressive environment and help train the T cells to recognize and attack the cancer,” said Zhang, who is a member of the Cancer Center at Illinois.

Since the optogenetic system requires light delivery directly to tissues, human clinical applications in tissues deeper than skin are currently limited. However, the Illinois group plans to implement their system in mice next to further study necroptosis and immune response in cancer and other inflammatory diseases. They also will further investigate the in vitro platform’s potential for training T cells for immune therapies.

“Understanding the cell signaling pathway for necroptosis is especially important because it has been known to be involved with diseases like neurodegenerative disease and inflammatory bowel disease. Knowing how necroptosis affects progression in these diseases is important. And if you don’t know the molecular mechanisms, you don’t really know what to target to slow the progression,” Oh said.

The National Institute of General Medical Sciences and National Institute of Mental Health of the National Institutes of Health, the National Science Foundation and the Cancer Center at Illinois supported this work. Zhang also is affiliated with the Beckman Institute for Advanced Science and Technology at Illinois.

The National Institutes of Health supported this work through grants R01GM132438 and R01MH124827.

Not everything in the brain is meant to last. As our brains assemble, trillions of neural connections have to be built or torn down at the right time and place. Otherwise, the seeds of conditions like autism can take root. Cold Spring Harbor Laboratory Assistant Professor Gabrielle Pouchelon studies how the brain is wired early in life. In doing so, she hopes to find the origins of various brain dysfunctions and new ways to treat them.

In a new study, Pouchelon and her team zero in on a process known as pruning. This is when the brain removes unnecessary connections between neurons. The pruning of long-lasting connections is relatively well-known. Pouchelon’s team focuses on special early connections that get cut to make way for long-lasting circuits in the mature brain. Though temporary, these early connections may play a critical role in shaping developing brain circuits.

Pouchelon’s lab has now discovered that a receptor protein named mGluR1 helps regulate the timing of these temporary connections in the mouse brain. Her team found that without mGluR1, neural connections stick around too long in the brain region that controls and processes touch via the whiskers. When the sensory circuit fails to mature properly, the mice demonstrate atypical behaviors. For example, they don’t stand on their hind legs and sniff around the way other mice do.

Importantly, the team notes that this critical step in circuit development occurs during the first week after birth. “The way the receptor works seems to be different than what has been described in adulthood,” Pouchelon says. “In the context of neurodevelopmental disorders, that means when we try to target developmental defects, we could have a totally different therapeutic effect at different stages during development.”

Pouchelon’s team hopes their discovery may serve as a guide for designing future therapeutics to treat brain dysfunction early. “The brain is a wonderful machine whose job is to adapt,” says Dimitri Dumontier, the postdoc in Pouchelon’s lab who co-led this study. “So, when you study neurodevelopmental disorders in adults or even teenagers, it is difficult to identify which mechanisms are causing the symptoms. That is why understanding early milestones of brain development is key.”

The hope is that by figuring out exactly how the brain matures, scientists can rescue this process early. This could help prevent symptoms of neurological disorders like autism from showing up in the first place. After all, the world is difficult enough to navigate as is. Pouchelon and Dumontier’s work could someday help make life easier for countless young people.

These models have also been shown to develop some surprising abilities. In 2022, MIT researchers reported that AI models can make accurate predictions about a patient’s race from their chest X-rays — something that the most skilled radiologists can’t do.

That research team has now found that the models that are most accurate at making demographic predictions also show the biggest “fairness gaps” — that is, discrepancies in their ability to accurately diagnose images of people of different races or genders. The findings suggest that these models may be using “demographic shortcuts” when making their diagnostic evaluations, which lead to incorrect results for women, Black people, and other groups, the researchers say.

“It’s well-established that high-capacity machine-learning models are good predictors of human demographics such as self-reported race or sex or age. This paper re-demonstrates that capacity, and then links that capacity to the lack of performance across different groups, which has never been done,” says Marzyeh Ghassemi, an MIT associate professor of electrical engineering and computer science, a member of MIT’s Institute for Medical Engineering and Science, and the senior author of the study.

The researchers also found that they could retrain the models in a way that improves their fairness. However, their approached to “debiasing” worked best when the models were tested on the same types of patients they were trained on, such as patients from the same hospital. When these models were applied to patients from different hospitals, the fairness gaps reappeared.

“I think the main takeaways are, first, you should thoroughly evaluate any external models on your own data because any fairness guarantees that model developers provide on their training data may not transfer to your population. Second, whenever sufficient data is available, you should train models on your own data,” says Haoran Zhang, an MIT graduate student and one of the lead authors of the new paper. MIT graduate student Yuzhe Yang is also a lead author of the paper, which will appear in Nature Medicine. Judy Gichoya, an associate professor of radiology and imaging sciences at Emory University School of Medicine, and Dina Katabi, the Thuan and Nicole Pham Professor of Electrical Engineering and Computer Science at MIT, are also authors of the paper.

Removing bias

As of May 2024, the FDA has approved 882 AI-enabled medical devices, with 671 of them designed to be used in radiology. Since 2022, when Ghassemi and her colleagues showed that these diagnostic models can accurately predict race, they and other researchers have shown that such models are also very good at predicting gender and age, even though the models are not trained on those tasks.

“Many popular machine learning models have superhuman demographic prediction capacity — radiologists cannot detect self-reported race from a chest X-ray,” Ghassemi says. “These are models that are good at predicting disease, but during training are learning to predict other things that may not be desirable.” In this study, the researchers set out to explore why these models don’t work as well for certain groups. In particular, they wanted to see if the models were using demographic shortcuts to make predictions that ended up being less accurate for some groups. These shortcuts can arise in AI models when they use demographic attributes to determine whether a medical condition is present, instead of relying on other features of the images.

Using publicly available chest X-ray datasets from Beth Israel Deaconess Medical Center in Boston, the researchers trained models to predict whether patients had one of three different medical conditions: fluid buildup in the lungs, collapsed lung, or enlargement of the heart. Then, they tested the models on X-rays that were held out from the training data.

Overall, the models performed well, but most of them displayed “fairness gaps” — that is, discrepancies between accuracy rates for men and women, and for white and Black patients.

The models were also able to predict the gender, race, and age of the X-ray subjects. Additionally, there was a significant correlation between each model’s accuracy in making demographic predictions and the size of its fairness gap. This suggests that the models may be using demographic categorizations as a shortcut to make their disease predictions.

The researchers then tried to reduce the fairness gaps using two types of strategies. For one set of models, they trained them to optimize “subgroup robustness,” meaning that the models are rewarded for having better performance on the subgroup for which they have the worst performance, and penalized if their error rate for one group is higher than the others.

In another set of models, the researchers forced them to remove any demographic information from the images, using “group adversarial” approaches. Both of these strategies worked fairly well, the researchers found.

“For in-distribution data, you can use existing state-of-the-art methods to reduce fairness gaps without making significant trade-offs in overall performance,” Ghassemi says. “Subgroup robustness methods force models to be sensitive to mispredicting a specific group, and group adversarial methods try to remove group information completely.”

Not always fairer

However, those approaches only worked when the models were tested on data from the same types of patients that they were trained on — for example, only patients from the Beth Israel Deaconess Medical Center dataset.

When the researchers tested the models that had been “debiased” using the BIDMC data to analyze patients from five other hospital datasets, they found that the models’ overall accuracy remained high, but some of them exhibited large fairness gaps.

“If you debias the model in one set of patients, that fairness does not necessarily hold as you move to a new set of patients from a different hospital in a different location,” Zhang says.

This is worrisome because in many cases, hospitals use models that have been developed on data from other hospitals, especially in cases where an off-the-shelf model is purchased, the researchers say.

“We found that even state-of-the-art models which are optimally performant in data similar to their training sets are not optimal — that is, they do not make the best trade-off between overall and subgroup performance — in novel settings,” Ghassemi says. “Unfortunately, this is actually how a model is likely to be deployed. Most models are trained and validated with data from one hospital, or one source, and then deployed widely.”

The researchers found that the models that were debiased using group adversarial approaches showed slightly more fairness when tested on new patient groups that those debiased with subgroup robustness methods. They now plan to try to develop and test additional methods to see if they can create models that do a better job of making fair predictions on new datasets.

The findings suggest that hospitals that use these types of AI models should evaluate them on their own patient population before beginning to use them, to make sure they aren’t giving inaccurate results for certain groups.

The research was funded by a Google Research Scholar Award, the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program, RSNA Health Disparities, the Lacuna Fund, the Gordon and Betty Moore Foundation, the National Institute of Biomedical Imaging and Bioengineering, and the National Heart, Lung, and Blood Institute.

In a study published June 26 in Nature Communications, the team reported finding major differences between postmortem and living prefrontal cortex brain tissues as they relate to one of the most abundant RNA modifications in the brain, known as adenosine-to-inosine (A-to-I) editing. This discovery will play a significant role in shaping the development of diagnostics and therapies for brain diseases.

While DNA holds the genetic blueprint for humans, RNA actually carries out its instructions to create functional proteins that play important roles in how the body functions, including the complex functions of the central nervous system. RNA’s function and stability are controlled by many modifications, each holding a specific purpose. These modifications, known as RNA editing, are a continuous process occurring in all our cells and tissues, facilitated by enzymes known as ADAR. This process can continue to occur in individual cells for some time after the death of the person whose tissues the cells were part of.

The conversion of adenosine nucleosides to inosine (A-to-I) is a common and well-studied RNA modification and is orchestrated by proteins in the ADAR family, primarily ADAR1 and ADAR2. In the mammalian brain, thousands of highly regulated A-to-I editing sites have been discovered across anatomical regions and cell types, some by Mount Sinai researchers. These sites are known to be involved in neuronal maturation and brain development. Aberrant regulation of A-to-I editing has been linked to neurological disorders.

“Until now, the investigation of A-to-I editing and its biological significance in the mammalian brain has been restricted to the analysis of postmortem tissues. By using fresh samples from living individuals, we were able to uncover significant differences in RNA editing activity that previous studies, relying only on postmortem samples, may have overlooked,” said Michael Breen, PhD, co-senior author of the study and Assistant Professor of Psychiatry, and Genetics and Genomic Sciences, at Icahn Mount Sinai. “We were particularly surprised to find that RNA editing levels were significantly higher in postmortem brain tissue compared to living tissue, which is likely due to postmortem changes such as inflammation and hypoxia that do not occur in living brains. Additionally, we discovered that RNA editing in living tissue tends to involve evolutionarily conserved and functionally important sites that are also dysregulated in human disease, emphasizing the need to study both living and postmortem samples for a comprehensive understanding of brain biology.”

After death, the lack of oxygen quickly damages brain cells, causing an irreversible cascade of damage that can alter ADAR expression and A-to-I editing. “We hypothesized that molecular responses to postmortem-induced hypoxic and immune responses can significantly alter the landscape of A-to-I editing. This can lead to misunderstandings about RNA editing in the brain if we only study postmortem tissues,” said Miguel Rodríguez de los Santos, PhD, co-first author of the study and a postdoctoral fellow in the Department of Psychiatry at Mount Sinai. “Studying living brain tissue provides us with a clearer picture of RNA editing biology in the human brain.”

To investigate, the research team anchored their study around the Living Brain Project, in which dorsolateral prefrontal cortex (DLPFC) tissues from living people are obtained during neurosurgical procedures for deep brain stimulation, an elective treatment for neurological illness. For comparison, a cohort of postmortem DLPFC tissues across three brain banks was assembled to match the living cohort for key demographic and clinical variables. The team investigated multiple genomic data types from the Living Brain Project, including bulk tissue RNA sampling, single-nuclei RNA sequencing, and whole-genome sequencing. The generation of this data is being described in multiple forthcoming Living Brain Project manuscripts.

The researchers identified more than 72,000 locations where A-to-I editing occurs more often or differently in postmortem than in living DLPFC brain tissue. They found higher levels of the enzymes ADAR and ADARB1, which are responsible for elevated editing patterns in postmortem brain tissues. Interestingly, they also found hundreds of sites with higher levels of A-to-I editing in living brain tissue. These sites are mostly found in the connections between neurons (called synapses) and are typically conserved through evolution, suggesting they play important roles in brain activity. Some well-known A-to-I editing sites were highly edited in living brains, indicating they may be involved in critical neuronal processes like synaptic plasticity, which is essential for learning and memory. However, many other A-to-I editing sites found in living brain tissues have unclear functions, and further research is needed to understand their impact on brain health.

“Utilizing fresh brain tissue from living human donors provided us the opportunity to investigate the brain without the confounds inherent to postmortem tissue analysis,” said Alexander W. Charney, MD, PhD, co-senior author of the study and Associate Professor of Psychiatry, Genetic and Genomic Sciences, Neuroscience, and Neurosurgery at Icahn Mount Sinai and co-lead of the Living Brain Project. “In doing so, we revealed more accurate insights into the prevalence and roles of A-to-I editing in the human brain. It is critical to note that our findings do not negate but instead provide missing context for using postmortem brain tissues in researching A-to-I regulation. Understanding these differences helps improve our knowledge of brain function and disease through the lens of RNA editing modifications, which can potentially lead to better diagnostic and therapeutic approaches.”

The research team will further analyze the RNA editing data to understand its implications better and to identify potential therapeutic targets for Parkinson’s disease. They are also expanding the research to include emerging work from this cohort that focuses on gene expression, proteomics, and multi-omics of the living brain.

“By harnessing the unique, transdisciplinary nature of the Living Brain Project, we can turn a cutting edge clinical care modality like deep brain stimulation into a platform for unprecedented insight into human brain biology that will give rise to new therapeutic opportunities,” said Brian Kopell, MD, co-first author of the study, Director of the Center for Neuromodulation at Mount Sinai and co-lead of the Living Brain Project

However, they are more likely to have identity difficulties and issues with trust. Secrecy and anonymity about their genetic parentage can have a profound impact on well-being say authors. They warn that children and adults conceived using donor gametes have not been centred in the assisted reproductive industry and more information is needed about adult wellbeing.

The study is published today in the British Journal of Obstetrics and Gynaecology by researchers King’s College London. The study is the first systematic review of studies investigating the psychological experiences of donor conceived people through childhood and adulthood and is the largest body of evidence for this group.

More than 70,000 donor conceived people have been born in the UK since 1991 when records began, and a significant unknown number before this date, however little is known about their long-term psychological outcomes.

The review looked at 50 studies and 4,666 donor conceived children and adults, mostly from high-income Anglophone countries, and found most studies showed equivalent or better outcomes in donor conceived people including higher wellbeing scores, self-esteem and relationship warmth.

The findings also showed children fared better when they were told they were donor conceived early. In the UK, donor anonymity has been against the law for those conceived after 2005 but children must wait until they are 18 years old to access information.

However, there is no legal requirement for families to tell their children the truth about their genetic lineage. The proliferation of at-home commercial DNA testing can reveal family secrets and yield life-changing results. It is often adults, who were conceived before 2005 and have no legal right to information about their genetic identity, who have been left out of the research and been left behind by the fertility industry.

First author Dr Charlotte Talbot, who graduated from King’s College London and is an Academic Foundation Doctor, affiliated with the University of Birmingham, said: “This is the largest body of evidence we have for wellbeing for donor conceived children and adults but it’s a complicated picture. While most outcomes are the same or better for this group than non-donor conceived people, qualitative studies revealed common themes relating to mistrust and concerns about genetic heritage.”

Senior author Professor Susan Bewley from King’s College London said: “Donor conceived children are always planned for and wanted, as one or more of their parents would have had fertility issues. This might explain better relationships with their family and higher wellbeing. However, much of the conversation around innovation in the assisted reproductive industry concentrates on the customers and potential parents rather than the people they want to create. We need to be better about putting donor conceived offspring’s needs and priorities at the centre.”

Laura Bridgens, Founder of Donor Conceived UK (DCUK), said: “The use of a gamete donor for conception is a life-long intergenerational process with far reaching social implications. DCUK welcomes this systematic review as it highlights the necessity for further consideration for the long-term needs and outcomes of donor conceived people into adulthood. There is a duty of care by the government and the fertility industry to listen to the voices of adult donor conceived people to create a future in which charity sector intervention is not needed to repair the mistakes of the past.”

Fish consumption is an important route of methyl mercury exposure, however, efforts to understand the health risk posed by mercury are further complicated by the fact that the nutritional benefits from fish may modify or reduce the toxicity posed by mercury. A new study appearing in the American Journal of Epidemiology based on data from a cohort of residents of a coastal community in Massachusetts creates a new framework that could untangle these questions, reduce confusion, and produce clearer guidance on fish consumption for pregnant mothers.

“We propose an alternative modelling approach to address limitations of previous models and to contribute thereby to improved evidence-based advice on the risks and benefits of fish consumption,” said the authors, who include Sally Thurston, PhD, with the University of Rochester Medical Center, Susan Korrick, MD, MPH, with Harvard T.H. Chan School of Public Health and Brigham and Women’s Hospital, and David Ruppert, PhD, with Cornell University. “In fish-eating populations, this can be addressed by separating mercury exposure into fish intake and average mercury content of the consumed fish.”

The new research comes from an analysis of data from the New Bedford Cohort, which was created to assess the health of children born to mothers residing near the New Bedford Harbor Superfund site in Massachusetts. The current study included 361 children from the cohort who were born between 1993 and 1998 and underwent neurodevelopment assessments, including tests for IQ, language, memory, and attention, at age eight years.

The researchers were able to measure mercury exposure during the third trimester of pregnancy through hair sample collected from the mothers after birth. While hair samples have been the traditional method to study maternal mercury exposure, this approach alone cannot distinguish between mothers who frequently consumed low-mercury fish compared to those who consumed a smaller quantity of high-mercury fish.

To overcome this limitation, the researchers instead created a model that includes estimates of mercury exposure per serving of fish. This was possible because mothers in the cohort also completed a food questionnaire and reported the type and frequency of fish and shellfish consumed during pregnancy. The authors estimated the average mercury levels by type of fish, and when combined with the information about the mother’s diet, they were able to create a more precise and detailed method to estimate the joint associations of pregnancy fish intake and fish mercury levels on neurodevelopment.

Using this model, the researchers found that the relation between pregnancy fish consumption and subsequent neurodevelopment varied depending on the estimated average mercury levels in the fish. Specifically, consuming low mercury-containing fish was beneficial, while consuming fish with higher levels of mercury was detrimental.

“Given methodologic limitations to previous analyses, future work expanding our alternative modelling approach to account for both the average mercury and nutritional content of fish could facilitate better estimation of the risk-benefit tradeoffs of fish consumption, a key component of many healthy diets,” said the authors.

The authors are in the process of applying this model to other large studies of maternal fish consumption, including the Seychelles Child Development Study, which Thurston serves on as an investigator.

The American Journal of Epidemiology study was supported with funding from the National Institute of Environmental Health Sciences.

The researchers had previously used similar methods — increasing the amount of the neurotrophic factor neurotrophin-3 in the inner ear — to promote the recovery of auditory responses in mice that had experienced acoustic trauma, and to improve hearing in middle-aged mice.

This study is the first to use the same approach in otherwise healthy young mice to create improved auditory processing, beyond what’s naturally occurring.

“We knew that providing Ntf3 to the inner ear in young mice increased the number of synapses between inner hair cells and auditory neurons, but we did not know what having more synapses would do to hearing,” said Gabriel Corfas, Ph.D., director of the Kresge Institute, who led the research team.

“We now show that animals with extra inner ear synapses have normal thresholds — what an audiologist would define as normal hearing — but they can process the auditory information in supranormal ways.”

The resulting paper, “From hidden hearing loss to supranormal auditory processing by neurotrophin 3-mediated modulation of inner hair cell synapse density,” was published in PLOS Biology.

About the paper

As in previous studies, the researchers altered the expression of the Ntf3 to increase the number of synapses between inner hair cells and neurons.

Inner hair cells exist inside the cochlea and convert sound waves into signals sent — via those synapses — to the brain.

This time, however, two groups of young mice were created and studied: one in which synapses were reduced, and a second — the supranormal hearing mice — in which synapses were increased.

“Previously, we have used that same molecule to regenerate synapses lost due to noise exposure in young mice, and to improve hearing in middle-aged mice, when they already start showing signs of age-related hearing loss,” said Corfas.

“This suggests that this molecule has the potential to improve hearing in humans in similar situations. The new results indicate the regenerating synapses or increasing their numbers will improve their auditory processing.”

Both groups of mice underwent a Gap-Prepulse Inhibition test, which measures their ability to detect very brief auditory stimuli.

For this test, the subject is placed in a chamber with a background noise, then a loud tone that startles the mouse is presented alone or preceded by a very brief silent gap.

That gap, when detected by the mouse, reduces the startle response. Researchers then determine how long the silent gap needs to be for the mice to detect it.

Mice with fewer synapses required a much longer silent gap. That result supports a hypothesis about the relationship between synapse density and hidden hearing loss in humans.

Hidden hearing loss describes a difficulty in hearing that cannot be detected by standard testing.

People with hidden hearing loss may struggle to understand speech — or discern sounds in the presence of background noise. And results of the Gap-Prepulse Inhibition test had been previously shown to be correlated with auditory processing in humans.

A surprising find

Less expected, however, were the results of the subjects with increased synapses.

Not only did they show enhanced peaks in measured Acoustic Brain Stem response, but the mice also performed better on the Gap-Prepulse Inhibition test, suggesting an ability to process an increased amount of auditory information.

“We were surprised to find that when we increased the number of synapses, the brain was able to process the extra auditory information. And those subjects performed better than the control mice in the behavioral test,” Corfas said.

Hair cell loss had once been believed to be the primary cause of hearing loss in humans as we age.

Now, however, it’s understood that the loss of inner hair cell synapses can be the first event in the hearing loss process, making therapies that preserve, regenerate and/or increase synapses exciting possible approaches for treating some hearing disorders.

“Some neurodegenerative disorders also start with loss of synapses in the brain,” Corfas said.

“Therefore, the lessons from the studies in the inner ear could help in finding new therapies for some of these devastating diseases.”

To date, many investigations in the field have established intuitive links that are less direct than that: Air pollution exposure while young is consistently associated with lung problems during childhood — and childhood lung problems are consistently associated with lung issues as an adult.

The current study, published in the American Journal of Respiratory and Clinical Care Medicine, is one of only a few to show the direct connection between childhood air pollution exposure and adult lung health, a connection not fully explained by air pollution impacts on lung health during childhood. It opens the possibility of yet-to-be-understood factors explaining the path from early air pollution exposure to respiratory maladies many years later.

The team drew upon the USC Children’s Health Study, a large-scale, decades-long study following cohorts of Southern Californians starting at school-age and, for many participants, continuing into adulthood. Importantly, the link between childhood air pollution exposure and adult bronchitis symptoms persisted even when the researchers adjusted for asthma or bronchitis symptoms early in life — a finding that came as a surprise.

“We would expect that these observable impacts on childhood respiratory health would explain the relationship between childhood air pollution exposure and adult respiratory health,” said corresponding author Erika Garcia, PhD, MPH, assistant professor of population and public health sciences at the Keck School of Medicine. “Our results suggest that childhood air pollution exposure has more subtle effects on our respiratory system that still impact us in adulthood.”

Safeguarding lung health, now and later

The focus on exposure during youth is motivated in part by the fact that children are particularly vulnerable to the effects of air pollution. Their respiratory and immune systems are still developing and compared to adults, they breathe in more air relative to their body mass.

Ultimately the concern is twofold, for the health of young people today and for their future health when they grow up. Notably, among study participants with recent bronchitis symptoms as adults, average childhood exposure to a pollutant called nitrogen dioxide fell far below annual Environmental Protection Agency standards — just a bit over half the limit that was set in 1971 and remains in place today.

“This study highlights the importance of lowering air pollution, and especially exposure during the critical period of childhood,” Garcia said. “Because there’s only so much that we can do as individuals to control our exposure, the need to protect children from the adverse effects of air pollution is better addressed at the policy level.”

The study population comprised 1,308 Children’s Health Study participants with an average age of 32 at their adult assessment. The researchers asked about recent bouts of bronchitis symptoms — having either bronchitis, chronic cough, or congestion or phlegm production not associated with a cold. One-quarter of participants had experienced bronchitis symptoms within the previous 12 months.

Presence of bronchitis symptoms was associated with exposure between birth and age 17 to two types of pollutants. One type groups together tiny particles in the air such as dust, pollen, ash from wildfires, industrial emissions and products from vehicle exhaust. The other, nitrogen dioxide, is a byproduct of combustion in automobiles, planes, boats and power plants that is known to hurt lung function.

Long-running health research proves vital to igniting discovery

For as comprehensive an analysis as possible, average pollutant exposure over childhood was based on month-by-month estimates. The researchers matched up family home address at each time point with contemporaneous local air quality measurements taken by the EPA and through the Children’s Health Study.

“We’re fortunate to have this fantastic and nuanced longitudinal study,” Garcia said. “We can learn a lot about how earlier experiences impact adult health. That’s thanks to a long-term team effort from the participants themselves, their families, the schools they attended and all the research staff and investigators who conducted interviews and generated and analyzed data over the years.”

The current study included additional analyses to rule out factors such as prenatal exposure to nitrogen dioxide, current air pollution exposure as adults and the effects of socioeconomic status in childhood or adulthood as drivers of bronchitis symptoms in adults.

Pollution exposure in youth may hurt lung health for some more than others

Garcia and her colleagues also found that the effect of nitrogen dioxide and particulate matter exposure during childhood on bronchitis symptoms among adults was stronger for those who had been diagnosed with asthma as kids.

“There may be a subpopulation that is more sensitive to the effects of air pollution,” Garcia said. “We may want to be especially careful to protect them from exposure, so we can improve their outcomes later in life. Reducing air pollution would have benefits not only for current asthma in children but also for their respiratory health as they grow into adulthood.”

She and her colleagues are following up to examine how the level of air pollution exposure at different ages during youth influences breathing issues as an adult. Other future research directions building on the current study’s results could include looking into other markers of childhood and adult respiratory health, such as how well asthma was controlled, or exploring a potential genetic component.

About this study

The study’s co-authors are Zoe Birnhak, Scott West, Steve Howland, Rob McConnell, Shohreh. Farzan, Theresa Bastain, Rima Habre and Carrie Breton, all of the Keck School of Medicine; and Frederick Lurmann and Nathan Pavlovic of the environmental consulting firm Sonoma Technology.

This research received support from the National Institutes of Health (UH3OD023287, P30ES007048).

According to a study at the University of Helsinki, some dog owners experience feelings similar to the post-natal baby blues — a short-term drop in mood and melancholy — when their dog is a puppy. Caring for a puppy gives rise to a variety of worries, fears and frustration, and it can be difficult to bond with the dog.

“The study found that these so-called ‘puppy blues’ manifest in three ways: anxiety, frustration and weariness. These often occur concurrently, but in some cases one or two of the three may be particularly prominent,” says Psychologist and Doctoral Researcher Aada Ståhl.

An anxious puppy owner’s thoughts are coloured by concerns about the puppy’s wellbeing and development, as well as about their own inadequacy in looking after their dog. Owners might blame themselves when things do not go as planned.

A frustrated puppy owner can experience dissatisfaction and stress as a result of the strain and unexpected challenges of caring for a puppy. They might find it difficult to build an emotional bond with the puppy, wish they had never got the puppy and consider relinquishing the dog.

For the exhausted puppy owner, puppyhood is a time of mental and physical strain. They might have trouble sleeping, and find the constant attention and time the puppy needs tiring and anxiety-inducing.

“Just under half of owners report having had significant negative experiences during their dog’s puppyhood phase, with only about a tenth reporting the most severe levels of strain. This is in line with the prevalence of postnatal depression. However, the negative feelings fade relatively quickly,” says Professor Hannes Lohi.

One interesting finding was that the longer the amount of time that had passed since puppyhood, the more positively people remembered it. In other words, the negative emotional content of memories of puppyhood ‘fades’ over time.

A phenomenon familiar to dog owners is now measurable for further research

The study first collected the experiences of over 100 dog owners who had experienced emotional strain after bringing a puppy home. Based on this data, a survey was developed to measure the ‘puppy blues’. The new survey collected responses from more than 2,000 dog owners, with measures taken to ensure the validity and reliability of the survey.

“Capturing the phenomenon in a measurable form is important if we are to better understand its characteristics, prevalence and duration. This will also allow us to improve understanding of the factors that may predispose owners to or protect them from the ‘puppy blues’, which will help us to develop prevention and support measures,” says Ståhl.

The study represents a new opening in the study of the relationship between humans and pets. Although the term ‘puppy blues’ is commonly used among dog owners, no comprehensive research had been done on the subject before. Exploring this phenomenon will raise awareness, which can help people to prepare for negative feelings and to better recognise and understand their own experiences.

The study is part of a wider project by Professor Hannes Lohi’s research group, which is investigating the relationship between owner and animal and its importance for wellbeing.

The Texas law prohibiting abortions after a fetal heartbeat could be detected — as early as five or six weeks — went into effect September 1, 2021. At the time, the law — Senate Bill 8, or S.B. 8 — was the most stringent state abortion law in the country. It did not allow exemptions for congenital anomalies.

The researchers’ analysis of monthly death certificate data in Texas and the rest of the United States found that between 2021 and 2022, infant deaths in Texas rose from 1,985 to 2,240, a year-over-year increase of 255 deaths. This corresponds to a 12.9 percent increase in infant deaths in Texas versus a 1.8 percent increase in infant deaths in the rest of the U.S. during the same period. The study defines infants as under 12 months old.

The study was published online June 24 in JAMA Pediatrics.

The findings come as more U.S. states enact stricter abortion laws following the U.S. Supreme Court’s 2022 Dobbs decision, the landmark ruling that overturned Roe v. Wade and returned abortion policymaking to the states.

To approximate the causal impact of S.B. 8, the authors narrowed their analysis to examine changes in the expected number of infant deaths in Texas from March to December 2022 — the time period that captures the first set of pregnancies under S.B. 8. The researchers estimate there were 216 excess infant deaths in Texas that would most likely not have occurred from March to December 2022 had the state’s abortion law not been in place. This is equivalent to a 12.7 percent increase above the expected 1,697 infant deaths for this time period. There were 1,913 observed deaths in Texas from March to December 2022.

An analysis of neonatal deaths — deaths in the first 28 days — found similar patterns, with an estimated 145 excess deaths in the post-policy period. These results were not observed in other states.

The new study is thought to be the first to examine how the Texas abortion ban may have impacted infant deaths in the state and is among the first to present evidence evaluating recent abortion bans and pre-viability restrictions. Prior research has shown that states with more abortion restrictions see more infant deaths than those without. The authors note that these earlier studies evaluate fundamentally different and less severe abortion restrictions and primarily examine correlation.

“Our study is particularly relevant given the June 2022 Dobbs Supreme Court decision that returned abortion lawmaking to states and subsequent rollbacks of reproductive rights in many states,” says Alison Gemmill, PhD, assistant professor in the Bloomberg School’s Department of Population, Family and Reproductive Health and one of the study’s lead authors. “These findings suggest that restrictive abortion policies may have important unintended consequences in terms of infant health and the associated trauma to families and medical costs.”

For their month-by-month causal analysis, the researchers drew from infant death certificates in Texas and 28 comparison states from 2018 through 2022. They excluded the District of Columbia and several states that had fewer than 10 infant deaths in any month from 2018 to 2022, as the exact counts are not provided in currently publicly available data. The researchers selected March 2022 as the first cohort exposed to the Texas abortion policy because these infants, if born full term, would have been approximately 10 to 14 weeks gestation when the Texas law went into effect in September 2021. Before S.B. 8’s enactment, people would have been able to seek termination in the event a fetal issue was detected during screening prior to 20 weeks gestation.

In an analysis of cause of death using all 2021 and 2022 death certificate data, the researchers found that Texas had atypical increases in infant deaths due to congenital anomalies, the leading cause of infant death. Infant deaths attributable to congenital anomalies increased 22.9 percent in Texas between 2021 and 2022 versus a decrease of 3.1 percent in the rest of the U.S. during the same period. Another divergent cause of death pattern in Texas was infant deaths from accidents, which increased by 21 percent in Texas versus a one percent increase in the rest of the U.S.

“Our results suggest that restrictive abortion policies that limit pregnant people’s ability to terminate pregnancies, particularly those with fetal abnormalities diagnosed later in pregnancy, may lead to increases in infant mortality,” says Suzanne Bell, PhD, MPH, assistant professor in the Bloomberg School’s Department of Population, Family and Reproductive Health and one of the study’s lead authors. “These findings make clear the potentially devastating consequences abortion bans can have on pregnant people and families who are unable to overcome barriers to this essential reproductive health service.”

The authors note that the data did not include maternal and clinical characteristics of infant deaths, thus limiting the authors’ ability to explore potential mechanisms behind these findings.

The researchers are currently studying the impact across socioeconomic groups that abortion bans have on live births and infant mortality in Texas and other states that banned abortion following Dobbs.

This study was supported by the Hopkins Population Center from the National Institute of Child Health and Human Development (P2CHD042854).

“Tell me if you dance and I will tell you who you are!” A study led by researchers at the Max Planck Institute for Empirical Aesthetics (MPIEA) in Frankfurt am Main, Germany, has shown that both amateur and professional dancers are less neurotic than people who do not dance. They are also more agreeable, more open, and more extraverted. The results of the study have recently been published in the journal Personality and Individual Differences.

In cooperation with Matthias Blattmann, CEO of Gutmann Dance School in Freiburg im Breisgau and Tanzloft GmbH, and Luisa Sancho-Escanero, dance director at the Pfalztheater Kaiserslautern, the MPIEA’s researchers analyzed data from 5,435 people from Sweden and 574 people from Germany, with regards to their Big Five Personality Traits “Openness,””Conscientiousness,””Extraversion,””Agreeableness,” and “Neuroticism.”

“What is unique about this work is that we have brought together very large samples from two different countries. Such data are generally scarce, and previous studies have often been based on rather small samples,” explains senior author Fredrik Ullén, Director at the MPIEA.

In Sweden, the research team was able to rely on an existing database that included data about peoples’ creative engagement and dance achievements. To collect dancer data in Germany, the researchers developed an online survey that was widely shared by dance institutions.

Previous research has found that musicians are more agreeable and more open to others than non-musicians. In the current study, this was also confirmed for dancers. But the researchers also found an interesting difference between the two groups: In comparison to musicians, dancers are not more neurotic, but — on the contrary — less neurotic than people who do not dance.

“In general, both dancers and singers show a high degree of extraversion in their personality — which may be due to the fact that their means of expression when dancing and singing is their body — and this is a very socially exposed situation, more than if you express through an instrument, for example. However, more in-depth investigations are needed to explore this further,” says lead author Julia F. Christensen of the MPIEA.

There was also some evidence of personality differences between dancers of different styles. Swing dancers, for example, seemed to be even less neurotic than Latin and Standard dancers. However, this needs to be confirmed with larger samples of dancers. In the future, the researchers hope to extend their research into dancers’ personalities to many other cultures and dance styles.

A new study in the journal Science Advances, conducted by a team of international researchers, has uncovered a biological explanation for long-term memories. It centers on the discovery of the role of a molecule, KIBRA, that serves as a “glue” to other molecules, thereby solidifying memory formation.

“Previous efforts to understand how molecules store long-term memory focused on the individual actions of single molecules,” explains André Fenton, a professor of neural science at New York University and one of the study’s principal investigators. “Our study shows how they work together to ensure perpetual memory storage.”

“A firmer understanding of how we keep our memories will help guide efforts to illuminate and address memory-related afflictions in the future,” adds Todd Sacktor, a professor at SUNY Downstate Health Sciences University and one of the study’s principal investigators.

It’s been long-established that neurons store information in memory as the pattern of strong synapses and weak synapses, which determines the connectivity and function of neural networks. However, the molecules in synapses are unstable, continually moving around in the neurons, and wearing out and being replaced in hours to days, thereby raising the question: How, then, can memories be stable for years to decades?

In a study using laboratory mice, the scientists focused on the role of KIBRA, or kidney and brain expressed protein, the human genetic variants of which are associated with both good and poor memory. They focused on KIBRA’s interactions with other molecules crucial to memory formation — in this case, protein kinase Mzeta (PKMzeta). This enzyme is the most crucial molecule for strengthening normal mammalian synapses that is known, but it degrades after a few days.

Their experiments reveal that KIBRA is the “missing link” in long-term memories, serving as a “persistent synaptic tag,” or glue, that sticks to strong synapses and to PKMzeta while also avoiding weak synapses.

“During memory formation the synapses involved in the formation are activated — and KIBRA is selectively positioned in these synapses,” explains Sacktor, a professor of physiology, pharmacology, anesthesiology, and neurology at SUNY Downstate. “PKMzeta then attaches to the KIBRA-synaptic-tag and keeps those synapses strong. This allows the synapses to stick to newly made KIBRA, attracting more newly made PKMzeta.”

More specifically, their experiments in the Science Advances paper show that breaking the KIBRA-PKMzeta bond erases old memory. Previous work had shown that randomly increasing PKMzeta in the brain enhances weak or faded memories, which was mysterious because it should have done the opposite by acting at random locations, but the persistent synaptic tagging by KIBRA explains why the additional PKMzeta was memory enhancing, by only acting at the KIBRA tagged sites.

“The persistent synaptic tagging mechanism for the first time explains these results that are clinically relevant to neurological and psychiatric disorders of memory,” observes Fenton, who is also on the faculty at NYU Langone Medical Center’s Neuroscience Institute.

The paper’s authors note that the research affirms a concept introduced in 1984 by Francis Crick. Sacktor and Fenton point out that his proposed hypothesis to explain the brain’s role in memory storage despite constant cellular and molecular changes is a Theseus’s Ship mechanism — borrowed from a philosophical argument stemming from Greek mythology in which new planks replace old ones to maintain Theseus’s Ship for years.

“The persistent synaptic tagging mechanism we found is analogous to how new planks replace old planks to maintain Theseus’s Ship for generations, and allows memories to last for years even as the proteins maintaining the memory are replaced,” says Sacktor. “FrancisCrick intuited this Theseus’s Ship mechanism, even predicting the role for a protein kinase. But it took 40 years to discover that the components are KIBRA and PKMzeta and to work out the mechanism of their interaction.”

The study also included researchers from Canada’s McGill University, Germany’s University Hospital of Münster, and University of Texas Medical School at Houston.

This work was supported by grants from the National Institutes of Health (R37 MH057068, R01 MH115304, R01 NS105472, R01 MH132204, R01 NS108190), the Natural Sciences and Engineering Research Council of Canada Discovery (203523), and the Garry and Sarah S. Sklar Fund.

Comparison between singles today and singles ten years ago

Throughout the world, marriage rates have been declining over past decades, while divorce rates and the proportions of single-person households have been on the rise. “It is notable that, particularly in Western industrialized countries, singlehood is no longer unconventional and now considered more socially acceptable than in the past,” stated Dr. Tita Gonzalez Avilés from the JGU Institute of Psychology. She analyzed data from the representative longitudinal Panel Analysis of Intimate Relationships and Family Dynamics (pairfam), which has been surveying the nature of romantic relationship and family dynamics in Germany since 2008. The most recent study is based on the information provided by 2,936 participants in different birth cohorts. The gathered material related to two separate time periods, namely 2008 to 2011 and 2018 to 2021. This allowed the researchers to differentiate between the satisfaction of earlier-born and later-born singles during adolescence (14-20 years), emerging adulthood (24-30 years), and established adulthood (34-40 years).

“Although we know that singlehood is gaining ground, we have not yet determined whether individuals are now more satisfied with this way of life,” added Gonzalez Avilés, explaining the purpose of the study. Their findings, which have recently appeared in the Personality and Social Psychology Bulletin, indicate that adolescent singles born in 2001 to 2003 were more often single and more satisfied with singlehood than the birth cohort born ten years. Furthermore, there were no cohort-related differences among emerging adults aged 24 to 30 years and established adults aged 34 to 40.

Multiple factors explain the higher satisfaction among adolescents

Although the difference in satisfaction between today and ten years ago is not very large, even among adolescents, it stands out from the historical developments among adults. Gonzalez Avilés and her co-authors postulate that this may be due to the fact that living as a single has become increasingly normative over time, especially among the younger generation. Furthermore, their attitudes towards romantic conventions have changed and they are more open to diverse relationship types. “We assume that adolescents nowadays may postpone entering into a stable relationship because they value their personal autonomy and individual fulfillment over a romantic partnership. However, these explanations are — for the time being — speculative and require further investigation,” concluded Gonzalez Avilés.

Several drugs combined into one daily pill for seniors who have trouble remembering to take their medications.

Drugs printed at your local pharmacy at personalized dosages that best suit your health needs.

These are just a few potential advantages of 3D drug printing, a new system for manufacturing drugs and treatments on-site at pharmacies, health care facilities and other remote locations.

In 2015, the Food and Drug Administration approved the first 3D-printed drug, Spritam (levetiracetam), for epilepsy. Several other manufacturers and drug companies are developing their own ones.

But the widespread adoption of 3D drug printing will require stringent quality control measures to ensure that people get the right medication and dosage. Even a tiny mismeasurement of a drug’s ingredient during the printing process could endanger a patient’s health.

In a new research paper, NIST research scientist Thomas P. Forbes assesses various approaches to ensuring that 3D drug printers work as designed. The journal article applies a “quality by design” analysis to evaluate the best procedures and protocols to ensure that 3D printers produce drugs at the correct dosages and with the correct mix of chemicals.

Though various methods exist for remotely printing drugs, Forbes focused on one of the most common: inkjet printers and similar systems that can print personalized medication on demand.

Like inkjet printers in homes, though larger, the printer has nozzles that deposit the drug’s liquified materials, or inks, into tiny wells on a tray or directly into capsules. Through freeze-drying and other processes, the liquid can be turned into a tablet or powder poured into a capsule. It can also be evaporated onto a thin film that dissolves in the mouth.

Forbes’ paper does not make any recommendations. Instead, his research identifies and tests several possible methods and techniques for maintaining quality control in 3D drug printing.

Jeanie Tryggestad, M.D., an associate professor of pediatrics in the OU College of Medicine, led the study, which is published in The Journal of Clinical Endocrinology & Metabolism. It marks one of the first times microRNA abundance has been explored to predict the progression of Type 2 diabetes in youth. The specific microRNAs in the study are involved in insulin resistance and other actions that can stress beta cells or cause their death. The research is significant because it points to a process that is necessary to understand in order to ultimately design a strategy for prevention.

“Type 2 diabetes in youth is so aggressive, and the decline of beta cell function in youth is much more than we see in adults,” Tryggestad said. “We believe that predicting what will cause beta cell dysfunction, and eventually preventing that dysfunction, is one of the keys for preventing or treating Type 2 diabetes.”

Tryggestad’s study showed that the microRNAs, at baseline, were nearly as effective as A1C measurement (average level of blood sugar) when predicting who would fail to respond to treatment for Type 2 diabetes. Treatment failure was defined as having an A1C of greater than 8% for six months or a circumstance that caused the study participant to go back on insulin without the ability to come back off. Circulating microRNAs also predicted a 20% decrease in beta cell function during the first six months of the study.

Currently, microRNAs can be measured only in a research setting, not in a clinic, but that may change in the future, Tryggestad said. The study’s implications are important not only for the predictive potential of microRNAs, but because they represent a mechanism, or part of the process by which Type 2 diabetes develops and worsens.

“Glucose and A1C are relevant to me as a clinician, but as a clinician-researcher, it’s important to have this additional piece of information about microRNAs because it points us toward a mechanism. It’s the mechanism that we need to understand to design a prevention. It adds a layer of understanding that we haven’t had before,” she said.

Addressing the dramatic increase in Type 2 diabetes in children is only becoming more critical. Each year in the United States, cases of Type 2 diabetes in youth increase by 5.3%. At that rate, the prevalence is expected to increase by a staggering 700% by the year 2060. Tryggestad said that today, more youth ages 15 to 19 are living with Type 2 diabetes than Type 1 diabetes — the first time that has ever happened.

The samples analyzed in this research came from participants in the landmark TODAY study (Treatment Options for Type 2 Diabetes in Adolescents and Youth). The OU College of Medicine played a major role in the multi-center clinical trial, which began recruiting participants in 2003 and ended in 2020. The trial featured 699 study participants, and Oklahoma enrolled more patients than any other participating site.

The trial was the first and largest of its kind to compare treatments for Type 2 diabetes in youth, but it has continued to yield information since the original study ended. The OU College of Medicine was awarded an additional grant to analyze microRNA samples taken during the first 10 years of the study.

New research, published today in Environment International proves for the first time that a wide range of PFAS (perfluoroalkyl substances) — chemicals which do not break down in nature — can permeate the skin barrier and reach the body’s bloodstream.

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

PFAS are already known to enter the body through other routes, for example being breathed in or ingested via food or drinking water, and they are known to cause adverse health effects such as a lowered immune response to vaccination, impaired liver function and decreased birth weight.

It has commonly been thought that PFAS are unable to breach the skin barrier, although recent studies have shown links between the use of personal care products and PFAS concentrations in human blood and breast milk. The new study is the most comprehensive assessment yet undertaken of the absorption of PFAS into human skin and confirms that most of them can enter the body via this route.

Lead author of the study, Dr Oddný Ragnarsdóttir carried out the research while studying for her PhD at the University of Birmingham. She explained: “The ability of these chemicals to be absorbed through skin has previously been dismissed because the molecules are ionised. The electrical charge that gives them the ability to repel water and stains was thought to also make them incapable of crossing the skin membrane.

“Our research shows that this theory does not always hold true and that, in fact, uptake through the skin could be a significant source of exposure to these harmful chemicals.”

The researchers investigated 17 different PFAS. The compounds selected were among those most widely used, and most widely studied for their toxic effects and other ways through which humans might be exposed to them. Most significantly, they correspond to chemicals regulated by the EU’s Drinking Water Directive.

In their experiments the team used 3D human skin equivalent models — multilayered laboratory grown tissues that mimic the properties of normal human skin, meaning the study could be carried out without using any animals. They applied samples of each chemical to measure what proportions were absorbed, unabsorbed, or retained within the models.

Of the 17 PFAS tested, the team found 15 substances showed substantial dermal absorption — at least 5% of the exposure dose. At the exposure doses examined, absorption into the bloodstream of the most regulated PFAS (perfluoro octanoic acid (PFOA)) was 13.5% with a further 38% of the applied dose retained within the skin for potential longer-term uptake into the circulation.

The amount absorbed seemed to correlate with the length of the carbon chain within the molecule. Substances with longer carbon chains showed lower levels of absorption, while compounds with shorter chains that were introduced to replace longer carbon chain PFAS like PFOA, were more easily absorbed. Absorption of perfluoro pentanoic acid for example was four times that of PFOA at 59%.

Study co-author, Dr Mohamed Abdallah, said “our study provides first insight into significance of the dermal route as pathway of exposure to a wide range of forever chemicals. Given the large number of existing PFAS, it is important that future studies aim to assess the risk of broad ranges of these toxic chemicals, rather than focusing on one chemical at a time.”

Study co-author, Professor Stuart Harrad, of the University of Birmingham’s School of Geography, Earth and Environmental Sciences, added: “This study helps us to understand how important exposure to these chemicals via the skin might be and also which chemical structures might be most easily absorbed. This is important because we see a shift in industry towards chemicals with shorter chain lengths because these are believed to be less toxic — however the trade-off might be that we absorb more of them, so we need to know more about the risks involved.”

In a world-first study published last weekend in the journal Cognition, a team of international researchers has reported some surprising findings relating to facial recognition.

The first discovery is that one’s ability to recognise faces has nothing to do with how extraverted, sociable, or gregarious a person is. What is clear, however, is that good facial recall is linked to the number of close, high-quality relationships that people have.

Researchers from the University of South Australia (UniSA), University of Western Australia (UWA) and Curtin University, along with US colleagues from Wellesley College and Harvard Medical School, undertook four separate studies involving more than 3000 people to tease out the relationship between facial recognition, social networks and personality traits.

In tests where participants memorised new faces or identified celebrity faces, their scores correlated with the number of close relationships they enjoyed.

“People who identified more faces typically had larger supportive social networks, which bodes well for their overall health and happiness,” says lead researcher UniSA psychologist Dr Laura Engfors.

“In concrete terms, the rise from the lowest (two) to the highest (28) number of faces that were successfully recognised on one test coincided with six additional close relationships, increasing from nine to 15. That’s an increase of two thirds and it is one extra strong social bond per four famous people recognised.”

The research did not find any link between facial recognition and a more social personality.

“Our findings rule out the idea that being sociable means you’ll probably be great at recognising faces. It also helps to dispel the common misconception that not recognising someone means you are less sociable.

“The ability to recognise faces more easily also means people may develop relationships faster.

“Imagine you’ve had an engaging conversation with someone you have only just met. A few weeks later you run into them again. If you recognise them quickly and easily, it opens the door to develop the rapport you established in your first meeting, helping the relationship to progress.

“On the flip side, if you don’t recognise them, you’ve missed the chance to build on that initial interaction,” Dr Engfors says.

Curtin University researcher and co-author Dr Linda Jeffery says being recognised by someone is a boost to a person’s self-esteem.

“It can make us feel important and valued, leading us to relate to that person more warmly, whereas we feel snubbed if someone we have met before does not recognise us.”

Wellesley College psychologist and co-author Associate Professor Jeremy Wilmer hopes the findings will be used to build stronger communities that facilitate human connection.

“Understanding that not everyone finds it easy to recognise people can help us to support those around us in social interactions,” Prof Wilmer says.

“Something as simple as name tags at a community barbecue or school event can make the difference between a connection built and a connection lost. Similarly, if you catch a flicker of uncertainty on someone’s face when you say hello, a subtle reminder to help them place you will be appreciated.”

People can test their own celebrity face recognition at the researchers’ citizen science website TestMyBrain.org.

The results, published in the June 21, 2024 online edition of New England Journal of Medicine, highlight the treatment’s potential to improve the quality of life for millions around the world affected by OSA.

“This study marks a significant milestone in the treatment of OSA, offering a promising new therapeutic option that addresses both respiratory and metabolic complications,” said Atul Malhotra, MD, lead author of the study, professor of medicine at University of California San Diego School of Medicine and director of sleep medicine at UC San Diego Health.

OSA can result in reduced oxygen levels in the blood and can also be associated with an increased risk of cardiovascular complications, such as hypertension and heart disease. Recent studies, also led by Malhotra, suggest that the number of OSA patients worldwide is close to 936 million.

Conducted in two Phase III, double-blinded, randomized, controlled trials, the new study cohort involved 469 participants diagnosed with clinical obesity and living with moderate-to-severe OSA. They were recruited from sites in nine different countries, including the U.S., Australia and Germany. Participants either used or did not use continuous positive airway pressure (CPAP) therapy, the most common sleep apnea treatment which uses a machine to maintain an open airway during sleep, preventing interruptions in breathing. Patients were administered either 10 or 15 mg of the drug by injection or a placebo. The impact of tirzepatide was evaluated over 52 weeks.

Researchers found that tirzepatide led to a significant decrease in the number of breathing interruptions during sleep, a key indicator used to measure the severity of OSA. This improvement was much greater than what was seen in participants that were given a placebo. Importantly, some participants that took the drug reached a point where CPAP therapy might not be necessary. Considerable data suggest that a drug therapy that targets both sleep apnea and obesity is beneficial rather than treating either condition alone.

Additionally, the drug therapy improved other aspects related to OSA, such as reducing the risk factors of cardiovascular diseases and improved body weight. The most common side effect reported was mild stomach issues.

“Historically, treating OSA meant using devices during sleep, like a CPAP machine, to alleviate breathing difficulties and symptoms,” Malhotra said. “However, its effectiveness relies on consistent use. This new drug treatment offers a more accessible alternative for individuals who cannot tolerate or adhere to existing therapies. We believe that the combination of CPAP therapy with weight loss will be optimal for improving cardiometabolic risk and symptoms. Tirzepatide can also target specific underlying mechanisms of sleep apnea, potentially leading to more personalized and effective treatment.”

Malhotra adds that having a drug therapy for OSA represents a significant advancement in the field.

“It means we can offer an innovative solution, signifying hope and a new standard of care to provide relief to countless individuals and their families who have struggled with the limitations of existing treatments,” said Malhotra. “This breakthrough opens the door to a new era of OSA management for people diagnosed with obesity, potentially transforming how we approach and treat this pervasive condition on a global scale.”

Next steps include conducting clinical trials to examine longer term effects of tirzepatide.

Co-authors of the study include: Ronald Grunstein, University of Sydney; Ingo Fietze, University Hospital Berlin; Terri Weaver, University of Illinois Chicago; Susan Redline, Ali Azarbarzin, and Scott Sands, Harvard Medical School; Richard Schwab, University of Pennsylvania; and Julia Dunn, Sujatro Chakladar, Mathijs Bunck, and Josef Bednarik, Eli Lilly and Company.

Funding support for the study came, in part, from Eli Lilly and Company.

“We wanted to get these proteins out of the cell membrane, so we redesigned them as hyperstable, soluble analogues, which look like membrane proteins but are much easier to work with,” explains Casper Goverde, a PhD student in the Laboratory of Protein Design and Immunoengineering (LPDI) in the School of Engineering.

In a nutshell, Goverde and a research team in the LPDI, led by Bruno Correia, used deep learning to design synthetic soluble versions of cell membrane proteins commonly used in pharmaceutical research. Whereas traditional screening methods rely on indirectly observing cellular reactions to drug and antibody candidates, or painstakingly extracting small quantities of membrane proteins from mammalian cells, the researchers’ computational approach allows them to remove cells from the equation. After designing a soluble protein analogue using their deep learning pipeline, they can use bacteria to produce the modified protein in bulk. These proteins can then bind directly in solution with molecular candidates of interest.

“We estimate that producing a batch of soluble protein analogues using E. coli is around 10 times less expensive than using mammalian cells,” adds PhD student Nicolas Goldbach.

The team’s research has recently been published in the journal Nature.

Flipping the script on protein design

In recent years, scientists have successfully harnessed artificial intelligence networks that use deep learning to design novel protein structures, for example by predicting them based on an input sequence of amino acid building blocks. But for this study, the researchers were interested in protein folds that already exist in nature; what they needed was a more accessible, soluble version of these proteins.

“We had the idea to invert this deep learning pipeline that predicts protein structure: if we input a structure, can it tell us the corresponding amino acid sequence?” explains Goverde.

To achieve this, the team used the structure prediction platform AlphaFold2 from Google DeepMind to produce amino acid sequences for soluble versions of several key cell membrane proteins, based on their 3D structure. Then, they used a second deep learning network, ProteinMPNN, to optimize those sequences for functional, soluble proteins. The researchers were pleased to discover that their approach showed remarkable success and accuracy in producing soluble proteins that maintained parts of their native functionality, even when applied to highly complex folds that have so far eluded other design methods.

“The holy grail of biochemistry”

A particular triumph of the study was the pipeline’s success in designing a soluble analogue of a protein shape known as the G-protein coupled receptor (GPCR), which represents around 40% of human cell membrane proteins and is a major pharmaceutical target.

“We showed for the first time that we can redesign the GPCR shape as a stable soluble analogue. This has been a long-standing problem in biochemistry, because if you can make it soluble, you can screen for novel drugs much faster and more easily,” says LPDI scientist Martin Pacesa.

The researchers also see these results as a proof-of-concept for their pipeline’s application to vaccine research, and even cancer therapeutics. For example, they designed a soluble analogue of a protein type called a claudin, which plays a role in making tumors resistant to the immune system and chemotherapy. In their experiments, the team’s soluble claudin analogue retained its biological properties, reinforcing the pipeline’s promise for generating interesting targets for pharmaceutical development.

For the study, rather than examine microbiome activity and composition linked to disease conditions — like anxiety and depression — the researchers wanted to flip the script and study the gut microbiome and brain in healthy, resilient people who effectively cope with different types of stress, including discrimination and social isolation.

“If we can identify what a healthy resilient brain and microbiome look like, then we can develop targeted interventions to those areas to reduce stress,” said Arpana Gupta, PhD, senior author and co-director of the UCLA Goodman-Luskin Microbiome Center. This is believed to be the first study to explore the intersection of resiliency, the brain, and the gut microbiome.

Gupta and her team focused on methods to cope with stress because research has shown that untreated stress can increase the risk of heart disease, stroke, obesity, and diabetes. While stress is an inevitable part of life, studying how to handle stress can help prevent developing diseases.

To conduct the study, published in Nature Mental Health, the researchers surveyed 116 people about their resiliency — like trust in one’s instincts and positive acceptance of change — and separated them into two groups. One group ranked high on the resiliency scale and the other group ranked low. The participants also underwent MRI imaging and gave stool samples two or three days before their scans.

The researchers found that people in the high resiliency group were less anxious and depressed, less prone to judge, and had activity in regions of the brain associated with emotional regulation and better cognition compared to the group with low resiliency. “When a stressor happens, often we go to this aroused fight or flight response, and this impairs the breaks in your brain,” Gupta said. “But the highly resilient individuals in the study were found to be better at regulating their emotions, less likely to catastrophize, and keep a level head,” added Desiree Delgadillo, postdoctoral researcher and one of the first authors.

The high resiliency group also had different microbiome activity than the low resiliency group. Namely, the high resiliency group’s microbiomes excreted metabolites and exhibited gene activity associated with low inflammation and a strong and healthy gut barrier. A weak gut barrier, otherwise known as a leaky gut, is caused by inflammation and impairs the gut barrier’s ability to absorb essential nutrients needed by the body while blocking toxins from entering the gut.

The researchers were surprised to find these microbiome signatures associated with the high resiliency group.

“Resilience truly is a whole-body phenomenon that not only affects your brain but also your microbiome and what metabolites that it is producing,” Gupta said. “We have this whole community of microbes in our gut that exudes these therapeutic properties and biochemicals, so I’m looking forward to building upon this research,” Delgadillo said.

The team’s future research will study whether an intervention to increase resilience will change brain and gut microbiome activity. “We could have treatments that target both the brain and the gut that can maybe one day prevent disease,” Gupta said.

A new UCLA Health study has found that resilient people exhibit neural activity in the brain regions associated with improved cognition and regulating of emotions, and were more mindful and better at describing their feelings. The same group also exhibited gut microbiome activity linked to a healthy gut, with reduced inflammation and gut barrier.

For the study, rather than examine microbiome activity and composition linked to disease conditions — like anxiety and depression — the researchers wanted to flip the script and study the gut microbiome and brain in healthy, resilient people who effectively cope with different types of stress, including discrimination and social isolation.

“If we can identify what a healthy resilient brain and microbiome look like, then we can develop targeted interventions to those areas to reduce stress,” said Arpana Gupta, PhD, senior author and co-director of the UCLA Goodman-Luskin Microbiome Center. This is believed to be the first study to explore the intersection of resiliency, the brain, and the gut microbiome.

Gupta and her team focused on methods to cope with stress because research has shown that untreated stress can increase the risk of heart disease, stroke, obesity, and diabetes. While stress is an inevitable part of life, studying how to handle stress can help prevent developing diseases.

To conduct the study, published in Nature Mental Health, the researchers surveyed 116 people about their resiliency — like trust in one’s instincts and positive acceptance of change — and separated them into two groups. One group ranked high on the resiliency scale and the other group ranked low. The participants also underwent MRI imaging and gave stool samples two or three days before their scans.

The researchers found that people in the h

Gupta and her team focused on methods to cope with stress because research has shown that untreated stress can increase the risk of heart disease, stroke, obesity, and diabetes. While stress is an inevitable part of life, studying how to handle stress can help prevent developing diseases.

To conduct the study, published in Nature Mental Health, the researchers surveyed 116 people about their resiliency — like trust in one’s instincts and positive acceptance of change — and separated them into two groups. One group ranked high on the resiliency scale and the other group ranked low. The participants also underwent MRI imaging and gave stool samples two or three days before their scans.

The researchers found that people in the high resiliency group were less anxious and depressed, less prone to judge, and had activity in regions of the brain associated with emotional regulation and better cognition compared to the group with low resiliency. “When a stressor happens, often we go to this aroused fight or flight response, and this impairs the breaks in your brain,” Gupta said. “But the highly resilient individuals in the study were found to be better at regulating their emotions, less likely to catastrophize, and keep a level head,” added Desiree Delgadillo, postdoctoral researcher and one of the first authors.

The high resiliency group also had different microbiome activity than the low resiliency group. Namely, the high resiliency group’s microbiomes excreted metabolites and exhibited gene activity associated with low inflammation and a strong and healthy gut barrier. A weak gut barrier, otherwise known as a leaky gut, is caused by inflammation and impairs the gut barrier’s ability to absorb essential nutrients needed by the body while blocking toxins from entering the gut.

The researchers were surprised to find these microbiome signatures associated with the high resiliency group.

“Resilience truly is a whole-body phenomenon that not only affects your brain but also your microbiome and what metabolites that it is producing,” Gupta said. “We have this whole community of microbes in our gut that exudes these therapeutic properties and biochemicals, so I’m looking forward to building upon this research,” Delgadillo said.

The team’s future research will study whether an intervention to increase resilience will change brain and gut microbiome activity. “We could have treatments that target both the brain and the gut that can maybe one day prevent disease,” Gupta said.

A new UCLA Health study has found that resilient people exhibit neural activity in the brain regions associated with improved cognition and regulating of emotions, and were more mindful and better at describing their feelings. The same group also exhibited gut microbiome activity linked to a healthy gut, with reduced inflammation and gut barrier.

For the study, rather than examine microbiome activity and composition linked to disease conditions — like anxiety and depression — the researchers wanted to flip the script and study the gut microbiome and brain in healthy, resilient people who effectively cope with different types of stress, including discrimination and social isolation.

“If we can identify what a healthy resilient brain and microbiome look like, then we can develop targeted interventions to those areas to reduce stress,” said Arpana Gupta, PhD, senior author and co-director of the UCLA Goodman-Luskin Microbiome Center. This is believed to be the first study to explore the intersection of resiliency, the brain, and the gut microbiome.

Gupta and her team focused on methods to cope with stress because research has shown that untreated stress can increase the risk of heart disease, stroke, obesity, and diabetes. While stress is an inevitable part of life, studying how to handle stress can help prevent developing diseases.

To conduct the study, published in Nature Mental Health, the researchers surveyed 116 people about their resiliency — like trust in one’s instincts and positive acceptance of change — and separated them into two groups. One group ranked high on the resiliency scale and the other group ranked low. The participants also underwent MRI imaging and gave stool samples two or three days before their scans.

The researchers found that people in the high resiliency group were less anxious and depressed, less prone to judge, and had activity in regions of the brain associated with emotional regulation and better cognition compared to the group with low resiliency. “When a stressor happens, often we go to this aroused fight or flight response, and this impairs the breaks in your brain,” Gupta said. “But the highly resilient individuals in the study were found to be better at regulating their emotions, less likely to catastrophize, and keep a level head,” added Desiree Delgadillo, postdoctoral researcher and one of the first authors.

The high resiliency group also had different microbiome activity than the low resiliency group. Namely, the high resiliency group’s microbiomes excreted metabolites and exhibited gene activity associated with low inflammation and a strong and healthy gut barrier. A weak gut barrier, otherwise known as a leaky gut, is caused by inflammation and impairs the gut barrier’s ability to absorb essential nutrients needed by the body while blocking toxins from entering the gut.

The researchers were surprised to find these microbiome signatures associated with the high resiliency group.

“Resilience truly is a whole-body phenomenon that not only affects your brain but also your microbiome and what metabolites that it is producing,” Gupta said. “We have this whole community of microbes in our gut that exudes these therapeutic properties and biochemicals, so I’m looking forward to building upon this research,” Delgadillo said.

The team’s future research will study whether an intervention to increase resilience will change brain and gut microbiome activity. “We could have treatments that target both the brain and the gut that can maybe one day prevent disease,” Gupta said.

Understanding the Study

Genomic disorders occur when there are changes or mutations in DNA that disrupt normal biological functions. These can lead to a range of health issues, including developmental delays and neurological problems. One type of complex DNA mutation involves a structure known as a duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP). This study delves into how these complex rearrangements form and their impact on human health.

Key Findings

The research team, led by PNRI Assistant Investigator Cláudia Carvalho, Ph.D., collaborated with her lab colleagues, study lead author Christopher Grochowski, Ph.D., from the James R. Lupski Lab at Baylor College of Medicine, and other scientists to analyze the DNA of 24 individuals with inverted triplications.

They discovered that these rearrangements are caused by segments of DNA switching templates during the repair process. Normally, DNA repair mechanisms use the undamaged complementary strand as a template to accurately repair the damaged DNA. However, sometimes during repair, the repair machinery may inadvertently switch to a different but similar sequence elsewhere in the genome.

These switches occur within pairs of inverted repeats — sections of DNA that are mirror images of each other. Inverted repeats can confuse the repair machinery, leading to the use of the wrong template, which can disrupt normal gene function and contribute to genetic disorders.

1. Structural Diversity: The study found that these inverted triplications generate a surprising variety of structural variations in the genome, which can lead to different health outcomes.
2. Gene Dosage Impact: These rearrangements can alter the number of copies of certain genes, known as gene dosage. The correct number of gene copies is crucial for normal human development and function. Changes in gene dosage can cause diseases like MECP2 duplication syndrome, a rare neurodevelopmental disorder.
3. Mapping Breakpoints: By using advanced DNA sequencing techniques, the researchers identified the precise locations where these DNA segments switch templates leading to an altered number of genes including MECP2.

Dr. Carvalho and Baylor scientists first observed this pathogenic genomic structure in 2011 while studying MECP2duplication syndrome. Only recently, with the advent of long-read sequencing technology, has it become possible to investigate in detail how it forms in the genome.

Implications for Rare Disease Research and Treatment

“This study sheds light on the intricate mechanisms driving genetic rearrangements and their profound impact on rare diseases,” said Dr. Cláudia Carvalho, PNRI’s lead scientist on the study. “By unraveling these complex DNA structures, we open new avenues for understanding the genetic causes of rare diseases and developing targeted treatments to improve patient outcomes.”

These findings are being applied in a follow-up study led by Baylor’s Davut Pehlivan, M.D., investigating how complex genomic structures influence the clinical features of MECP2 duplication syndrome and their impact on targeted therapeutic approaches.

But it’s too soon to know if the so-called “blood oranges” are a viable crop for the Florida citrus industry, says Ali Sarkhosh, a UF/IFAS associate professor of horticultural sciences. Sarkhosh’s post-doctoral associate Fariborz Habibi explains further.

“Although blood oranges typically command higher prices than other common varieties, such as navel or Valencia oranges, it is unclear if farmers could substantially increase their per-acre income by adding them to their crop selection and then storing them for internal color development,” said Habibi, lead author of the study. “Improved fruit quality from the storage method presents a promising opportunity for the Florida citrus industry. However, further study is needed before recommending anything to growers.”

The fruit is rich in anthocyanins, which have been linked to various health benefits, including anti-inflammatory and antioxidant properties. They also contain other beneficial phytochemicals such as vitamin C, flavonoids and dietary fiber.

“Fruit can also develop internal color under similar conditions at home. However, the fruit in the supermarket should have a good internal color and be ready for consumption,” Sarkhosh said.

For this research, scientists harvested fruit from a research plot at the UF/IFAS North Florida Research and Education Center in Quincy.

Scientists found that storing the blood oranges at 40 to 53 degrees enhances anthocyanin, phenolic content, and antioxidants. When they lowered the temperatures 43 to 46 degrees, they also preserved fruit firmness, weight loss and sugar content.

“Attributes such as firmness are crucial for maintaining the overall quality, texture and taste of the blood oranges during storage,” said Habibi.

Blood oranges get their name from their deep red flesh. Their skin contains a type of antioxidant pigment. The fruit is commonly grown in countries like Italy and Spain, which have the Mediterranean climate – cold, but above 32 degrees — that helps them grow. In the United States, blood oranges grow primarily in California, but are not grown commercially yet in Florida.

Anthocyanin develops when the fruit is exposed to cold temperatures between 46 and 59 degrees for at least 20 days. Such conditions are rare in Florida’s subtropical climate.

Their work — published today in leading journal Nature Communications — could have significant, wide-ranging impacts across a suite of industries, from food production to human health.

Enzymes are central to life and key to developing innovative drugs and tools to address society’s challenges. They have evolved over billions of years through changes in the amino acid sequence that underpins their 3D structure. Like beads on a string, each enzyme is composed of a sequence of several hundred amino acids that encodes its 3D shape.

With one of 20 amino acid ‘beads’ possible at each position, there is enormous sequence diversity possible in nature. Upon formation of their 3D shape, enzymes carry out a specific function such as digesting our dietary proteins, converting chemical energy into force in our muscles, and destroying bacteria or viruses that invade cells. If you change the sequence, you can disrupt the 3D shape, and that typically changes the functionality of the enzyme, sometimes rendering it completely ineffective.

Finding ways to improve the activity of enzymes would be hugely beneficial to many industrial applications and, using modern tools in molecular biology, it is simple and cost-efficient to engineer changes in the amino acid sequences to facilitate improvements in their performance. However, randomly introducing as little as three or four changes to the sequence can lead to a dramatic loss of their activity.

Here, the scientists report a promising new strategy to rationally engineer an enzyme called “beta-lactamase.” Instead of introducing random mutations in a scattergun approach, researchers at the Broad Institute and Harvard Medical School developed an algorithm that takes into account the evolutionary history of the enzyme.

“At the heart of this new algorithm is a scoring function that exploits thousands of sequences of beta-lactamase from many diverse organisms. Instead of a few random changes, up to 84 mutations over a sequence of 280 were generated to enhance functional performance,” said Dr Amir Khan, Associate Professor in Trinity College Dublin’s School of Biochemistry and Immunology, one of the co-authors of the research.

“And strikingly, the newly designed enzymes had both improved activity and stability at higher temperatures.”

Eve Napier, a second-year PhD student at Trinity College Dublin, determined the 3D experimental structure of a newly designed beta-lactamase, using a method called X-ray crystallography.

Her 3D map revealed that despite changes to 30% of the amino acids, the enzyme had an identical structure to the wild-type beta-lactamase. It also revealed how coordinated changes in amino acids, introduced simultaneously, can efficiently stabilise the 3D structure — in contrast to individual changes that typically impair the enzyme structure.

Eve Napier said: “Overall, these studies reveal that proteins can be engineered for improved activity by dramatic ‘jumps’ into new sequence space.

“The work has wide ranging applications in industry, in processes that require enzymes for food production, plastic-degrading enzymes, and those relevant to human health and disease, so we are quite excited for the future possibilities.”

About 800 million people worldwide have low back pain, and it is a leading cause of disability and reduced quality of life.

Repeated episodes of low back pain are also very common, with seven in 10 people who recover from an episode going on to have a recurrence within a year.

Current best practice for back pain management and prevention suggests the combination of exercise and education. However, some forms of exercise are not accessible or affordable to many people due to their high cost, complexity, and need for supervision.

A clinical trial by Macquarie University’s Spinal Pain Research Group has looked at whether walking could be an effective, cost-effective and accessible intervention.

The trial followed 701 adults who had recently recovered from an episode of low back pain, randomly allocating participants to either an individualised walking program and six physiotherapist-guided education sessions over six months, or to a control group.

Researchers followed the participants for between one and three years, depending on when they joined, and the results have now been published in the latest edition of The Lancet.

The paper’s senior author, Macquarie University Professor of Physiotherapy, Mark Hancock, says the findings could have a profound impact on how low back pain is managed.

“The intervention group had fewer occurrences of activity limiting pain compared to the control group, and a longer average period before they had a recurrence, with a median of 208 days compared to 112 days,” Professor Hancock says.

“Walking is a low-cost, widely accessible and simple exercise that almost anyone can engage in, regardless of geographic location, age or socio-economic status.

“We don’t know exactly why walking is so good for preventing back pain, but it is likely to include the combination of the gentle oscillatory movements, loading and strengthening the spinal structures and muscles, relaxation and stress relief, and release of ‘feel-good’ endorphins.

“And of course, we also know that walking comes with many other health benefits, including cardiovascular health, bone density, healthy weight, and improved mental health.”

Lead author Dr Natasha Pocovi says in addition to providing participants with longer pain-free periods, the program was very cost-effective.

“It not only improved people’s quality of life, but it reduced their need both to seek healthcare support and the amount of time taken off work by approximately half,” she says.

“The exercise-based interventions to prevent back pain that have been explored previously are typically group-based and need close clinical supervision and expensive equipment, so they are much less accessible to the majority of patients.

“Our study has shown that this effective and accessible means of exercise has the potential to be successfully implemented at a much larger scale than other forms of exercise.”

To build on these findings, the team now hopes to explore how they can integrate the preventive approach into the routine care of patients who experience recurrent low back pain.

Santosh Kumar, associate professor of development and global health economics at Notre Dame’s Keough School of Global Affairs, is co-author of the study, published in Communications Medicine. Kumar’s research explores the intersection of global health and poverty reduction. His latest work evaluates the relationship between anemia and school attendance in India.

The study investigated whether there was a link between anemia and school attendance in more than 250,000 adolescents ages 15 to 18. Earlier observational studies have shown a link between anemia and attendance, even after accounting for variables such as gender and household wealth, according to Kumar. But the new study, which applied more rigorous econometric statistical analysis, did not find such a link, he said.

“Most previous research on this topic has used conventional study designs or focused on small geographical areas, which limits its policy relevance,” Kumar said. “Earlier estimates may have been distorted by unobserved household factors related to both anemia and school attendance. So in this study, we focused on the relationship between anemia and attendance among adolescents who were living in the same household.

“Ultimately,” Kumar said, “we found that the link between anemia and schooling is more muted than previously suggested by studies that did not consider household-level factors.”

The findings have important implications for policymakers seeking to improve education in low- and middle-income countries like India, Kumar said. India has widespread school attendance issues and struggles with health conditions such as anemia caused by iron deficiency, particularly in children and adolescents. The country has pushed to improve educational outcomes, in keeping with the United Nations’ Sustainable Development Goals, Kumar said. But to achieve that, he said, more research is needed to pinpoint an evidence-based intervention.

This study is part of an ongoing project to do that work and was co-authored with Jan-Walter De Neve of the University of Heidelberg, Omar Karlsson of Lund University in Sweden, Rajesh Kumar Rai of Harvard University and Sebastian Vollmer of the University of Göttingen. The project received funding from the Alexander von Humboldt Foundation, the Swedish Research Council and the West Bengal State Department of Health and Family Welfare in India.

The latest study builds on an earlier one in which Kumar and fellow researchers helped evaluate the results of an iron fortification school lunch program for students ages 7 and 8 in India. That study showed that fortification reduced anemia but did not affect students’ performance in school. A forthcoming study, set to launch in summer 2024, will look at iron fortification for children ages 3 to 5. The research hypothesis is that an early-age nutritional intervention among preschoolers would make a significant impact on physical and cognitive development.

“Our findings have implications for policymakers who want to improve educational outcomes and reduce poverty,” Kumar said. “Effective policies are based on evidence. We need more rigorous statistical analysis to examine the causal relationship between anemia and education.

“This work ties into my larger research agenda, which explores the intersection of global health and poverty reduction. I want to use my academic research to support human dignity by helping to identify evidence-based health policies that will make a tangible difference in people’s lives.”

“I was shocked at how many households were above the new 200 ppm guideline,” said Gabriel Filippelli, a biochemist at Indiana University who led the new study. “I assumed it was going to be a more modest number. And results for the 100 ppm guideline are even worse.”

Remediating the roughly 29 million affected households using traditional “dig and dump” soil removal methods could cost upward of $1 trillion, the study calculated. The study was published in GeoHealth, an open-access AGU journal that publishes research investigating the intersection of human and planetary health for a sustainable future. Filippelli is the former editor-in-chief of GeoHealth.

National lead problem “nowhere near over”

Lead is a heavy metal that can accumulate in the human body, with toxic effects. In children, exposure to lead is associated with lower educational outcomes. In the United States, the burden of lead exposure has historically fallen on lower-income communities and communities of color because of redlining and other discriminatory practices. Lead pollution can come from aging water pipes, old paint, and remnant gasoline and industrial pollution, but today, most lead exposure are from contaminated soils and dust, even after lead-containing infrastructure was removed.

The Centers for Disease Control and Prevention first set a limit on the concentration of lead in blood in 1991 at 10 micrograms per deciliter, and it lowered that limit several times until reaching the current limit of 3.5 micrograms per deciliter. But the EPA’s soil lead screening level remained unchanged for more than 30 years until the January announcement. Some states had established their own lower guidelines; California has the lowest screening level, at 80 ppm.

The lag is likely due to “the immensity and ubiquity of the problem,” the study authors wrote. “The scale is astounding, and the nation’s lead and remediation efforts just became substantially more complicated.” That’s because once the EPA lowers a screening limit, they need to tell people what to do if their soils exceed it.

When the EPA lowered the screening level, Filippelli and his co-authors decided to make use of the database of 15,595 residential soil samples from the contiguous United States that they’d collected over the years to find out how many exceeded the new guideline.

Household health hazard

About 25% of the residential soil samples, collected from yards, gardens, alleys, and other residential spots, exceeded the new 200 ppm level, the study found. (Only 12% of samples had exceeded the older, 400 ppm level.) Extrapolating across the country, that equates to roughly 29 million households.

The EPA issued separate guidance for households with multiple sources of exposure, such as both lead-contaminated soil and lead pipes, setting the level in those situations at 100 ppm. In practice, that’s most urban households, Filippelli said. Forty percent of households exceed that limit, increasing the number of affected households to nearly 50 million, the study found.

Typically, contaminated soils are remediated with removal — colloquially, “dig and dump.” But the practice is costly and typically only used after an area is placed on the National Priority List for remediation, a process that can take years. To remediate all contaminated households with “dig and dump” would cost between $290 billion and $1.2 trillion, the authors calculated.

A cheaper option is “capping”: burying the contaminated soil with about a foot of soil or mulch. A geotechnical fabric barrier can also be installed. Most lead contamination is in the top 10 to 12 inches of soil, Filippelli said, so this simple method either covers up the problem or dilutes it to an acceptable level.

“Urban gardeners have been doing this forever anyway, with raised beds, because they’re intuitively concerned about the history of land use at their house,” Filippelli said.

And capping is quicker.

“A huge advantage of capping is speed. It immediately reduces exposure,” Filippelli said. “You’re not waiting two years on a list to have your yard remediated while your child is getting poisoned. It’s done in a weekend.“

Capping still requires time and effort; residents must find clean soil, transport it to their home and spread it out. But the health benefits likely outweigh those costs, Filippelli said.

Because capping has been done more informally, there’s still a lot to be learned about its lifespan and sustainability, Filippelli said. That’s where the research will go next.

Despite the “staggering” scale of the problem, “I’m really optimistic,” Filippelli said. “Lead is the most easily solvable problem that we have. We know where it is, and we know how to avoid it. It’s just a matter of taking action.”

Maps: https://www.mapmyenvironment.com/

Since 1958, Sweden has registered all cancer patients in the National Cancer Register. Swedish researchers have now used this register to study all cancer survivors who had cancer as a child, adolescent or adult to examine outcomes in later life. The results have been published in the scientific journal The Lancet Regional Health — Europe.

“If you’ve had cancer as a child or adolescent, you have an increased risk of almost all diagnoses in the future. This study lays the foundation for understanding why this is so and what decision-makers need to take into account when it comes to cancer care,” says Laila Hübbert, researcher at Linköping University and consultant at the Cardiology Clinic at Vrinnevi Hospital in Norrköping.

The study’s data spans 63 years. From this data, approximately 65,000 cancer patients under the age of 25 were compared with a control group of 313,000 individuals (a ratio of 1:5), where age, sex and housing situation were matched with the patient group. From other registers, the researchers retrieved information on morbidity, mortality and demography.

The researchers found that the cancer survivors were about three times more likely to develop cancer later in life, 1.23 times more likely to have cardiovascular disease and had a 1.41 times higher risk of accidents, poisoning and suicide.

At present, the healthcare system usually follows up cancer survivors five years after the end of treatment. In other words, you are usually considered healthy if the cancer has not returned after five years, and no further follow-up is planned. But the current study, and also previous ones, show that this is probably not enough.

“Cancer survivors carry with them a fragility for the rest of their lives that puts them at higher risk of new diseases. It’s mainly the chemotherapy and radiation treatment that increases the risk of cardiovascular disease. This means that patients shouldn’t be released prematurely without planned and ongoing follow-up. It’s important to identify these risk factors and diseases early,” says Laila Hübbert.

The researchers have also seen that socioeconomic factors play a major role in the risk of disease and death after cancer in young years. Thanks to a cross-check of registers, the researchers were able to see that the risk increases for those with a lower level of education, a foreign background, or who remain unmarried. At the same time, this study shows that the risk of disease and death after cancer in children and adolescents is the same regardless of where you live in Sweden.

Martin Singull is a professor of mathematical statistics and has worked closely with the clinics in order to analyse and combine the large amounts of data that come from many different sources.

“We have used proven statistical models. But it’s the complexity of the data that makes it challenging. It comes from different sources, and we also want to be able to pick out the information we want. That’s why we’ve also collaborated with computer scientist Robin Keskisärkkä, who has built the database,” says Martin Singull.

The next step for the researchers is to break down the results and probe into specific questions and understand why things look the way they do. This will include looking more at socioeconomic factors, cardiovascular disease linked to cancer, so-called cardio-oncology, and other forms of cancer.

“There aren’t really many countries that can carry out such a comprehensive survey. In Sweden, we have such fine comprehensive and high-quality national registers so it’s unique to be able to do this,” says Laila Hübbert.

And while most families have bedtime rituals to help their little ones ease into nighttime, many rely on strategies that may increase sleep challenges long term, according to the University of Michigan Health C.S. Mott Children’s Hospital National Poll on Children’s Health.

Overall, one in four parents describe getting their young child to bed as difficult — and these parents are less likely to have a bedtime routine, more likely to leave on a video or TV show, and more likely to stay with their child until they’re asleep.

“Our report reinforces the common struggle of getting young children to sleep. When this transition to bedtime becomes a nightly conflict, some parents may fall into habits that work in the moment but could set them up for more sleep issues down the road,” said Mott Poll co-director Sarah Clark, M.P.H.

“Establishing a consistent bedtime routine is crucial. When children don’t get enough rest, it can impact their physical development, emotional regulation and behavior.”

Nearly one in five parents say they have given their kids melatonin to help with sleep while a third stay in the room until their child completely dozes off, according to the nationally representative poll that includes responses from 781 parents of children ages one to six surveyed in February.

Nighttime worries interfere with sleep

Parents share common reasons behind bedtime struggles, with nearly a quarter saying their child’s sleep is often or occasionally delayed due to being worried or anxious.

A particular challenge, parents say, is when children don’t stay asleep. More than a third of parents say their child wakes up upset or crying, with more than 40% saying their child moves to their parents’ bed and about 30% saying children insist that the parent sleep in their room.

“Many young children go through stages when they become scared of the dark or worry that something bad might happen, causing them to delay bedtime or become distressed by parents leaving the room. Bad dreams or being awakened in the middle of the night can also disrupt sleep,” Clark said.

“Although this is a normal part of a child’s development, it can be frustrating when parents already feel tired themselves at the end of the day. Parents should find a balance between offering reassurance and comfort while maintaining some boundaries that help ensure everyone — both kids and adults — get adequate sleep.”

More findings from the report, plus Clark’s recommendations for helping young children fall and stay asleep:

Stick to a regular bedtime routine

Most parents polled report having a bedtime routine for their child, often including brushing teeth, reading bedtime stories and/or bathing. Less than half also say their child has a drink of water or snack, turns off devices, prays and talks about their day.

Other bedtime habits include holding a blanket or stuff animal or sucking a pacifier or fingers.

Not only does having a consistent bedtime routine help make the nighttime transition smoother, Clark says, it also provides one-on-one time, allowing the child to get their parent’s full attention.

“A predictable bedtime routine provides a sense of security and comfort and signals to the child that it’s time to slow down,” she said.

“Knowing what to expect next can reduce anxiety and help children feel safe and relaxed. Having this dedicated time with parents also promotes bonding and emotional connection, creating positive associations with bedtime.”

Nearly two-thirds of parents also said children staying up to play was a major factor in delaying sleep. Clark says, highlighting the need to wind down at least an hour before bed.

Promote an environment conducive to sleep

A little less than half of parents polled say their child sleeps in their own bedroom while less than a quarter share a bedroom with siblings or in the parents’ bedroom. One in 10 kids spend part the night in their own bedroom and part of the night with parents.

More than two-fifths of parents polled said noise from other rooms interfered with their child’s sleep.

“The sleep environment can have a major effect on a child’s sleep quality, including getting to sleep and staying asleep through the night,” Clark said.

“When possible, children should have their own bed in a room that is quiet, without a lot of noise from other family members.”

Many parents polled also use a nightlight or crack the bedroom door so the child isn’t in complete darkness, Clark says, but parents should make sure the light does not shine directly at the child’s face.

Some parents also play calming music or stories to help their child go to sleep, while others use a white noise machine or app. However, Clark cautions to keep white noise machines at no more than 50 decibels and placed at least seven feet from the child’s bed to prevent unintended damage to the child’s hearing.

Talk to a doctor before using aids like melatonin

Many types of melatonin products are advertised as being appropriate for children but these products have not undergone rigorous testing for safety and effectiveness, and their side effects and long term impact on a child’s growth and development are unknown, Clark says.

“Although melatonin is a natural hormone that regulates sleep-wake cycles and may be fine to use occasionally, parents shouldn’t rely on it as a primary sleep aid,” Clark said.

“Parents who are considering giving melatonin to their young child should consult with their pediatrician to discuss options and rule out other causes of sleep problems first.”

If using melatonin, parents should also start with the lowest dose possible.

In addition, it’s important to keep electronics such as tablets or televisions out of children’s bedroom, as the blue light emitted by many of these screens interferes with the natural production of melatonin.

Offer comfort but enforce boundaries

Parents can help ease little ones’ anxiety by allowing extra time to let them talk about their day, which might draw out specific worries and give parents a chance to provide compassion and reassurance, Clark said.

Rather than remaining in the room, parents can also offer to check on the child every few minutes, which acknowledges the child’s fears and offers a reassuring presence, but still maintains a calm sleep environment and promotes sleep independence.

“Families can incorporate comforting rituals to help transform nighttime fears into a calming experience,” Clark said.

Have a consistent approach when children wake up in the night

Some children are prone to vivid dreams or nightmares and may have difficulty getting back to sleep. Parents should decide on their approach to this situation and stick with it, Clark says, whether it’s taking the child back to bed or allowing them to stay in the parents’ room.

“Being consistent in carrying out that approach will help the child adjust and be more likely to return to sleep,” Clark said.

Ease into changes in sleep patterns, such as dropping naps

For young children, a major sleep-related transition is discontinuing daytime naps. In general, children ages one to two should get 11-14 hours of sleep with naps while the amount of recommended sleep decreases slightly from ages three to six.

If children are taking longer to fall asleep at nap time, resisting naps or suddenly having difficulty falling asleep at night or waking up earlier than usual in the morning, it may be time to drop the nap, Clark says.

“Parents may need to adjust sleep routines gradually to transition to changes to a child’s sleep patterns,” Clark said.

Other changes that can affect a child’s sleep include transitioning from a crib to a toddler bed, starting school, having a change in their daytime routine, or being outdoors for longer than usual.

Although some of these observations were made decades ago, the exact role of vitamin B6 in mental illness is still largely unclear. What is clear, however, is that an increased intake of vitamin B6 alone, for example in the form of dietary supplements, is insufficient to prevent or treat disorders of brain function.

Publication in eLife

A research team from Würzburg University Medicine has now discovered another way to increase vitamin B6 levels in cells more effectively: namely by specifically inhibiting its intracellular degradation. Antje Gohla, Professor of Biochemical Pharmacology at the Department of Pharmacology and Toxicology at Julius-Maximilians-Universität Würzburg (JMU), is responsible for this.

Other participants come from the Rudolf Virchow Center for Integrative and Translational Bioimaging at JMU, the Leibniz-Forschungsinstitut für Molekulare Pharmakologie-FMP Berlin and the Institute for Clinical Neurobiology at Würzburg University Hospital. The team has now published the results of their investigations in the scientific journal eLife.

Enzyme Blockade Improves Learning Ability

“We were already able to show in earlier studies that genetically switching off the vitamin B6-degrading enzyme pyridoxal phosphatase in mice improves the animals’ spatial learning and memory capacity,” explains Antje Gohla. In order to investigate whether such effects can also be achieved by pharmacological agents, the scientists have now looked for substances that bind and inhibit pyridoxal phosphatase.

With success: “In our experiments, we identified a natural substance that can inhibit pyridoxal phosphatase and thus slow down the degradation of vitamin B6,” explains the pharmacologist. The working group was actually able to increase vitamin B6 levels in nerve cells that are involved in learning and memory processes. The name of this natural substance: 7,8-Dihydroxyflavone.

New Approach for Drug Therapy

7,8-Dihydroxyflavone has already been described in numerous other scientific papers as a molecule that can improve learning and memory processes in disease models for mental disorders. The new knowledge of its effect as an inhibitor of pyridoxal phosphatase now opens up new explanations for the effectiveness of this substance. This could improve the mechanistic understanding of mental disorders and represent a new drug approach for the treatment of brain disorders, the scientists write in their study.

The team also considers it a great success that 7,8-Dihydroxyflavone has been identified as an inhibitor of pyridoxal phosphatase for the first time — after all, this class of enzymes is considered to be particularly challenging for drug development.

A Long Way to a Drug

When will people benefit from this discovery? “It’s too early to say,” explains Marian Brenner, a first author of the study. However, there is much to suggest that it could be beneficial to use vitamin B6 in combination with inhibitors of pyridoxal phosphatase for various mental disorders and neurodegenerative diseases.

In a next step, Gohla and her team now want to develop improved substances that inhibit this enzyme precisely and highly effectively. Such inhibitors could then be used to specifically test whether increasing cellular vitamin B6 levels is helpful in mental or neurodegenerative diseases.

Antimicrobial resistance of pathogens is a worldwide problem, and recognized by the WHO as one of the top global public health and development threats. There are two ways to fight this: by developing new drugs, or by preventing the development of resistance. ‘We know that temperature affects the mutation rate in bacteria’, explains Timo van Eldijk, co-first author of the paper. ‘What we wanted to find out was how the increase in temperature associated with fever influences the mutation rate towards antibiotic resistance.’

Three antibiotics

‘Most studies on resistance mutations were done by lowering the ambient temperature, and none, as far as we know, used a moderate increase above normal body temperature,’ Van Eldijk reports. Together with Master’s student Eleanor Sheridan, Van Eldijk cultured E. coli bacteria at 37 or 40 degrees Celsius, and subsequently exposed them to three different antibiotics to assess the effect. ‘Again, some previous human trials have looked at temperature and antibiotics, but in these studies the type of drug was not controlled.’ In their laboratory study, the team used three different antibiotics with different modes of action: ciprofloxacin, rifampicin, and ampicillin.

The results showed that for two of the drugs, ciprofloxacin and rifampicin, increased temperature led to an increase in the mutation rate towards resistance. However, the third drug, ampicillin, caused a decrease in the mutation rate towards resistance at fever temperatures. ‘To be certain of this result, we actually replicated the study with ampicillin in two different labs, at the University of Groningen and the University of Montpellier, and got the same result,’ says Van Eldijk.

Fever-suppressing drugs

The researchers hypothesized that a temperature dependence of the efficacy of ampicillin could explain this result, and confirmed this in an experiment. This explains why ampicillin resistance is less likely to arise at 40 degrees Celsius. ‘Our study shows that a very mild change in temperature can drastically change the mutation rate towards resistance to antimicrobials,’ concludes Van Eldijk. ‘This is interesting, as other parameters such as the growth rate do not seem to change.’

If the results are replicated in humans, this could open the way to tackling antimicrobial resistance by lowering the temperature with fever-suppressing drugs, or by giving patients with a fever antimicrobial drugs with higher efficacy at higher temperatures. The team concludes in the paper: ‘An optimized combination of antibiotics and fever suppression strategies may be a new weapon in the battle against antibiotic resistance.’

A paper just published in Scientific Reports- Nature by Sergio Dempsey as first author with colleagues Dr Soroush Safaei, Dr Gonzalo Maso Talou at Auckland Bioengineering Institute, along with co-author Dr Holdsworth (Mātai and FMHS & CBR at the University of Auckland), describes the new metric based on 4D flow MRI technology.

This innovative metric is particularly crucial because increased vascular pulsatility is linked to several brain conditions, including Alzheimer’s disease and other forms of dementia. By accurately measuring how pulsatility is transmitted in the brain, researchers can better understand the underlying mechanism of these diseases and potentiall guide development f new treatments.

Current MRI methods face limitations due to anatomical variations and measurement constraints. The new technique removes this issue by integrating thousands of measurements across all brain vessels, rather than looking one spot at a time as the traditional methods. This provides a richer metric representative of the entire brain.

“The ability to measure how pulsatility is transmitted through the brain’s arteries could revolutionise our approach to neurological diseases, and support research in vascular damage hypotheses” explained Mr. Dempsey. “Our method allows for a detailed assessment of the brain’s vascular health, which is often compromised in neurodegenerative disorders.”

The study also highlighted the potential to enhance clinical assessments and research on brain health. By integrating this new metric into routine diagnostic procedures, healthcare providers can offer more precise and personalised care plans for individuals at risk of or suffering from cognitive impairments.

In addition to its implications for patient care, the researchers have made their tools publicly available, integrating them into pre-existing open-source software. This enables scientists and clinicians worldwide to adopt the advanced methodology, fostering further research and collaboration in the field of neurology.

The research team is planning further studies to explore the applications of this technique in larger and more diverse populations, beginning with the “Digital Twin Dementia Study” starting at Mātai later this month. Results from the initial study of the metric also identified important sex differences in vascular dynamics which has initiated a new study focussing on sex-related dynamics which is anticipated to begin at Mātai and the Centre for Advanced MRI (CAMRI) in November.

Depending on the threat, innate immune sensors can assemble complexes such as inflammasomes or PANoptosomes. The inflammasome can be thought of like an emergency broadcast system that is activated quickly, while the PANoptosome is more like an emergency response unit that generally integrates more signals and components to respond to the threat. How innate immune sensors work — what triggers them to act — has been a mystery, which researchers have been chipping away at for decades.

Nucleotide-binding oligomerization domain-like receptors (NLRs) are a large family of important molecules involved in inflammatory signaling. They are generally thought to function as innate immune sensors that detect threats. However, the specific roles of several NLRs in sensing are not yet understood. Scientists at St. Jude conducted a large screen, testing a specific NLR, NLRC5, to see what threats activate it. Through their efforts, they discovered that depletion of nicotinamide adenine dinucleotide (NAD), a molecule essential in energy production, triggers NLRC5-mediated cell death through PANoptosis.

“One of the biggest questions in the fields of immunology and innate immunity is what the various members of the NLR family are sensing, and what their functions are,” said corresponding author Thirumala-Devi Kanneganti, PhD, St. Jude Department of Immunology vice chair. “NLRC5 was an enigmatic molecule, but now we have the answer — it is acting as an innate immune sensor and cell death regulator, driving inflammatory cell death, PANoptosis, by forming a complex.”

Identifying the NLRC5 trigger

Scientists in the Kanneganti lab conducted a rigorous screen to get to the bottom of what threats trigger NLRC5. This included looking at pathogens such as bacteria and viruses, as well as pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) that can be released by or mimic an infection or the cause of an injury or illness, as well as other danger signals such as cytokines (immune signaling molecules).

The researchers also looked at heme, the component of hemoglobin responsible for carrying oxygen. Infections or disease can cause red blood cells to rupture in a process called hemolysis. This releases hemoglobin into the bloodstream. When hemoglobin breaks down into its components, it releases free heme, which is known to cause significant inflammation and organ damage. The researchers tested many different combinations of pathogens, PAMPs and DAMPs to see if NLRC5 was required for a response.

“Among all the combinations we tested, we identified that the combination of heme plus PAMPs or cytokines specifically induces NLRC5-dependent inflammatory cell death, PANoptosis,” said co-first author Balamurugan Sundaram, PhD, St. Jude Department of Immunology. “Our results showed for the first time that NLRC5 is central to responses to hemolysis, which can occur during infections, inflammatory diseases and cancers.”

Energy depletion triggers NLRC5 function

Upon identifying the heme-containing PAMP, DAMP and cytokine combinations that trigger NLRC5-dependent inflammatory cell death, the researchers further investigated how NLRC5 is regulated. They found that NAD levels drive NLRC5 protein expression. If NAD is depleted, that sounds an alarm that there is a threat the immune system should recognize. The researchers found that depletion of NAD is sensed by NLRC5, triggering PANoptosis.

“By supplementing with the NAD precursor, nicotinamide, we reduced NLRC5 protein expression and PANoptosis,” said co-first author Nagakannan Pandian, PhD, St. Jude Department of Immunology. “Therapeutically, nicotinamide has been widely studied as a nutrient supplement, and our findings suggest it could be helpful in treating inflammatory diseases.”

The researchers also discovered that NLRC5 is in an NLR network with NLRP12, which come together with other cell death molecules and form an NLRC5-PANoptosome complex that triggers inflammatory cell death. The finding builds on previous research by the Kanneganti lab showcasing the role of NLRP12 in PANoptosis.

A promising target for therapeutic development

NLRs are associated with diseases related to infection, inflammation, cancers and aging. This makes them intriguing targets for the development of novel therapeutics. The work of the Kanneganti lab shows that deleting Nlrc5 can provide protection against inflammatory cell death through PANoptosis and prevent disease pathology in hemolytic and inflammatory disease models, making NLRC5 an exciting therapeutic prospect.

“The fundamental knowledge that we have gained into how innate immune sensing works can be translated to numerous diseases and conditions,” Kanneganti said. “Aging, infectious disease, inflammatory disorders — things for which there are no targeted therapies, this could be an option.”

Authors and funding

The study’s other authors are Emily Alonzo, Department of Research and Development at Cell Signaling Technology; and Hee Jin Kim, Hadia Abdelaal, Omkar Indari, Roman Sarkar, Rebecca Tweedell, Jonathan Klein, Shondra Pruett-Miller and Peter Vogel, all of St. Jude, and Raghvendra Mall, formerly of St. Jude now of the Technology Innovation Institute, Abu Dhabi.

The study was supported by grants from the National Institutes of Health (AI101935, AI124346, AI160179, AR056296 and CA253095) and ALSAC, the fundraising and awareness organization of St. Jude.

Male reproductive disorders are a growing issue due to the global decrease in sperm count and quality. Concerningly, chemicals like DEHP, which can be found in food storage containers, pharmaceuticals, and building materials, have been found to be one of the contributing factors. The toxicity of DEHP is due to its ability to mimic the hormones in our bodies, leading to long-term effects on health.

“The scientific community is aware of the fact that the current generation of men produce half as much sperm compared to the previous one,” said CheMyong Jay Ko (EIRH), a professor of veterinary medicine. “Although it is shocking, not much attention is paid to understanding the causes.”

The researchers used the Barker hypothesis as a guiding principle for their study. Proposed by the British physician and epidemiologist David Barker, the hypothesis argued that the nine months in utero are one of the most critical periods in a person’s life and can shape their future health trajectories.

“The Barker hypothesis primarily focuses on nutrition and we wanted to test whether the mother’s diet could change the health of the next generation,” Ko said. “Additionally, unlike the previous generation, we are constantly exposed to chemicals like DEHP, which can alter how our bodies function. We wanted to ask whether the exposure to both these factors can cause growing babies to have lesser functioning reproductive systems.”

In the past, both the Ko lab and other research groups have shown that prenatal exposure to DEHP decreases testosterone levels and causes fertility defects in male mice. Additionally, scientists have shown that maternal high-fat diet can also decrease sperm counts in male offspring. However, the effects of both together had not been studied.

The researchers used four groups of pregnant mice; one was a control and the other three were either exposed to DEHP, or a high-fat diet, or a combination of the two. They then followed each litter, which contained an average of 6 male and 6 female pups.

“Surprisingly, we found that a high-fat diet had a more damaging effect on the male reproductive systems compared to DEHP alone and the pups born from mothers who had been treated with both had the worst outcomes,” Ko said.

The researchers measured the weight of the body and different reproductive organs in pups during different stages of growth and puberty. They found that although the body weight of pups born from moms on a high-fat diet alone or in combination with DEHP was higher than the other pups, the weight of the reproductive organs was lower. They also found that these mice produced less sperm and had lower testosterone levels. By staining the tissues, the researchers found that the reproductive organs had abnormal cells, which were contributing to the gonadal dysfunction.

“In our studies, we used these mice as a model. Although we need to confirm these results in humans, this study should serve as a warning to our generation that we need to be careful about our environment and diet during pregnancy,” Ko said.

In the study, which appears June 14 in Nature Medicine, the researchers showed that they could train a machine learning model, a type of artificial intelligence platform, to detect circulating tumor DNA (ctDNA) based on DNA sequencing data from patient blood tests, with very high sensitivity and accuracy. They made successful demonstrations of the technology in patients with lung cancer, melanoma, breast cancer, colorectal cancer and precancerous colorectal polyps.

“We were able to achieve a remarkable signal-to-noise enhancement, and this enabled us, for example, to detect cancer recurrence months or even years before standard clinical methods did so,” said study co-corresponding author Dr. Dan Landau, a professor of medicine in the division of hematology and medical oncology at Weill Cornell Medicine and a core faculty member of the New York Genome Center.

The study’s co-first author, and co-corresponding author, was Dr. Adam Widman, a postdoctoral fellow in the Landau Lab who is also a breast cancer oncologist at MSK. The other co-first authors were Minita Shah of NYGC, Dr. Amanda Frydendahl of Aarhus University, and Daniel Halmos of NYGC and Weill Cornell Medicine.

Liquid biopsy technology has been slow to realize its great promise. Most approaches to date have targeted relatively small sets of cancer-associated mutations, which are often too sparsely present in the blood to be detected reliably, resulting in cancer recurrences that go undetected.

Several years ago, Dr. Landau and colleagues developed an alternative approach based on whole-genome-sequencing of DNA in blood samples. They showed that they could gather much more “signal” this way, enabling more sensitive — and logistically simpler — detection of tumor DNA. Since then, this approach has been increasingly adopted by liquid biopsy developers.

In the new study, the researchers leapt ahead again, using an advanced machine learning strategy (similar to that of ChatGPT and other popular AI applications) to detect subtle patterns in sequencing data — in particular, to distinguish patterns suggestive of cancer from those suggestive of sequencing errors and other “noise.”

In one test, the researchers trained their system, which they call MRD-EDGE, to recognize patient-specific tumor mutations in 15 colorectal cancer patients. Following the patients’ surgery and chemotherapy, the system predicted from blood data that nine had residual cancer. Five of these patients were found — months later, with less sensitive methods — to have cancer recurrence. But there were no false negatives: none of the patients MRD-EDGE deemed free of tumor DNA experienced recurrence during the study window.

MRD-EDGE showed similar sensitivity in studies of early-stage lung cancer and triple-negative breast cancer patients, with early detection of all but one recurrence, and tracking of tumor status during treatment.

The researchers demonstrated that MRD-EDGE can detect even mutant DNA from precancerous colorectal adenomas — the polyps from which colorectal tumors develop.

“It had not been clear that these polyps shed detectable ctDNA, so this is a significant advance that could guide future strategies aimed at detecting premalignant lesions,” said Dr. Landau, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and a hematologist/oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.

Lastly, the researchers showed that even without pre-training on sequencing data from patients’ tumors, MRD-EDGE could detect responses to immunotherapy in melanoma and lung cancer patients — weeks before detection with standard X-ray-based imaging.

“On the whole, MRD-EDGE addresses a big need, and we’re excited about its potential and working with industry partners to try to deliver it to patients,” Dr. Landau said.

The research in this story was supported in part by the National Cancer Institute, part of the National Institutes of Health, through grant number R01 CA266619.

That’s in part because human breast milk contains a unique blend of approximately 200 prebiotic sugar molecules that help prevent disease and support the growth of healthy gut bacteria. However, most of these sugars remain difficult, if not impossible, to manufacture.

New research led by scientists at the University of California, Berkeley, and the University of California, Davis, shows how genetically engineered plants may help close this gap.

In a new study published today in the journal Nature Food, the study team reprogrammed plants’ sugar-making machinery to produce a diverse array of these human milk sugars, also called human milk oligosaccharides. The findings could lead to healthier and more affordable formula for babies, or more nutritious non-dairy plant milk for adults.

“Plants are these phenomenal organisms that take sunlight and carbon dioxide from our atmosphere and use them to make sugars. And they don’t just make one sugar — they make a whole diversity of simple and complex sugars,” said study senior author Patrick Shih, an assistant professor of plant and microbial biology and an investigator at UC Berkeley’s Innovative Genomics Institute. “We thought, since plants already have this underlying sugar metabolism, why don’t we try rerouting it to make human milk oligosaccharides?”

All complex sugars — including human milk oligosaccharides — are made from building blocks of simple sugars, called monosaccharides, which can be linked together to form a vast array of chains and branched chains. What makes human milk oligosaccharides unique are the specific set of linkages, or rules, for connecting simple sugars together that are found in these molecules.

To convince plants to make human milk oligosaccharides, study first author Collin Barnum engineered the genes responsible for the enzymes that make these specific linkages. Working with Daniela Barile, David Mills and Carlito Lebrilla at UC Davis, he then introduced the genes into the Nicotiana benthamiana plant, a close relative of tobacco.

The genetically modified plants produced 11 known human milk oligosaccharides, along with a variety of other complex sugars with similar linkage patterns.

“We made all three major groups of human milk oligosaccharides,” Shih said. “To my knowledge, no one has ever demonstrated that you could make all three of these groups simultaneously in a single organism.“

Barnum then worked to create a stable line of N. benthamiana plants that were optimized to produce a single human milk oligosaccharide called LNFP1.

“LNFP1 is a five-monosaccharide-long human milk oligosaccharide that is supposed to be really beneficial, but so far cannot be made at scale using traditional methods of microbial fermentation,” said Barnum, who completed the work as a graduate student at UC Davis. “We thought that if we could start making these larger, more complex human milk oligosaccharides, we could solve a problem that that industry currently can’t solve.”

Currently, a small handful of human milk oligosaccharides can be manufactured using engineered E. coli bacteria. However, isolating the beneficial molecules from other toxic byproducts is a costly process, and only a limited number of baby formulas include these sugars in their mixtures.

As part of the study, Shih and Barnum worked with collaborator Minliang Yang at North Carolina State University to estimate the cost of producing human milk oligosaccharides from plants at an industrial scale and found that it would likely be cheaper than using microbial platforms.

“Imagine being able to make all the human milk oligosaccharides in a single plant. Then you could just grind up that plant, extract all the oligosaccharides simultaneously and add that directly into infant formula,” Shih said. “There would be a lot of challenges in implementation and commercialization, but this is the big goal that we’re trying to move toward.”

Additional authors include Bruna Paviani, Garret Couture, Chad Masarweh, Ye Chen, Yu-Ping Huang, David A. Mills, Carlito B. Lebrilla and Daniela Barile of UC Davis; Kasey Markel of UC Berkeley; and Minliang Yang of North Carolina State University.

This work was supported in part by the National Institutes of Health (NIGMS T32 Training Program), the U.S. Department of Energy and the National Center for Complementary and Integrative Health (R00AT009573)

If animators wish to give nostalgia more consideration in a future film, new data from researchers at the USC Dornsife College of Letters, Arts and Sciences could guide them in determining how to animate this sort of “mixed emotion.”

What’s new: In a recent study, the USC Dornsife neuroscientists found that brains display distinct neural activity when experiencing emotions such as bittersweetness.

• The advance could help solve a longstanding scientific debate: whether “mixed emotions” arise from unique activity in the brain, or if we’re just flip-flopping back and forth between positive and negative feelings.

Why it matters: Mixed emotions are a common experience, but they’ve been understudied scientifically for several reasons.

• Emotions are often thought to exist only on a spectrum from negative to positive.
• It’s easier to study one feeling at a time.

In his words: “It’s hard to evoke these complex emotions in a realistic way inside the lab,” says Jonas Kaplan, associate professor (research) of psychology and co-author of the study, published in the journal Cerebral Cortex in April.

Key findings:

• Mixed feelings elicited unique neural activity in the amygdala and nucleus accumbens areas of the brain.
• This activity was different than the brain activity seen when a subject reported a purely positive or negative emotion.

What else? The researchers could predict when someone was going to shift emotions.

• Particular regions of the brain, like the insular cortex, displayed significant changes as subjects reported an emotional transition.

“Not only did we find brain activity that was correlated with mixed emotions, but we found that it held steady over time,” says Anthony Vaccaro, lead author of the study and a postdoctoral researcher at the Neuroendocrinology of Social Ties Lab at USC Dornsife. Vaccaro recently completed his PhD in psychology at USC Dornsife. “You’re not ping-ponging between negative and positive. It’s a very unique, mixed emotion over a long period.”

Graphs show consistent brain activity during positive, negative and mixed emotions, demonstrating that mixed emotions are distinct from other feelings. (Image: Jonas Kaplan.)

How they did it: As study subjects watched a poignant animated short film, researchers monitored their brain activity using a magnetic resonance imaging (MRI) machine.· The researchers chose One Small Step by TAIKO Studios for its ability to evoke simultaneous happy and sad feelings. · After the first viewing, participants rewatched the video without MRI and indicated when they experienced positive, negative or mixed emotions. The researchers then compared these reports with the MRI imaging results.

Opportunity: The study lays out practical groundwork for future scientific research into this understudied phenomenon, research that Kaplan says would also be beneficial for understanding human psychology.

• “There’s a certain sophistication that’s required to sit with a mixed emotion and to allow yourself to feel positive and negative at the same time. Looking into that more, exploring the benefits of being able to accept positive and negativity at the same time within yourself, is something we think is worth study,” he says.

What’s next: Kaplan and Vaccaro will next look at how emotional reactions fluctuate in group settings, such as watching a movie together in a cinema.

The study does not prove that delivery of a low-birth-weight infant causes memory and thinking problems. It only shows an association.

“Previous research has shown that people who have had a low-birth-weight delivery have a higher risk of cardiovascular disease and high blood pressure,” said study author Diana C. Soria-Contreras, PhD, of the Harvard T.H. Chan School of Public Health in Boston, Massachusetts. “Our study found that a history of having a child with a low birth weight may also be a marker of poorer cognition later in life.”

The study involved 15,323 female participants with an average age of 62 at completion of thinking and memory tests. All the participants had at least one birth. Of the total participants, 1,224 people, or 8%, had a history of low-birth-weight delivery. Low birth weight was defined as less than 5.5 pounds for pregnancies lasting more than 20 weeks.

Participants completed a questionnaire about their pregnancy complications, birth outcomes, birth weight and other information.

They also completed a series of thinking and memory tests.

Researchers then combined average scores of the two tests of participants’ memory and ability to quickly and accurately respond to a situation as well as the two tests of learning and working memory. Higher scores indicated better memory and thinking. On average, the difference in scores between those with and without a low-birth-weight delivery was -0.06 for speed and attention tests and -0.05 for learning and working memory. This is comparable to the difference associated with one to two additional years of age in this population.

The results were similar after researchers adjusted for factors that could affect both birth weight and cognitive function, such as age, smoking status and high blood pressure. The results were also similar when researchers did not include people with premature deliveries, pregnancies with twins or other multiples or those affected by pregnancy-related high blood pressure disorders.

In addition, they found that the more low-birth-weight deliveries people had, the lower their scores were.

“Future research is needed to confirm our findings and to look at whether screening women with a history of low-birth-weight deliveries for cognitive issues and taking steps to promote their brain health could help prevent or delay cognitive impairment and dementia later on,” Soria-Contreras said.

A limitation of the study is that most of the participants were non-Hispanic white people, so results may not be generalizable to other populations.

The study was supported by the National Institute of Mental Health, the National Institute of Environmental Health Sciences, the National Institute on Aging and the Office of Research on Women’s Health.

The custom-built robot was used to treat wet neovascular age-related macular degeneration (AMD), administering a one-off, minimally invasive dose of radiation, followed by patients’ routine treatment with injections into their eye.

In the landmark trial, published today in The Lancet, it was found that patients then needed fewer injections to effectively control the disease, potentially saving around 1.8 million injections per year around the world.

Wet AMD is a debilitating eye disease, where abnormal new blood vessels grow into the macula, the light sensing-layer of cells inside the back of the eyeball. The vessels then start to leak blood and fluid, typically causing a rapid, permanent and severe loss of sight.

Globally, around 196 million people have AMD and the Royal College of Ophthalmologists estimates that the disease affects more than 700,000 people in the UK. The number of people with AMD is expected to increase 60% by 2035, due to the country’s ageing population.

Wet AMD is currently treated with regular injections into the eye. Initially, treatment substantially improves a patient’s vision. But, because the injections don’t cure the disease, fluid will eventually start to build up again in the macula, and patients will require long-term, repeated injections. Most people require an injection around every 1-3 months, and eye injections, costing between £500 and £800 per injection, have become one of the most common NHS procedures.

The new treatment can be targeted far better than existing methods, aiming three beams of highly focused radiation into the diseased eye. Scientists found that patients having robotic radiotherapy required fewer injections to control their disease compared to standard treatment.

The study found that the robotically controlled device saves the NHS £565 for each patient treated over the first two years, as it results in fewer injections.

The study lead and first author on the paper, Professor Timothy Jackson, King’s College London and Consultant Ophthalmic Surgeon at King’s College Hospital said: “Research has previously tried to find a better way to target radiotherapy to the macula, such as by repurposing devices used to treat brain tumours. But so far nothing has been sufficiently precise to target macular disease that may be less than 1 mm across.

“With this purpose-built robotic system, we can be incredibly precise, using overlapping beams of radiation to treat a very small lesion in the back of the eye.

“Patients generally accept that they need to have eye injections to help preserve their vision, but frequent hospital attendance and repeated eye injections isn’t something they enjoy. By better stabilising the disease and reducing its activity, the new treatment could reduce the number of injections people need by about a quarter. Hopefully, this discovery will reduce the burden of treatment that patients have to endure.”

Dr Helen Dakin, University Research Lecturer at the University of Oxford said: “We found that the savings from giving fewer injections are larger than the cost of robot-controlled radiotherapy. This new treatment can therefore save the NHS money that can be used to treat other patients, while controlling patients’ AMD just as well as standard care.”

The research was jointly funded by the National Institute for Health and Care Research (NIHR) and the Medical Research Council (MRC) and recruited 411 participants across 30 NHS hospitals. A Lancet-commissioned commentary that accompanied the article described it as a “landmark trial.”

This study was led by researchers from King’s College London and doctors at King’s College Hospital NHS Foundation Trust, in collaboration with the University of Oxford, the University of Bristol and Queen’s University in Belfast.

Understanding what contributes to patients’ inactivity is the focus of a world first study from the University of South Australia. Here, researchers have found that people with knee OA unconsciously believe that activity may be dangerous to their condition, despite medical advice telling them otherwise.

The study found that of those surveyed, 69% of people with knee pain had stronger implicit (unconscious) beliefs that exercise was dangerous than the average person without pain.

It’s an interesting finding that not only highlights the conflicted nature of pain and exercise, but also that what people say and what people think, deep down, may be entirely different things.

Lead researcher, and UniSA PhD candidate based at SAHMRI, Brian Pulling, says the research provides valuable insights for clinicians treating people with knee OA.

“Research shows that physical activity is good for people with knee OA, but most people with this condition do not move enough to support joint or general health,” Pulling says.

“To understand why people with OA might not be active, research studies typically use questionnaires to assess fear of moving. But unfortunately, questionnaires are limited — what we feel deep down (and how our system naturally reacts to something that is threatening) may be different to what we report. And we still know that many people are avoiding exercise, so we wanted to know why.”

To assess this, the researchers developed a tool that can detect and evaluate people’s implicit beliefs about exercise; that is, whether they unconsciously think activity is dangerous for their condition.

“We found that that even among those who said they were not fearful about exercise, they held unconscious beliefs that movement was dangerous,” Pulling says.

“Our research shows that people have complicated beliefs about exercise, and that they sometimes say one thing if asked directly yet hold a completely different implicit belief.

“People are not aware that what they say doesn’t match what they choose on the new task; they are not misrepresenting their beliefs.

“This research suggests that to fully understand how someone feels about an activity, we must go beyond just asking directly, because their implicit beliefs can sometimes be a better predictor of actual behaviour than what people report. That’s where our tool is useful.”

The online implicit association test presents a series of words and images to which a participant must quickly associate with being either safe or dangerous. The tool intentionally promotes instant responses to avoid deliberation and other influencing factors (such as responding how they think they should respond).

Associate Professor Tasha Stanton says that the new tool has the potential to identify a group of people who may have challenges increasing their activity levels and undertaking exercise.

“What people say and what people do are often two different things, Assoc Prof Stanton says.

“Having access to more accurate and insightful information will help health professionals better support their patients to engage with activity and exercise. It may also open opportunities for pain science education, exposure-based therapy, or cognitive functional therapy…things that would not usually be considered for someone who said that they were not scared to exercise.”

Researchers are now looking to see if implicit beliefs are directly associated with behaviour and are asking for people to complete the Implicit Association Test (takes seven minutes). At the end of the test participants are given their results in comparison to the rest of the population.

To take the test, please click here: https://unisasurveys.qualtrics.com/jfe/form/SV_0OZKUqzBNtiKGF0

For people without severe visual impairments, sight is the most vital sense. Yet, the information our eyes provide isn’t always a faithful depiction of reality. One fascinating phenomenon that highlights this is the visual saltation illusion. When a series of light points flicker rapidly in the peripheral vision, we may mistake their true positions, thinking the flash is jumping from its original location to another spot. It appears as if a rabbit is jumping from one spot to another, which is why it’s also called the “visual rabbit illusion.”

In traditional experiments, this illusion is studied using three flashes that appear in two locations: the first two flashes at the exact same location on the left and the third flash on the right. Under these conditions, an illusion is created as the second flash is perceived roughly halfway between the two points.

But is this the only condition for the illusion to occur? Researchers at Kyushu University decided to experiment by changing the location of the second flash to see if that impacted the illusion. They fixed the first and third flashes in the peripheral vision, modified the flash duration and intervals to ensure the illusion occurred, and then conducted three experiments.

Their findings indicate that participants misperceived the second flash, placing it near the midpoint between the first and last flash. This illusion occurred regardless of whether the second flash was at the same location as the third or even further to the right of the third flash. “It’s like a rabbit hopping back to the middle after the brain processes it,” comments Sheryl Anne Manaligod de Jesus, the first author of the study and a doctoral student at Kyushu University’s Graduate School of Design.

Additionally, the researchers found that the flashes do not need to be presented in a line for the illusion to happen. Even when the second flash appeared above or below the midpoint, its perceived location still tended to be near the center. This happens because when our visual system receives flashes in rapid succession, the brain processes them as a whole, leading to a perceptual reorganization of the flashes into a simpler, more coherent pattern.

One way to further investigate the visual saltation illusion’s mechanisms is by providing the experimental results to artificial intelligence. Comparing human and AI responses could indicate whether our visual pathways are simpler or more complex than we imagine.

What we “see” is not solely dependent on our vision, it is often a construction of our brain, influenced by attention and memory. This questions the reliability of eyewitness testimony. “Our brain sometimes uses future events to interpret the past,” says de Jesus, “This is called postdiction, meaning that how we perceive a past event, like the second flash, is influenced by what happens afterward. This results in the fascinating illusion of the flash appearing in a place, where it never really was.”

As the study suggests, our peripheral vision, especially with fast-moving objects, is not completely reliable. Further research into visual saltation illusions is needed to help us better understand visual processing and potentially improve our peripheral vision. After studying how position changes affected the perceived “rabbit,” the team’s next step is to explore how attention impacts the illusion.

Where hops the rabbit? Or do we see a rabbit or a duck? How much does our brain mislead our sense of the visual world? Despite needing more research to fully understand these illusions, their power to enrich our lives with unique and enjoyable experiences is clear. As Professor Hiroyuki Ito, the supervisor of de Jesus and the second author from Kyushu University’s Faculty of Design, remarks, “The most important thing is to enjoy the illusions.”

One of the most common reasons for bypassing the COVID vaccine is concern about side effects like tiredness, muscle and joint pain, chills, headache, fever, nausea and feeling generally unwell. But a new study, led by UC San Francisco, has found that the symptoms indicate a robust immune response that is likely to lessen the chances of infection.

The study, which appears online June 10 in Annals of Internal Medicine, is based on symptom reports and antibody responses from 363 people, who had the Pfizer-BioNTech or Moderna mRNA vaccines when they were first introduced.

After the second dose of the vaccine, the researchers found that those with seven or more symptoms had nearly double the antibody levels of those who did not have symptoms. The participants were mainly in their forties to sixties and had not had the virus.

About 40% of the people in the study also wore a device to monitor their temperature, breathing and heart rate. The researchers found that those whose skin temperature increased by 1 degree Celsius after the second dose had three times the antibody levels six months later, compared to those whose temperature did not increase.

An absence of side effects does not mean the vaccine is not working

“Generally, we found that the higher the number of side effects, the higher the level of antibodies,” said first author Ethan Dutcher, MD, PhD, a postdoctoral researcher in the UCSF Department of Psychiatry and Behavioral Sciences, and the Weill Institute for Neurosciences. “But this wasn’t a hard rule: some people without side effects had better antibodies than some people with side effects.”

As the virus has evolved and fatality rates have fallen, many people are underestimating its impact. “The toll of COVID is still high for some — sickness, lost work, lasting fatigue and the dreaded long COVID,” said co-senior author Elissa Epel, PhD, a vice chair in the UCSF Department of Psychiatry and Behavioral Sciences. “While the symptoms from vaccination can be very unpleasant, it’s important to remember that they don’t come close to the disease’s potential complications,” she said.

“With COVID-19 vaccines likely here to stay, identifying what predicts a strong antibody response will remain important,” said co-senior author Aric Prather, PhD, professor in the UCSF Department of Psychiatry and Behavioral Sciences.

The latest recommendations from the Centers for Disease Control and Prevention are that everyone 6 months and older should receive the updated vaccine, and those 65 and older should receive an additional dose.

Co-Authors: Ashley Mason, PhD, and Frederick Hecht, MD, of UCSF; James E. Robinson, MD, of Tulane University; and Stacy Drury, MD, PhD, of Tulane University and Boston Children’s Hospital.

Funding: National Institutes of Health (R24AG048024, 5U24AG066528 and U54CA260581).

Disclosures: Epel is on the scientific advisory boards of Meru Health and Oura Health. Mason has receiving consultancy fees from Oura Health. Prather is an advisor to NeuroGeneces and L-New Co.

How many times have you made a “to do” list, and although the most important task is at the top, you seem to be working your way up from the bottom or distracted by something else entirely? While we might chide ourselves for procrastinating, sometimes the more we try to overcome it, the more stressed we feel and the cycle continues. That is how it was for graduate student Saya Kashiwakura from the Graduate School of Arts and Sciences at the University of Tokyo, so she decided to investigate why.

“I have struggled with procrastination since childhood. I would clean my room when I needed to study for a test and prioritize aikido practice over my postgraduate research. This habit of putting off important tasks has been a constant challenge,” said Kashiwakura. “I wanted to change my behavior, as I realized that I was not confronting the future impact of my actions.”

This inspired Kashiwakura to examine the relationship between procrastination and the procrastinator’s perspective on time, particularly their view of the future. When she began researching procrastination, she was surprised to discover that many more people suffer from it than she had imagined and found it reassuring her problems were not unique.

Previous research has shown that a feature of procrastination is disregard for the future or difficulty linking present actions with future outcomes. However, the reasons for this have been unclear. Kashiwakura and co-author Professor Kazuo Hiraki, also from UTokyo, proposed that it might be because severe procrastinators have a more pessimistic outlook. 

The researchers surveyed 296 participants in Japan in their 20s for their views on stress and well-being, and importantly how these changed over time. This included asking about their experiences from 10 years in the past through to the present, and their expectations for 10 years in the future. From the results, participants were clustered into one of four groups (for example, if they thought their situation would improve or would stay the same), and then each group was divided into severe, middle and low procrastinators. 

“Our research showed that optimistic people — those who believe that stress does not increase as we move into the future — are less likely to have severe procrastination habits,” explained Kashiwakura. “This finding helped me adopt a more light-hearted perspective on the future, leading to a more direct view and reduced procrastination.” 

It was not only the level of stress people experienced, but how their perception of it changed over the 20-year time period discussed, which influenced their procrastination habits. Surprisingly, a relationship wasn’t found between procrastination and negative views on well-being, such as one’s attitude towards oneself, or not yet finding purpose and goals in life.

Using these results, the team wants to develop ways to help people nurture a more optimistic mindset and overcome procrastination. “We hope our findings will be particularly useful in the education sector. We believe that students will achieve better outcomes and experience greater well-being when they can comprehend their procrastination tendencies scientifically, and actively work on improving them, rather than blaming themselves,” said Kashiwakura. 

“Thoughts can change with just a few minutes of watching a video or be shaped by years of accumulation. Our next step is to investigate which approach is appropriate this time, and how we can develop the ‘right’ mindset to lead a happier and more fulfilling life.”

######

Paper Title

Saya Kashiwakura and Kazuo Hiraki. Future optimism group based on the chronological stress view is less likely to be severe procrastinators. Scientific Reports. 30 May 2024. DOI: 10.1038/s41598-024-61277-y

Useful Links:

Graduate School of Arts and Sciences: https://www.c.u-tokyo.ac.jp/eng_site/info/about/education/GSAS/ 

Funding:

This research was funded by CREST of JST, grant number JPMJCR18A4 and supported by JST [Moonshot R&D][Grant Number JPMJMS2293-04].

Competing interests

None.

Research Contact:

Ms. Saya Kashiwakura

Graduate School of Arts and Sciences

The University of Tokyo, 3-8-1 Komaba,

Meguro-ku, Tokyo, 153-8902, Japan

Email: [email protected] 

Press contact:
Mrs. Nicola Burghall (she/her)
Public Relations Group, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, Japan
[email protected]

About the University of Tokyo

The University of Tokyo is Japan’s leading university and one of the world’s top research universities. The vast research output of some 6,000 researchers is published in the world’s top journals across the arts and sciences. Our vibrant student body of around 15,000 undergraduate and 15,000 graduate students includes over 4,000 international students. Find out more at www.u-tokyo.ac.jp/en/ or follow us on X at @UTokyo_News_en.

The study results, published June 5 in The EMBO Journal, shed new light, researchers say, on the way the altered mitochondrial membranes found in people with metabolic diseases such as Barth syndrome, a rare genetic disorder that weakens the heart, fail to enable cellular power production.

Metabolism is a set of biochemical reactions central to making energy to fuel life and to getting rid of substances a body no longer needs. Metabolic diseases include forms of high cholesterol that run in families. Approximately one in three adults have some form of a metabolic syndrome, according to the National Heart, Lung, and Blood Institute.

Building on previous research, the Johns Hopkins scientists sought to better understand the interaction of two components in the mitochondrial membrane: cardiolipin, a fatty compound, or lipid, and proteins that transport the building blocks of adenosine triphosphate, or ATP, an energy molecule made by the mitochondria that fuels cell metabolism.

“Down the line, a better understanding of protein-lipid interactions could help researchers find new therapeutic targets for a wide range of metabolic diseases, including Barth syndrome,” says senior author Steven Claypool, Ph.D., professor of physiology at the Johns Hopkins University School of Medicine.

He says previous studies suggested it’s likely that protein-lipid interactions in mitochondrial membranes play an important role in regulating mitochondria’s powerhouse activities.

The researchers conducted their experiments in samples of yeast with mutations, or alterations, in a mitochondrial membrane protein called AAC and samples of human cells that modeled a person with a mutation of the protein ANT1 who was diagnosed with metabolic disease, symptoms of which include weakness in the heart and skeletal muscles, exercise intolerance and hyperlactatemia, or elevated lactate levels in the blood.

The protein in yeast, AAC, is the equivalent of ANT in humans, Claypool says.

Looking at three areas where cardiolipin binds to the AAC proteins in yeast, Claypool and his colleagues found that when they introduced mutations into AAC2 to disrupt these interactions, cardiolipin could no longer bond to the protein, which weakened its structure and lowered its function.

Similarly, in the cell model of the person with mutations in ANT1, the protein’s structure was weakened, limiting its ability to transport ATP across the mitochondrial membrane.

“These findings indicate that when the interaction between cardiolipin and proteins break down, the entire process that makes mitochondria our powerhouse is disrupted,” says first author Nanami Senoo, Ph.D., a postdoctoral fellow in Claypool’s lab.

Claypool says few studies have detailed individual protein-lipid interactions, and many more experiments will be needed to “understand the full complement of mechanisms and roles that these interactions have in the membrane.”

Mitochondrial membranes contain a lot of proteins, many of which associate with lipids.

“This discovery opens up new possibilities for understanding the complexities of how our cells produce energy,” Claypool says. “In the future, we plan to explore how other protein-lipid interactions contribute to energy production.”

Other scientists who contributed to the study are Matthew G. Baile, Oluwaseun B. Ogunbona, James A. Saba, Teona Munteanu, Yllka Valdez, Kevin Whited and Macie S. Sheridan of Johns Hopkins; Dinesh K. Chinthapalli, Bodhisattwa Saha, Abraham O. Oluwole, Dror Chorev and Carol V. Robinson of University of Oxford; Vinaya K. Golla, Nathan N. Alder and Eric R. May of University of Connecticut.

Funding for this study was provided by the National Institutes of Health (R01HL108882, R01HL165729, R35GM119762, T32GM007445 and T32GM136577), the American Heart Association, the Uehara Memorial Foundation, the Barth Syndrome Foundation and the Royal Society Newton International Fellowship.

The study, by Bangor University and Technion- Israel Institute of Technology, published in the scientific journal People and Nature, involved city-dwellers, and showed how paying visual attention to greenery, rather than human-made structures, can alleviate anxiety and enhance restorative feelings.

The 117 urban residents who took part in the study, were guided on a 45-minute urban walk, while wearing eye-tracking glasses. They were instructed to focus their gaze on trees, plants, lawns and flowers, man-made structures or a mix of both. This unique methodology revealed that a participants’ focus on nature was associated with improvements in various mental health metrics, including anxiety levels and feelings of restorativeness.

Dr Whitney Fleming, a lecturer in Human Geography at Bangor University explained the findings, saying,

“We found that the individuals who were guided to direct their gaze more frequently at green elements reported a significant reduction in anxiety, with trees showing the most substantial positive effect.”

The study highlights a strong link between observing green elements, especially trees, and an increase in perceived restorativeness, suggesting that even brief interactions with nature can provide mental health benefits.”

Urban Design Implications

These insights offer valuable guidance for urban planners and architects, suggesting that integrating more natural features into city landscapes can play a crucial role in enhancing the mental well-being of residents. “The Nature Gaze” study supports the idea of urban environments that promote engagement with nature, highlighting a simple yet effective strategy for improving urban mental health.

“We are proposing that if we can couple basic income with environmental protection, we can save two birds with one stone,” says first author U. Rashid Sumaila of the University of British Columbia in Vancouver.

Sumaila has been working on ending harmful fishery subsidies worldwide, but many people who rely on fisheries for their livelihoods, especially those in developing countries, say they need the subsidies to support their families. “One of the ways we can deal with this is to give the people basic income. With that, we could achieve sustainability goals without compromising people’s livelihoods,” he says.

The research team estimated that it would cost $41 trillion to provide the entire world population of 7.7 billion people with a basic income, or $442 billion to fund only 9.9 million people living below the poverty line in less developed countries. In return, giving basic income to the entire world population could boost the global GDP by $163 trillion, which is about 130% of the current GDP.

Every dollar spent on implementing basic income can generate as much as $7 in economic impacts, the analysis shows. “If you give someone one dollar, they will spend part of the money to buy food or pay rent. And people that are paid for the food and accommodation will use part of this for their own consumption and so on. The dollar will trickle up throughout society. Our calculations show that the economic impact of that dollar will be much greater than its original amount,” Sumaila says.

The team also explored ways to fund basic income. They estimated that taxing CO₂ emitters alone can generate about $2.3 trillion a year, enough to provide a basic income for all people living below the poverty line in less developed countries.

The researchers also suggested other alternative options to finance basic income programs, such as a plastic pollution tax or redirecting harmful oil, gas, agriculture, and fisheries subsidies to fund the program. These approaches can address two of the biggest challenges around the world — reducing environmental degradation and alleviating poverty.

Real world examples have shown the benefits of basic income programs. For example, in Indonesia, villages that received a basic income have substantially lower deforestation rates than those without it.

“It’s not easy to implement carbon taxes, but that doesn’t stop our academics from reporting the evidence we have. Besides, we are not taxing everyone, just those who pollute the environment. They should pay for the damage they caused,” Sumaila says.

Basic income can also be a proactive program, Sumaila says. When crises like pandemics or natural disasters hit, communities can be more resilient.

“We saw during COVID-19, governments around the world were coming up with all sorts of programs to support people who suddenly lost their ability to earn income. If we had basic income in place, we didn’t have to scramble,” Sumaila says.

The study will be published on June 7 in the journal Science Advances.

Before surgeons remove the pancreas from patients with severe, painful chronic pancreatitis, they first harvest insulin-producing tissue clusters, called islets, and transplant them into the vasculature of the liver. The goal of the transplant is to preserve a patient’s ability to control their own blood-glucose levels without insulin injections.

Unfortunately, the process inadvertently destroys 50-80% of islets, and one-third of patients become diabetic after surgery. Three years post-surgery, 70% of patients require insulin injections, which are accompanied by a list of side effects, including weight gain, hypoglycemia and fatigue.

In the new study, researchers transplanted islets from the pancreas to the omentum — the large, flat, fatty tissue that covers the intestines — instead of the liver. And, to create a healthier microenvironment for the islets, the researchers adhered the islets to the omentum with an inherently antioxidant and anti-inflammatory biomaterial, which rapidly transforms from a liquid to a gel when exposed to body temperature.

In studies with mouse and non-human primates, the gel successfully prevented oxidative stress and inflammatory reactions, significantly improving survival and preserving function of transplanted islets. It marks the first time a synthetic antioxidant gel has been used to preserve function of transplanted islets.

“Although islet transplantation has improved over the years, long-term outcomes remain poor,” said Northwestern’s Guillermo A. Ameer, who led the study. “There is clearly a need for alternative solutions. We have engineered a cutting-edge synthetic material that provides a supportive microenvironment for islet function. When tested in animals, we were successful. It kept islet function maximized and restored normal blood sugar levels. We also report a reduction in units of insulin that animals required.”

“With this new approach, we hope that patients will no longer have to choose between living with the physical pain of chronic pancreatitis or the complications of diabetes,” added Jacqueline Burke, a research assistant professor of biomedical engineering at Northwestern and the paper’s first author.

An expert in regenerative engineering, Ameer is the Daniel Hale Williams Professor of Biomedical Engineering at Northwestern’s McCormick School of Engineering, a Professor of Surgery at Northwestern University Feinberg School of Medicine and founding director of the Center for Advanced Regenerative Engineering.

‘Compromised quality of life’

For patients living without a pancreas, side effects such as managing blood-sugar levels can be a lifelong struggle. By secreting insulin in response to glucose, islets help the body maintain glycemic control. Without functioning islets, people must closely monitor their blood-sugar levels and frequently inject insulin.

“Living without functional islets places a great burden on patients,” Burke said. “They must learn to count carbs, dose insulin at the appropriate time and continuously monitor blood glucose. This consumes much of their time and mental energy. Even with great care, exogeneous insulin therapy is not as effective as islets for maintaining glucose control. Patients with out-of-range blood glucose will develop complications, such as blindness and amputation. Our goal is for this biomaterial to preserve the islets, so patients can live a normal life — a life without diabetes.”

“It’s a compromised quality of life,” Ameer said. “Instead of multiple insulin injections, we would love to collect and preserve as many islets as possible.”

But, unfortunately, the current standard of care for preserving islets often leads to poor outcomes. After the surgery to remove the pancreas, surgeons isolate islets from the pancreas and transplant them to the liver through portal vein infusion. This intraportal perfusion procedure has several common complications. Islets in direct contact with blood flow undergo an inflammatory response, more than half of the islets die, and transplanted islets can cause dangerous clots in the liver. For those reasons, physicians and researchers have been searching for an alternate transplantation site.

In previous clinical studies, researchers transplanted islets to the omentum instead of the liver in order to bypass issues with clotting. To secure the islets on the omentum, physicians used plasma from the patients’ own blood to form a biologic gel. While the omentum appeared to work better than the liver as a transplantation site, several issues, including clots and inflammation, remained.

“There’s been significant interest in the research and medical communities to find an alternate islet transplantation site,” Ameer said. “The results from the omentum study were encouraging, but outcomes were varied. We believe that’s because the use of the patients’ blood and the added components required to create the biologic gel can affect reproducibility among patients.”

A citrate solution

To protect the islets and improve outcomes, Ameer turned to the citrate-based biomaterials platform with inherent antioxidant properties developed in his laboratory. Used in products approved by U.S. Food and Drug Administration for musculoskeletal surgeries, citrate-based biomaterials have demonstrated the ability to control the body’s inflammatory responses. Ameer set out to investigate whether a version of these biomaterials with biodegradable and temperature-responsive phase-changing properties would provide a superior alternative to a biologic gel obtained from blood.

In cell cultures, both mouse and human islets stored within the citrate-based gel maintained viability much longer than islets in other solutions. When exposed to glucose, the islets secreted insulin, demonstrating normal functionality. Moving beyond cell cultures, Ameer’s team tested the gel in small and large animal models. Liquid at room temperature, the material turns into a gel at body temperature, so it’s simple to apply and easily stays in place.

In the animal studies, the gel effectively secured the islets onto the omentum of the animals. Compared to the current methods, more islets survived, and, over time, the animals restored normal blood glucose levels. According to Ameer, the success is partially due to the new material’s biocompatibility and antioxidant nature.

“Islets are very sensitive to oxygen,” Ameer said. “They are affected by both too little oxygen and too much oxygen. The material’s innate antioxidant properties protect the cells. Plasma from your own blood doesn’t offer the same level of protection.”

Integrating into tissues

After about three months, the body resorbed 80-90% of the biocompatible gel. But, at that point, it was no longer needed.

“What was fascinating is that the islets regenerated blood vessels,” Ameer said. “The body generated a network of new blood vessels to reconnect the islets with the body. That is a major breakthrough because the blood vessels keep the islets alive and healthy. Meanwhile, our gel is simply resorbed into the surrounding tissue, leaving little evidence behind.”

Next, Ameer aims to test his hydrogel in animal models over a longer period of time. He said the new hydrogel also could be used for various cell replacement therapies, including stem cell-derived beta cells for treating diabetes.

The study, “Phase-changing citrate macromolecule combats oxidative pancreatic islet damage, enables islet engraftment and function in the omentum,” was supported by the U.S. Department of Defense and the National Science Foundation.

“COVID-19 forced educators to adjust their educational best practices to an unfamiliar virtual classroom, and professional development was no different,” said Karen Jo Matsler, assistant professor in practice for UTeach at UTA and lead author on the study.

Ramon Lopez, professor of physics, was coprincipal investigator on the project. Chandralekha Singh from the University of Pittsburgh was a co-author.

QIS is a new field of science and technology that combines physical science, math, computer science and engineering, and it is key to everyday items like cellphones and solar technology. However, most high schools don’t teach the subject, preventing students from acquiring the skills they need to pursue lucrative jobs.

As part of a $1 million grant from the National Science Foundation in 2021, Matsler and her colleagues aimed to teach QIS to high school science teachers, who could then bring this newly acquired knowledge to their classrooms.

“However, the pandemic made us scrap our original plans for in-person training to an online environment,” Matsler said. “We knew that teaching QIS online would be challenging, but we were pleasantly surprised how well it worked.”

Matsler, Lopez and the team found that what worked best for teaching QIS online was sending participants some of the material in advance to allow them to become familiar with the topics. Then during the sessions, the educators used Zoom — with features such as chat, polling and breakout rooms — to keep the individuals engaged in learning. They also led activities where the learners had a chance to practice teaching the material, another technique that helped individuals stay engaged.

To avoid cognitive overload, the team found main discussions needed to be kept at 15 to 30 minutes, each with breakout sessions lasting five to seven minutes, with a total session time of about 90 to 120 minutes.

“This gave participants ample opportunities to discuss the quantum concepts in small groups varying from two to six participants,” Matsler said. “During these small discussions, leaders rotated in and out of the rooms to check on the participants, clarify instructions and answer questions.”

The instructors also recommend “icebreaker” activities to increase community engagement in virtual learning.

“These icebreaker activities can easily be used to engage students, take attendance and gauge how much the individuals know about the upcoming subject lesson,” Matsler said. “A key element to all of this online learning is making sure the learners feel they are in a safe community to learn and exchange ideas.”

The team also found that short, relevant videos helped teach complicated topics. They recommend keeping the chat function operational during videos to allow participants to ask questions and stay engaged.

“Ideally, QIS is taught in a classroom with hands-on activities to allow learners to see and touch how things like maglev trains and quantum levitation work,” Matsler said. “However, our experiences show that embedding appropriate pedagogy and content with online learning can be effective at teaching these topics. Understanding there is an effective virtual option is important as the country ramps up its efforts to accelerate quantum research and development to stay competitive with other countries in this field.”

By allowing the cells to grow closer together, this new membrane helps researchers to better control the growth and function of the key cells and tissues of any organ, enabling them to more accurately model a wide range of diseases and test therapeutics.

The research appears June 4 in the journal Science Advances.

Often no larger than a USB flash drive, organ-on-a-chip (OOC) systems have revolutionized how researchers study the underlying biology of the human body, whether it’s creating dynamic models of tissue structures, studying organ functions or modeling diseases. These platforms are designed to stimulate cell growth and differentiation in a way that best mimics the organ of interest. Researchers can even populate these tools with human stem cells to generate patient-specific organ models for pre-clinical studies.

But as the technology has evolved, problems in the chip’s design have also emerged — most notably with the materials used to create the membranes that form the support structure for the specialized cells to grow on. These membranes are typically composed of polymers that don’t degrade, creating a permanent barrier between cells and tissues. While the extracellular membranes in human organs are often less than one micron thick, these polymer membranes are anywhere from 30 to 50 microns, hindering communication between cells and limiting cell growth.

“We want to handle the tissues in these chips just like a pathologist would handle biopsy samples or even living tissues from a patient, but this wasn’t possible with the standard polymer membranes because the extra thickness prevented the cells from forming structures that more closely resemble tissues in the human body,” said Samira Musah, an assistant professor of biomedical engineering and medicine at Duke. “We thought, ‘Wouldn’t it be nice if we could get a protein-based material that mimics the structure of these natural membranes and is thin enough for us to slice and study?'”

This question led Musah and George (Xingrui) Mou, a PhD student in Musah’s lab and first author on the paper, to silk fibroin, a protein created by silkworms that can be electronically spun into a membrane. When examined under a microscope, silk fibroin looks like spaghetti or a Jackson Pollock painting. Made out of long, intertwining fibers, the porous material better mimics the structure of the extracellular matrix found in human organs, and it has previously been used to create scaffolds for purposes like wound healing.

“The silk fibroin allowed us to bring the membrane thickness down from 50 microns to five or fewer, which gets us an order of magnitude closer to what you’d see in a living organism,” explained Mao.

To test this new membrane, Musah and Mao applied the material to their kidney chip models. Made out of a clear plastic and roughly the size of a quarter, this OOC platform is meant to resemble a cross section of a human kidney — specifically the glomerular capillary wall, a key structure in the organ made from clusters of blood vessels that is responsible for filtering blood.

Once the membrane was in place, the team added human induced pluripotent stem cell derivatives into the chip. They observed that these cells were able to send signals across the ultrathin membrane, which helped the cells differentiate into glomerular cells, podocytes and vascular endothelial cells. The platform also triggered the development of endothelial fenestrations in the growing tissue, which are holes that allow for the passage of fluid between the cellular layers.

By the end of the test, these different kidney cell types had assembled into a glomerular capillary wall and could efficiently filter molecules by size.

“The new microfluidic chip system’s ability to simulate in vivo-like tissue-tissue interfaces and induce the formation of specialized cells, such as fenestrated endothelium and mature glomerular podocytes from stem cells, holds significant potential for advancing our understanding of human organ development, disease progression, and therapeutic development,” said Musah.

As they continue to optimize their model, Musah and colleagues are hoping to use this technology to better understand the mechanisms behind kidney disease. Despite affecting more than 15 percent of American adults, researchers lack effective models for the disease. Patients are also often not diagnosed until the kidneys have been substantially damaged, and they are often required to undergo dialysis or receive a kidney transplant.

“Using this platform to develop kidney disease models could help us discover new biomarkers of the disease,” said Mao. “This could also be used to help us screen for drug candidates for several kidney disease models. The possibilities are very exciting.”

“This technology has implications for all organ-on-a-chip models,” said Musah. “Our tissues are made up of membranes and interfaces, so you can imagine using this membrane to improve models of other organs, like the brain, liver, and lungs, or other disease states. That’s where the power of our platform really lies.”

This work was supported by a Whitehead Scholarship in Biomedical Research, Chair’s Research Award from the Department of Medicine at Duke University, MEDx Pilot Grant on Biomechanics in Injury or Injury Repair, Burroughs Wellcome Fund PDEP Career Transition Ad Hoc Award, Duke Incubation Fund from the Duke Innovation & Entrepreneurship Initiative, Genetech Research Award, a George M. O’Brien Kidney Center Pilot Grant (P30 DK081943), an NIH Director’s New Innovator Grant (DP2DK138544).

Nanoparticles are contained in a large number of products, but they are also produced during wear and tear as well as through combustion processes (see box). “We absorb these substances from the environment via our food, cosmetics or the air we breathe,” explains Bürki. Some of these nanoparticles are suspected of harming babies in the womb. Low birth weight, autism and respiratory diseases are among the possible consequences for the child.

Mysterious remote effect

It is still unclear how the nanoparticles affect the unborn child. “We already know that the placental barrier retains many nanoparticles or at least delays their transport to the embryo,” says Bürki. However, damage to the fetal tissue occurs, even if no particles have been detected in the fetus. The Empa team is now getting to the bottom of this long-range effect of nanoparticles. Together with clinical partners from the Cantonal Hospital of St. Gallen and research partners from the University of Geneva, the Amsterdam University Medical Center and the Leibniz Institute for Environmental Medical Research in Düsseldorf, the team is investigating the consequences of common nanoparticles such as titanium dioxide or diesel soot on the function of the placenta and their indirect damage to embryonic development.

For this purpose, the team used fully functional human placentas that were made available after planned caesarean sections. “Human placental tissue is the only way to obtain meaningful results on the transport and effect of nanoparticles,” says the Empa researcher. “The structure, metabolism and interaction of maternal and fetal tissue are unique and species-specific.”

The experiments showed that nanoparticles in placental tissue disrupt the production of a large number of messenger substances. And it is these messengers that can trigger serious changes in embryonic development, such as disturbed blood vessel formation.

These effects can be visualized in laboratory models using chicken eggs. The blood vessels in the egg actually grow at an enormous speed and density to enable embryonic development. A dense network of fine blood vessels covers the inside of the eggshell. The situation is strikingly different in eggs treated with the altered messenger substances from the nanoparticle-treated placenta: In the experiments, the blood vessel system was not as dense but rather coarse-meshed. “Nanoparticles apparently have an indirect effect on the child in the womb by inhibiting the formation of blood vessels via messenger substances,” says Tina Bürki.

Health consequences

The researchers are currently investigating the entirety of the messenger substances released by a nanoparticle-treated placenta, the so-called secretome. Uncontaminated, the interplay of hormones, inflammatory mediators and signaling substances for the formation of organ systems resembles a perfectly tuned orchestra. It is already clear that the communication between the placenta and the unborn child is disrupted by the presence of nanoparticles and damages the formation of blood vessels. However, initial results show that the development of the nervous system does not appear to be affected. Future analyses will show what other disorders the nanoparticles can trigger indirectly. “As the effects can have an impact on the health of the pregnant woman and the development of her child, these findings should be taken into account in the risk assessment of nanomaterials,” says the researcher.

The clinical partner, the Cantonal Hospital of St. Gallen, is also interested. As Thomas Rduch from the Women’s Clinic and also a Clinical Research Fellow at Empa puts it: “A healthy placenta is of utmost importance for the development of the child. Correct risk assessments of environmental pollution are therefore crucial for pregnant women.”

The placenta

The placenta is an organ that forms exclusively during pregnancy. It supplies the child in the womb with nutrients and also serves as a filter for environmental influences. This so-called placental barrier offers the unborn child a certain degree of protection against pathogens or harmful substances. However, some substances, such as environmental estrogens can pass through the placental barrier and are suspected of being associated with various diseases.

Nanoparticles

Nanoparticles are only a few millionths of a millimeter in size. They include titanium dioxide, for example, which can be found in many foods, cosmetics and medicines. Silicon dioxide is found in paints and printing paper, for example, and is also used as a food additive. Other nanoparticles come from environmental pollution processes such as plastic abrasion (nanoplastics) or industrial soot. They can enter the human body via the respiratory tract, the digestive tract or the skin.

“We urgently need new ways to prevent this type of stroke, which occurs at younger ages and with a higher death rate than other types of stroke,” said study author Jos Peter Kanning, MSc, of University Medical Center Utrecht in the Netherlands. “Our current surgical treatments for brain aneurysms have a risk of permanent disability and death that often outweighs the potential benefits, so preventing rupture with a non-invasive drug would be very beneficial.”

For the study, researchers looked at 4,879 people who had ruptured brain aneurysms, called aneurysmal subarachnoid hemorrhages. Those people were each compared to nine people of the same age and sex, for a total of 43,911 people who did not have ruptured brain aneurysms.

Then researchers looked at electronic health records to see what prescription drugs people took.

They found that four drugs were associated with a decreased risk of having a ruptured brain aneurysm: the high blood pressure drug lisinopril; the cholesterol drug simvastatin; the diabetes drug metformin; and the drug tamsulosin, prescribed for enlarged prostate.

After adjusting for other factors that could affect the risk of stroke, such as high blood pressure, smoking, alcohol abuse and total number of other health conditions, researchers found that people currently taking lisinopril were 37% less likely to have a ruptured brain aneurysm than those not taking the drug. People taking simvastatin were 22% less likely to have a stroke. Those taking metformin were 42% less likely to have a stroke and those taking tamsulosin were 45% less likely.

Researchers also found an increased risk of having a ruptured brain aneurysm for people taking four drugs: the blood thinner warfarin; the antidepressant venlafaxine; the antipsychotic and antiemetic drug prochlorperazine; and the painkiller co-codamol.

“Future research is needed to investigate these associations and determine whether these drugs are effective in reducing the risk of hemorrhagic stroke,” Kanning said. “This work could also help us identify additional risk factors for subarachnoid hemorrhage, potentially leading to new therapies to manage aneurysms.”

A limitation of the study was that researchers looked at drug prescriptions. It is possible that people may not take their drugs or may take them incorrectly.

The study was supported by the European Research Council.

Researchers at the Li Lab have developed oral insulin drops that when placed under the tongue are quickly and efficiently absorbed by the body, potentially replacing the need for insulin injections.

The drops contain a mixture of insulin and a unique cell-penetrating peptide (CPP) developed by Dr. Shyh-Dar Li and colleagues.

A little help from a peptide guide

“Insulin is a complicated molecule,” explains lead researcher Dr. Li, a professor in the faculty of pharmaceutical sciences. “In pill form, it’s easily destroyed in the stomach. Insulin also needs to be rapidly available in the blood, but as a large molecule, it cannot get through cells easily on its own.” The peptide, sourced from fish byproducts, opens a pathway for insulin to cross over.

Pre-clinical tests showed that insulin with the peptide effectively reaches the bloodstream whereas without the peptide, insulin remains stuck in the inside lining of the mouth.

“Think of it as a guide that helps insulin navigate through a maze to reach the bloodstream quickly. This guide finds the best routes, making it easier for insulin to get where it needs to go,” said Dr. Jiamin Wu, a postdoctoral researcher in the Li Lab.

Two versions of the peptide are described in recent articles in the Journal of Controlled Release (here and here). The UBC team is working to license the technology to a commercial partner.

Keeping medications on track

Healthy people get their insulin naturally from the pancreas to regulate glucose after a meal. Diabetes patients cannot produce sufficient insulin and need to get it from an outside source.

Unregulated glucose can be very dangerous, so diabetes patients must monitor their glucose levels and take insulin to lower it when necessary. While injections are the fastest way to get insulin into the blood, patients typically need at least three to four injections per day, which can affect their quality of life. Adherence to this regimen is challenging, and over time this can cause severe complications such as eye, kidney and nerve damage, potentially leading to limb amputations.

“My lab has been working on needle-free insulin alternatives these past three years,” said Dr. Li. “We tried nasal sprays before landing on oral drops, which are easy and convenient. Hopefully, the oral drops open up a new possibility for diabetes patients — making it easier to take their medications and regulate their blood glucose to maintain their health in the long run.”

Two inhalable insulin products (Exubera, Afrezza) were approved earlier but the effects were suboptimal and shown to increase the risk of lung cancer development. These products have been withdrawn. Dr. Li aims to achieve rapid, pain-free delivery of insulin without significant side effects. The new needle-free technology is expected to reduce the risk of cross-contamination, needle pricks, accidental infections and unsafe disposal of contaminated needles.

Restless leg syndrome can cause an unpleasant crawling sensation in the legs and an overwhelming urge to move them. Some people experience the symptoms only occasionally, while others get symptoms every day. Symptoms are usually worse in the evening or at night-time and can severely impair sleep.

Despite the condition being relatively common — up to one in 10 older adults experience symptoms, while 2-3% are severely affected and seek medical help — little is known about its causes. People with restless leg syndrome often have other conditions, such as depression or anxiety, cardiovascular disorders, hypertension, and diabetes, but the reason why is not known.

Previous studies had identified 22 genetic risk loci — that is, regions of our genome that contain changes associated with increased risk of developing the condition. But there are still no known ‘biomarkers’ — such as genetic signatures — that could be used to objectively diagnose the condition.

To explore the condition further, an international team led by researchers at the Helmholtz Munich Institute of Neurogenomics, Institute of Human Genetics of the Technical University of Munich (TUM) and the University of Cambridge pooled and analysed data from three genome-wide association studies. These studies compared the DNA of patients and healthy controls to look for differences more commonly found in those with restless leg syndrome. By combining the data, the team was able to create a powerful dataset with more than 100,000 patients and over 1.5 million unaffected controls.

The results of the study are published today in Nature Genetics.

Co-author Dr Steven Bell from the University of Cambridge said: “This study is the largest of its kind into this common — but poorly understood — condition. By understanding the genetic basis of restless leg syndrome, we hope to find better ways to manage and treat it, potentially improving the lives of many millions of people affected worldwide.”

The team identified over 140 new genetic risk loci, increasing the number known eight-fold to 164, including three on the X chromosome. The researchers found no strong genetic differences between men and women, despite the condition being twice as common in women as it is men — this suggests that a complex interaction of genetics and the environment (including hormones) may explain the gender differences we observe in real life.

Two of the genetic differences identified by the team involve genes known as glutamate receptors 1 and 4 respectively, which are important for nerve and brain function. These could potentially be targeted by existing drugs, such as anticonvulsants like perampanel and lamotrigine, or used to develop new drugs. Early trials have already shown positive responses to these drugs in patients with restless leg syndrome.

The researchers say it would be possible to use basic information like age, sex, and genetic markers to accurately rank who is more likely to have severe restless leg syndrome in nine cases out of ten.

To understand how restless leg syndrome might affect overall health, the researchers used a technique called Mendelian randomisation. This uses genetic information to examine cause-and-effect relationships. It revealed that the syndrome increases the risk of developing diabetes.

Although low levels of iron in the blood are thought to trigger restless leg syndrome — because they can lead to a fall in the neurotransmitter dopamine — the researchers did not find strong genetic links to iron metabolism. However, they say they cannot completely rule it out as a risk factor.

Professor Juliane Winkelmann from TUM, one of senior authors of the study, said: “For the first time, we have achieved the ability to predict restless leg syndrome risk. It has been a long journey, but now we are empowered to not only treat but even prevent the onset of this condition in our patients.”

The results were presented today at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting by Steven Frank, M.D., professor of Radiation Oncology and executive director of the Particle Therapy Institute at The University of Texas MD Anderson Cancer Center.

With a median follow-up of three years, the progression-free survival (PFS) rate was 83% and 83.5% for IMPT and IMRT, respectively, and IMPT was statistically non-inferior to IMRT. There was a significant reduction of malnutrition with IMPT, with 24% of patients sustaining their nutrition with less than 5% weight loss during treatment compared with 14% of those receiving IMRT. Additionally, there was a significant reduction of feeding-tube dependence with IMPT at 28%, compared to 42% with IMRT.

“The results of this multi-center Phase III randomized trial provide evidence for IMPT as a new standard-of-care treatment approach for the management of head and neck tumors,” Frank said. “This is significant for patients as it represents a curative, de-intensified option compared to traditional radiation therapy.”

Proton therapy has both biological and physical advantages over traditional radiation therapy using photons. Unlike photons, protons have mass and can be stopped by the human body. This allows proton radiation to be delivered specifically to the targeted area, limiting the amount that reaches nearby normal tissues. This trial represents the largest randomized Phase III trial to date to investigate proton therapy in comparison to traditional radiation.

The trial enrolled 440 patients at 21 sites in the U.S., with 219 receiving IMRT and 221 receiving IMPT. Patients were stratified based on human papillomavirus (HPV) status, smoking status and whether they had received induction chemotherapy. The primary endpoint of the study was the PFS rate at three years.

“Historically, these kind of large-scale trials to confirm the benefits of proton therapy have been challenging, due in part to relatively few patients having access to proton therapy centers,” Frank said.” Encouraging results like these demonstrate the benefits of proton therapy and hopefully help pave the way for increased access for patients in need.”

This study was funded by grants from the National Institutes of Health (NIH)/National Cancer Institute (NCI) (U19CA021239, R03CA188162, R56DE025248) and Hitachi. Frank reports proton-related grant funding by Hitachi and honoraria fees from Ion Beam Applications S.A. (IBA). He also has non-proton related health care relationships with Boston Scientific (consulting fees), Affirmed Pharma (NIH grant), and C4 Imaging (founder, scientific advisory committee, patents/royalties, ownership interest). 

Research has shown that noise from airplanes and helicopters flying overhead are far more bothersome to people than noise from other modes of transportation, and a growing body of research suggests that aircraft noise is also contributing to negative health outcomes.

One of the latest studies, led by Boston University School of Public Health (BUSPH) and Oregon State University (OSU) indicates that airplane noise may increase one’s risk of developing cardiometabolic diseases, a cluster of conditions such as heart attack, stroke, diabetes, and hypertension.

Published in the journal Environment International, the study found that people who were exposed to airplane noise levels at 45 dB or more were more likely to have higher self-reported body mass index (BMI), with the highest BMI measures linked to aircraft noise levels at 55 dB or above. Airplane noise exposure at 45 dB or above was also associated with having higher BMI in middle to late adulthood from early adulthood. For comparison, the sound of a whisper is 30 dB, a library setting is 40 dB, and a typical conversation at home is 50 dB.

BMI is an indicator of general obesity, which can lead to cardiometabolic diseases, as well as a range of other health issues. The study is the first to explore a connection between aircraft noise exposure and obesity nationwide in the United States; past studies on this subject have focused on European populations, and results have varied.

“Prior research has shown that aircraft noise can elevate stress responses and disturb sleep, but there has been mixed evidence of any links with body mass index,” says study lead and corresponding author Dr. Matthew Bozigar, assistant professor of epidemiology at OSU. “We were surprised to see a fairly robust link between aircraft noise and higher body mass index among women across the US.”

These new findings underscore the role of the environment on one’s risk of chronic disease.

‘Obesity has become very stigmatized, but what is important to remember is that it is linked with poor cardiometabolic health outcomes, and that it has strong environmental drivers,” Dr. Bozigar says. “This is disheartening, but also promising, in the sense that we could potentially enact policies to mitigate these drivers of obesity.”

For the study, Dr. Bozigar and colleagues examined airplane noise exposure and self-reported BMI and other individual characteristics among nearly 75,000 participants living around 90 of the major US airports. The participants were selected from the Nurses’ Health Studies (NHS), ongoing, prospective studies of US female nurses who have completed biennial questionnaires since the 1970s and 1980s.

The team examined aircraft noise levels every five years from 1995 to 2010, using a day-night estimate (DNL) that captures the average noise level over a 24-hour period and applies a 10 dB adjustment for aircraft noise occurring at night, when background noise is low. The current policy-related threshold for significant noise impacts is above DNL 65 dB. The team assessed BMI measures at multiple thresholds below that (less than 45 dB; 45-54 dB; 55 dB and above; and continuous exposure at 45 dB or above) for the nurses’ geocoded residential addresses.

Although the team acknowledges that BMI is a suboptimal metric, the independent and strong association between more aircraft noise exposure and higher BMI that they observed is notable. There were also regional differences, with stronger associations among participants on the West Coast and those who live in arid conditions.

“We can only hypothesize about why we saw these regional variations, but one reason may relate to the era of regional development, building characteristics, and climate which may affect factors such as housing age, design, and level of insulation,” says study senior author Dr. Junenette Peters, associate professor of environmental health at BUSPH. “Regional differences in temperature and humidity may influence behaviors such as window opening, so perhaps study participants living in the West were more exposed to aircraft noise due to open windows or housing type, which allowed more noise to penetrate.”

Similarly, the stronger associations observed in arid climates, many of which are also in the Western US, may relate to the way noise travels under various atmospheric conditions, Dr. Peters says.

Future research should explore this link between aircraft noise exposure and obesity further, as well as broader inequities in environmental noise exposure, particularly among other populations. Previous data suggest that Black, Hispanic, and low-income populations are disproportionately exposed to aircraft noise. The participants in the NHS study groups were primarily White and of mid-level socioeconomic status.

“We need to study the potential health impacts of environmental injustices in transportation noise exposures alongside other environmental drivers of poor health outcomes” Dr. Bozigar says. “There is a lot more to figure out, but this study adds evidence to a growing body of literature that noise negatively impacts health.”

New research by the University of South Australia has found a connection between pleasant weather conditions and higher investment in lottery-like stocks.

Lottery-like stocks are cheap compared to other stocks and, like lottery tickets, they can be seen as an opportunity to make a substantial gain. However, the chance of a higher return is minimal, and it’s therefore considered a high-risk investment. A study by UniSA finance researchers discovered that when the weather is sunny and skies are blue, investors are more likely to engage in these types of investments.

Dr Reza Bradrania, Senior Lecturer of Finance and member of UniSA’s Centre for Markets, Values and Inclusion, says studies in psychology have shown that weather has a significant effect on human moods and behaviour. It can explain about 40% of daily variation in moods and sunshine in particular can have a large impact on how we feel.

“Since being in a good mood spurs people to take more risks, we were curious to see if weather, as an important factor that impacts human moods, relates to demand for lottery-like stocks which are highly risky and have lottery features like casino or lotto products,” Dr Bradrania says.

“The idea is that investors who are in a good mood because of sunny weather tend to have more optimistic expectations or beliefs about the future payoff of lottery stocks. This investigation was important as it has implications on how weather can influence investors’ judgements and choices and in particular impact their financial decisions.”

“To our knowledge this is the first study of its kind to investigate how weather plays a role in our investment decisions and in particular the demand for and the performance of lottery-like stocks which have implications for financial markets.”

Dr Bradrania and PhD student Ya Gao gathered 36 years’ worth of weather data including hourly sky cloud cover, wind speed rate, rain depth and air temperature from major weather stations across US cities. Price data of common stocks from over this period (1983 to 2019) was also examined.

“We found that on days with pleasant weather conditions, investors were more likely to be risk-taking and optimistic and invest more in lottery-like stocks, which further results in high demand and higher price for these stocks. However, their price is adjusted later, which resulted in significant loss,” Dr Bradrania says.

“Overoptimism is associated with overconfidence in many cases and investors who are overconfident tend to trade lottery-like stocks more. The research suggests weather relates to gambling preference and influences our judgment and choices. It also provides some guidance on investment decisions depending on weather conditions.”

When an embryo develops, many types of cells with different functions need to be generated. For example, some cells will become part of the eye and record visual stimuli, while others will be part of the gut and help digest food. To determine their roles, cells are constantly communicating with each other using chemical signals.

Thanks to this communication, during development, everything is well synchronized and coordinated, and yet there is no central control responsible for this. The cell collective is self-organized and orchestrated by the interactions between the individuals. Each cell reacts to signals of its neighbors. Based on such self-organization, the mammalian embryo develops from a single fertilized egg cell into a multicellular organism.

David Brückner and Gašper Tkačik from the Institute of Science and Technology Austria (ISTA) have now established a mathematical framework that helps analyze this process and predict its optimal parameters. Published in PNAS, this approach represents a unifying mathematical language to describe biological self-organization in embryonic development and beyond.

The self-assembling embryo

In nature, self-organization is all around us: we can observe it in fish schools, bird flocks, or insect collectives, and even in microscopic processes regulated by cells. NOMIS fellow and ISTA postdoc David Brückner is interested in getting a better understanding of these processes from a theoretical standpoint. His focus lies on embryonic development — a complex process governed by genetics and cells communicating with each other.

During embryonic development, a single fertilized cell turns into a multicellular embryo containing organs with lots of different features. “For many steps in this developmental process, the system has no extrinsic signal that directs it what to do. There is an intrinsic property of the system that allows it to establish patterns and structures,” says Brückner. “The intrinsic property is what is known as self-organization.” Even with unpredictable factors — which physicists call “noise” — the embryonic patterns are formed reliably and consistently. In recent years, scientists have gained a deeper understanding of the molecular details that drive this complex process. A mathematical framework to analyze and quantify its performance, however, was lacking. The language of information theory provides answers.

Bridging expertise

“Information theory is a universal language to quantify structure and regularity in statistical ensembles, which are a collection of replicates of the same process. Embryonic development can be seen as such a process that reproducibly generates functional organisms that are very similar but not identical,” says Gašper Tkačik, professor at ISTA and expert in this field. For a long time, Tkačik has been studying how information gets processed in biological systems, for instance in the fly embryo. “In the early fly embryo, patterns are not self-organized,” he continues. “The mother fly puts chemicals into the egg that instruct the cells on what actions to take.” As the Tkačik group had already developed a framework for this system, Brückner reached out to develop one for the mammalian embryo as well. “With Gašper’s expertise in information theory, we were able to put it together,” Brückner adds excitedly.

Beyond embryo development?

During embryonic development, cells exchange signals and are constantly subject to random, unpredictable fluctuations (noise). Therefore, cellular interactions must be robust. The new framework measures how these interactions are possibly optimized to withstand noise. Using computer simulations of interacting cells, the scientists explored the conditions under which a system can still have a stable final result despite introducing fluctuations.

Although the framework has proven to be successful on three different developmental models that all rely on chemical and mechanical signaling, additional work will be required to apply it to experimental recordings of developmental systems. “In the future, we want to study more complex models with more parameters and dimensions,” Tkačik says. “By quantifying more complex models, we could also apply our framework to experimentally measured patterns of chemical signals in developing embryos,” adds Brückner. For this purpose, the two theoretical scientists will team up with experimentalists.

Additionally, the brain’s response to serotonin stimulation is strongly linked to the distribution of serotonin receptors (proteins activated by serotonin) and the connection patterns of DRN serotonin neurons. “We clearly see from the high-field MRI images which areas in the brain are activated and deactivated during the awake state and under anesthesia when we activate serotonin neurons in the DRN,” lead author Dr. Hiroaki Hamada said. “A previous study showed that the cerebral cortex and the basal ganglia were mostly deactivated under anesthesia, which we also observed, however, in awake states these areas are significantly activated.”

Our brains are made of tens of billions of nerve cells called neurons. These cells communicate with each other through biomolecules called neurotransmitters. Serotonin, a type of neurotransmitter, is produced by serotonin neurons in our brains and influences many of our behavioral and cognitive functions such as memory, sleep, and mood.

“Learning about the brain’s serotonin system can help us understand how we adapt our behaviors and how mood therapy medication works. But it was hard to study how serotonin from the DRN affects the entire brain. First, because electric stimulation of the DRN can also activate neurons that don’t use serotonin to communicate with each other, and second, using drugs can affect other serotonin in the brain,” explained Dr. Hiroaki Hamada, a former PhD student at OIST’s Neural Computation Unit and lead author of a paper on this study published in the journal Nature Communications.

Previous studies by researchers at the Neural Computation Unit have shown that serotonin neurons in the DRN promote adaptive behaviors in mice associated with future rewards. Dr. Hamada and his collaborators wanted to understand the mechanisms in the brain that cause these adaptive behaviors.

“We knew that DRN serotonin activation has strong effects on behavior, but we didn’t know how this serotonin activation affects different parts of the brain,” Prof. Kenji Doya, leader of the Neural Computation Unit, stated.

Observing the entire brain’s response to DRN serotonin activation

The researchers used a novel technique called opto-functional MRI to address this question. They used a method called optogenetics to selectively activate serotonin neurons in the DRN with light and observed the entire brain’s response using functional MRI (Magnetic Resonance Imaging). They utilized the latest MRI scanner with a strong magnetic field to achieve the high resolution needed to study the small brains of mice. The mice were put in the MRI scanner and serotonin neurons were stimulated at regular intervals to see how this affected the whole brain.

They found that DRN serotonin stimulation causes activation of the cerebral cortex and the basal ganglia, brain areas involved in many cognitive functions. This result was very different from a previous study performed under anesthesia. Additionally, the brain’s response to serotonin stimulation is strongly linked to the distribution of serotonin receptors (proteins activated by serotonin) and the connection patterns of DRN serotonin neurons.

“We clearly see from the high-field MRI images which areas in the brain are activated and deactivated during the awake state and under anesthesia when we activate serotonin neurons in the DRN,” Dr. Hamada said. “A previous study showed that the cerebral cortex and the basal ganglia were mostly deactivated under anesthesia, which we also observed, however, in awake states these areas are significantly activated.”

The cerebral cortex and the basal ganglia are parts of the brain critical for many cognitive processes, including motor activity and behaviors to gain rewards such as food and water. Activation of DNR serotonin neurons can therefore lead to changes in motivation and behavior.

Patience and stimulating your own serotonin

Combining the new technique of high field MRI and optogenetics presented many obstacles that Dr. Hamada had to overcome. “We introduced and adapted a method previously used by our collaborators and established many new procedures at OIST. For me, the main challenge was using the new MRI machine at the time, so I needed to have patience and stimulate my own serotonin. I started doing a lot of exercise after that,” he laughed.

Seeing activations in the DRN for the first time was a standout moment for Dr. Hamada. In the beginning, he used the same light intensity that his collaborators used, but this was too weak to see the brain responses in the MRI. He then used bigger optical fibers and increased the intensity to stimulate the DRNs.

Prof. Doya noted that the next important milestone to achieve is understanding exactly how this brain-wide activation of serotonin occurs: “It’s important to find out what is the actual molecular mechanism allowing this activation in our brain. People who would like to get better at adjusting their behavior and thinking in different situations could also find it helpful to learn more about how serotonin helps control our moods.”

The virus, called Apocryptovirus odysseus, along with 18 others that are closely related to it, was discovered through a computational screen of human neuron data — an effort aimed at elucidating the connection between RNA viruses and neuroinflammatory disease. The virus is associated with severe inflammation in humans infected with the parasite Toxoplasma gondii, leading the team to hypothesize that it exacerbates toxoplasmosis disease.

“We discovered A. odysseus in human neurons using the open-science Serratus platform to search through more than 150,000 RNA viruses” said Purav Gupta, first author on the study, recent high school graduate and current undergraduate student at U of T’s Donnelly Centre for Cellular and Biomolecular Research. “Serratus identifies RNA viruses from public data by flagging an enzyme called RNA-dependent RNA polymerase, which facilitates replication of viral RNA. This enzyme allows the virus to reproduce itself and for the infection to spread.”

The study was published recently in the journal Virus Evolution.

The parasite T. gondii is far-reaching, infecting an estimated one-third of the global population. It can live in any non-blood cell type, including neurons, forming cysts inside cells. The parasite is transmitted to nearby cells when the infected cell ruptures.

T. gondii infections often go unnoticed because they only lead to symptoms in rare cases. Regardless, toxoplasmosis merits investigation considering how widespread it is and the potential effects it may have on pregnant women and those who are immunocompromised, Gupta said.

“We believe the virus and parasite work hand-in-hand to cause disease in the human host, where the virus hides inside the parasite, like a soldier in a trojan horse, to gain entry to the human brain,” said Gupta. “Our research marks the first time that scientists have connected toxoplasmosis to a virus.”

The newly discovered A. odysseus is found in two hypervirulent strains of the T. gondii parasite, referred to as RUB and COUGAR.

RUB has been documented in French Guinea to cause severe fever and organ failure, while COUGAR has been shown in British Columbia to be connected to ocular toxoplasmosis — the leading cause of infectious blindness. Researchers found the strains in different geographical locations at different times, demonstrating their potentially wide-ranging impacts.

Symptoms of toxoplasmosis can be aggravated by a hyperactivated human immune response. The virus-carrying parasite triggers this type of response when the immune system senses the foreign RNA of the virus.

“The group of 19 RNA viruses we found are strong biomarkers for parasitic infection,” said Artem Babaian, principal investigator on the study and assistant professor of molecular genetics at the Donnelly Centre and the Temerty Faculty of Medicine. “It’s obvious now that the A. odysseus virus could be a valuable marker of disease-causing infections, like severe toxoplasmosis, in humans or other animals. The next step is to test if this raises the possibility that treating a parasite’s viruses could be an effective means of treating symptoms that arise from parasitic infections.”

Zoonotic viruses that infect other living things in our environment in order to reach us are expected to cause the majority of emerging infectious diseases in humans, Babaian noted. “This study underscores the importance of looking beyond the viruses that infect humans directly into the extended virome,” he said.

This research was supported by the Canadian Institutes of Health Research.

The findings will improve clinical diagnostic services for patients with neurodevelopmental disorders.

Through rigorous genetic analysis, the researchers discovered that mutations in a small non-coding gene called RNU4-2 cause a collection of developmental symptoms that had not previously been tied to a distinct genetic disorder. Non-coding genes are parts of DNA that do not produce proteins. The investigators used whole-genome sequencing data in the United Kingdom’s National Genomic Research Library to compare the burden of rare genetic variants in 41,132 non-coding genes between 5,529 unrelated cases with intellectual disability and 46,401 unrelated controls.

The discovery is significant, as it represents one of the most common single-gene genetic causes of such disorders, ranking second only to Rett syndrome among patients sequenced by the United Kingdom’s Genomic Medicine Service. Notably, these mutations are typically spontaneous and not inherited, providing important insights into the nature of the condition.

“We performed a large genetic association analysis to identify rare variants in non-coding genes that might be responsible for neurodevelopmental disorders,” says the study’s first author Daniel Greene, PhD, Assistant Professor of Genetics and Genomics Sciences at Icahn Mount Sinai and a Visitor at the University of Cambridge. “Nowadays, finding a single gene that harbors genetic variants responsible for tens of thousands of patients with a rare disease is exceptionally unusual. Our discovery eluded researchers for years due to various sequencing and analytical challenges.”

More than 99 percent of genes known to harbor mutations that cause neurodevelopmental disorders encode proteins. The researchers hypothesized that non-coding genes, which don’t produce proteins, could also host mutations leading to intellectual disability. Neurodevelopmental disorders, which often appear before grade school, involve developmental deficits affecting personal, social, academic, or occupational functioning. Intellectual disability specifically includes significant limitations in intellectual functioning (e.g., learning, reasoning, problem-solving) and adaptive behavior (e.g., social and practical skills).

“The genetic changes we found affect a very short gene, only 141 units long, but this gene plays a crucial role in a basic biological function of cells, called gene splicing, which is present in all animals, plants and fungi,” says senior study author Ernest Turro, PhD, Associate Professor of Genetics and Genomic Sciences at Icahn Mount Sinai and a Visitor at the University of Cambridge. “Most people with a neurodevelopmental disorder do not receive a molecular diagnosis following genetic testing. Thanks to this study, tens of thousands of families will now be able to obtain a molecular diagnosis for their affected family members, bringing many diagnostic odysseys to a close.”

Next, the researchers plan to explore the molecular mechanisms underlying this syndrome experimentally. This deeper understanding aims to provide biological insights that could one day lead to targeted interventions.

“What I found remarkable is how such a common cause of a neurodevelopmental disorder has been missed in the field because we’ve been focusing on coding genes,” says Heather Mefford, MD, PhD, of the Center for Pediatric Neurological Disease Research at St. Jude Children’s Research Hospital who was not involved with the research. “This study’s discovery of mutations in non-coding genes, especially RNU4-2, highlights a significant and previously overlooked cause. It underscores the need to look beyond coding regions, which could reveal many other genetic causes, opening new diagnostic possibilities and research opportunities.”

The paper is titled “Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders.”

The remaining authors of the paper are Chantal Thys (KU Leuven, Belgium); Ian R. Berry, MD (University of Bristol, UK); Joanna Jarvis, MD (Birmingham Womens’ Hospital, UK); Els Ortibus, MD, PhD (KU Leuven, Belgium); Andrew D. Mumford, MD (University of Bristol, UK); and Kathleen Freson, PhD (KU Leuven, Belgium).

The work was supported, in part, by NIH awards R01HL161365 and R03HD111492.

A new University of Washington study, published May 21 in Developmental Science, is the first to compare the amount of music and speech that children hear in infancy. Results showed that infants hear more spoken language than music, with the gap widening as the babies get older.

“We wanted to get a snapshot of what’s happening in infants’ home environments,” said corresponding author Christina Zhao, a UW research assistant professor of speech and hearing sciences. “Quite a few studies have looked at how many words babies hear at home, and they’ve shown that it’s the amount of infant-directed speech that’s important in language development. We realized we don’t know anything about what type of music babies are hearing and how it compares to speech.”

Researchers analyzed a dataset of daylong audio recordings collected in English-learning infants’ home environments at ages 6, 10, 14, 18 and 24 months. At every age, infants were exposed to more music from an electronic device than an in-person source. This pattern was reversed for speech. While the percentage of speech intended for infants significantly increased with time, it stayed the same for music.

“We’re shocked at how little music is in these recordings,” said Zhao, who is also the director of the Lab for Early Auditory Perception (LEAP), housed in the Institute for Learning & Brain Sciences (I-LABS). “The majority of music is not intended for babies. We can imagine these are songs streaming in the background or on the radio in the car. A lot of it is just ambient.”

This differs from the highly engaging, multi-sensory movement-oriented music intervention that Zhao and her team had previously implemented in lab settings. During these sessions, music played while infants were given instruments and researchers taught caregivers how to synchronize their babies’ movement with music. A control group of babies then came to the lab just to play.

“We did that twice,” Zhao said. “Both times, we saw the same result: that music intervention was enhancing infant’s neural responses to speech sounds. That got us thinking about what would happen in the real world. This study is the first step into that bigger question.”

Past studies have largely relied on qualitative and quantitative parental reports to examine musical input in infants’ environments, but parents tend to overestimate the amount they talk or sing to their children.

This study closes the gap by analyzing daylong auditory recordings made with Language Environment Analysis (LENA) recording devices. The recordings, originally created for a separate study, documented infants’ natural sound environment for up to 16 hours per day for two days at each recording age.

Researchers then crowdsourced the process of annotating the LENA data through the citizen science Zooniverse platform. Volunteers were asked to determine if there was speech or music in the clip. When speech or music was identified, listeners were then asked whether it came from an in-person or electronic source. Finally, they judged whether the speech or music was intended for a baby.

Since this research featured a limited sample, researchers are now interested in expanding their dataset to determine if the result can be generalized to different cultures and populations. A follow-up study will examine the same type of LENA recordings from infants in Latinx families. Since audio recordings lack context, researchers are also interested in when music moments are happening in infants’ lives.

“We’re curious to see whether music input is correlated with any developmental milestones later on for these babies,” Zhao said. “We know speech input is highly correlated with later language skills. In our data, we see that speech and music input are not correlated — so it’s not like a family who tends to talk more will also have more music. We’re trying to see if music contributes more independently to certain aspects of development.”

Other co-authors were Lindsay Hippe, former UW undergraduate honors thesis student and incoming master’s student in clinical research speech-language pathology; Victoria Hennessy, LEAP research assistant/lab manager; and Naja Ferjan Ramírez, assistant professor of linguistics and adjunct research professor for I-LABS. This study was funded by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health.

Seasonal flu vaccines cover influenza B and the more common influenza A but do not stimulate the broadest possible range of immune responses against both viruses. In addition, people whose immune systems have been weakened by age or illness may not respond effectively to the flu shot.

Small-molecule drugs that block neuraminidase, a major surface glycoprotein of the influenza virus, can help treat early infection, but they provide limited benefit when the infection is more severe, and they are generally less effective in treating influenza B infections. Thus, another way to combat this virus is needed.

Reporting in the journal Immunity, the VUMC researchers describe how, from the bone marrow of an individual previously vaccinated against influenza, they isolated two groups of monoclonal antibodies that bound to distinct parts of the neuraminidase glycoprotein on the surface of influenza B.

One of the antibodies, FluB-400, broadly inhibited virus replication in laboratory cultures of human respiratory epithelial cells. It also protected against influenza B in animal models when given by injection or through the nostrils.

Intranasal antibody administration may be more effective and have fewer systemic side effects than more typical routes — intravenous infusion or intramuscular injection — in part because intranasal antibodies may “trap” the virus in the nasal mucus, thereby preventing infection of the underlying epithelial surface, the researchers suggested.

These findings support the development of FluB-400 for the prevention and treatment of influenza B and will help guide efforts to develop a universal influenza vaccine, they said.

“Antibodies increasingly have become an interesting medical tool to prevent or treat viral infections,” said the paper’s corresponding author, James Crowe Jr., MD. “We set out to find antibodies for the type B influenza virus, which continues to be a medical problem, and we were happy to find such especially powerful molecules in our search.”

Crowe, who holds the Ann Scott Carell Chair, is University Distinguished Professor of Pediatrics and director of the Vanderbilt Vaccine Center, which has isolated monoclonal antibodies against a host of viral infections, including COVID-19.

The paper’s first author, Rachael Wolters, DVM, PhD, is a former graduate student in the Crowe lab. Other VUMC co-authors are Elaine Chen, PhD, Ty Sornberger, Luke Myers, Laura Handal, Taylor Engdahl, Nurgen Kose, Lauren Williamson, PhD, Buddy Creech, MD, and Katherine Gibson-Corley, DVM, PhD.

This study was supported in part by National Institutes of Health grants T32AI112541, K01OD036063 and U01AI150739, NIH-HHS contracts 75N93019C00074 and 75N93019C00073, and the Collaborative Influenza Vaccine Innovation Centers program of the National Institute of Allergy and Infectious Diseases.

In the first two years of life, children experience a somewhat narrow set of objects and faces, but with many different viewpoints and under varying lighting conditions. Inspired by this developmental insight, the researchers introduced a new machine learning approach that uses information about spatial position to train AI visual systems more efficiently. They found that AI models trained on the new method outperformed base models by up to 14.99%. They reported their findings in the May issue of the journal Patterns.

“Current approaches in AI use massive sets of randomly shuffled photographs from the internet for training. In contrast, our strategy is informed by developmental psychology, which studies how children perceive the world,” said Lizhen Zhu, the lead author and doctoral candidate in the College of Information Sciences and Technology at Penn State.

The researchers developed a new contrastive learning algorithm, which is a type of self-supervised learning method in which an AI system learns to detect visual patterns to identify when two images are derivations of the same base image, resulting in a positive pair. These algorithms, however, often treat images of the same object taken from different perspectives as separate entities rather than as positive pairs. Taking into account environmental data, including location, allows the AI system to overcome these challenges and detect positive pairs regardless of changes in camera position or rotation, lighting angle or condition and focal length, or zoom, according to the researchers.

“We hypothesize that infants’ visual learning depends on location perception. In order to generate an egocentric dataset with spatiotemporal information, we set up virtual environments in the ThreeDWorld platform, which is a high-fidelity, interactive, 3D physical simulation environment. This allowed us to manipulate and measure the location of viewing cameras as if a child was walking through a house,” Zhu added.

The scientists created three simulation environments — House14K, House100K and Apartment14K, with ’14K’ and ‘100K’ referring to the approximate number of sample images taken in each environment. Then they ran base contrastive learning models and models with the new algorithm through the simulations three times to see how well each classified images. The team found that models trained on their algorithm outperformed the base models on a variety of tasks. For example, on a task of recognizing the room in the virtual apartment, the augmented model performed on average at 99.35%, a 14.99% improvement over the base model. These new datasets are available for other scientists to use in training through www.child-view.com.

“It’s always hard for models to learn in a new environment with a small amount of data. Our work represents one of the first attempts at more energy-efficient and flexible AI training using visual content,” said James Wang, distinguished professor of information sciences and technology and advisor of Zhu.

The research has implications for the future development of advanced AI systems meant to navigate and learn from new environments, according to the scientists.

“This approach would be particularly beneficial in situations where a team of autonomous robots with limited resources needs to learn how to navigate in a completely unfamiliar environment,” Wang said. “To pave the way for future applications, we plan to refine our model to better leverage spatial information and incorporate more diverse environments.”

Collaborators from Penn State’s Department of Psychology and Department of Computer Science and Engineering also contributed to this study. This work was supported by the U.S. National Science Foundation, as well as the Institute for Computational and Data Sciences at Penn State.

The research, which was published in April in the journal Appetite, provides a collection of carefully curated images of minimally processed and ultra-processed foods matched on 26 characteristics, including macronutrients, sodium, dietary fiber, calories, price, and visual characteristics such as a color and portion size.

The work was based on the NOVA classification system — “nova” means new in Portuguese — which groups foods into four categories based on their level of processing. Nutrition researchers at the University of São Paulo in Brazil developed the scale while studying the country’s sharp increase in obesity rates.

The scale has its detractors.

“A major criticism of the NOVA scale is that it’s difficult to use or that foods are classified differently by different people,” said Alexandra DiFeliceantonio, corresponding author and assistant professor at the Fralin Biomedical Research Institute. “We found that people with education in nutrition generally agreed on the food classifications, providing some data that it might not be a valid criticism.”

What they did

The NOVA system assigns food to four categories: unprocessed or minimally processed, such as fresh fruit, legumes, or plain yogurt; processed culinary ingredients, such as cooking oils, butter, and salt; processed foods, which combine the two above through simple methods suc as cheese, canned vegetables, or freshly baked bread; and ultra-processed foods, such as soft drinks, flavored yogurt, processed meat, and most packaged breads, made through industrial processing and additives rarely found in a home pantry.

To develop the picture set, a team of psychologists, neuroscientists, and registered dietitians selected foods to represent either minimally processed or ultra-processed foods.

The foods were prepared in a lab, visually represented through professional photography, and controlled for consistency. Researchers also gathered price, food weights, and nutritional information — calories, macronutrients, sodium, and dietary fiber — for the food in each image.

Study participants rated images across a range of qualities to generate a final set of 28 pictures matched across 26 characteristics. To objectively measure NOVA classification, researchers recruited 67 nutrition professionals and asked them to classify the foods as minimally or ultra-processed.

“With this food picture set we can start to infer that any differences between food pictures is due to the degree of food processing, and not all these other factors that we know are potentially impactful,” said Zach Hutelin, the study’s lead author and a Fralin Biomedical Research Institute-based graduate student in the translational biology, medicine and health Ph.D. program.

Why this matters

Ultra-processed foods are linked with increased risk of developing obesity, Type 2 diabetes, heart disease, and cancer. They represent more than half of calories consumed in the United States, Canada, and the United Kingdom and have been identified as a global threat to public health.

“There is very little experimental research on ultra-processed foods, and part of what’s been holding us back is better tools for measuring and assessing their effects,” said DiFeliceantonio, who is also associate director of the Fralin Biomedical Research Institute’s Center for Health Behaviors Research. “The more tools we can provide, the more we can learn.”

The Virginia Tech team is making the pictures and associated data accessible through the Virginia Tech Data Repository of the Virginia Tech University Libraries. This will allow scientists to test hypotheses in behavioral economic and neuroimaging studies.

In the DiFeliceantonio lab, the photos are being used with functional MRI to reveal associated brain activity, with the images isolating the effects of food processing from other characteristics.

The study was funded by a National Science Foundation graduate research fellowship, the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and a grant from the Seale Innovation Fund, which supports innovative pilot research projects at the Fralin Biomedical Research Institute. DiFeliceantonio received a grant from the fund to investigate metabolic, neural, and behavioral data to better understand how our brains process nutrient availability and food preference.

Subjective cognitive decline is when a person reports memory and thinking problems before any decline is large enough to show up on standard tests.

“Understanding the earliest signs of Alzheimer’s disease is even more important now that new disease-modifying drugs are becoming available,” said study author Rebecca E. Amariglio, PhD, of Harvard Medical School in Boston. “Our study found early suspicions of memory problems by both participants and the people who knew them well were linked to higher levels of tau tangles in the brain.”

The study involved 675 adults with an average age of 72 who did not have cognitive impairment on formal testing. All had brain scans for amyloid plaques. Of this group, 60% had elevated levels of amyloid, meaning they were at risk for developing cognitive impairment due to Alzheimer’s disease even though, at the time of the scan, they were cognitively normal. Participants did not know if they had elevated levels of amyloid.

Each participant had a study partner — a spouse, child or friend — who could answer questions about the participant’s thinking and memory skills and ability to perform daily tasks. In 65% of cases, partners lived with participants.

Each participant and their partner completed a questionnaire to assess the participant’s subjective cognitive decline. Questions included, “Compared to one year ago, do you feel that your memory has declined substantially?” and “Compared to one year ago, do you have more difficulty managing money?” Participants’ and partners’ scores were recorded with higher scores indicating greater complaints about memory.

Researchers also reviewed brain scans for levels of tau tangles. Greater tau is also a risk factor for Alzheimer’s disease and is at higher levels in people with elevated amyloid.

Researchers found participants with higher levels of tau tangles in the brain had higher scores of complaints on the memory questionnaire. Their partners also scored them higher. This association was stronger in participants who had elevated levels of amyloid plaques.

“Our study included a high percentage of people with elevated amyloid, and for this reason we were able to also see that memory complaints were associated with higher tau tangles,” said Amariglio. “Our findings suggest that asking older people who have elevated Alzheimer’s disease biomarkers about subjective cognitive decline may be valuable for early detection. This is particularly important since it is predicted that treatments given at the earliest diagnosable form of the disease will be the most effective in slowing the disease.”

Limitations of the study include that most participants were white and highly educated. Amariglio noted future studies should follow people for longer periods of time and include more participants from other racial and ethnic groups, as well as people with different levels of education.

In a study published last month in Nature Communications, researchers from Tokyo Medical and Dental University (TMDU) have revealed that growing donor skin in another species yields surprisingly robust and functional skin grafts.

The gold standard for treating burn wounds is autologous skin grafting, a process in which sheets of skin containing both the epidermis (the outer layer) and the dermis (the deeper layer) are transferred from other parts of the patient’s body to cover the wounded area. However, for large wounds it can be difficult to harvest enough skin from the limited donor sites. Split-thickness grafts that contain mostly epidermis with only some of dermis can be used to cover larger areas, but they do not include features like hair and sweat glands, and are more prone to shrinkage and scarring.

“As alternatives to autologous skin grafts, artificial skin substitutes including cultured epidermis and reconstituted skins have been developed,” says the lead author of the study Dr. Hisato Nagano. “These options are inferior, though, as cultured epidermis can only be used for shallow wounds, and the engraftment rate of reconstituted skins is low.”

To provide proof-of-concept for a new way to produce autologous skin grafts, the researchers generated skin grafts by introducing a mutation into mouse fetuses that made them unable to grow mature epidermis. These fetuses were then injected with mouse stem cells and allowed to develop normally until birth, when their skin growth was analyzed.

“The results were very surprising,” explains Dr. Naoaki Mizuno, the corresponding author. “Not only were the chimeric mice born covered with large patches of skin derived from the injected cells, but these patches also survived up to 3 months when grafted onto mature mice, and even grew fur.”

Intriguingly, injecting the same mutated mouse embryos with human skin cells yielded similar results: as the mice developed in utero, they grew sheets of human skin that mimicked the structure and organization of mature epidermis.

“Our findings suggest that semi-autologous skin grafts containing hair follicles and other skin appendages can be generated in vivo and engrafted successfully,” says Dr. Hiromitsu Nakauchi, senior author.

Given that mouse embryos can only grow small amounts of skin, the next step would be to scale up the process to larger animals with a longer gestation period to generate large human skin grafts. This approach, which involves generating only skin tissue, could help avoid ethical concerns about using human-animal chimeras to produce organs for medical use.

The study will be published on May 29 in JAMA Network Open. It is the latest publication from the Apple Women’s Health Study, a longitudinal study of menstrual cycles, gynecological conditions, and overall women’s health conducted by Harvard Chan School, the National Institute of Environmental Health Sciences, and Apple.

“Our findings can lead to a better understanding of menstrual health across the lifespan and how our lived environment impacts this critical vital sign,” said co-principal investigator Shruthi Mahalingaiah, assistant professor of environmental, reproductive, and women’s health at Harvard Chan School.

While previous studies have shown trends towards earlier menarche over the past five decades, data has been limited on how these trends present within different racial groups and socioeconomic statuses. Additionally, few studies have had sufficient data to identify any trends regarding time to menstrual cycle regularity.

The researchers used the Apple Women’s Health Study’s large, diverse dataset to fill this research gap. Participants who enrolled in the study between November 2018 and March 2023 — 71,341 in total — self-reported the age at which they first began menstruating and their race and socioeconomic status. The researchers divided the participants into five age brackets: born between 1950-1969, 1970-1979, 1980-1989, 1990-1999, and 2000-2005. Ages of menarche were defined as early (younger than 11 years old), very early (younger than 9), and late (ages 16 and above). A subset of participants (61,932) self-reported the time it took for their menstrual cycle to become regular and were divided into five categories: up to two years, between three and four years, longer than five years, hasn’t become regular, or became regular with use of hormones. Another subset (9,865) provided their body mass index (BMI) at their age of menarche.

The study found that as birth year increased (meaning younger participants), average age at menarche decreased and time from menarche to menstrual cycle regularity increased. Among participants born from 1950-1969, the average age at menarche was 12.5 years, and the rates of early and very early menarche were 8.6% and 0.6%, respectively. Among participants born from 2000-2005, the average age of menarche was 11.9 years, and the rates of early and very early menarche were 15.5% and 1.4%, respectively. Across the two groups, the percentage of participants who reached menstrual cycle regularity within two years of menarche decreased from 76% to 56%. The researchers observed that these trends were present among all sociodemographic groups but were most pronounced among the participants who identified as Black, Hispanic, Asian, or mixed race, and who rated themselves as belonging to a low socioeconomic status.

The findings showed that BMI at age of menarche could explain part of the trend toward periods starting earlier — in other words, that childhood obesity, a risk factor for early puberty and a growing epidemic in the U.S., could be a contributing factor to earlier menarche. Other possible factors that might explain the trend include dietary patterns, psychological stress and adverse childhood experiences, and environmental factors such as endocrine-disrupting chemicals and air pollution.

“Continuing to investigate early menarche and its drivers is critical,” said corresponding author Zifan Wang, postdoctoral research fellow in Harvard Chan School’s Department of Environmental Health. “Early menarche is associated with higher risk of adverse health outcomes, such as cardiovascular disease and cancer. To address these health concerns — which our findings suggest may begin to impact more people, with disproportionate impact on already disadvantaged populations — we need much more investment in menstrual health research.”

The authors noted some limitations to the study, including that it relies heavily on retrospective self-reporting.

Other Harvard Chan School authors included Gowtham Asokan, Jukka-Pekka Onnela, Michelle Williams, Russ Hauser, and Brent Coull.

The study was made possible by funding from Apple, Inc. and the National Institutes of Health (grant Z01ES103333).

Growing evidence suggests air pollution, which comprises toxic gases and particulate matter, might contribute to the onset of mental health problems. It is thought that pollution could negatively affect mental health via numerous pathways, including by compromising the blood-brain barrier, promoting neuroinflammation and oxidative stress, and directly entering the brain and damaging tissue.

Despite youth being a key period for the onset of these problems, until now, relatively few studies have investigated the associations of air and noise exposure during early life with mental health.

In this new study, researchers sought to examine the long-term impact of air and noise pollution exposure during pregnancy, early childhood and adolescence on three common mental health problems: psychotic experiences (including hallucinations, such as hearing or seeing things that others cannot, and delusions, such as having very paranoid thoughts), depression and anxiety.

To investigate this, the team used data from over 9,000 participants from Bristol’s Children of the 90s birth cohort study (also known as the Avon Longitudinal Study of Parents and Children), which recruited over 14,000 pregnant women from the Bristol area between 1991 and 1992, and has followed the lives of the women, the children and their partners ever since.

By linking participants’ early childhood data with their mental health reports at the ages of 13, 18 and 24 years, researchers were able to use this to map against outdoor air and noise pollution in South West England at different time points.

Researchers found that relatively small increases in fine particulate matter during pregnancy and childhood were associated with more psychotic experiences and depression symptoms many years later in teenage years and early-adulthood. These associations persisted after considering many related risk factors, such as family psychiatric history, socioeconomic status, and other area-level factors such as population density, deprivation, greenspace and social fragmentation.

The team found that every 0.72 micrograms per cubic meter increase in fine particulate matter (PM_2.5) during pregnancy and childhood was associated with an 11 per cent increased odds and 9 per cent increased odds for psychotic experiences, respectively; while exposure in pregnancy was associated with a 10 per cent increased odds for depression. In contrast, higher noise pollution exposure in childhood and teenage years was subsequently associated with more anxiety symptoms.

Dr Joanne Newbury, Sir Henry Wellcome Postdoctoral Research Fellow in the University’s Bristol Medical School: Population Health Sciences (PHS) and the study’s lead author, said: “Childhood, adolescence, and early adulthood are critical periods for the development of psychiatric disorders: worldwide, nearly two-thirds of those affected become unwell by the age of 25. Our findings add to a growing body of evidence — from different populations, locations, and using different study designs — suggesting a detrimental impact of air pollution (and potentially noise pollution) on mental health.

“This is a major concern, because air pollution is now such a common exposure, and rates of mental health problems are increasing globally. Given that pollution is also a preventable exposure, interventions to reduce exposure, such as low emissions zones, could potentially improve mental health. Targeted interventions for vulnerable groups including pregnant women and children could also provide an opportunity for more rapid reductions in exposure.

“It is important to emphasise that these findings, by themselves, do not prove a causal association. However, other recent studies have shown that low emissions zones appear to have a positive impact on mental health.”

The research, which involved researchers from King’s College London, University College London and Cardiff University, was funded by the University of Bristol, Wellcome, Economic and Social Research Council (ESRC), Medical Research Council (MRC), National Institute for Health and Care Research (NIHR), and the Natural Environment Research Council (NERC).

The new findings provide conclusive evidence that introducing peanuts into babies’ diets early will increase the probability of long-term prevention of peanut allergy.

Lead investigator Professor Gideon Lack from King’s College London said: “Decades of advice to avoid peanuts has made parents fearful of introducing peanuts at an early age. The evidence is clear that early introduction of peanut in infancy induces long term tolerance and protects children from allergy well into adolescence. This simple intervention will make a remarkable difference to future generations and see peanut allergies plummet.”

Results from the LEAP-Trio trial are published today in the NEJM Evidence by researchers from King’s College London and sponsored and co-funded by the US National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID).

Peanut allergy is rising in Western countries. The prevalence of peanut allergy is about 2% in young children in North America, UK, Western Europe, and Australia. For some, even small amounts of peanuts can lead to a life-threatening allergic reaction. This, as well as conflicting advice, has made parents and caregivers fearful of introducing peanuts into diets.

The new research findings come from the LEAP-Trio study, building on the results of the Learning Early About Peanut Allergy (LEAP) clinical trial. In the first trial, half of the participants were asked to regularly consume peanut from infancy until age 5 years, while the other half were asked to avoid peanuts during that period. Researchers found that early introduction of peanut reduced the risk of peanut allergy at age 5 by 81%.

The investigators followed up both groups from age 6 to age 12 or older. In that period, children could choose to eat peanut in whatever amount and frequency they wanted. They found that 15.4% of participants from the early childhood peanut-avoidance group and 4.4% from the early childhood peanut-consumption group had peanut allergy at age 12 or older. These results show that regular, early peanut consumption reduce the risk of peanut allergy in adolescence by 71% compared to early peanut avoidance.

Professor George Du Toit, Co-Lead Investigator from King’s College London said: “This is a safe and highly effective intervention which can be implemented as early as 4 months of age. The infant needs to be developmentally ready to start weaning and peanut should be introduced as a soft pureed paste or as peanut puffs.”

The researchers also found that although participants in the LEAP peanut-consumption group ate more peanut throughout childhood than the other participants overall, the frequency and amount of peanut consumed varied widely in both groups and included periods of not eating peanut. This shows that the protective effect of early peanut consumption lasts without the need to consistently eat peanut products throughout childhood and early adolescence.

The LEAP-Trio study team tested the adolescents for peanut allergy primarily through an oral food challenge. This involved giving participants gradually increasing amounts of peanut in a carefully controlled setting to determine if they could safely consume at least 5 grams of peanut, the equivalent of more than 20 peanuts. The study team also surveyed participants about their recent patterns of peanut consumption and verified the self-reports through measurements of peanut in dust from participants’ beds, a technique previously validated by LEAP investigators.

Professor Lack, who is the Head of the Children’s Allergy Service at Guy’s and St Thomas’ NHS Foundation Trust, added: “Early consumption of peanut will prevent more than 100,000 new cases of peanut allergy every year worldwide.”

However, these viral strains have reduced immunogenicity, which makes them less effective in activating patients’ immune responses against tumours.

Now, a study led by the University of Barcelona, the Bellvitge Biomedical Research Institute (IBIDELL) and the University of Munich (Germany) has developed a new strain of vaccinia virus, which can replicate in tumour cells while maintaining increased immunogenicity. Specifically, it can to induce so-called immunogenic cell death in tumour cells.

The study, published in the journal Molecular Therapy, has been carried out with the support of the Spanish Association Against Cancer (AECC) and the collaboration of the State Research Agency (AEI). The new therapeutic tool, which has been tested in a wide variety of mouse models, has been shown to have reduced toxicity and a high capacity and efficiency to activate immune responses against tumours. The virus is also effective in different cancer treatments, such as melanoma, colon and kidney cancer.

“In addition, we achieved the total disappearance of tumours in a very significant way when we administered the virus repeatedly,” notes expert Juan J. Rojas, first author of the study and principal investigator of the Immunity, Inflammation and Cancer group of the Faculty of Medicine and Health Sciences of the UB and IBIDELL.

The discovery of this new viral strain represents a significant advance in viral immunotherapy research and demonstrates its therapeutic potential for treating cancer patients.

Since 2003, H5N1 influenza viruses have circulated in 23 countries, primarily affecting wild birds and poultry with about 900 human cases, primarily among people who have had close contact with infected birds. In the past few years, however, a highly pathogenic avian influenza virus called HPAI H5N1 has spread to infect more than 50 animal species, and in late March, the United States reported a viral outbreak among dairy cows in Texas. To date, 52 cattle herds across nine states have been affected, with two human infections detected in farm workers with conjunctivitis. Although the virus has so far shown no genetic evidence of acquiring the ability to spread from person-to-person, public health officials are closely monitoring the dairy cow situation as part of overarching pandemic preparedness efforts.

To assess the risk of H5N1 infection by consuming raw milk, researchers from the University of Wisconsin-Madison and Texas A&M Veterinary Medical Diagnostic Laboratory fed droplets of raw milk from infected dairy cattle to five mice. The animals demonstrated signs of illness, including lethargy, on day 1 and were euthanized on day 4 to determine organ virus levels. The researchers discovered high levels of virus in the animals’ nasal passages, trachea and lungs and moderate-to-low virus levels in other organs, consistent with H5N1 infections found in other mammals.

In addition to the mice studies, the researchers also tested to determine which temperatures and time intervals inactivate H5N1 virus in raw milk from dairy cows. Four milk samples with confirmed high H5N1 levels were tested at 63 degrees Celsius (145.4 degrees Fahrenheit) for 5, 10, 20 and 30 minutes, or at 72 degrees Celsius (161.6 degrees Fahrenheit) for 5, 10, 15, 20 and/or 30 seconds. Each of the time intervals at 63℃ successfully killed the virus. At 72℃, virus levels were diminished but not completely inactivated after 15 and 20 seconds. The authors emphasize, however, that their laboratory study was not identical to large-scale industrial pasteurization of raw milk and reflect experimental conditions that should be replicated with direct measurement of infected milk in commercial pasteurization equipment.

In a separate experiment, the researchers stored raw milk infected with H5N1 at 4℃ (39.2 degrees Fahrenheit) for five weeks and found only a small decline in virus levels, suggesting that the virus in raw milk may remain infectious when maintained at refrigerated temperatures.

To date, the U.S. Food and Drug Administration concludes that the totality of evidence continues to indicate that the commercial milk supply is safe. While laboratory benchtop studies provide important, useful information, there are limitations that challenge inferences to real world commercial processing and pasteurization. The FDA conducted an initial survey of 297 retail dairy products collected at retail locations in 17 states and represented products produced at 132 processing locations in 38 states. All of the samples were found to be negative for viable virus. These results underscore the opportunity to conduct additional studies that closely replicate real world conditions. FDA, in partnership with USDA, is conducting pasteurization validation studies — including the use of a homogenizer and continuous flow pasteurizer. Additional results will be made available as soon as they are available.

The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, funded the work of the University of Wisconsin-Madison researchers.

Healthier lives and improved well-being are among the United Nations’ global Sustainable Development Goals. Positively, a recent study shows that life expectancy worldwide is projected to increase by about 4.5 years by 2050. Much of this is thanks to public health efforts to prevent disease and improved survival from illnesses, such as cardiovascular disorders. However, heart disease is still the leading cause of death worldwide, with 26 million people estimated to be affected by heart failure.

Once heart failure has occurred, it has a tendency to reoccur along with other health issues, such as kidney and muscle problems. Researchers in Japan wanted to understand what causes this recurrence and the deterioration of other organs, and whether it can be prevented.

“Based on our earlier research, we hypothesized that recurrence may be caused by stress experienced during heart failure accumulating in the body, particularly in hematopoietic stem cells,” explained Project Professor Katsuhito Fujiu from the Graduate School of Medicine at the University of Tokyo. Hematopoietic stem cells are found in bone marrow and are the source of blood cells and a type of immune cell called macrophages, which help to protect heart health.

By studying mice with heart failure, the researchers found evidence of stress imprinting on the epigenome, that is, chemical changes occurred to the mice’s DNA. An important signaling pathway, called the transforming growth factor beta, which is involved in regulating many cellular processes, was suppressed in the hematopoietic stem cells of mice with heart failure, leading to the production of dysfunctional immune cells.

This change persisted over an extended period of time, so when the team transplanted bone marrow from mice with heart failure into healthy mice, they found that the stem cells continued to produce dysfunctional immune cells. The latter mice later developed heart failure and became prone to organ damage.

“We termed this phenomenon stress memory because the stress from heart failure is remembered for an extended period and continues to affect the entire body. Although various other types of stress might also imprint this stress memory, we believe that the stress induced by heart failure is particularly significant,” said Fujiu.

The good news is that by identifying and understanding these changes to the TGF-β signaling pathway, new avenues are now open for potential future treatments. “Completely new therapies could be considered to prevent the accumulation of this stress memory during hospitalization for heart failure,” said Fujiu. “In animals with heart failure, supplementing additional active TGF-β has been shown to be a potential treatment. Correcting the epigenome of hematopoietic stem cells could also be a way to deplete stress memory.”

Now that it has been identified, the team hopes to develop a system that can detect and prevent the accumulation of stress memory in humans, with a long-term goal of being able to not only prevent the recurrence of heart failure, but also catch the condition before it can fully develop.

Innovative methods have also been bolstered with new tools, and a growth in the use of robotics since the 1980s has moved health care forward significantly. Assistant Professor Zhenhua Tian has pressed forward another step in the march of progress using robotics and noninvasive acoustics, and his team’s work has been published in Science Advances.

Robot-assisted surgery

Surgery using robots has been invasive since its invention because cutting is involved and often other instruments are inserted into the incision. However, because robotic-assisted tools can be smaller, the cuts also tend to be smaller than traditional surgeries, making robotics a preferred choice. This form of surgery has proven its benefits and has grown in use over time, with advantages to patients including

• Less discomfort and bleeding
• Less time in the hospital
• Faster recovery periods

In fact, according to the American College of Surgeons, 1.8 percent of surgeries included a robot in 2012. By 2018, that percentage had risen to 15.1 percent and continues to rise through advancements in robotics. Some of the most common procedures involving robotics include appendectomies, hysterectomies, and gastric bypasses.

Noninvasive sound treatment

While robotic-assisted surgery has its share of advantages, Tian’s team has taken that idea a step beyond its current state: Team members are developing a method of moving small targets, such as cells and medicine, within a body that is noninvasive. That means the method requires no cuts.

The secret is found in acoustic energy emitters that Tian’s team uses to surround and capture particles, working like invisible tweezers. The emitters create 3D acoustic vortex fields that can pass through barriers such as bone and tissue, crossing over one another to form tiny ring-shaped acoustic traps. Micro- to millimeter-sized objects caught at the center of an acoustic trap can be moved and rotated. Tian received a 2024 National Science Foundation Faculty Early Career Development Program (CAREER) award for the acoustic vortex development.

“The ability to move cells and drugs around inside veins without breaking the skin creates new opportunities in medicine,” said Tian. “As we continue the work on this research, I anticipate we will find a host of new applications.”

By mounting an acoustic vortex emitter onto a robotic platform, the acoustic vortex beam can be moved at the micrometer scale. Accordingly, the particle trapping area can be precisely set in a 3D space, and moving a particle after its capture can be engineered. When moving a tiny object along the winding path of a blood vessel, this can be a critical feature.

More than medicine

While Tian’s team is able to move a small object behind a solid structure, the acoustic vortex beams can move particles within both gases and liquids as well. Although the current approach targets small particles within those substances, integrating the acoustic energy emitters together with robotics has applications beyond surgery and very small particles. Contactless, robotic manipulation has potential in many other applications across engineering, biology, and chemistry research. Some of those include

• Controlling microrobots
• Handling delicate bioparticles, such as exosomes and cells
• Transporting hazardous reagent droplets
• Controlling self-assembly of colloidal materials
• Arranging nanomaterials for composite fabrication

“When we were recently participating in a STEM expo, the children who visited us enjoyed putting small beads into the invisible acoustic fields generated by our devices, but we would like to offer the opportunity for them to move larger objects,” said Tian. “Next year, we hope to have a larger emitter that can hold a ping pong ball. It will be interesting to see how we plug that approach into our other research.”

This peptide originates from within a long non-coding RNA (lncRNA) called LOUP. According to the researchers, the human genome encodes over 20,000 lncRNAs, making it the largest group of genes produced from the genome. But despite this abundance, scientists know little about why lncRNAs exist or what they do. This is why lncRNA is sometimes referred to as the “dark matter of the genome.”

The study, published May 23 in the Proceedings of the National Academy of Sciences (PNAS), is one of the very few in the existing literature to chip away at the mysteries of lncRNA. It also presents a new strategy for conducting high-throughput screening to rapidly identify functional lncRNAs in immune cells. The pooled-screen approach allows researchers to target thousands of genes in a single experiment, which is a much more efficient way to study uncharacterized portions of the genome than traditional experiments which focus on one gene at a time.

The research was led by immunologist Susan Carpenter, a professor and Sinsheimer Chair of UC Santa Cruz’s Molecular, Cell, and Developmental Biology Department. She studies the molecular mechanisms involved in protection against infection. Specifically, she focuses on the processes that lead to inflammation to determine the role that lncRNAs play in these pathways.

“Inflammation is a central feature of just about every disease,” she said. “In this study, my lab focused on trying to determine which lncRNA genes are involved in regulating inflammation.”

This meant studying lncRNAs in a type of white blood cell known as a monocyte. They used a modification of the CRISPR/Cas9 technology, called CRISPR inhibition (CRISPRi), to repress gene transcription and find out which of a monocyte’s lncRNAs play a role in whether it differentiates into a macrophage — another type of white blood cell that’s critical to a well-functioning immune response.

In addition, the researchers used CRISPRi to screen macrophage lncRNA for involvement in inflammation. Unexpectedly, they located a region that is multifunctional and can work as an RNA as well as containing an undiscovered peptide that regulates inflammation.

Understanding that this specific peptide regulates inflammation gives drugmakers a target to block the molecular interaction behind that response in order to suppress it, Carpenter said. “In an ideal world, you would design a small molecule to disrupt that specific interaction, instead of, say, targeting a protein that might be expressed throughout the body,” she explained. “We’re still a long way from targeting these pathways with that level of precision, but that’s definitely the goal. There’s a lot of interest in RNA therapeutics right now.”

Co-authors of the study from UC Santa Cruz include Haley Halasz, Eric Malekos, Sergio Covarrubias, Samira Yitiz, Christy Montano, Lisa Sudek, and Sol Katzman, along with researchers at UCSF and MIT. The research was supported with funding from the National Institute of General Medical Sciences (R35GM137801 to Carpenter) and the National Institute of Allergy and Infectious Diseases (F31AI179201 to Malekos).

In a new study of 11 affected individuals, researchers from Newcastle University, the Wellcome Sanger Institute, the Great North Children’s Hospital, and their collaborators were able to link mutations in the NUDCD3 gene to Severe Combined Immunodeficiency and Omenn syndrome¹ – rare and life-threatening immunodeficiency disorders. These mutations prevented the normal development of diverse immune cells needed to combat different pathogens².

The findings, published today (24 May) in Science Immunology, open opportunities for early diagnosis and intervention for this condition.

Severe Combined Immunodeficiency (SCID) and Omenn syndrome are both rare genetic disorders that leave children without a functional immune system and at risk of life-threatening infections. Without urgent treatment, such as stem cell transplants to replace the faulty immune system, many affected will not survive their first year.

While newborn screening methods can flag T cell deficiency, knowledge of the specific genetic cause increases confidence in the diagnosis of SCID and informs the choice of curative therapy. Currently this remains out of reach for at least 1 in 10 affected families.

In this new study, researchers from Newcastle University, the Wellcome Sanger Institute and their collaborators studied 11 children across four families, two of whom had SCID while the other nine had Omenn syndrome. All had inherited mutations that disrupted the function of the NUDCD3 protein, which had not previously been linked to the immune system.

Using detailed studies of patient-derived cells and mouse models, the team demonstrated that NUDCD3 mutations impair a crucial gene-rearranging process called V(D)J recombination, essential for generating the diverse T cell receptors and antibodies needed to recognise and fight different pathogens.

While mice engineered with the same NUDCD3 mutations had milder immune problems, the human patients faced severe, life-threatening consequences. Two patients did survive, however, after receiving a stem cell transplant — reinforcing the importance of early diagnosis and intervention.

Dr Gosia Trynka, author of the study at the Wellcome Sanger Institute and science director at Open Targets, said: “For babies born with high-risk immunodeficiencies, early detection can mean the difference between life and death. These diseases leave newborns essentially defenceless against pathogens that most of us can easily fend off. The identification of this new disease gene will help clinicians to make a prompt molecular diagnosis in affected patients, meaning they can receive life-saving treatments more quickly.”

Professor Sophie Hambleton, senior author of the study at Newcastle University and practicing paediatric immunologist at the Great North Children’s Hospital, said: “SCID and Omenn syndrome are devastating disorders, requiring complex and timely treatments. The more we can understand about its underlying causes, the better we can look after affected babies. Our research is aimed at filling in the gaps so that families can achieve a molecular diagnosis while we continue learning more about how the immune system works in health and disease. We are deeply grateful to the families whose invaluable participation in this study will help future generations.”

Notes

1. Children with severe combined immunodeficiency disorder completely lack the T cells needed to combat infections, while those with Omenn syndrome have abnormal T cells that not only fail to combat infections but also mount attacks on the body’s own tissues. They require urgent infection management and treatment.

2. Specifically, the mutant NUDCD3 could not regulate RAG1, a key enzyme needed in V(D)J recombination. This caused RAG1 to get trapped within cell nucleoli instead of facilitating the gene rearrangements that build immune diversity.

A University of Washington team has developed an artificial intelligence system that lets a user wearing headphones look at a person speaking for three to five seconds to “enroll” them. The system, called “Target Speech Hearing,” then cancels all other sounds in the environment and plays just the enrolled speaker’s voice in real time even as the listener moves around in noisy places and no longer faces the speaker.

The team presented its findings May 14 in Honolulu at the ACM CHI Conference on Human Factors in Computing Systems. The code for the proof-of-concept device is available for others to build on. The system is not commercially available.

“We tend to think of AI now as web-based chatbots that answer questions,” said senior author Shyam Gollakota, a UW professor in the Paul G. Allen School of Computer Science & Engineering. “But in this project, we develop AI to modify the auditory perception of anyone wearing headphones, given their preferences. With our devices you can now hear a single speaker clearly even if you are in a noisy environment with lots of other people talking.”

To use the system, a person wearing off-the-shelf headphones fitted with microphones taps a button while directing their head at someone talking. The sound waves from that speaker’s voice then should reach the microphones on both sides of the headset simultaneously; there’s a 16-degree margin of error. The headphones send that signal to an on-board embedded computer, where the team’s machine learning software learns the desired speaker’s vocal patterns. The system latches onto that speaker’s voice and continues to play it back to the listener, even as the pair moves around. The system’s ability to focus on the enrolled voice improves as the speaker keeps talking, giving the system more training data.

The team tested its system on 21 subjects, who rated the clarity of the enrolled speaker’s voice nearly twice as high as the unfiltered audio on average.

This work builds on the team’s previous “semantic hearing” research, which allowed users to select specific sound classes — such as birds or voices — that they wanted to hear and canceled other sounds in the environment.

Currently the TSH system can enroll only one speaker at a time, and it’s only able to enroll a speaker when there is not another loud voice coming from the same direction as the target speaker’s voice. If a user isn’t happy with the sound quality, they can run another enrollment on the speaker to improve the clarity.

The team is working to expand the system to earbuds and hearing aids in the future.

Additional co-authors on the paper were Bandhav Veluri, Malek Itani and Tuochao Chen, UW doctoral students in the Allen School, and Takuya Yoshioka, director of research at AssemblyAI. This research was funded by a Moore Inventor Fellow award, a Thomas J. Cabel Endowed Professorship and a UW CoMotion Innovation Gap Fund.

The concept of oceanic boundlessness refers to a sense of unity, blissfulness, insightfulness, and spiritual experience often associated with psychedelic sessions.

In one of the first brain imaging studies in psychedelic research, investigators found a specific association between the experiential, psychedelic state and whole-brain dynamic connectivity changes. While previous research has shown increases in static global brain connectivity under psychedelics, the current study shows that this state of hyperconnectivity is dynamic (changing over time) and its transition rate coincides with the feeling of oceanic boundlessness, a hallmark dimension of the psychedelic state.

Lead investigator Johannes G. Ramaekers, PhD, Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, says, “Psilocybin has been one of the most studied psychedelics, possibly due to its potential contribution in treating different disorders, such as obsessive-compulsive disorder, death-related anxiety, depression, treatment-resistant depression, major depressive disorder, terminal cancer-associated anxiety, demoralization, smoking, and alcohol and tobacco addiction. What was not fully understood is what brain activity is associated with these profound experiences.”

Psilocybin generates profound alterations both at the brain and the experiential level. The brain’s tendency to enter a hyperconnected-hyperarousal pattern under psilocybin represents the potential to entertain variant mental perspectives. The findings of the new study illuminate the intricate interplay between brain dynamics and subjective experience under psilocybin, providing insights into the neurophysiology and neuro-experiential qualities of the psychedelic state.

Dr. Ramaekers adds, “Taken together, averaged and dynamic connectivity analyses suggest that psilocybin alters brain function such that the overall neurobiological pattern becomes functionally more connected, more fluid, and less modular.”

Previously acquired functional magnetic resonance imaging (fMRI) data were analyzed for two groups of people; one group of 22 individuals received a single dose of psilocybin, the other 27 participants received a placebo. During the drug’s peak effects, participants who received psilocybin reported substantial phenomenological changes compared to placebo. Also, brain connectivity analysis showed that a pattern characterized by global region-to-region connectivity was re-appearing across the acquisition time in the psilocybin group, potentially accounting for the variant mental associations that participants experience.

Moreover, this hyperconnected pattern was linked to oceanic boundlessness and unity, which indicates an important mapping between brain dynamics and subjective experience, pointing towards “egotropic effects” (vs hallucinergic) of the drug.

PhD candidate and co-author of the paper Larry Fort, University of Liège, emphasizes: “Psychedelic drugs like psilocybin are often referred to as hallucinogens both scientifically and colloquially. As such, we expected that the hallucinatory dimensions of experience would correlate the highest with psilocybin’s hyperconnected pattern. However, hallucinatory experience had a strong, but weaker correlation with this pattern than ego-modifying experiences. This led us to formulate the term ‘egotropic’ to draw attention to these ego-modifying effects as important, perhaps even more so than their hallucinogenic counterparts.”

Editor-in-Chief of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Cameron S. Carter, MD, University of California Irvine, comments, “This study uses readily available resting state fMRI images acquired after psilocybin ingestion to provide new insights into the neurophysiological mechanisms underlying the subjective and clinical effects of the drug. It sets the stage for future studies using other psychedelic agents to examine whether the dynamic connectivity effects reflect a general mechanism for the therapeutic effects of these compounds.

Lead investigator Athena Demertzi, PhD, Physiology of Cognition, GIGA-CRC In Vivo Imaging Center, University of Liège, adds, “We were pleasantly surprised to learn that the brain pattern of hyperconnected regions was further characterized by lower global signal amplitude, which works as a proxy to heightened cortical arousal. So far, this is the first time that such approximation of arousal levels using fMRI was attempted in psychedelic research. This might be an important correlation as we move towards a full characterization of brain states under psychedelics.”

She concludes, “Given the resurgence in research regarding the psychotherapeutic applications of psychedelic drugs, our results are pertinent to understanding how subjective experience under psychedelics influences beneficial clinical outcomes. Is the effect driven by ego-dissolution? By hallucinations? As such, our work exemplifies how the strong inter-relatedness between egotropic effects of moderate dose psilocybin and its hyperconnected brain pattern can inform clinical focus on specific aspects of phenomenology, such as ego-dissolutions. With this information, healthcare professionals may learn how to best engineer psychedelic therapy sessions to produce the best clinical outcomes.”

“These groundbreaking findings advance our understanding of where, how, and when genetic risk contributes to mental disorders such as schizophrenia, post-traumatic stress disorder, and depression,” said Joshua A. Gordon, M.D., Ph.D., director of NIH’s National Institute of Mental Health (NIMH). “Moreover, the critical resources, shared freely,willhelp researchers pinpoint genetic variants that are likely to play a causal role in mental illnesses and identify potential molecular targets for new therapeutics.”

The research is published across 15 papers in Science, Science Advances, and Scientific Reports. The papers report findings along several key themes:

• Population-level analyses that link genetic variants, regulatory elements, and different molecular forms of expressed genes to regulatory networks at the cellular level, in both the developing brain and adult brain
• Single-cell-level maps of the prefrontal cortex from individuals diagnosed with mental disorders and neurodevelopmental disorders
• Experimental analyses validating the function of regulatory elements and genetic variants associated with quantitative trait loci (segments of DNA that are linked with observable traits)

The analyses expand on previous findings, exploring multiple cortical and subcortical regions of the human brain. These brain areas play key roles in a range of essential processes, including decision-making, memory, learning, emotion, reward processing, and motor control.

Approximately 2% of the human genome is composed of genes that code for proteins. The remaining 98% includes DNA segments that help regulate the activity of those genes. To better understand how brain structure and function contribute to mental disorders, researchers in the NIMH-funded PsychENCODE Consortium are using standardized methods and data analysis approaches to build a comprehensive picture of these regulatory elements in the human brain.

In addition to these discoveries, the papers also highlight new methods and tools to help researchers analyze and explore the wealth of data produced by this effort. These resources include a web-based platform offering interactive visualization data from diverse brain cell types in individuals with and without mental disorders, known as PsychSCREEN. Together, these methods and tools provide a comprehensive, integrated data resource for the broader research community.

The papers focus on the second phase of findings from the PsychENCODE Consortium. This effort aims to advance our understanding of how gene regulation impacts brain function and dysfunction.

“These PsychENCODE Consortium findings shed new light on how gene risk maps onto brain function across developmental stages, brain regions, and disorders,” said Jonathan Pevsner, Ph.D., chief of the NIMH Genomics Research Branch. “The work lays a strong foundation for ongoing efforts to characterize regulatory pathways across disorders, elucidate the role of epigenetic mechanisms, and increase the ancestral diversity represented in studies.”

The PsychENCODE papers published in Science and Science Advances are presented as a collection on the Science website.

The study is the largest and most comprehensive so far on the spread of mental disorders in social networks, with more than 700,000 ninth-grade pupils from 860 Finnish schools participating. The adolescents were followed from the end of ninth grade for a median of 11 years.

The researchers demonstrated that the number of classmates diagnosed with a mental disorder was associated with a higher risk of receiving a mental disorder diagnosis later in life.

“The observed link was the strongest during the first year of follow-up in the study. This was not explained by a number of factors related to parents, school and residential area. The link was most pronounced in the case of mood, anxiety and eating disorders,” says Associate Professor Christian Hakulinen of the University of Helsinki.

Research enabled by comprehensive Finnish registers

According to Hakulinen, prior studies have yielded similar results: for example, American researchers have observed indications of depressive symptoms potentially being transmitted from one individual to another in social networks.

In prior research, however, social networks have typically been chosen independently by the research subjects, which may result in bias in the data. Hakulinen points out that school classes are social networks well suited to research, as people are usually not able to choose their classmates.

“Defining the social networks and following adolescents were made possible by extensive Finnish registers. The findings significantly deepen our understanding of how mental health problems develop and affect other people in our social networks,” he says.

Hakulinen nevertheless notes that the connection observed in the study is not necessarily causal. Furthermore, the study did not investigate how mental disorders can potentially be transmitted between individuals.

“It may be possible, for instance, that the threshold for seeking help for mental health issues is lowered when there are one or more people in your social network who have already sought help for their problems. In fact, this kind of normalisation of diagnosis and treatment can be considered beneficial contagion of mental disorders,” Hakulinen says.

More preventive measures?

Mental disorders are a significant global challenge, adversely affecting individuals, society and the economy. According to Hakulinen, anxiety and mood symptoms in particular have in recent years increased among young people.

Previous studies have shown that, in roughly half of all cases, the onset of mental disorders in adulthood occurs when people are under 18. In fact, Hakulinen emphasises the importance of preventive measures and early intervention.

“When taking preventive measures, it’s worthwhile considering that mental disorders can spread from one adolescent to another,” Hakulinen says.

The study involved a total of 713,809 Finnish citizens born between 1985 and 1997. The adolescents were investigated from the end of comprehensive school until they received their first mental disorder diagnosis, relocated from the country or died. At the latest, the follow-up was discontinued at the end of 2019, resulting in a median follow-up period of 11.4 years.

The study received funding from the European Research Council (ERC) and the Research Council of Finland.

In an advance that could prevent that kind of device failure, MIT engineers have found a simple and general way to eliminate fibrosis by coating devices with a hydrogel adhesive. This adhesive binds the devices to tissue and prevents the immune system from attacking it.

“The dream of many research groups and companies is to implant something into the body that over the long term the body will not see, and the device can provide therapeutic or diagnostic functionality. Now we have such an ‘invisibility cloak,’ and this is very general: There’s no need for a drug, no need for a special polymer,” says Xuanhe Zhao, an MIT professor of mechanical engineering and of civil and environmental engineering.

The adhesive that the researchers used in this study is made from cross-linked polymers called hydrogels, and is similar to a surgical tape they previously developed to help seal internal wounds. Other types of hydrogel adhesives can also protect against fibrosis, the researchers found, and they believe this approach could be used for not only pacemakers but also sensors or devices that deliver drugs or therapeutic cells.

Zhao and Hyunwoo Yuk SM ’16, PhD ’21, a former MIT research scientist who is now the chief technology officer at SanaHeal, are the senior authors of the study, which will appear in Nature. MIT postdoc Jingjing Wu is the lead author of the paper.

Preventing fibrosis

In recent years, Zhao’s lab has developed adhesives for a variety of medical applications, including double-sided and single-sided tapes that could be used to heal surgical incisions or internal injuries. These adhesives work by rapidly absorbing water from wet tissues, using polyacrylic acid, an absorbent material used in diapers. Once the water is cleared, chemical groups called NHS esters embedded in the polyacrylic acid form strong bonds with proteins at the tissue surface. This process takes about five seconds.

Several years ago, Zhao and Yuk began exploring whether this kind of adhesive could also help keep medical implants in place and prevent fibrosis from occurring.

To test this idea, Wu coated polyurethane devices with their adhesive and implanted them on the abdominal wall, colon, stomach, lung, or heart of rats. Weeks later, they removed the device and found that there was no visible scar tissue. Additional tests with other animal models showed the same thing: Wherever the adhesive-coated devices were implanted, fibrosis did not occur, for up to three months.

“This work really has identified a very general strategy, not only for one animal model, one organ, or one application,” Wu says. “Across all of these animal models, we have consistent, reproducible results without any observable fibrotic capsule.”

Using bulk RNA sequencing and fluorescent imaging, the researchers analyzed the animals’ immune response and found that when devices with adhesive coatings were first implanted, immune cells such as neutrophils began to infiltrate the area. However, the attacks quickly quenched out before any scar tissue could form.

“For the adhered devices, there is an acute inflammatory response because it is a foreign material,” Yuk says. “However, very quickly that inflammatory response decayed, and then from that point you do not have this fibrosis formation.”

One application for this adhesive could be coatings for epicardial pacemakers — devices that are placed on the heart to help control the heart rate. The wires that contact the heart often become fibrotic, but the MIT team found that when they implanted adhesive-coated wires in rats, they remained functional for at least three months, with no scar tissue formation.

Mechanical cues

The researchers also tested a hydrogel adhesive that includes chitosan, a naturally occurring polysaccharide, and found that this adhesive also eliminated fibrosis in animal studies. However, two commercially available tissue adhesives that they tested did not show this antifibrotic effect because the commercially available adhesives eventually detached from the tissue and allowed the immune system to attack.

In another experiment, the researchers coated implants in hydrogel adhesives but then soaked them in a solution that removed the polymers’ adhesive properties, while keeping their overall chemical structure the same. After being implanted in the body, where they were held in place by sutures, fibrotic scarring occurred. This suggests that there is something about the mechanical interaction between the adhesive and the tissue that prevents the immune system from attacking, the researchers say.

“Previous research in immunology has been focused on chemistry and biochemistry, but mechanics and physics may play equivalent roles, and we should pay attention to those mechanical and physical cues in immunological responses,” says Zhao, who now plans to further investigate how those mechanical cues affect the immune system.

Yuk, Zhao, and others have started a company called SanaHeal, which is now working on further developing tissue adhesives for medical applications.

“As a team, we are interested in reporting this to the community and sparking speculation and imagination as to where this can go,” Yuk says. “There are so many scenarios in which people want to interface with foreign or manmade material in the body, like implantable devices, drug depots, or cell depots.”

The research was funded by the National Institutes of Health and the National Science Foundation.

In aggressive cases of leukemia, the only chance for a cure is to replace the diseased blood system with a healthy one. Although the transplantation of donor blood stem cells is a well-established form of treatment, it is an onerous process for patients. First, chemotherapy is used to remove the body’s own blood stem cells as well as most of the blood cells. Only then do the attending physicians intravenously administer the stem cells from a suitable donor to the patient. This procedure is associated with side effects and potential complications.

The team led by Professor Lukas Jeker from the Department of Biomedicine at the University of Basel has taken a different approach. Writing in the journal Nature, the team describes how all blood cells can be removed from a leukemia sufferer in a targeted manner while a new blood system is built up at the same time. The results represent the successful completion of a project funded by the European Research Council with a Consolidator Grant of EUR 2.4 million.

Mixing console for blood systems

The system established by the researchers in Jeker’s team can be imagined as a mixing console, where a DJ gradually fades down the level of the first song while raising the volume of the second until the first track dies away completely and only the second is audible.

The fading-down process works as follows: Specific antibodies coupled to a cytotoxic drug recognize all blood cells in the patient’s body based on a surface structure. This marker is common to all the different types of blood cell (both healthy and diseased) but does not appear on other cells of the body. Bit by bit, the antibody-drug conjugate therefore recognizes and destroys all cells of the diseased blood system.

While this is taking place, the second song also starts — that is, the patient receives a transplant of new, healthy blood cells from a suitable donor. To prevent the antibody-drug conjugates from also attacking the new blood stem cells, or the blood cells they produce, the researchers use genetic engineering techniques to modify the donor stem cells in a targeted manner. Specifically, they introduce a small change in the surface molecule so that the antibodies don’t recognize the new blood cells. The researchers refer to this targeted modification of the donor stem cells as “shielding,” because it acts like a protective shield against the cancer treatment.

Elaborate search for suitable regulators

The two first authors of the study, Simon Garaudé and Dr. Romina Matter-Marone, worked with an interdisciplinary team of bioinformaticians, biochemists, genetic engineering specialists, and clinicians from academia and industry to select the best-suited target structure — and the best protective modification for the fading-down process — from the multitude of surface molecules on blood cells. The chosen molecule, known as CD45, proved extremely promising in trials on mice and human cells in the laboratory.

“We needed a surface molecule that appeared with approximately the same frequency on all blood cells if possible, including the leukemia cells, but that wasn’t present on other cells in the body,” explains Jeker. CD45 met this requirement and, at the same time, was also suitable for “shielding” — in other words, it could be modified on the donor blood stem cells in such a way that these cells were protected from the cancer treatment but the function of CD45 remained completely normal.

Applications beyond cancer

“The new approach could pave the way for new treatment options for patients whose state of health is incompatible with the chemotherapy needed for stem cell transplantation,” says joint first author Romina Matter-Marone. Although further tests and optimization are needed, the aim is for initial clinical trials to begin in just a few years’ time.

The “mixing console for blood systems” also opens up further possibilities, as joint first author Simon Garaudé explains: “We show how cells that are ‘invisible’ to a blood cell remover can be used to swap out the entire blood system.” This, he says, is an important step toward a programmable blood system that could also assume functions on demand — for example, to correct a serious genetic defect or to impart resistance to specific viruses such as HIV.

“Timely identification of infants at highest risk of RSV-related morbidity is key to prevention,” said lead author Brittney M. Snyder, PhD, assistant professor, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center. “Our personalized risk prediction tool may have applications in allocating expensive and/or limited immunoprophylaxis (immunization with nirsevimab or palivizumab) to achieve the greatest benefit and in promoting RSV prevention among families with high-risk infants.”

More than half of RSV LRTIs are among healthy, term infants who are generally considered low risk. These infants are, in fact, at risk for requiring intensive care unit -level care, and some may die from their illness. Early immunization with nirsevimab is recommended for all infants by the Centers for Disease Control & Prevention, yet in October 2023 nirsevimab was in short supply and the CDC recommended giving it only to high-risk infants who weren’t eligible for immunization with palivizumab.Both products, which prevent RSV LRTI in newborns and young children, are monoclonal antibodies (nirsevimab is long-acting and only requires one dose, while palivizumab is short-acting and requires monthly injections during RSV season).

In the population-based study by Dr. Snyder and colleagues including children insured by the Tennessee Medicaid Program, the researchers assessed infants who did not receive RSV immunoprophylaxis in the first year of life. They gathered demographic and clinical data from administrative health care encounters and linked birth certificates. “To predict whether these infants developed severe RSV LRTI requiring ICU admission during the first year of life, we developed a multivariable logistic regression model. The model includes demographic and clinical variables collected at or shortly after birth-19 variables in all, such as prenatal smoking, delivery method, maternal age and assisted breathing (ventilation) during birth hospitalization,” said lead biostatistician Tebeb Gebretsadik, MPH, Department of Biostatistics, Vanderbilt University Medical Center.

Among 429,365 infants in the study, 713 had severe RSV LRTI requiring ICU admission. The tool had good predictive accuracy and internal validation that indicated a good fit.

“Our objective was to develop a personalized tool for use in all newborns using readily available birth and postnatal data to predict risk of RSV LRTI requiring ICU admission, useful for prioritizing RSV prevention products with limited availability,” said Principal Investigator Tina V. Hartert, MD, MPH, professor of medicine and pediatrics at Vanderbilt University Medical Center. Even though the recent nirsevimab shortage has, fortunately, eased up, it is not known whether shortages will occur in the future. “This tool may be particularly helpful in prioritizing which infants should be immunized during times of limited availability of RSV prevention medicines. Using the tool to identify if their infant is at high risk for RSV infection requiring ICU care may also persuade vaccine-hesitant families to accept RSV immunoprophylaxis, by showing them their newborn is at high risk,” she added.

“To ensure compatibility with nirsevimab and maternal vaccination, our tool was developed for use in all infants,” concluded co-author Niek Achten, MD, postdoctoral fellow in pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands, who imagined the need for such a tool. “In addition to use in the United States during times of limited availability, our tool may prove useful in countries with budgetary constraints needing to prioritize administration to the highest risk infants.”

The authors note that next steps to ensure optimal usefulness include validation of the tool in external populations, further cost-effectiveness analyses and decision curve analyses.

The drug-like inhibitors block the virus from entering the body’s respiratory cells — specifically, they target hemagglutinin, a protein on the surface of type A influenza viruses. The findings, published in the Proceedings of the National Academy of Sciences on May 16, 2024, represent an important step forward in developing a drug that can prevent influenza infection.

“We’re trying to target the very first stage of influenza infection since it would be better to prevent infection in the first place, but these molecules could also be used to inhibit the spread of the virus after one’s infected,” says corresponding author Ian Wilson, DPhil, the Hansen Professor of Structural Biology at Scripps Research.

The inhibitors will need to be further optimized and tested before they can be assessed as antivirals in humans, but the researchers say that these molecules ultimately have the potential to help prevent and treat seasonal flu infections. And, unlike vaccines, the inhibitors likely wouldn’t need to be updated yearly.

The researchers had previously identified a small molecule, F0045(S), with a limited capacity to bind and inhibit H1N1 type A influenza viruses.

“We began by developing a high-throughput hemagglutinin binding assay that allowed us to rapidly screen large libraries of small molecules and found the lead compound F0045(S) with this process,” says corresponding author Dennis Wolan, PhD, senior principal scientist at Genentech and former associate professor at Scripps Research.

In this study, the team aimed to optimize F0045(S)’s chemical structure to design molecules with better drug-like properties and more specific binding ability to the virus. To start, the Wolan lab used “SuFEx click-chemistry,” which was first developed by two-time Nobel laureate and co-author K. Barry Sharpless, PhD, to generate a large library of candidate molecules with various tweaks to F0045(S)’s original structure. When they screened this library, the researchers identified two molecules — 4(R) and 6(R) — with superior binding affinity compared to F0045(S).

Next, Wilson’s lab produced X-ray crystal structures of 4(R) and 6(R) bound to the flu hemagglutinin protein so that they could identify the molecules’ binding sites, determine the mechanisms behind their superior binding ability, and identify areas for improvement.

“We showed that these inhibitors bind much more tightly to the viral antigen hemagglutinin than the original lead molecule did,” says Wilson. “By using click-chemistry, we basically extended the compounds’ ability to interact with influenza by making them target additional pockets on the antigen surface.”

When the researchers tested 4(R) and 6(R) in cell culture to verify their antiviral properties and safety, they found 6(R) was non-toxic and had more than 200-times improved cellular antiviral potency compared to F0045(S).

Finally, the researchers used a targeted approach to further optimize 6(R) and develop compound 7, which proved to have even better antiviral ability.

“This is the most potent small-molecule hemagglutinin inhibitor developed to date,” says corresponding author Seiya Kitamura, who worked on the project as a postdoctoral fellow at Scripps Research and is now an assistant professor at the Albert Einstein College of Medicine.

In future studies, the team plans to continue to optimize compound 7 and to test the inhibitor in animal models of influenza.

“In terms of potency, it will be hard to improve the molecule any further, but there are many other properties to consider and optimize, for example, pharmacokinetics, metabolism and aqueous solubility,” says Kitamura.

Because the inhibitors developed in this study only target H1N1 strains of influenza, researchers are also working to develop equivalent drug-like inhibitors to target other strains of influenza such as H3N2 and H5N1.

This work was supported by the NIH, the Nathan Shock Institute of Aging Research, and Einstein-Montefiore.

“We found that both daily high heat events and extreme temperatures that lasted several days increased the risk of asthma hospital visits,” said corresponding author Morgan Ye, MPH, research data analyst, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco School of Medicine. “Understanding the impacts of climate-sensitive events such as extreme heat on a vulnerable population is the key to reducing the burden of disease due to climate change.”

Ms. Ye and colleagues looked at 2017-2020 electronic health records from the UCSF Benioff Children’s Hospital Oakland, which included data on asthma hospital visits by patients of the hospital, some of whom are from Benioff Oakland’s Federally Qualified Health Center, and demographics including patients’ zip codes. They used data from the PRISM Climate Group of Oregon State University to determine the timing of daily maximum (daytime heat waves) and minimum (nighttime heat waves) for each zip code. The researchers restricted their analyses to the region’s warm season (June to September). To evaluate the potential range of effects of different heat wave measurements, they used 18 different heat wave definitions, including the 99^th, 97.5^th and 95^th percentile of the total distribution of the study period for one, two or three days.

They designed the study in a way that allowed them to determine the association between each heat wave definition and a hospital visit. They repeated the analysis for Bay Area and Central California zip codes.

The team discovered that daytime heat waves were significantly associated with 19 percent higher odds of children’s asthma hospital visits, and longer duration of heat waves doubled the odds of hospital visits. They did not observe any associations for nighttime heat waves.

According to Ye, “We continue to see global temperatures rise due to human-generated climate change, and we can expect a rise in health-related issues as we observe longer, more frequent and severe heat waves. Our research suggests that higher temperatures and increased duration of these high heat days are associated with increased risk of hospital visits due to asthma. Children and families with lower adaptation capacity will experience most of the burden. Therefore, it is important to obtain a better understanding of these heat-associated health risks and susceptible populations for future surveillance and targeted interventions.”

The authors note that past research has suggested positive associations between extreme heat and asthma, but findings regarding hospitalizations and emergency room visits have been conflicting. Additionally, many other studies have focused on respiratory hospitalizations and not hospitalizations for asthma, specifically, and have not included or had a focus on children. This study is also unique because it investigated the effect of daily high temperatures but also the effects of persistent extreme temperatures.

The San Francisco Bay Area and California overall are unique areas of interest because the state is considered a coastal region with less prevalence of cooling units, such as air conditioners. While temperatures may not reach the extremes experienced in other parts of the country, this study demonstrates that even milder extreme heat temperatures may significantly impact health. These effects are more pronounced in climate-susceptible populations, including children and those who are medically vulnerable, such as those served by the urban pediatric health center in this study. The authors hope these study results will lead to more equitable health outcomes and reduce racial/ethnic disparities observed in climate-sensitive events.

“These results can be used to inform targeted actions and resources for vulnerable children and alleviate health-related stress during heat waves,” they conclude.

“We have developed a game-changing, accessible tool that could help ensure that more people suffering from stroke are in the right place at the right time to receive critical, life-restoring care,” said senior author Joshua Bernstock, MD, PhD, MPH, a clinical fellow in the Department of Neurosurgery at Brigham and Women’s Hospital.

Most strokes are ischemic, in which blood flow to the brain is obstructed. LVO strokes are an aggressive type of ischemic stroke that occurs when an obstruction occurs in a major artery in the brain. When blood supply to the brain is compromised, the lack of oxygen and nutrients causes brain cells to die within minutes. LVO strokes are major medical emergencies and require the swift treatment with mechanical thrombectomy, a surgical procedure that retrieves the blockage.

“Mechanical thrombectomy has allowed people that otherwise would have died or become significantly disabled be completely restored, as if their stroke never happened,” said Bernstock. “The earlier this intervention is enacted, the better the patient’s outcome is going to be. This exciting new technology has the potential to allow more people globally to get this treatment faster.”

The research team previously targeted two specific proteins found in capillary blood, one called glial fibrillary acidic protein (GFAP), which is also associated with brain bleeds and traumatic brain injury, and one called D-dimer. In this study, they demonstrated that the levels of these blood-based biomarkers combined with field assessment stroke triage for emergency destination (FAST-ED) scores could identify LVO ischemic strokes while ruling out other conditions such as bleeding in the brain. Brain bleeds cause similar symptoms to LVO stroke, making them hard to distinguish from one another in the field, yet treatment for each is vastly different.

In this prospective, observational diagnostic accuracy study, the researchers looked at data from a cohort of 323 patients coded for stroke in Florida between May 2021 and August 2022. They found that combining the levels of the biomarkers GFAP and D-dimer with FAST-ED data less than six hours from the onset of symptoms allowed the test to detect LVO strokes with 93 percent specificity and 81 percent sensitivity. Other findings included that the test ruled out all patients with brain bleeds, signaling that the technology may ultimately also be employed to detect intracerebral hemorrhage in the field.

Bernstock’s team also sees promising potential future use of this accessible diagnostic tool in low- and middle-income countries, where advanced imaging is not always available. It might also be useful in assessing patients with traumatic brain injuries. Next, they are carrying out another prospective trial to measure the test’s performance when used in an ambulance. They have also designed an interventional trial that leverages the technology to expedite the triage of stroke patients by having them bypass standard imaging and move directly to intervention.

“In stroke care, time is brain,” Bernstock said. “The sooner a patient is put on the right care pathway, the better they are going to do. Whether that means ruling out bleeds or ruling in something that needs an intervention, being able to do this in a prehospital setting with the technology that we built is going to be truly transformative.”

Disclosures: Edoardo Guade declares grant funding from the UK Research and Innovation small business research initiative. Edoardo Guade and Joshua Bernstock have positions and equity in Pockit Diagnostics Ltd. Joshua Bernstock also has an equity position in Treovir Inc. and is on the boards of Centile Bio and NeuroX1.

Funding: This study was supported by Innovate UK grant 104640 and by private funding.

The sweet taste receptor, expressed in taste bud cells, conveys sweetness from the mouth when it is activated. Earlier this month, a study in PLOS One, led by another Monell researcher, delved into how the sweet-taste receptor might be the first stop in a metabolic surveillance system for sugar. The receptor is also expressed in certain intestinal cells, where it may facilitate glucose absorption and assimilation, as part of this system.

The team found that stimulation and inhibition of TAS1R2-TAS1R3 demonstrates that it helps regulate glucose metabolism in humans and may have implications for managing such metabolic disorders as diabetes. Glucose is the primary type of sugar found in human blood, making it a key source of energy for cells.

“Our objective was to determine whether TAS1R2-TAS1R3 influences glucose metabolism in two directions,” said Monell Member Paul Breslin, PhD, Professor of Nutritional Sciences, Rutgers University, and senior author on the paper.

They showed that a TAS1R2-TAS1R3 agonist (sucralose, a zero-calorie sweetener) or a TAS1R2-TAS1R3 antagonist (lactisole, a sodium salt that inhibits sweet taste) mixed with a glucose meal acutely altered human glucose tolerance in different ways. Here, an agonist binds to a receptor and stimulates a cell and an antagonist binds to a receptor and prevents stimulation.

“The novelty of our findings is that the receptor we studied in this experiment impacts blood glucose and insulin during a glucose meal differently, depending on whether it is stimulated or inhibited,” said Breslin. This work provides further evidence that taste receptors help regulate metabolism and nutrient handling.

Plasma insulin levels were measured in study participants given an oral glucose tolerance test (OGTT), which follows blood sugar levels before and after a person drinks a liquid meal containing glucose. Participants’ ratings of perceived sucralose sweetness correlated with early increases in plasma glucose, as well as increases in plasma insulin levels when sucralose was added to the OGTT. The added sucralose tended to accelerate the release of insulin to the glucose load. On the other hand, participants’ sensitivity to lactisole-driven inhibition of sweetness was correlated with decreased plasma glucose levels. Lactisole also tended to slow insulin release.

“When glucose stimulates taste receptors before being absorbed into the body, signals are sent via the mouth and intestine to regulatory organs such as the pancreas. Perhaps, we could devise ways of using TAS1R2-TAS1R3 to help the body handle glucose better by anticipating when glucose will appear in the blood,” said Breslin. When the body senses glucose, it speeds up the absorption to deliver glucose to tissues that may need it and possibly also to prevent glucose from moving too far along the intestine, which may not be good for maintaining a healthy gut microbiome.

“This system is elegant in its simplicity,” said Breslin. The same taste receptor is all over the body — the mouth, gastrointestinal tract, pancreas, liver, and fat cells, with the last three being major metabolic regulatory tissues, all part of the body’s 24/7 metabolic watch.

Is there a relationship between a person’s health status and the activity of their TAS1R2-TAS1R3 receptors? Study authors say likely, suggesting that the degree of receptor activation exerts acute influences on plasma glucose and insulin levels and their timing of onset, which is important for metabolic health.

The team maintains that, in general, the current dietary habits of excessive consumption of food and beverages high in sucrose, high fructose corn syrup, and high-potency sweeteners could hyperstimulate TAS1R2-TAS1R3, contributing to the improper regulation of glucose in the blood. This could lead to a diagnosis of metabolic syndrome, a cluster of risk factors including elevated plasma glucose and insulin insensitivity (along with obesity, hypertension, and elevated plasma fats) that increases the risk of heart disease, stroke, and diabetes. The authors say that future studies should examine the effects of TAS1R2-TAS1R3 stimulation and inhibition in people who are at risk for metabolic syndrome to determine the therapeutic potential of manipulating TAS1R2-TAS1R3 for better metabolic control instead of worse.

“Studies like these — using Monell’s technical capability and deep expertise in the chemical senses — show that the sweet taste receptor TAS1R2-TAS1R3 helps to regulate glucose differently, depending on the sweetness of the food or beverage,” said Breslin. The team’s hope is to apply what they learned to make what we eat and drink healthier.

“A small metabolic change for the positive can add a lot more to the life and health of humans when compounded over decades and millions of people,” said Breslin.

But some scientists worry that the remarkable success of the first COVID-19 vaccines may work against updated versions, undermining the utility of an annual vaccination program. A similar problem plagues the annual flu vaccine campaign; immunity elicited by one year’s flu shots can interfere with immune responses in subsequent years, reducing the vaccines’ effectiveness.

A new study by researchers at Washington University School of Medicine in St. Louis helps to address this question. Unlike immunity to influenza virus, prior immunity to SARS-CoV-2, the virus that causes COVID-19, doesn’t inhibit later vaccine responses. Rather, it promotes the development of broadly inhibitory antibodies, the researchers report.

The study, available online in Nature, shows that people who were repeatedly vaccinated for COVID-19 — initially receiving shots aimed at the original variant, followed by boosters and updated vaccines targeting variants — generated antibodies capable of neutralizing a wide range of SARS-CoV-2 variants and even some distantly related coronaviruses. The findings suggest that periodic re-vaccination for COVID-19, far from hindering the body’s ability to recognize and respond to new variants, may instead cause people to gradually build up a stock of broadly neutralizing antibodies that protect them from emerging SARS-CoV-2 variants and some other coronavirus species as well, even ones that have not yet emerged to infect humans.

“The first vaccine an individual receives induces a strong primary immune response that shapes responses to subsequent infection and vaccination, an effect known as imprinting,” said senior author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine. “In principle, imprinting can be positive, negative or neutral. In this case, we see strong imprinting that is positive, because it’s coupled to the development of cross-reactive neutralizing antibodies with remarkable breadth of activity.”

Imprinting is the natural result of how immunological memory works. A first vaccination triggers the development of memory immune cells. When people receive a second vaccination quite similar to the first, it reactivates memory cells elicited by the first vaccine. These memory cells dominate and shape the immune response to the subsequent vaccine.

In the case of the flu vaccine, imprinting has negative effects. Antibody-producing memory cells crowd out new antibody-producing cells, and people develop relatively few neutralizing antibodies against the strains in the newer vaccine. But in other cases, imprinting can be positive, by promoting the development of cross-reactive antibodies that neutralize strains in both the initial and subsequent vaccines.

To understand how imprinting influences the immune response to repeat COVID-19 vaccination, Diamond and colleagues including first author Chieh-Yu Liang, a graduate student, studied the antibodies from mice or people who had received a sequence of COVID-19 vaccines and boosters targeting first the original and then omicron variants. Some of the human participants also had been naturally infected with the virus that causes COVID-19.

The first question was the strength of the imprinting effect. The researchers measured how many of the participants’ neutralizing antibodies were specific for the original variant, the omicron variant or both. They found that very few people had developed any antibodies unique to omicron, a pattern indicative of strong imprinting by the initial vaccination. But they also found few antibodies unique to the original variant. The vast majority of neutralizing antibodies cross-reacted with both.

The next question was how far the cross-reactive effect extended. Cross-reactive antibodies, by definition, recognize a feature shared by two or more variants. Some features are shared only by similar variants, others by all SARS-CoV-2 variants or even all coronaviruses. To assess the breadth of the neutralizing antibodies, the researchers tested them against a panel of coronaviruses, including SARS-CoV-2 viruses from two omicron lineages; a coronavirus from pangolins; the SARS-1 virus that caused the 2002-03 SARS epidemic; and the Middle Eastern Respiratory Syndrome (MERS) virus. The antibodies neutralized all the viruses except MERS virus, which comes from a different branch of the coronavirus family tree than the others.

Further experiments revealed that this remarkable breadth was due to the combination of original and variant vaccines. People who received only the vaccines targeting the original SARS-CoV-2 variant developed some cross-reactive antibodies that neutralized the pangolin coronavirus and SARS-1 virus, but the levels were low. After boosting with an omicron vaccine, though, the cross-reactive neutralizing antibodies against the two coronavirus species increased.

Taken together, the findings suggest that regular re-vaccination with updated COVID-19 vaccines against variants might give people the tools to fight off not only the SARS-CoV-2 variants represented in the vaccines, but also other SARS-CoV-2 variants and related coronaviruses, possibly including ones that have not yet emerged.

“At the start of the COVID-19 pandemic, the world population was immunologically naïve, which is part of the reason the virus was able to spread so fast and do so much damage,” said Diamond, also a professor of molecular microbiology and of pathology & immunology. “We do not know for certain whether getting an updated COVID-19 vaccine every year would protect people against emerging coronaviruses, but it’s plausible. These data suggest that if these cross-reactive antibodies do not rapidly wane — we would need to follow their levels over time to know for certain — they may confer some or even substantial protection against a pandemic caused by a related coronavirus.”

“The drug is a genetically engineered version of the missing enzyme in iTTP, and we showed that it was able to reverse the disease process in a patient with an extremely severe form of this condition,” said lead author Pavan K. Bendapudi, MD, an investigator in the Division of Hematology and Blood Transfusion Service at Massachusetts General Hospital and an assistant professor of Medicine at Harvard Medical School.

iTTP results from an autoimmune attack against an enzyme called ADAMTS13 that is responsible for cleaving a large protein involved in blood clotting. The current mainstay of therapy for this life-threatening blood disorder is plasma exchange, which removes the harmful autoantibodies and provides extra ADAMTS13. Plasma exchange induces a clinical response in most patients but can restore at best only about half of normal ADAMTS13 activity. By contrast, a recombinant form of human ADAMTS13 (rADAMTS13) offers the possibility of greatly increased ADAMTS13 delivery.

rADAMTS13 was recently approved for patients with congenital thrombotic thrombocytopenic purpura, which occurs in patients born with complete loss of the ADAMTS13 gene. It’s questionable whether rADAMTS13 could be effective in iTTP given the presence of inhibitory anti-ADAMTS13 autoantibodies, but Bendapudi and his colleagues received permission from the US Food and Drug Administration to utilize rADAMTS13 donated from the manufacturer under a compassionate use protocol in a dying patient with treatment-resistant iTTP.

“We found that rADAMTS13 rapidly reversed this patient’s disease process despite the current dogma that inhibitory autoantibodies against ADAMTS13 would render the drug useless in this condition,” said Bendapudi. “We were the first physicians to use rADAMTS13 to treat iTTP in the United States, and in this case it helped to save the life of a young mother.”

Bendapudi noted that the infused rADAMTS13 overwhelmed the inhibitory autoantibodies in the patient and reversed the thrombotic effects of iTTP. This impact was observed almost immediately upon administration of rADAMTS13, after daily plasma exchange had failed to induce remission.

“I think rADAMTS13 has the potential to replace the current standard of care in acute iTTP. We will need larger, well-designed trials to evaluate this possibility,” said Bendapudi.

A phase 2b randomized clinical trial of rADAMTS13 in iTTP was recently initiated.

Increases are expected to be largest in countries where life expectancy is lower, contributing to a convergence of increased life expectancy across geographies. The trend is largely driven by public health measures that have prevented and improved survival rates from cardiovascular diseases, COVID-19, and a range of communicable, maternal, neonatal, and nutritional diseases (CMNNs).

This study indicates that the ongoing shift in disease burden to non-communicable diseases (NCDs) — like cardiovascular diseases, cancer, chronic obstructive pulmonary disease, and diabetes — and exposure to NCD-associated risk factors — such as obesity, high blood pressure, non-optimal diet, and smoking — will have the greatest impact on disease burden of the next generation.

As the disease burden continues to shift from CMNNs to NCDs and from years of life lost (YLLs) to years lived with disability (YLDs), more people are expected to live longer, but with more years spent in poor health. Global life expectancy is forecasted to increase from 73.6 years of age in 2022 to 78.1 years of age in 2050 (a 4.5-year increase). Global healthy life expectancy (HALE) — the average number of years a person can expect to live in good health — will increase from 64.8 years in 2022 to 67.4 years in 2050 (a 2.6-year increase).

To come to these conclusions, the study forecasts cause-specific mortality; YLLs; YLDs; disability-adjusted life years (DALYs, or lost years of healthy life due to poor health and early death); life expectancy; and HALE from 2022 through 2050 for 204 countries and territories.

“In addition to an increase in life expectancy overall, we have found that the disparity in life expectancy across geographies will lessen,” said Dr. Chris Murray, Chair of Health Metrics Sciences at the University of Washington and Director of the Institute for Health Metrics and Evaluation (IHME). “This is an indicator that while health inequalities between the highest- and lowest-income regions will remain, the gaps are shrinking, with the biggest increases anticipated in sub-Saharan Africa.”

Dr. Murray added that the biggest opportunity to speed up reductions in the global disease burden is through policy interventions aimed to prevent and mitigate behavioral and metabolic risk factors.

These findings build upon the results of the GBD 2021 risk factors study, also released today in The Lancet. This accompanying study found that the total number of years lost due to poor health and early death (measured in DALYs) attributable to metabolic risk factors has increased by 50% since 2000. Read more on the risk factors report at https://bit.ly/GBDRisks2021.

The study also puts forth various alternative scenarios to compare the potential health outcomes if different public health interventions could eliminate exposure to several key risk factor groups by 2050.

“We forecast large differences in global DALY burden between different alternative scenarios to see what is the most impactful on our overall life expectancy data and DALY forecasts,” said Dr. Stein Emil Vollset, first author of the study who leads the GBD Collaborating Unit at the Norwegian Institute of Public Health. “Globally, the forecasted effects are strongest for the ‘Improved Behavioral and Metabolic Risks’ scenario, with a 13.3% reduction in disease burden (number of DALYs) in 2050 compared with the ‘Reference’ (most likely) scenario.”

The authors also ran two more scenarios: one focused on safer environments and another on improved childhood nutrition and vaccination.

“Though the largest effects in global DALY burden were seen from the ‘Improved Behavioral and Metabolic Risk’ scenario, we also forecasted reductions in disease burden from the ‘Safer Environment’ and ‘Improved Childhood Nutrition and Vaccination’ scenarios beyond our reference forecast, said Amanda E. Smith, Assistant Director of Forecasting at IHME. “This demonstrates the need for continued progress and resources in these areas and the potential to accelerate progress through 2050.”

“There is immense opportunity ahead for us to influence the future of global health by getting ahead of these rising metabolic and dietary risk factors, particularly those related to behavioral and lifestyle factors like high blood sugar, high body mass index, and high blood pressure,” continued Dr. Murray.

In one of the studies, about 10% of children and 35% of adults who got an antibiotic prescription during an office visit had no specific reason for the antibiotic in their record.

The rate of this type of prescribing is especially high in adults treated seen in emergency departments and in adults seen in clinics who have Medicaid coverage or no insurance, the studies show. But the issue also occurs in children.

Without information about what drove these inappropriate prescriptions, it will be even harder for clinics, hospitals and health insurers to take steps to ensure that antibiotics are prescribed only when they’re really needed, the researchers say.

Overuse and misuse of antibiotics raise the risk that bacteria will evolve to resist the drugs and make them less useful for everyone. Inappropriately prescribed antibiotics may also end up doing more harm than good to patients.

“When clinicians don’t record why they are prescribing antibiotics, it makes it difficult to estimate how many of those prescriptions are truly inappropriate, and to focus on reducing inappropriate prescribing,” said Joseph Ladines-Lim, M.D., Ph.D., first author of both of the new studies and a combined internal medicine/pediatrics resident at Michigan Medicine, U-M’s academic medical center.

“Our studies help contextualize the estimates of inappropriate prescribing that have been published previously,” he added. “Those estimates don’t distinguish between antibiotic prescriptions that are considered inappropriate due to inadequate coding and antibiotic prescriptions truly prescribed for a condition that they can’t treat.”

Ladines-Lim worked with U-M pediatrician and health care researcher Kao-Ping Chua, M.D., Ph.D., on the new studies. The one on outpatient prescribing by insurance status is in the Journal of General Internal Medicine and the one on trends in emergency department prescribing is in Antimicrobial Stewardship and Healthcare Epidemiology.

Building on previous research

Chua and colleagues recently published findings about trends in inappropriate antibiotic prescribing in outpatients under age 65, suggesting about 25% were inappropriate. But that number includes antibiotic prescriptions written for infectious conditions that antibiotics don’t help, such as colds, and antibiotic prescriptions that aren’t associated with any diagnoses that could be a plausible antibiotic indication.

The new studies add more nuance to that finding, by looking more closely at these two different types of inappropriate prescriptions.

Most antibiotic stewardship efforts to date have focused on reducing the use of the first type of inappropriate prescription — those written for infectious but antibiotic-inappropriate conditions like colds. The new studies show such patients still account for 9% to 22% of all antibiotic prescriptions, depending on the setting and age group.

But since doctors and other prescribers aren’t required to run a test for a bacterial infection or list a specific diagnosis in order to prescribe antibiotics, symptoms provide potential clues to why they might have written a prescription anyway.

So some of those 9% to 22% of all people receiving antibiotics may have also had a secondary bacterial infection that the clinician suspected based on symptoms.

However, it’s impossible to know.

As for those with no infection-related diagnoses or symptoms in their records who got antibiotics, the researchers suggest that clinicians may not have bothered to add these diagnoses or symptoms to the patient record inadvertently — or even deliberately, to try to avoid the scrutiny of antibiotic watchdogs.

But the researchers also speculate that the lower rate of diagnosis documentation in patients in the healthcare safety net may also have to do with the way healthcare organizations are reimbursed.

Often, clinics and hospitals receive a fixed amount from Medicaid to care for all their patients with that type of coverage. So they aren’t incentivized to create records that are as detailed as for privately insured patients, whose care traditionally is reimbursed under a fee-for-service model.

“This could actually be a matter of health equity if people with low incomes or no insurance are being treated differently when it comes to antibiotics,” says Ladines-Lim, who has also studied antibiotic use related to immigrant and asylum-seeker health and will soon begin a fellowship in infectious diseases.

He said that private and public insurers, and health systems, may need to incentivize accurate diagnosis coding for antibiotic prescriptions — or at least make it easier for providers to document why they’re giving them.

That might even include steps such as requiring providers to record the reason for antibiotic prescribing before prescriptions can be sent to pharmacies through electronic health record systems.

After all, Ladines-Lim said, physicians often have to list a diagnosis that justifies tests they order, such as CT scans or x-rays. With antibiotic resistance posing an international threat to patients who have antibiotic-susceptible conditions, similar steps to justify prescriptions of antibiotics might be advisable.

In addition to Ladines-Lim and Chua, the other authors of the two articles are Michael A. Fischer, M.D., M.S. of Boston Medical Center and Boston University, and Jeffrey A. Linder, M.D., M.P.H. of Northwestern University Feinberg School of Medicine.

The research was funded by a Resident Research Grant from the American Academy of Pediatrics, a Physician Investigator Award from Blue Cross Blue Shield Foundation of Michigan, and a Research Grant from the National Med-Peds Residents’ Association.

What we see is not simply just a neural representation of the pattern of light in the eye, but an interpretation of this image, to which our needs and expectations contribute. These factors are shaped by earlier experiences and also depend on inner states like our behavioral activity and our vigilance or attentiveness — often collectively known as “arousal.” In a new study recently published in the journal PLoS Biology, researchers from LMU, the University of Freiburg, and the Bernstein Center for Computational Neuroscience analyzed neural activity in the visual thalamus. This is an area of the brain that receives visual signals directly from the eye via the optic nerve before processing them and passing them on. More specifically, they investigated the thalamic dorsal lateral geniculate nucleus (dLGN), the primary interface for visual signals from the retina to the visual cortex.

What happens in the thalamus?

“It’s long been known that the neurons of the dLGN, like the neurons in other thalamic nuclei, exhibit conspicuous patterns of activity that are related to arousal,” explains LMU Professor Laura Busse, lead investigator of the study and soon to be principal investigator in the SyNergy Cluster of Excellence. Two state-dependent firing modes had been described in particular: burst firing, which tends to occur during states of low arousal and behavioral inactivity; and tonic firing, which is observed during states of vigilance. “This led to the hypothesis that thalamic nuclei use burst and tonic firing modes to dynamically control or modify the information flow to and between cortical areas according to the state of arousal of the animal.” However, this proposition has not yet been experimentally tested. “The neural mechanisms by which arousal influences the processing of visual information remain largely unexplained.”

In the new study, Busse’s team directly compared the activity measured in the thalamus with the degree of arousal. “Arousal is reflected in the pupil diameter of mammals, with larger pupils indicating an aroused state,” explains the neurobiologist. In this way, we can make inferences about the state of arousal of an animal from changes in the size of their pupils. The coupled investigation of thalamic and pupil activity helped Busse’s team obtain a clear perspective on the connection between thalamic activity and degree of arousal.

Sensory impressions are modulated

“We discovered that during certain phases of pupil dilation and constriction, different patterns of neural activation occur,” says Professor Christian Leibold from the University of Freiburg and the Bernstein Center for Computational Neuroscience, one of the senior authors of the study. “The electrical activity in the visual thalamus is coupled with the pupil dynamics over timeframes ranging from seconds to several minutes.” This modulation of neural activity patterns during arousal was robust: It did not depend on other factors, such as what the animal saw or whether it was moving, sitting still, or moving its eyes.

“Our research therefore shows that fundamental visual information is transmitted with differential encoding to ‘higher’ areas of the brain like the visual cortex in different phases of arousal,” summarizes neurobiologist Laura Busse. This supplies a first mechanistic explanation for how visual perception can be influenced by changes in the state of arousal. “Our results support the hypothesis that arousal-dependent modulation is not a singular process, but probably an interplay of changes taking place over various timescales.”

AlphaFold2, an artificial intelligence system that predicts protein structures, has made it possible for scientists to identify and conjure an almost infinite number of drug candidates for the treatment of neuropsychiatric disorders. However recent studies have sown doubt about the accuracy of AlphaFold2 in modeling ligand binding sites, the areas on proteins where drugs attach and begin signaling inside cells to cause a therapeutic effect, as well as possible side effects.

In a new paper, Bryan Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology and director of the NIMH Psychoactive Drug Screening Program at the University of North Carolina School of Medicine, and colleagues at UCSF, Stanford and Harvard determined that AlphaFold2 can yield accurate results for ligand binding structures, even when the technology has nothing to go off of. Their results were published in Science.

“Our results suggest that AF2 structures can be useful for drug discovery,” said Roth, senior author who holds a joint appointment at the UNC Eshelman School of Pharmacy. “With a nearly infinite number of possibilities to create drugs that hit their intended target to treat a disease, this sort of AI tool can be invaluable.”

AlphaFold2 and Prospective Modeling

Much like weather forecasting or stock market prediction, AlphaFold2 works by pulling from a massive database of known proteins to create models of protein structures. Then, it can simulate how different molecular compounds (like drug candidates) fit into the protein’s binding sites and produce wanted effects. Researchers can use the resulting combinations to better understand protein interactions and create new drug candidates.

To determine the accuracy of AlphaFold2, researchers had to compare the results of a retrospective study against that of a prospective study. A retrospective study involves researchers feeding the prediction software compounds they already know bind to the receptor. Whereas, a prospective study requires researchers to use the technology as a fresh slate, and then feed the AI platform information about compounds that may or may not interact with the receptor.

Researchers used two proteins, sigma-2 and 5-HT2A, for the study. These proteins, which belong to two different protein families, are important in cell communication and have been implicated in neuropsychiatric conditions such as Alzheimer’s disease and schizophrenia. The 5-HT2A serotonin receptor is also the main target for psychedelic drugs which show promise for treating a large number of neuropsychiatric disorders.

Roth and colleagues selected these proteins because AlphaFold2 had no prior information about sigma-2 and 5-HT2A or the compounds that might bind to them. Essentially, the technology was given two proteins for which it wasn’t trained on — essentially giving the researchers a “blank slate.”

First, researchers fed the AlphaFold system the protein structures for sigma-2 and 5-HT2A, creating a prediction model. Researchers then accessed physical models of the two proteins that were produced using complex microscopy and x-ray crystallography techniques. With a press of a button, as many as 1.6 billion potential drugs were targeted to the experimental models and AlphaFold2 models. Interestingly, every model had a different drug candidate outcome.

Successful Hit Rates

Despite the models having differing results, they show great promise for drug discovery. Researchers determined that the proportion of compounds that actually altered protein activity for each of the models were around 50% and 20% for the sigma-2 receptor and 5-HT2A receptors, respectively. A result greater than 5% is exceptional.

Out of the hundreds of millions of potential combinations, 54% of the drug-protein interactions using the sigma-2 AlphaFold2 protein models were successfully activated through a bound drug candidate. The experimental model for sigma-2 produced similar results with a success rate of 51%.

“This work would be impossible without collaborations among several leading experts at UCSF, Stanford, Harvard, and UNC-Chapel Hill,” Roth said. “Going forward we will test whether these results might be applicable to other therapeutic targets and target classes.”

The findings were presented at the 10^th European Stroke Organisation Conference in Basel, Switzerland and simultaneously published in the New England Journal of Medicine.¹

Professor Craig Anderson, Director of Global Brain Health at The George Institute for Global Health and lead investigator on the study, said that although more research was needed, the results provided a potential pathway to improving outcomes in patients with the most deadly type of stroke.

“Our study shows clear benefits from administering early blood pressure lowering treatment to patients with intracerebral haemorrhage in the ambulance, although overall there was no difference in outcome from this early intervention for all patients with suspected stroke.

“In fact, in patients with a final diagnosis of ischaemic stroke, it actually worsened their outcome, so the ability to make a reliable diagnosis at this early stage is key to harnessing the benefits of very early blood pressure treatment.”

The Intensive ambulance-delivered blood pressure reduction in hyper-acute stroke trial (INTERACT4) was a multicentre, randomised, open-label, blinded-outcome study conducted across dozens of ambulance services in China.

2404 ambulance-assessed patients with suspected acute stroke causing a motor deficit within two hours of onset and elevated systolic blood pressure (≥150mmHg) were randomly assigned to immediate blood pressure-lowering (target 130-140mmHg) or usual blood pressure (BP) management in hospital.

The pre-hospital ambulance-initiated BP reduction group with haemorrhagic stroke had a 30% lower likelihood of a poor functional outcome whereas the group with cerebral ischaemia had an equivalent 30% higher likelihood of a poor functional outcome, when compared to patients with these stroke types who received usual care BP management upon arrival at the hospital.

Overall, the effects of pre-hospital BP reduction had a balanced benefit and harm effect so that there was no overall difference in the functional outcome between those who received the usual care in all the stroke patients. Between-group rates of serious adverse events were similar.

Around 80 percent of strokes worldwide are ischaemic, caused by the loss of blood flow to an area of the brain due to a blockage in a blood vessel, leading to a loss of neurological function.¹

Intracerebral haemorrhage (ICH) represents over a quarter of all cases of stroke and occurs when blood leaks out of a blood vessel into the brain tissue. ICH is the most deadly type of stroke, with up to one third of patients dying in 30 days, and it is more common in China where the study was conducted.²

“All treatments for acute stroke are highly time dependent — brain cells die rapidly when deprived of oxygen. But knowing the best treatment approach to take before being able to identify the type of stroke a patient has experienced, is difficult without brain imaging,” Professor Anderson said.

“The results do not support in-ambulance administration of blood pressure lowering treatment in patients with suspected acute stroke — that is clear.

“But in the last few years, we’ve seen the introduction of mobile stroke ambulances equipped with a CT scanner and other diagnostic tools that aim to identify cases of ischaemic stroke for early administration of clot-busting treatment.

“But our results do support the case for in-ambulance treatment to be administered to patients with haemorrhagic stroke as well.

“In the meantime, while acute stroke treatment happens in the hospital, quicker diagnosis and swift action as soon as the patient arrives at the emergency department is critical to preserving brain function.”

References

1. GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet Neurology 2021;20:795-820
2. Wu S, et al. Stroke in China: advances and challenges in epidemiology, prevention and management. The Lancet Neurology 2019;18:394-405

Patients who underwent infertility were particularly likely — 2.16 times as likely as those who conceived naturally — to undergo hospitalization for dangerously high blood pressure or hypertension.

“Postpartum checkups are necessary for all patients, but this study indicates they are particularly important for patients who undergo infertility treatment to achieve a conception,” said Rei Yamada, an obstetrics and gynecology resident at Rutgers Robert Wood Johnson Medical School and lead author of the study.

The study authors say their results support standards of care that now call for an initial postpartum checkup three weeks after delivery, standards that some health systems have yet to adopt. Much of the elevated risk came in the first month after delivery, particularly for patients who developed dangerously high blood pressure.

“And these results aren’t the only ones to indicate that follow-up should occur early,” said Cande Ananth, chief of the Division of Epidemiology and Biostatistics in the Department of Obstetrics, Gynecology, and Reproductive Sciences at Rutgers Robert Wood Johnson Medical School and senior author of the study. “We have been involved in a series of studies over the past few years that have found serious risks of heart disease and stroke to various high-risk patient populations within those initial 30 days after delivery — risks that could be mitigated with earlier follow-up care.”

The study analyzed the Nationwide Readmissions Database, which contains nationally representative data on about 31 million hospital discharges and readmissions per year. The database contains diagnosis codes, which let researchers find specific populations and identify reasons for readmission.

The researchers used data from more than 31 million patients who were discharged following delivery from 2010 to 2018, including 287,813 patients who had undergone any infertility treatment.

Although infertility treatment predicted a sharply elevated risk of heart disease, the study authors said the relative youth of infertility treatment patients kept their overall risk fairly low. Just 550 of every 100,000 women who received infertility treatment and 355 of every 100,000 who conceived naturally were hospitalized with cardiovascular disease in the year after delivery.

The cause of the elevated risk of heart disease associated with infertility treatment remains unclear. The increase in heart disease could stem from the infertility treatments themselves, the underlying medical issues that made patients infertile or some other cause.

“Looking forward, I’d like to see if different types of infertility treatment and, importantly, medications are associated with different risk levels,” said Yamada. “Our data gave no information about which patients had undergone which treatment. More detailed information might also provide insight into how infertility treatment impacts cardiovascular outcomes.”

“Our system can determine what type of object it encounters as fast as a blindfolded person, just by feeling it and deciding whether it is a tennis ball or an apple, for example,” says Zhibin Zhang, docent at the Department of Electrical Engineering at Uppsala University.

He and his colleague Libo Chen performed the study in close cooperation with researchers from the Signals and Systems Division at Uppsala University, who provided data processing and machine learning expertise, and a group of researchers from the Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics at Karolinska Institutet.

Drawing inspiration from neuroscience, they have developed an artificial tactile system that imitates the way the human nervous system reacts to touch. The system uses electrical pulses that process dynamic tactile information in the same way as the human nervous system. “With this technology, a prosthetic hand would feel like part of the wearer’s body,” Zhang explains.

The artificial system has three main components: an electronic skin (e-skin) with sensors that can detect pressure by touch; a set of artificial neurons that convert analogue touch signals into electrical pulses; and a processor that processes the signals and identifies the object. In principle, it can learn to identify an unlimited number of objects, but in their tests the researchers have used 22 different objects for grasping and 16 different surfaces for touching.

“We’re also looking into developing the system so it can feel pain and heat as well. It should also be able to feel what material the hand is touching, for example, whether it is wood or metal,” says Assistant Professor Libo Chen, who led the study.

According to the researchers, interactions between humans and robots or prosthetic hands can be made safer and more natural thanks to tactile feedback. The prostheses can also be given the ability to handle objects with the same dexterity as a human hand.

“The skin contains millions of receptors. Current e-skin technology cannot deliver enough receptors, but this technology makes it possible, so we would like to produce artificial skin for a whole robot,” says Chen.

The technology could also be used medically, for example, to monitor movement dysfunctions caused by Parkinson’s disease and Alzheimer’s disease, or to help patients recover lost functionality after a stroke.

“The technology can be further developed to tell if a patient is about to fall. This information can be then used to either stimulate a muscle externally to prevent the fall or prompt an assistive device to take over and prevent it,” says Zhang.

The new tool improves on existing risk assessment tools for heart failure by harnessing the power of machine learning (ML) and artificial intelligence (AI) to determine patient-specific risks of developing unfavorable outcomes with heart failure.

“Heart failure is a progressive condition that affects not only quality of life but quantity as well. All heart failure patients are not the same. Each patient is on a spectrum along the continuum of risk of suffering adverse outcomes,” said researcher Sula Mazimba, MD, a heart failure expert. “Identifying the degree of risk for each patient promises to help clinicians tailor therapies to improve outcomes.”

About Heart Failure

Heart failure occurs when the heart is unable to pump enough blood for the body’s needs. This can lead to fatigue, weakness, swollen legs and feet and, ultimately, death. Heart failure is a progressive condition, so it is extremely important for clinicians to be able to identify patients at risk of adverse outcomes.

Further, heart failure is a growing problem. More than 6 million Americans already have heart failure, and that number is expected to increase to more than 8 million by 2030. The UVA researchers developed their new model, called CARNA, to improve care for these patients. (Finding new ways to improve care for patients across Virginia and beyond is a key component of UVA Health’s first-ever 10-year strategic plan.)

The researchers developed their model using anonymized data drawn from thousands of patients enrolled in heart failure clinical trials previously funded by the National Institutes of Health’s National Heart, Lung and Blood Institute. Putting the model to the test, they found it outperformed existing predictors for determining how a broad spectrum of patients would fare in areas such as the need for heart surgery or transplant, the risk of rehospitalization and the risk of death.

The researchers attribute the model’s success to the use of ML/AI and the inclusion of “hemodynamic” clinical data, which describe how blood circulates through the heart, lungs and the rest of the body.

“This model presents a breakthrough because it ingests complex sets of data and can make decisions even among missing and conflicting factors,” said researcher Josephine Lamp, of the University of Virginia School of Engineering’s Department of Computer Science. “It is really exciting because the model intelligently presents and summarizes risk factors reducing decision burden so clinicians can quickly make treatment decisions.”

By using the model, doctors will be better equipped to personalize care to individual patients, helping them live longer, healthier lives, the researchers hope.

“The collaborative research environment at the University of Virginia made this work possible by bringing together experts in heart failure, computer science, data science and statistics,” said researcher Kenneth Bilchick, MD, a cardiologist at UVA Health. “Multidisciplinary biomedical research that integrates talented computer scientists like Josephine Lamp with experts in clinical medicine will be critical to helping our patients benefit from AI in the coming years and decades.”

Findings Published

The researchers have made their new tool available online for free at https://github.com/jozieLamp/CARNA.

In addition, they have published the results of their evaluation of CARNA in the American Heart Journal. The research team consisted of Lamp, Yuxin Wu, Steven Lamp, Prince Afriyie, Nicholas Ashur, Bilchick, Khadijah Breathett, Younghoon Kwon, Song Li, Nishaki Mehta, Edward Rojas Pena, Lu Feng and Mazimba. The researchers have no financial interest in the work.

The project was based on one of the winning submissions to the National Heart, Lung and Blood Institute’s Big Data Analysis Challenge: Creating New Paradigms for Heart Failure Research. The work was supported by the National Science Foundation Graduate Research Fellowship, grant 842490, and NHLBI grants R56HL159216, K01HL142848 and L30HL148881.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

Previously, it was commonly assumed that having an inner voice had to be a human universal. But in recent years, researchers have become aware that not all people share this experience.

According to postdoc and linguist Johanne Nedergård from the University of Copenhagen, people describe the condition of living without an inner voice as time-consuming and difficult because they must spend time and effort translating their thoughts into words:

“Some say that they think in pictures and then translate the pictures into words when they need to say something. Others describe their brain as a well-functioning computer that just does not process thoughts verbally, and that the connection to loudspeaker and microphone is different from other people’s. And those who say that there is something verbal going on inside their heads will typically describe it as words without sound.”

Harder to remember words and rhymes

Johanne Nedergård and her colleague Gary Lupyan from the University of Wisconsin-Madison are the first researchers in the world to investigate whether the lack of an inner voice, or anendophasia as they have coined the condition, has any consequences for how these people solve problems, for example how they perform verbal memory tasks.

People who reported that they either experienced a high degree of inner voice or very little inner voice in everyday life were subjected to one experiment that aimed to determine whether there was a difference in their ability to remember language input and one about their ability to find rhyme words. The first experiment involved the participants remembering words in order — words that were similar, either phonetically or in spelling, e.g. “bought,” “caught,” “taut” and “wart.”

“It is a task that will be difficult for everyone, but our hypothesis was that it might be even more difficult if you did not have an inner voice because you have to repeat the words to yourself inside your head in order to remember them,” Johanne Nedergård explains and continues:

“And this hypothesis turned out to be true: The participants without an inner voice were significantly worse at remembering the words. The same applied to an assignment in which the participants had to determine whether a pair of pictures contained words that rhyme, e.g. pictures of a sock and a clock. Here, too, it is crucial to be able to repeat the words in order to compare their sounds and thus determine whether they rhyme.”

In two other experiments, in which Johanne Nedergård and Gary Lupyan tested the role of the inner voice in switching quickly between different tasks and distinguishing between figures that are very similar, they did not find any differences between the two groups. Despite the fact that previous studies indicate that language and the inner voice play a role in these types of experiments.

“Maybe people who don’t have an inner voice have just learned to use other strategies. For example, some said that they tapped with their index finger when performing one type of task and with their middle finger when it was another type of task,” Johanne Nedergård says.

The results of the two researchers’ study have just been published in the article “Not everybody has an inner voice: Behavioural consequences of anendophasia” in the scientific journal Psychological Science.

Does it make a difference?

According to Johanne Nedergård, the differences in verbal memory that they have identified in their experiments will not be noticed in ordinary everyday conversations. And the question is, does not having an inner voice hold any practical or behavioural significance?

“The short answer is that we just don’t know because we have only just begun to study it. But there is one field where we suspect that having an inner voice plays a role, and that is therapy; in the widely used cognitive behavioural therapy, for example, you need to identify and change adverse thought patterns, and having an inner voice may be very important in such a process. However, it is still uncertain whether differences in the experience of an inner voice are related to how people respond to different types of therapy,” says Johanne Nedergård, who would like to continue her research to find out whether other language areas are affected if you do not have an inner voice.

“The experiments in which we found differences between the groups were about sound and being able to hear the words for themselves. I would like to study whether it is because they just do not experience the sound aspect of language, or whether they do not think at all in a linguistic format like most other people,” she concludes.

About the study

Johanne Nedergård’s and Gary Lupyan’s study comprised almost a hundred participants, half of whom experienced having very little inner voice and the other half very much inner voice.

The participants were subjected to four experiments, e.g. remembering words in sequence and switching between different tasks. The study has been published in the scientific journal Psychological Science.

Johanne Nedergård and Gary Lupyan have dubbed the condition of having no inner voice anendophasia, which means without an inner voice.

Led by Wolynes, the D.R. Bullard-Welch Foundation Professor of Science, professor of chemistry, biosciences and physics and astronomy and co-director of the Center for Theoretical Biological Physics (CTBP), the team focused on deciphering the complex energy landscapes of de-evolved, putative protein sequences corresponding to pseudogenes.

Pseudogenes are segments of DNA that once encoded proteins but have since lost their ability to do so due to sequence degradation — a phenomenon referred to as devolution. Here, devolution represents an unconstrained evolutionary process that occurs without the usual evolutionary pressures that regulate functional protein-coding sequences.

Despite their inactive state, pseudogenes offer a window into the evolutionary journey of proteins.

“Our paper explains that proteins can de-evolve,” Wolynes said. “A DNA sequence can, by mutations or other means, lose the signal that tells it to code for a protein. The DNA continues to mutate but does not have to lead to a sequence that can fold.”

The researchers studied junk DNA in a genome that has de-evolved. Their research revealed that a mutation accumulation in pseudogene sequences typically disrupts the native network of stabilizing interactions, making it challenging for these sequences, if they were to be translated, to fold into functional proteins.

However, the researchers observed instances where certain mutations unexpectedly stabilized the folding of pseudogenes at the cost of altering their previous biological functions.

They identified specific pseudogenes, such as cyclophilin A, profilin-1 and small ubiquitin-like modifier 2 protein, where stabilizing mutations occurred in regions crucial for binding to other molecules and other functions, suggesting a complex balance between protein stability and biological activity.

Moreover, the study highlights the dynamic nature of protein evolution as some previously pseudogenized genes may regain their protein-coding function over time despite undergoing multiple mutations.

Using sophisticated computational models, the researchers interpreted the interplay between physical folding landscapes and the evolutionary landscapes of pseudogenes. Their findings provide evidence that the funnellike character of folding landscapes comes from evolution.

“Proteins can de-evolve and have their ability to fold compromised over time due to mutations or other means,” Wolynes said. “Our study offers the first direct evidence that evolution is shaping the folding of proteins.”

Along with Wolynes, the research team includes lead author and applied physics graduate student Hana Jaafari ; CTBP postdoctoral associate Carlos Bueno ; University of Texas at Dallas graduate student Jonathan Martin; Faruck Morcos, associate professor in the Department of Biological Sciences at UT-Dallas; and CTBP biophysics researcher Nicholas P. Schafer.

The implications of this research extend beyond theoretical biology with potential applications in protein engineering, Jaafari said.

“It would be interesting to see if someone at a lab could confirm our results to see what happens to the pseudogenes that were more physically stable,” Jaafari said. “We have an idea based on our analysis, but it’d be compelling to get some experimental validation.”

Oregon Health & Science University is part of the randomized, double-blind Phase 3 trial that is evaluating the experimental drug aficamten, which was developed by Cytokinetics to treat the obstructive form of hypertrophic cardiomyopathy, or HCM. Of the 282 adults participating in the trial, 19 enrolled through OHSU — the most of any trial center.

“By having more oxygen available during exercise, patients with obstructive hypertrophic cardiomyopathy can more easily walk, perform household chores, and do other everyday tasks,” said cardiologist Ahmad Masri, M.D., M.S., who co-wrote today’s paper and directs the OHSU Knight Cardiovascular Institute’s Hypertrophic Cardiomyopathy Center. “Our latest clinical trial results suggest aficamten is a promising treatment for HCM.”

HCM affects about 1 in 500 people and is one of the most common causes of sudden death for youth and otherwise healthy athletes. Often caused by inherited gene mutations, it thickens heart muscles and makes it difficult for the heart to work as it should. It causes shortness of breath and reduces people’s ability to exercise. The obstructive form of HCM reduces blood flow out of the heart.

About half of the trial’s participants were given the experimental drug, and the other half took a placebo and served as the study’s control group. Scientists measured the participants’ oxygen levels while they used treadmills or bicycles. Those who took aficamten had a significant increase in their maximum oxygen use — 1.7 milliliters per kilogram per minute more than those in the control group.

Having an increased peak oxygen uptake can improve a patient’s ability to be physically active, whereas reduced oxygen uptake can increase the risk of experiencing heart failure, needing a heart transplant, and dying.

Non-drug treatment options for obstructive HCM include surgery to remove excess heart muscle. In 2022, the Food and Drug Administration also approved mavacamten as the first drug designed to target the underlying cause of obstructive HCM. However, mavacamten may increase the risk of heart failure and it interacts with several commonly used medications. As a result, patients who use mavacamten must also undergo intense monitoring.

During the past decade, OHSU has been involved in many research studies exploring new HCM treatment options. It has been a center for several mavacamten studies and is participating in gene therapy research. The university is also currently involved in four other aficamten trials that are evaluating it as a potential treatment for various forms of HCM and in different types of patients, including children.

“This is an exciting time for treating HCM,” Masri said. “While we continue to offer traditional surgical and procedural therapies for HCM, we are now also able to offer patients other treatment options: therapies that were recently approved by the FDA and investigational therapies that are available by participating in clinical trials.”

Much research in cell biology has traditionally centered on understanding how cells react to chemical signals such as diffusible signaling molecules. However, cells also respond to mechanical stimuli such as cell density, size, and substrate stiffness by expressing specific genes. Yet, the mechanisms by which mechanical regulators perceive mechanical stimuli have remained largely unexplored.

In this research, human embryonic stem cells (hESCs) were employed by the researchers to delve into how cells detect and react to mechanical signals. Through an examination of the transcriptome of hESCs cultivated under different cell densities, the researchers pinpointed a key player known as “ETV4,” responsible for mediating variations in stem cell density and controlling differentiation.

Furthermore, the team deciphered the intricate mechanism through which ETV4 perceives mechanical cues. Initially, integrin receptors¹ recognize alterations in cell density, subsequently modulating the endocytosis of a cell surface receptor, namely the Fibroblast Growth Factor Receptor (FGFR). Mechanical regulation of FGFR endocytosis determines the protein stability of ETV4 by ERK signaling.

During the differentiation process of stem cells, ETV4 plays a role in directing the formation of mesendoderm in regions characterized by low cell density while promoting neuroectoderm development in areas of high cell density. The researchers discovered that a new mechanotransducer ETV4 bridges cell density dynamics to stem cell differentiation.

POSTECH Professor Jiwon Jang who led the research stated, “We’ve uncovered the importance of mechanical cues in regulating stem cell differentiation along with the pivotal involvement of ETV4.” He expressed optimism by saying, “Given ETV4’s substantial implications as a critical oncogene, we envision leveraging this insight to devise technologies aimed at controlling cancer cells through mechanical cues.”

The research was conducted with support from the Biomedical Technology Development Program, the Basic Research Program for Individuals, the Group Research and Basic Research Lab Program, and the Smart Specialization Infrastructure Project of the National Research Foundation of Korea.The research was conducted with support from the Biomedical Technology Development Program, the Basic Research Program for Individuals, the Group Research and Basic Research Lab Program, and the Smart Specialization Infrastructure Project of the National Research Foundation of Korea.

1. Integrin receptor: A transmembrane receptor facilitating the cell to the extracellular matrix connections and is involved in intracellular signal transduction by transmitting physicochemical changes inside and outside the cell in both directions

Looking to gain new insights into the generation of PCs, researchers at Baylor College of Medicine and collaborating institutions identified the genes that were preferentially expressed by emerging PCs to guide their development. They discovered a ‘training program’ driving PC development from stem cells and subsequent maturation into active acid-secreting cells. Published in Cell Stem Cell, the findings can lead to new strategies to regulate PC function in different disease settings.

“PCs secrete hydrochloric acid, which generates the strongly acidic environment in the stomach with beneficial effects, such as killing bacteria in contaminated food, facilitating food digestion and promoting absorption of minerals including phosphate, calcium and iron. But acid can also be dangerous, causing conditions from reflux to peptic ulcers to gastric bleeds that can be life-threatening,” said corresponding author Dr. Jason Mills, Herman Brown Endowed Professor of medicine — gastroenterology and co-director of the Texas Medical Center Digestive Disease Center (DDC) at Baylor.

Studying how these cells are generated can help scientists understand conditions in which the stomach stops making PCs, which results in an acid-free stomach that promotes gastric cancer. Or the opposite, conditions in which the stomach makes too many PCs and too much acid.

“Our first step was to generate enough PCs to study their development and maturation,” said co-first author of the study, Dr. Mahliyah Adkins-Threats, a graduate student in the Mills lab while she was working on this project. “PCs are long-lived (about two months), so we needed a system that would allow us to characterize the PC differentiation process in a shorter time.”

The researchers worked with a mouse model in which they eliminated existing PCs. “This triggered the production of new cells in which we were able to capture a first glimpse into the molecular and morphological steps involved when cells in the gastric epithelium commit to becoming PCs and then mature,” Adkins-Threats said.

Using single-cell RNA sequencing, a technique to identify the genes expressed by a cell, the team identified what genes the cells were turning on or off as they became more mature PCs.

The researchers discovered that of all the genes expressed by the cells, there was one, estrogen-related receptor gamma (ERRγ), a gene involved in regulating cell metabolism, that was expressed in both very young parietal cells and in fully functional parietal cells. ERRγ was sufficient for the cells to develop into PCs.

“Progenitor PC cells that were committed to expressing ERRγ, were destined to eventually become mature PCs,” said Mills, a member of and co-associate director for cancer education at the Dan L Duncan Comprehensive Cancer Center. “Our findings indicate that ERRγ is responsible for regulating the differentiation and maturation of these acid secreting PCs.”

“Importantly, when we deleted the Esrrg gene in the gastric epithelium, whole gastric sections completely lacked any PC lineage cells, indicating that this geneis not only sufficient but also required for stem cells to commit to the PC lineage,” Adkins-Threats said. “We see ERRγ as the ‘trainer’ of these young stem cells; it’s the one gene that orchestrates the dynamics of the metabolic pathways that shape stem cells into fully mature PCs.”

Co-first author Sumimasa Arimura, Yang-Zhe Huang, Margarita Divenko, Sarah To, Heather Mao, Yongji Zeng, Jenie Y. Hwang, Joseph R. Burclaffand Shilpa Jainalso contributed to this work. The authors are affiliated with one of the following institutions: Baylor College of Medicine, Washington University atSt. Louis, University of North Carolina at Chapel Hill, North Carolina State University, University of Texas Health at San Antonio and Cincinnati Children’s Hospital Medical Center.

This study was supported by the following grants: National Science Foundation-Graduate Research Fellowship Program DGE-2139839/1745038, as well as multiple grants from the National Institutes of Health including: T32 DK077653, T32 GM007067, a pilot award from the NIDDK-funded DDC (P30 DK56338), NIDDK R01 DK094989 and DK110406 and NCI R01 CA239645.

As often as four days a week, Boeing EA-18G Growler electronic attack aircraft based at the nearby Naval Air Station Whidbey Island fly loops overhead as pilots practice touch-and-go landings. The noise is immense, around the level of a loud rock concert. “It interrupts your day,” Wilbur said. “You’re unable to have a pleasant evening at home. You can’t communicate. You constantly try to organize your day around being gone when the jets are flying.”

New research from the University of Washington shows that the noise isn’t just disruptive — it presents a substantial risk to public health. Published May 9 in the Journal of Exposure Science and Environmental Epidemiology, an analysis of the Navy’s own acoustic monitoring data found that more than 74,000 people are exposed to noise levels associated with adverse health effects.

“Military aircraft noise is substantially more intense and disturbing than commercial jet noise,” said lead author Giordano Jacuzzi, a graduate student in the UW College of the Environment. “Noise exposure has many downstream effects beyond just annoyance and stress — high levels of sleep disturbance, hearing impairment, increased risk of cardiovascular disease — these have real impacts on human health and quality of life. We also found that several schools in the area are exposed to levels that have been shown to put children at risk of delayed learning.”

Guided by conversations with community members and local advocacy groups, researchers analyzed four weeks of acoustic and flight operations data collected by the Navy in 2020 and 2021, in addition to prior-year data collected by a private acoustics company and the National Park Service. Researchers then mapped noise exposure across the region to estimate how much noise specific communities were exposed to in an average year.

Researchers estimated that two-thirds of Island County residents, including everyone in the cities of Oak Harbor and Coupeville, were exposed to potentially harmful levels of noise, as was 85% of the population of the Swinomish Indian Reservation.

In total, an estimated 74,316 people were exposed to average noise levels that posed a risk of annoyance, 41,089 of whom were exposed to nighttime noise levels associated with adverse effects on sleep. Another 8,059 people — most of whom lived within fairly close proximity to aircraft landing strips — were exposed to noise levels that can pose a risk of hearing impairment over time.

“Our bodies produce a lot of stress hormone response to noise in general, it doesn’t matter what kind of noise it is. But particularly if it’s this repeated acute noise, you might expect that stress hormone response to be exacerbated,” said co-author Edmund Seto, a UW professor of environmental and occupational health sciences. “What was really interesting was that we’re reaching noise exposure levels that are actually harmful for hearing. Usually I only think of hearing in the context of working in factories or other really, really loud occupational settings. But here, we’re reaching those levels for the community.”

Taken as a whole, the potential harms can be quite serious, Seto said. “Imagine people trying to sleep, or children in school trying to understand their teachers and you’ve got these jets flying.”

Every monitoring station on Whidbey Island measured noise events in excess of 100 decibels when jets were flying. In some instances, noise levels were “off the charts” — exceeding the limits of models used to predict the health effects of noise exposure around the world.

“We found it striking that Growler noise exceeds the scientific community’s current understanding of the potential health outcomes,” said co-author Julian Olden, a UW professor of aquatic and fishery sciences. “For this reason, our estimates of health impacts are conservative.”

The noise has been the subject of community disputes and legal controversy since 2013, when the U.S. Navy moved more Growler jets onto Whidbey Island and increased the number of flights to more than 110,000 per year. Bob Wilbur is a member and the current chair of Citizens of Ebey’s Reserve, a community group that has sued the Navy over the jet noise and increased flight operations. The group also helped facilitate the UW study, and Wilbur is a co-author.

Like other military aircraft, the Growlers’ noise differs significantly from commercial jets — louder and deeper, the kind of sound that people feel before they hear.

“It’s the intensity, the intermittent nature of the noise, and the low-frequency energy specifically,” Jacuzzi said. “Those three things are very different than what you experience from normal commercial flights, which are predictable and high in altitude. When Growlers fly over a home, they emit a rumbling noise that penetrates windows and shakes walls.”

While commercial jet noise has been the subject of extensive study, research into military aircraft noise is relatively rare. Previous UW-led research found that military flights were the largest cause of noise pollution on the Olympic Peninsula. While discussing that study, Whidbey residents complained that the noise disturbed their sleep and interfered with students’ schoolwork, which prompted this new line of inquiry. While conducting this study, researchers worked closely with community members and advocacy groups and held multiple webinars to share results and shape future work.

“Our research was motivated by the growing chorus of complaints by Washingtonians across multiple counties,” Olden said. “We believe the science speaks for itself. It’s no longer a question of whether noise impacts people, but how, where and how much these effects are experienced.”

Other authors are Lauren Kuehne of Omfishient Consulting, and Anne Harvey and Christine Hurley of Sound Defense Alliance. This research was funded by the UW Population Health Initiative.

Addressing a longstanding gap in surgical and trauma care, this advancement holds potential for patient implementation. Patients experiencing acute trauma often require platelet transfusions to manage bleeding; storage constraints restrict their utility in prehospital scenarios. Synthetic platelet-like particles (PLPs) offer a potential alternative for promptly addressing uncontrolled bleeding.

The team has engineered platelet-like particles capable of traveling through the bloodstream and then homing to the site of tissue damage, where they augment the clotting process and then support subsequent wound healing. The approach addresses an unmet clinical need in trauma care and surgical practice.

“This work represents a pivotal moment in biomedical engineering, showcasing the tangible translational potential of Platelet-Like Particles,” remarked Lyon. “This remarkable collaborative effort has led to a solution that not only addresses critical clinical needs but also suggests a paradigm shift in treatment modalities.”

The study’s comprehensive approach involved rigorous testing in larger animal models of traumatic injury and illustrated that the intervention is extremely well tolerated across a range of models.

Ashley Brown, corresponding author on the study and an associate professor in the joint biomedical engineering program at North Carolina State University and the University of North Carolina at Chapel Hill, said, “In the mouse and pig models, healing rates were comparable in animals that received platelet transfusions and synthetic platelet transfusions and both groups fared better than animals that did not receive either transfusion.”

One of the study’s most significant findings is that these particles can be excreted renally, presenting a breakthrough in elimination pathways associated with injectable, synthetic biomaterials. The remarkable safety profile demonstrated in the study makes it safe and effective in trauma and surgical interventions. This advancement could potentially lead to improved medical treatments and outcomes for patients undergoing such procedures.

Lyon noted, “Given the success of our research and the effectiveness of the synthetic platelets, the team is pushing forward on a path aimed at eventually seeing clinical implementation of this technology.”

Introns are perhaps one of our genome’s biggest mysteries. They are DNA sequences that interrupt the sensible protein-coding information in your genes, and need to be “spliced out.” The human genome has hundreds of thousands of introns, about 7 or 8 per gene, and each is removed by a specialized RNA protein complex called the “spliceosome” that cuts out all the introns and splices together the remaining coding sequences, called exons. How this system of broken genes and the spliceosome evolved in our genomes is not known.

Over his long career, Manny Ares, UC Santa Cruz distinguished professor of molecular, cellular, and developmental biology, has made it his mission to learn as much about RNA splicing as he can.

“I’m all about the spliceosome,” Ares said. “I just want to know everything the spliceosome does — even if I don’t know why it is doing it.”

In a new paper published in the journal Genes and Development, Ares reports on a surprising discovery about the spliceosome that could tell us more about the evolution of different species and the way cells have adapted to the strange problem of introns. The authors show that after the spliceosome is finished splicing the mRNA, it remains active and can engage in further reactions with the removed introns.

This discovery provides the strongest indication we have so far that spliceosomes could be able to reinsert an intron back into the genome in another location. This is an ability that spliceosomes were not previously believed to possess, but which is a common characteristic of “Group II introns,” distant cousins of the spliceosome that exist primarily in bacteria.

The spliceosome and Group II introns are believed to share a common ancestor that was responsible for spreading introns throughout the genome, but while Group II introns can splice themselves out of RNA and then directly back into DNA, the “spliceosomal introns” that are found in most higher-level organisms require the spliceosome for splicing and were not believed to be reinserted back into DNA. However, Ares’s lab’s finding indicates that the spliceosome might still be reinserting introns into the genome today. This is an intriguing possibility to consider because introns that are reintroduced into DNA add complexity to the genome, and understanding more about where these introns come from could help us to better understand how organisms continue to evolve.

Building on an interesting discovery

An organism’s genes are made of DNA, in which four bases, adenine (A), cytosine (C), guanine (G) and thymine (T) are ordered in sequences that code for biological instructions, like how to make specific proteins the body needs. Before these instructions can be read, the DNA gets copied into RNA by a process known as transcription, and then the introns in that RNA have to be removed before a ribosome can translate it into actual proteins.

The spliceosome removes introns using a two-step process that results in the intron RNA having one of its ends joined to its middle, forming a circle with a tail that looks like a cowboy’s “lariat,” or lasso. This appearance has led to them being named “lariat introns.” Recently, researchers at Brown University who were studying the locations of the joining sites in these lariats made an odd observation — some introns were actually circular instead of lariat shaped.

This observation immediately got Ares’s attention. Something seemed to be interacting with the lariat introns after they were removed from the RNA sequence to change their shape, and the spliceosome was his main suspect.

“I thought that was interesting because of this old, old idea about where introns came from,” Ares said. “There is a lot of evidence that the RNA parts of the spliceosome, the snRNAs, are closely related to Group II introns.”

Because the chemical mechanism for splicing is very similar between the spliceosomes and their distant cousins, the Group II introns, many researchers have theorized that when the process of self-splicing became too inefficient for Group II introns to reliably complete on their own, parts of these introns evolved to become the spliceosome. While Group II introns were able to insert themselves directly back into DNA, however, spliceosomal introns that required the help of spliceosomes were not thought to be inserted back into DNA.

“One of the questions that was sort of missing from this story in my mind was, is it possible that the modern spliceosome is still able to take a lariat intron and insert it somewhere in the genome?” Ares said. “Is it still capable of doing what the ancestor complex did?”

To begin to answer this question, Ares decided to investigate whether it was indeed the spliceosome that was making changes to the lariat introns to remove their tails. His lab slowed the splicing process in yeast cells, and discovered that after the spliceosome released the mRNA that it had finished splicing introns from, it hung onto intron lariats and reshaped them into true circles. The Ares lab was able to reanalyze published RNA sequencing data from human cells and found that human spliceosomes also had this ability.

“We are excited about this because while we don’t know what this circular RNA might do, the fact that the spliceosome is still active suggests it may be able to catalyze the insertion of the lariat intron back into the genome,” Ares said.

If the spliceosome is able to reinsert the intron into DNA, this would also add significant weight to the theory that spliceosomes and Group II introns shared a common ancestor long ago.

Testing a theory

Now that Ares and his lab have shown that the spliceosome has the catalytic ability to hypothetically place introns back into DNA like their ancestors did, the next step is for the researchers to create an artificial situation in which they “feed” a DNA strand to a spliceosome that is still attached to a lariat intron and see if they can actually get it to insert the intron somewhere, which would present “proof of concept” for this theory.

If the spliceosome is able to reinsert introns into the genome, it is likely to be a very infrequent event in humans, because the human spliceosomes are in incredibly high demand and therefore do not have much time to spend with removed introns. In other organisms where the spliceosome isn’t as busy, however, the reinsertion of introns may be more frequent. Ares is working closely with UCSC Biomolecular Engineering Professor Russ Corbett-Detig, who has recently led a systematic and exhaustive hunt for new introns in the available genomes of all intron-containing species that was published in the journal Proceedings of the National Academy of Sciences (PNAS) last year.

The paper in PNAS showed that intron “burst” events far back in evolutionary history likely introduced thousands of introns into a genome all at once. Ares and Corbett-Detig are now working to recreate a burst event artificially, which would give them insight into how genomes reacted when this happened.

Ares said that his cross-disciplinary partnership with Corbett-Detig has opened the doors for them to really dig into some of the biggest mysteries about introns that would probably be impossible for them to understand fully without their combined expertise.

“It is the best way to do things,” Ares said. “When you find someone who has the same kind of questions in mind but a different set of methods, perspectives, biases, and weird ideas, that gets more exciting. That makes you feel like you can break out and solve a problem like this, which is very complex.”

While melanoma may be found less frequently in people with darker complexions than fair ones, this potentially serious form of cancer can strike anyone. The study, which consisted of 492,597 patients with melanoma, suggests that added vigilance in early screening is particularly needed for Black men, whose cancers are often found at later stages, leading to worse outcomes compared to white patients.

“We compared non-Hispanic Black patients to white patients and saw striking differences in how patients presented with the disease,” says surgical oncologist Tina Hieken, M.D., senior author of the study and a researcher at Mayo Clinic Comprehensive Cancer Center. “We saw more extremity melanoma, and more later-stage disease.”

Extremity melanoma refers to skin cancer that can develop on the arms, legs, hands and feet. Various factors, including social risk factors and biological components, could be at play, but further research is needed to help determine why these differences exist.

Revealing differences in sex-based immune response

The research found that Black female patients with melanoma fared better than Black male patients.

Men tended to be older at diagnosis and more likely to have cancer that had spread to their lymph nodes compared to women. This translated to worse survival rates. The researchers learned that Black men with stage 3 melanoma have only a 42% chance of surviving for five years, compared to 71% for Black women.

Most research on melanoma hasn’t focused on how race and sex affect outcomes and hasn’t looked at the influence of race and ethnicity across all groups. Dr. Hieken says the study highlights the need to understand these differences better, noting that this is the first large study to confirm that sex-based differences in melanoma outcomes exist within the non-Hispanic Black population.

“When we talk about later-stage melanoma patients who are female versus male in that non-Hispanic Black patient cohort who ended up doing worse, some biological things may be going on here that are interesting,” says Dr. Hieken.

One theory centers on variations in immune response.

“Several immune signals suggest that women may respond better to some immunotherapies than males,” says Dr. Hieken.

Identifying the need

Researchers note that more studies focused on melanoma in a broader range of people, including more Black participants in clinical trials, is key to bridging this knowledge gap and potentially identifying more effective treatments.

“We want to broaden and deepen our reach to better understand the disease that affects all patients,” says Dr. Hieken.

She underscores the role played by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery in this study.

“What we’ve done with the Kern Center, with this study and others, is to identify the need,” says Dr. Hieken. “We have a rich, integrated, multidisciplinary clinical research practice in melanoma, and we want to address clinical needs and knowledge gaps relevant to our practice.”

A wake-up call in the battle against melanoma

Dr. Hieken notes that this study is a wake-up call for everyone battling to diagnose and cure melanoma, regardless of the patient’s sex or skin tone.

She emphasizes that healthcare professionals should carefully examine areas like palms, soles and under fingernails, where melanoma might be more challenging to spot on darker skin.

“We can incorporate screening for skin lesions or lesions under the nails into the visit for patients as part of their regular checkups,” says Dr. Hieken. “What we want to do is elevate care for our patients.”

The Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery and Breast and Melanoma Surgical Oncology in the Department of Surgery supported this research.

Publishing in the journal Cell Host & Microbe, the study describes an approach that provides step-by-step directions for the immune system to generate the elusive, yet necessary antibodies for a successful HIV vaccine.

“HIV is the fastest-evolving virus known. So it’s been a long-standing goal in HIV research to create a vaccine that can generate broadly neutralizing antibodies that can recognize diverse HIV strains,” said lead author Kevin Wiehe, Ph.D., associate professor in the Department of Medicine at Duke University School of Medicine and director of research at DHVI.

Wiehe and colleagues started with an engineered version of a broadly neutralizing antibody in its original state, before any mutations occurred. Knowing that the antibody will need to mutate to keep up with the ever-changing HIV virus, the researchers then added sequential mutations one-by-one to determine which mutations were essential for the antibody to broadly neutralize HIV.

Doing this allowed them to figure out what the exact points were along the route to arrive at broadly neutralizing antibodies. They then developed a vaccine which gave the immune system the turn-by-turn directions to follow that mutational route.

Using mice specially bred to encode for the original version of the antibody, the researchers demonstrated that the guidance system approach triggered the immune system to start churning out the sought-after antibodies.

“This paper shows that our mutation-guided vaccine strategy can work,” said Wiehe, adding that the technique could also be used in vaccines for other diseases. “This strategy potentially gives us a way to design vaccines to direct the immune system to make any antibody we want, which could be a broadly neutralizing antibody for all coronavirus variants, or an anti-cancer antibody.”

Wiehe said the next challenge will be to reproduce the study in primates and then humans.

In addition to Wiehe, study authors includes Kevin O. Saunders, Victoria Stalls, Derek W. Cain, Sravani Venkatayogi, Joshua S. Martin Beem, Madison Berry, Tyler Evangelous, Rory Henderson, Bhavna Hora, Shi-Mao Xia, Chuancang Jiang, Amanda Newman, Cindy Bowman, Xiaozhi Lu, Mary E. Bryan, Joena Bal, Aja Sanzone, Haiyan Chen, Amanda Eaton, Mark A. Tomai, Christopher B. Fox, Ying Tam, Christopher Barbosa, Mattia Bonsignori, Hiromi Muramatsu, S. Manir Alam, David Montefiori, Wilton B. Williams, Norbert Pardi, Ming Tian, Drew Weissman, Frederick W. Alt, Priyamvada Acharya, and Barton F. Haynes.

The study received funding support from the National Institute of Allergy and Infectious Diseases, a part of the National Institutes of Health (UM1AI144371, 1U19AI135902-01, P01AI131251-01).

The finding, from a study led by scientists at Washington State University and the Pacific Northwest National Laboratory, provides new clues as to why night shift workers are more prone to diabetes, obesity and other metabolic disorders.

“There are processes tied to the master biological clock in our brain that are saying that day is day and night is night and other processes that follow rhythms set elsewhere in the body that say night is day and day is night,” said senior study author Hans Van Dongen, a professor in the WSU Elson S. Floyd College of Medicine. “When internal rhythms are dysregulated, you have this enduring stress in your system that we believe has long-term health consequences.”

Though more research is needed, Van Dongen said the study shows that these disrupted rhythms can be seen in as little as three days, which suggests early intervention to prevent diabetes and obesity is possible. Such intervention could also help lower the risk of heart disease and stroke, which is elevated in night shift workers as well.

Published in the Journal of Proteome Research, the study involved a controlled laboratory experiment with volunteers who were put on simulated night or day shift schedules for three days. Following their last shift, participants were kept awake for 24 hours under constant conditions — lighting, temperature, posture and food intake — to measure their internal biological rhythms without interference from outside influences.

Blood samples drawn at regular intervals throughout the 24-hour period were analyzed to identify proteins present in blood-based immune system cells. Some proteins had rhythms closely tied to the master biological clock, which keeps the body on a 24-hour rhythm. The master clock is resilient to altered shift schedules, so these protein rhythms didn’t change much in response to the night shift schedule.

However, most other proteins had rhythms that changed substantially in night shift participants compared to the day shift participants.

Looking more closely at proteins involved in glucose regulation, the researchers observed a nearly complete reversal of glucose rhythms in night shift participants. They also found that processes involved in insulin production and sensitivity, which normally work together to keep glucose levels within a healthy range, were no longer synchronized in night shift participants. The researchers said this effect could be caused by the regulation of insulin trying to undo the glucose changes triggered by the night shift schedule. They said this may be a healthy response in the moment, as altered glucose levels may damage cells and organs, but could be problematic in the long run.

“What we showed is that we can really see a difference in molecular patterns between volunteers with normal schedules and those with schedules that are misaligned with their biological clock,” said Jason McDermott, a computational scientist with PNNL’s Biological Sciences Division. “The effects of this misalignment had not yet been characterized at this molecular level and in this controlled manner before.”

The researchers’ next step will be to study real-world workers to determine whether night shifts cause similar protein changes in long-term shift workers.

“More than one-third of people with neuropathy experience sharp, prickling or shock-like pain, which increases their rates of depression and decreases quality of life,” said study author Melissa A. Elafros, MD, PhD, of the University of Michigan in Ann Arbor and a member of the American Academy of Neurology. “People with neuropathy also have an increased risk of earlier death, even when you take into account other conditions they have, so identifying and treating people with or at risk for neuropathy is essential.”

The study involved 169 people from an outpatient internal medicine clinic serving mainly Medicaid patients in Flint, Michigan. The participants had an average age of 58 years and 69% were Black people. One-half of the people had diabetes, which can cause neuropathy. A total of 67% had metabolic syndrome, which is defined as having excess belly fat plus two or more of the following risk factors: high blood pressure, higher than normal triglycerides (a type of fat found in the blood), high blood sugar and low high-density lipoprotein (HDL) cholesterol, or “good” cholesterol. These risk factors are also associated with neuropathy.

All participants were tested for distal symmetric polyneuropathy. Information about other health conditions was also collected.

A total of 73% of the people had neuropathy. Of those, 75% had not been previously diagnosed with the condition. Nearly 60% of those with neuropathy were experiencing pain.

Of those with neuropathy, 74% had metabolic syndrome, compared to 54% of those who did not have neuropathy.

After adjusting for other factors that could affect the risk of neuropathy, researchers found that people with metabolic syndrome were more than four times more likely to have neuropathy than people who did not have the syndrome.

Researchers were also looking for any relationship between race and income and neuropathy, as few studies have been done on those topics. There was no relationship between low income and neuropathy. For race, Black people had a decreased risk of neuropathy. Black people made up 60% of those with neuropathy and 91% of those without neuropathy.

“The amount of people with neuropathy in this study, particularly undiagnosed neuropathy, was extraordinarily high with almost three fourths of the study population,” Elafros said. “This highlights the urgent need for interventions that improve diagnosis and management of this condition, as well as the need for managing risk factors that can lead to this condition.” A limitation of the study is that it is a snapshot in time; it did not follow people to see who developed neuropathy over time. It also did not look at reasons why people were not able to manage risk factors that can lead to neuropathy.

The study was supported by the National Institute of Neurological Disorders and Stroke, National Institute of Diabetes and Digestive and Kidney Diseases and National Center for Advancing Translational Sciences.

Work of the group, led by Keng Ioi Vong, Ph.D., and Sangmoon Lee, M.D. Ph.D., both from the laboratory of Joseph G. Gleeson, M.D., at the UC San Diego School of Medicine Department of Neurosciences and the Rady Children’s Institute for Genomic Medicine, reveals the first link between spina bifida and a common chromosomal microdeletion in humans. The study demonstrates that individuals carrying this chromosomal deletion — present in one of 2,500 live births — demonstrate a risk of spina bifida more than 10 times greater than the general public.

The study also underscores the potential role of a common food supplement in reducing the risk of spina bifida. The findings were recently published in the journal Science.

Gleeson, Rady Professor in the Department of Neuroscience and director of neuroscience at Rady Children’s Institute for Genomic Medicine, is the senior author of the study. He explained that spina bifida, also known as meningomyelocele, affects one in every 3,000 newborns. Unfortunately, the causes are mostly unknown. A few mutations were reported but could only explain a tiny fraction of risk, Gleeson added.

To uncover the genetic causes of the disease, Gleeson’s UC San Diego lab joined with colleagues from across the globe to establish the Spina Bifida Sequencing Consortium in 2015. The consortium began focusing on a tiny deletion in chromosome 22. Chromosome microdeletions refer to a condition in which several genes in a chromosome are missing. The group’s target condition, known as 22q11.2del, has been implicated in a number of other disorders. They began looking for 22q11.2del in spinal bifida patients.

“All patients we recruited have the most severe form of spina bifida, and all underwent best-practice comprehensive genomic sequencing,” Gleeson said. “We identified 22q11.2del in 6 out of 715 patients. This may not seem a high percentage, but this is by far the most common single genetic variation that could contribute to spina bifida.”

He went on to say the group identified eight additional spina bifida patients who carried the deletion from a cohort of approximately 1,500 individuals recruited because of the presence of the common 22q11.2 deletion, Gleeson said.

The researchers then narrowed the cause among the many genes in the 22q11.2 deletion to a single gene known as CRKL. Gleeson explained that there are nine other genes in this chromosomal region that could have been the cause. He said the team began a process of elimination, “knocking out” each of the mouse genes one-by-one, when they received a fortuitous email from Dolores Lamb from Weil Cornell College of Medicine. Lamb had noted some of the mice in their vivarium that were missing Crkl and showed spina bifida. (Vong explained that researchers use all capital letters to describe the gene in humans, and lower-case for mice. )Lamb’s group heard about the Gleeson lab project throughs the Spina Bifida Association.

“This finding really got us excited because it meant that CRKL disruption might be sufficient for spina bifida,” said Vong, co-first author of the study. “We removed the mouse Crkl gene ourselves and confirmed that some of the mice developed neural tube defects, including spina bifida.” Most of the other genes in 22q11.2 deletion were subsequently excluded, he added.

They next turned their attention to how folic acid may modulate CRKL-mediated spina bifida. Vong noted that prior studies in humans demonstrated that folic acid (also known as vitamin B-9) supplementation prior to conception reduces the incidence of spina bifida and other neural tube defects by up to 30-50 percent, but the mechanisms are still a mystery.

“When we deprived the Crkl mutant female mice of folic acid in their chow, many more of their offspring had neural tube defects, and the severity increased dramatically,” Vong explained. “This suggests that folic acid taken by pregnant women may not only reduce the risk, but also the severity of neural tube defects in their offspring.”

“We hope our findings can help the research community to better understand causes of neural tube defects, especially the causes attributable to common genetic findings like 22q11.2 deletion,” Gleeson said. “We also hope our findings can contribute to healthy pregnancies, improved women’s health, and improved outcomes for children.”

Co-authors associated with the University of San Diego School of Medicine Department of Neurosciences, as well as with Rady Children’s Institute for Genomic Medicine, (in addition to Joseph G. Gleeson Sangmoon Lee and Keng Ioi Vong) are: Renee George, Bryn Gerding, Kiely N. James, Valentina Stanley, Nan Jiang, Kameron Alu, Naomi Meave, Fiza Jiwani, Isaac Tang, Ashna Nisal, Ishani Jhamb, Arzoo Patel, Aakash Patel, Jennifer McEvoy-Venneri, Chelsea Barrows, Celina Shen, Yoo-Jin Ha and Robyn Howarth. Other co-authors include Hal S. Meltzer, of the University of California San Diego Rady Children’s Hospital Department of Neurosurgery; Anna S. Nidhiry, of Rady Children’s Institute for Genomic Medicine; and the Spina Bifida Sequencing Consortium.

This work was supported by the Center for Inherited Disease Research grant HHSN268201700006I, the Yale Center for Genomic Analysis, the Broad Institute, the UC Irvine Genomics Core, the UCSD Institute for Genomic Medicine, the UCSD Transgenic Core, UCSD Microscopy Core grant P30 NS047101, and Columbia Microscopy Core grant S10 OD032447- 01. Other support came from the National Institutes of Health, including National Institute of Diabetes and Digestive and Kidney Diseases, and by support from the Howard Hughes Medical Institute and Rady’s Children Institute for Genomic Medicine to Joseph G. Gleeson.

“Osteoporosis can occur for many reasons such as hormonal changes, aging, and lifestyle factors,” said Swanson, an associate professor in the Division of Endocrinology, Metabolism, and Diabetes. “But some patients I see don’t have an explanation for their osteoporosis.

“Therefore, it’s important to look for novel risk factors and consider what else changes across the lifespan like bone does — sleep is one of those,” she added.

How bone density and sleep change over time

In people’s early- to mid-20s, they reach what is called peak bone mineral density, which is higher for men than it is for women, Swanson said. This peak is one of the main determinants of fracture risk later in life.

After reaching this peak, a person’s bone density remains roughly stable for a couple of decades. Then, when women enter the menopausal transition, they experience accelerated bone loss. Men also experience bone density decline as they age.

Sleep patterns also evolve over time. As people get older, their total sleep time decreases, and their sleep composition changes. For instance, sleep latency, which is the time it takes to fall asleep, increases with age. On the other hand, slow wave sleep, which is deep restorative sleep, decreases as we age.

“And it’s not just sleep duration and composition that change. Circadian phase preference also changes across the lifespan in both men and women,” Swanson said, referring to people’s preference for when they go to sleep and when they wake up.

How can sleep relate to our bone health?

Genes that control our internal clock are present in all of our bone cells, Swanson said.

“When these cells resorb and form bone, they release certain substances into the blood that let us estimate how much bone turnover is going on at a given time,” she said.

These markers of bone resorption and formation follow a daily rhythm. The amplitude of this rhythm is larger for markers of bone resorption — which refers to the process of breaking down bones — than it is for markers of bone formation, she said.

“This rhythmicity is likely important for normal bone metabolism and suggests that sleep and circadian disturbance could directly affect bone health,” she said.

Researching the connection between sleep and bone health

To further understand this relationship, Swanson and colleagues researched how markers of bone turnover responded to cumulative sleep restriction and circadian disruption.

For this study, participants lived in a completely controlled inpatient environment. The participants did not know what time it was, and they were put on a 28-hour schedule instead of a 24-hour day.

“This circadian disruption is designed to simulate the stresses endured during rotating night shift work and is roughly equivalent to flying four time zones west every day for three weeks,” she said. “The protocol also caused participants to get less sleep.”

The research team measured bone turnover markers at the beginning and end of this intervention and found significant detrimental changes in bone turnover in both men and women in response to the sleep and circadian disruption. The detrimental changes included declines in markers of bone formation that were significantly greater in younger individuals in both sexes compared to the older individuals.

In addition, young women showed significant increases in the bone resorption marker.

If a person is forming less bone while still resorbing the same amount — or even more — then, over time, that could lead to bone loss, osteoporosis, and increased fracture risk, Swanson said.

“And sex and age may play an important role, with younger women potentially being the most susceptible to the detrimental impact of poor sleep on bone health,” she said.

Research in this area is ongoing, she added.

The toll cancer takes on lives in the U.S. has declined during the last 28 years, but not equitably. Disparities persist in many historically marginalized communities — including communities disadvantaged by race, socioeconomic status, sexual orientation or gender identity, and geographic location — despite NCI community outreach and engagement programs designed to address them.

Formed in 1971, the NCI recognizes 72 NCI-Designated Cancer Centers, including Dana-Farber. Improving community outreach and engagement has long been an important initiative for NCI, but it was not until 2012 that NCI-DCCs were required to rigorously define their catchment areas, the geographic areas that each center “serves or intends to serve in the research it conducts, the communities it engages, and the outreach it performs.” Beginning in 2016, NCI-DCCs were required to provide specific descriptions of community outreach and engagement interventions.

“The purpose of this review is to help us learn what has been working and also what has been missing in terms of community outreach and engagement efforts,” says Christopher Lathan, MD, MS, MPH, Chief Clinical Access and Equity Officer and Associate Chief Medical Officer at Dana-Farber. “It is imperative that we ensure everyone has access to the latest scientific advances, and that takes a sustained and dedicated focus on community outreach and engagement, clinical access, and health equity.”

NCI-DCCs have initiated several interventions intended to decrease health disparities and increase access to innovative medicines, clinical trials, and preventive services and reported many positive results. For instance, a program initiated by Dana-Farber in 2012 to provide diagnostic and patient navigation services to a local federally qualified health center that serves a predominantly Black community helped reduce time to cancer diagnosis from 32 to 12 days.

Due to an intense focus on scientific research, NCI-DCCs have yielded incredible advances in cancer prevention and treatment. But, the investigators conclude, efforts to reduce disparities must be as focused, integrated, and sustained as those made to advance science. According to the authors, “Until recently, our NCI-DCCs have not matched their scientific focus with an intense focus on the inclusion of historically marginalized patients in research trials, access to treatment advances, and development of innovative care delivery interventions to improve access in marginalized communities.” The newer emphasis on community outreach and engagement must be expanded to give everyone the same opportunities to benefit from the groundbreaking advancement in diagnosis and treatment.

The investigators note that most NCI-DCC community outreach and engagement work has been focused on education and disparities research rather than on the deliberate expansion of care and interventions. Programs that successfully reduced disparities have yet to be widely shared or replicated in ways that broaden their impact. Further, according to the authors, “Many patients, especially those from historically marginalized communities, or those who do not have traditional political or financial capital, feel that it is difficult to share their experiences, thoughts, and ideas for change directly with institutions themselves.” In producing the review itself, the authors were committed to representing the views of those who are impacted most; one of the authors, Barry Nelson, is a patient advocate who was integral to the writing process from start to finish.

The authors recommend the following:

1. NCI-DCCs should engage the communities most impacted and marginalized in a proactive, bidirectional manner and integrate this engagement into the research and diagnostic efforts across the entire cancer center.
2. NCI-DCCs should broaden clinical access for patients across the spectrum of cancer services. This includes investing in the collection of demographic data (area measures of poverty, granular race, ethnicity, sexual orientation and gender identity data) across the enterprise and using evidence-based interventions via a highly developed implementation core that connects clinical operations, health care delivery research, and the basic/translation research enterprise. Interventions should be integrated with the healthcare delivery system, not exist outside of it.
3. NCI-DCCs should commit to evolving their current structure of community outreach and engagement by committing to utilizing their economic power to improve local communities via job training, educational collaborations, and health promotion. They should provide healthcare education to their workforce and catchment area communities.
4. NCI-DCCs should establish and implement governance policies and standards, clearly demonstrating their commitment to elevating and empowering those patient voices so as to facilitate equitable decision-making for inclusion, transparency, and professional integrity.

“We can and must make a marked impact on the health outcomes of historically marginalized communities,” says Lathan. “What is the use of developing new therapies if the communities that could benefit the most are the very ones that cannot access them?”

Now, new research from scientists at UC San Diego’s Scripps Institution of Oceanography and San Diego State University (SDSU) finds deep-sea fish and sediments collected from near the Catalina Island offshore dump site are contaminated with numerous DDT-related chemicals.

The study, published May 6 in the journal Environmental Science and Technology Letters and funded by the National Oceanic and Atmospheric Administration, suggests that the DDT-related chemicals dumped into the ocean decades ago may still be making their way into marine food webs.

Since the rediscovery of the offshore dump site near Catalina Island, scientists have been working to discern the extent and severity of the problem today. Of particular urgency are the questions of whether the decades-old chemicals, now settled on the seafloor thousands of feet underwater, are staying put or whether they are circulating in marine ecosystems where the compounds could be harming wildlife or even posing health risks to humans.

“These are deep-sea organisms that don’t spend much time at the surface and they are contaminated with these DDT-related chemicals,” said Lihini Aluwihare, a professor of ocean chemistry at Scripps and co-author of the study. “Establishing the current distribution of DDT contamination in deep-sea food webs lays the groundwork for thinking about whether those contaminants are also moving up through deep-ocean food webs into species that might be consumed by people.”

From 1948 until at least 1961, barges contracted by DDT-producer Montrose Chemical Corporation would motor from the Port of Los Angeles out toward Catalina and pump manufacturing waste laden with sulfuric acid and up to 2% pure DDT directly into the Pacific Ocean. Legal until 1972, this offshore dumping largely escaped public scrutiny because it was overshadowed by Montrose’s other waste disposal practice: Pumping a more dilute acidic slurry that also contained DDT through L.A. County sewers and into the ocean off Palos Verdes. An estimated 100 tons of DDT ended up in the sediments of the Palos Verdes Shelf, and the Environmental Protection Agency declared it an underwater Superfund Site in 1996. In 2000, a judge ordered the company to pay $140 million to remedy the environmental damages. Research has since linked the DDT pollution on the Palos Verdes Shelf to contamination and health problems in local wildlife including sea lions, dolphins, bottom-feeding fish, and even coastal California condors (likely from consuming dead marine mammals).

In 2011, UC Santa Barbara researcher David Valentine used an undersea robot to rediscover Montrose’s offshore dumping near Catalina at a place now known as Dumpsite 2. The findings leapt into the public consciousness in 2020 when the Los Angeles Times published the first in a series of expose?s unspooling the region’s toxic legacy of offshore dumping.

Valentine and Scripps researchers have helped map the extent of the dumping. To date, they’ve found DDT-related chemicals across an area of the seafloor larger than the city of San Francisco. What’s still unknown is if that pollution is staying put or if it is moving through the undersea environment in ways that pose dangers to marine life or humans.

Beginning in 2021, Aluwihare, study co-author Eunha Hoh of SDSU, and other collaborators began a series of research efforts to work on two key questions: Are the DDT-related chemicals lurking on the seafloor near Dumpsite 2 being stirred up and ingested by marine life in the deep? And could they identify a kind of chemical fingerprint unique to the contamination from Dumpsite 2 and other offshore dump sites that could be used to distinguish them from pollutants emanating from the Palos Verdes Shelf?

The team opportunistically collected sediment samples and deep-sea animals from the water column in the San Pedro Basin near Dumpsite 2 to test for a wide range DDT-related compounds. The research cruises to collect these samples were funded by the National Science Foundation and the Schmidt Ocean Institute.

Typically, testing for DDT looks for four to eight chemicals, but a 2016 paper co-authored by Hoh and Aluwihare identified 45 DDT-related chemicals in the blubber of dolphins from off the coast of Southern California. The results demonstrated that wildlife was being exposed to a much larger suite of DDT compounds in the real world. In the present study, the team tested for this larger suite of DDT-related chemicals, known as DDT+, in hopes that it could help develop a chemical fingerprint for Dumpsite 2 and the other offshore dump sites used by Montrose. Also, testing for DDT+ will provide a more holistic picture of the degree of contamination in sediment and animals that might otherwise go undetected.

When the researchers analyzed the sediments for the presence of DDT+ they found no fewer than 15 chemicals, 14 of which had been previously detected in birds and marine mammals in Southern California.

The researchers collected 215 fish spanning three common species near Dumpsite 2. Chemical analysis revealed that the fish contained 10 DDT-related compounds, all of which were also present in the sediment samples.

Two of the fish species were collected between 546 meters (1,791 feet) and 784 meters (2,572 feet) — Cyclothone acclinidens and Melanostigma pammelas — and the third, Leuroglossus stilbius, was collected between 546 meters (1,791 feet) and the surface. The species collected at shallower depths contained a lower concentration of contaminants and were missing a pair of DDT-related compounds that were present in the deepest fishes.

“None of these fish species are known to feed in the sediment of the seafloor,” said Anela Choy, biological oceanographer at Scripps and co-author of the study. “There must be another mechanism that is exposing them to these contaminants. One possibility is that there are physical or biological processes resuspending sediments around Dumpsite 2 and allowing these contaminants to enter deeper water food webs.”

The findings can’t yet rule out the Palos Verdes Superfund Site as a potential source of the contamination in the fish, said Aluwihare. But several lines of evidence uncovered in the study — the lower overall concentrations and two missing DDT-related compounds in the shallower water fish species, as well as the overlap between contaminants found in the sediment and those found in marine mammals and birds — point to the alarming possibility that pollution is moving from the seafloor and into the marine food web.

“Regardless of the source, this is evidence that DDT compounds are making their way into the deep ocean food web,” said Margaret Stack, an environmental chemist at SDSU and the study’s lead author. “That is cause for concern because it’s not a big leap for it to end up in marine mammals or even humans.”

Hoh said understanding the pathways by which the DDT-related chemicals are entering the food web is vital and “will help us figure out what to do as far as mitigation and what not to do in terms of offshore development that could make this problem worse by stirring up these contaminants.”

Aluwihare said more work needs to be done to pinpoint the source of the DDT contaminants they found in the deep-sea fish and establish whether the same contamination exists in larger, open-ocean fish species that are consumed by people.

Numerous additional studies are ongoing to answer these urgent questions. Researchers at Scripps and SDSU are currently analyzing samples from fish species targeted by recreational anglers and commercial fisheries, including basses and sanddab, for DDT+. Comparing the chemicals and their concentrations found in these fish with sediment samples collected from the Palos Verdes Shelf and Dumpsite 2 may allow the team to determine the source of the toxins in these fish.

“We are still seeing this DDT contamination in deep-sea organisms and ocean sediments more than 50 years after they were dumped there,” said Hoh. “I’m not sure if that company expected the consequences of their pollution to last this long, but they have.”

In addition to Aluwihare, Stack, Choy, and Hoh, Raymmah Garcia, Tran Nguyen,, Paul Jensen, and Johanna Gutleben of Scripps as well as, William Richardot, and Nathan Dodder of SDSU co-authored the study.

A stroke often leads to motor impairment, which is traditionally linked to the extent of damage to the corticospinal tract (CST), a crucial brain pathway for motor control. Signaling along the CST is involved in a variety of movements, including walking, reaching, and fine finger movements like writing and typing. However, stroke recovery outcomes aren’t fully predicted by damage to the CST, suggesting other factors are at play.

The new observational study from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group examines how one such factor could be white matter hyperintensities (WMHs) — areas of age-related damage in the brain’s white matter, which represent vascular dysfunction and are known to impact cognitive functions. The goal of the ENIGMA Stroke Recovery working group, a National Institute of Neurological Disorders and Stroke (NINDS) -funded part of the ENIGMA Consortium, is to understand how changes in the brain after stroke relate to functional outcomes and recovery. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 65 research studies and 10 countries, comprising the most extensive multisite retrospective stroke data collaboration to date.

“We are grateful for our many collaborators around the world who lead independent stroke research programs and who are willing to come together and enable large-scale investigations into these critical questions about the role of overall brain health in stroke recovery and rehabilitation,” says Dr. Liew, an associate professor at the Keck School of Medicine of USC, who also has joint appointments at the Chan Division of Occupational Science and Occupational Therapy, the Division of Biokinesiology and Physical Therapy and the USC Viterbi School of Engineering.

The study analyzed data from 223 stroke patients across four countries and found that larger WMH volumes were associated with more severe motor impairment after a stroke (e.g., difficulty moving or using their arm for daily tasks), independent of CST damage. WMHs are related to chronic hypertension, diabetes, high cholesterol, and smoking, among other factors and conditions, and have been strongly related to cognitive impairment, but not extensively studied in the context of motor impairment. Interestingly, the relationship between CST damage and motor impairment varied based on WMH severity. Patients with mild WMHs showed a typical relationship between CST damage and motor impairment, while patients with moderate to severe WMHs did not have this relationship. Instead, motor impairment was related to WMH volume, not CST damage.

These findings suggest that WMHs, indicative of cerebrovascular damage from a variety of sources, could provide additional context to understand an individual’s potential for recovery post-stroke. Therefore, assessing WMH volume could improve predictive models for stroke recovery.

“WMHs are related to overall cardiovascular and brain health as we age. By integrating assessments of age-related brain health, we may be better able to predict stroke recovery and tailor rehabilitation to individual needs. This personalized approach could open avenues to improve outcomes after stroke,” says Jennifer K. Ferris, PhD, of Simon Fraser University and the BC Centre for Disease Control, and lead author of the study.

The researchers’ next step is to pursue longitudinal studies to confirm their findings. This insight lays the groundwork for developing more accurate markers for recovery, which could transform post-stroke care and rehabilitation.

“Dr. Liew and her team’s work is integral to our mission to advance stroke research and discovery by using novel imaging technologies to study the structural and functional changes in the brain,” says Stevens INI Director Arthur W. Toga, PhD. “We know that stroke is a leading cause of serious long-term disability, which has a considerable impact on public health. Studies such as this are a part of our goal to usher in a new era of precision rehabilitation that uses data-driven decision-making based on brain imaging and other noninvasive measures to identify personalized rehabilitation strategies.”

Her research and teaching focus on positive psychology, media and new communication technologies, and media and spirituality. The study, published April 13 in Society for Research in Child Development (SRCD), investigates how adolescents perceive and engage with digital communication, including connectedness, positive social comparison, authentic self-presentation, civil participation and self-control.

“This was such an amazing research study to be part of as we all are craving more nuanced answers on how digital technologies affect our children,” said Janicke-Bowles.

Janicke-Bowles’ research contributes to the understanding of digital flourishing (positive social media experiences) among adolescents, highlighting the importance of supportive parental mediation and digital skills in promoting positive digital engagement. Moving forward, interventions aimed at enhancing digital flourishing should consider the role of parental guidance and support in shaping adolescents’ online experiences.

• Adolescents who flourish in their digital communication over time are more likely to have parents who know their way around technology and who actively support their children to positively communicate online.
• For adolescents who digitally flourish less, their self-control over digital communication decreases.
• To increase digital flourishing, interventions can aim in assisting adolescents in their control over their digital communication and encourage parents to take an active role in their young adults’ digital communication.

These findings underscore the significance of parental influence and support in fostering positive digital communication experiences among adolescents.

In addition to her recent research, Janicke-Bowles has a distinguished history of exploring the intersection of media and psychology. As a member of a research team from Florida State and Penn State universities, she received a $1.9 million grant from the John Templeton Foundation to investigate the impact of media content on self-transcendent emotions. Her academic journey, spanning from clinical and media psychology in Germany to mass communication in the United States, underscores her commitment to understanding the profound effects of media on human experiences.

The T cells of the immune system are the main players in the defense against viral infections and tumor cells. On the other hand, they attack the body’s own healthy tissue in autoimmune reactions, which can even be fatal. The body must therefore keep a tight control on T cell activity.

A large number of molecules and messenger are involved in the highly complex regulation of T cell activity. Only recently have researchers discovered that another group of immune cells contibutes to the control of T cell activity. Natural killer cells (NK cells) are part of the innate immunity, i.e. the rapid response force that quickly detects and eliminates infected or malignant cells.

“Studies have shown that NK cells can also kill activated T cells and thus limit their proliferation,” says Michael Platten, Head of Department at the DKFZ and Director of the Neurological University Clinic Mannheim. “However, until now we did not know which feature characterizes T cells as a target for the NK cell.”

When screening activated T cells from healthy donors, Platten’s team identified the protein B7H6 as a recognition molecule for NK cell attacks in a new study. Activated T cells from the blood of patients with autoimmune diseases, cancer or viral infections expose large amounts of B7H6 on their surface. Co-culture experiments in the culture dish showed that NK cells recognize the activated T cells by their B7H6 expression. In contrast, T cells whose B7H6 gene was destroyed with the CRISPR-Cas were protected from the lethal attack of the NK cells.

“The elimination of T cells by NK cells is triggered by an intrinsic mechanism of the T cells. The activated T cells temporarily identify themselves as targets for NK-induced cell lysis,” explains Michael Kilian, first author of the publication, and adds: “This may limit excessive activation and expansion of T cells as a control mechanism to curb destructive immune responses.”

Immune checkpoint inhibitor therapies are neutralized by NK cells

“We now know a number of so-called checkpoint molecules that reduce or enhance the activation of T cells and thus modulate the course of immune reactions. B7H6 can now be classified as a further inhibitory immune checkpoint on T cells,” explains study leader Platten.

Some widespread cancer therapies with drugs from the checkpoint inhibitor (ICI) group are targeting certain inhibitory checkpoint molecules. They activate the immune system against the tumor by releasing the immune brakes. Could the B7H6-mediated elimination of tumor-reactive T cells possibly counteract the effect of ICI cancer immunotherapy? The researchers tested this using tissue samples from patients with esophageal cancer who had received ICI therapy. Those patients who had not responded to ICI had a higher number of NK cells in the tumor tissue and actually had a shorter progression-free survival time.

Cellular immunotherapy more effective in the absence of NK cells

Cellular immunotherapies are becoming increasingly important in cancer medicine. For example, some forms of blood cancer are now often treated with so-called CAR-T cells, which are equipped with customized receptors against the cancer. However, the success of therapy is often limited as the number of therapeutic cells in the patient’s body declines rapidly.

The therapeutic CAR-T cells also carry B7H6 on the cell surface. Could NK cells be responsible for the rapid decline in their numbers after the start of therapy? Experiments with a humanized mouse model suggest this: if NK cells were added during CAR-T cell treatment of leukaemia, the number of therapeutic cells decreased, while the tumour load increased.

“NK control of T cells has the potential to interfere with various forms of cancer immunotherapy. By specifically intervening in this process, it may be possible to modulate T cell immune responses in the future,” explains Michael Platten, head of the current study. With the help of the CRISPR-Cas gene scissors, the researchers now want to protect CAR-T cells from elimination by NK cells in a clinical trial together with the Department of Haematology and Oncology at Heidelberg University Hospital and thus improve the effectiveness of cellular immunotherapy.

Now, Northwestern University researchers have used statistical physics to confirm the theory that underlies this famous axiom.

The study will be published on May 3 in the journal Science Advances.

In the 1940s, Austrian psychologist Fritz Heider introduced social balance theory, which explains how humans innately strive to find harmony in their social circles. According to the theory, four rules — an enemy of an enemy is a friend, a friend of a friend is a friend, a friend of an enemy is an enemy and, finally, an enemy of a friend is an enemy — lead to balanced relationships.

Although countless studies have tried to confirm this theory using network science and mathematics, their efforts have fallen short, as networks deviate from perfectly balanced relationships. Hence, the real question is whether social networks are more balanced than expected according to an adequate network model. Most network models were too simplified to fully capture the complexities within human relationships that affect social balance, yielding inconsistent results on whether deviations observed from the network model expectations are in line with the theory of social balance.

The Northwestern team, however, successfully integrated the two key pieces that make Heider’s social framework work. In real life, not everyone knows each other, and some people are more positive than others. Researchers have long known that each factor influences social ties, but existing models could only account for one factor at a time. By simultaneously incorporating both constraints, the researchers’ resulting network model finally confirmed the famous theory some 80 years after Heider first proposed it.

The useful new framework could help researchers better understand social dynamics, including political polarization and international relations, as well as any system that comprises a mixture of positive and negative interactions, such as neural networks or drug combinations.

“We have always thought this social intuition works, but we didn’t know why it worked,” said Northwestern’s István Kovács, the study’s senior author. “All we needed was to figure out the math. If you look through the literature, there are many studies on the theory, but there’s no agreement among them. For decades, we kept getting it wrong. The reason is because real life is complicated. We realized that we needed to take into account both constraints simultaneously: who knows whom and that some people are just friendlier than others.”

“We can finally conclude that social networks align with expectations that were formed 80 years ago,” added Bingjie Hao, the study’s first author. “Our findings also have broad applications for future use. Our mathematics allows us to incorporate constraints on the connections and the preference of different entities in the system. That will be useful for modeling other systems beyond social networks.”

Kovács is an assistant professor of Physics and Astronomy at Northwestern’s Weinberg College of Arts and Sciences. Hao is a postdoctoral researcher in his laboratory.

What is social balance theory?

Using groups of three people, Heider’s social balance theory maintains the assumption that humans strive for comfortable, harmonious relationships. In balanced relationships, all people like each other. Or, if one person dislikes two people, those two are friends. Imbalanced relationships exist when all three people dislike each other, or one person likes two people who dislike each other, leading to anxiety and tension. Studying such frustrated systems led to the 2021 Nobel Prize in physics to Italian theoretical physicist Giorgio Parisi, who shared the prize with climate modelers Syukuro Manabe and Klaus Hasselmann.

“It seems very aligned with social intuition,” Kovács said. “You can see how this would lead to extreme polarization, which we do see today in terms of political polarization. If everyone you like also dislikes all the people you don’t like, then that results in two parties that hate each other.”

However, it has been challenging to collect large-scale data where not only friends but also enemies are listed. With the onset of Big Data in the early 2000s, researchers tried to see if such signed data from social networks could confirm Heider’s theory. When generating networks to test Heider’s rules, individual people serve as nodes. The edges connecting nodes represent the relationships among individuals.

If the nodes are not friends, then the edge between them is assigned a negative (or hostile) value. If the nodes are friends, then the edge is marked with a positive (or friendly) value. In previous models, edges were assigned positive or negative values at random, without respecting both constraints. None of those studies accurately captured the realities of social networks.

Finding success in constraints

To explore the problem, Kovács and Hao turned to four large-scale, publicly available signed network datasets previously curated by social scientists, including data from (1) user-rated comments on social news site Slashdot; (2) exchanges among Congressional members on the House floor; (3) interactions among Bitcoin traders; and (4) product reviews from consumer review site Epinions.

In their network model, Kovács and Hao did not assign truly random negative or positive values to the edges. For every interaction to be random, every node would need to have an equal chance of encountering one another. In real life, however, not everyone actually knows everyone else within a social network. For example, a person might not ever encounter their friend’s friend, who lives on the other side of the world.

To make their model more realistic, Kovács and Hao distributed positive or negative values based on a statistical model that describes the probability of assigning positive or negative signs to the interactions that exist. That kept the values random — but random within limits given by constraints of the network topology. In addition to who knows whom, the team took into account that some people in life are just friendlier than others. Friendly people are more likely to have more positive — and fewer hostile — interactions.

By introducing these two constraints, the resulting model showed that large-scale social networks consistently align with Heider’s social balance theory. The model also highlighted patterns beyond three nodes. It shows that social balance theory applies to larger graphlets, which involve four and possibly even more nodes.

“We know now that you need to take into account these two constraints,” Kovács said. “Without those, you cannot come up with the right mechanisms. It looks complicated, but it’s actually fairly simple mathematics.”

Insights into polarization and beyond

Kovács and Hao currently are exploring several future directions for this work. In one potential direction, the new model could be used to explore interventions aimed at reducing political polarization. But the researchers say the model could help better understand systems beyond social groups and connections among friends.

“We could look at excitatory and inhibitory connections between neurons in the brain or interactions representing different combinations of drugs to treat disease,” Kovács said. “The social network study was an ideal playground to explore, but our main interest is to go beyond investigating interactions among friends and look at other complex networks.”

The code and data behind the paper, “Proper network randomization is key to assessing social balance,” are available on Github: https://github.com/hbj153/signed_null

“I didn’t expect to see pollutant concentrations breach health benchmarks in bedrooms within an hour of gas stove use, and stay there for hours after the stove is turned off,” said Stanford Doerr School of Sustainability Professor Rob Jackson, senior author of the May 3 study in Science Advances. Pollution from gas and propane stoves isn’t just an issue for cooks or people in the kitchen, he said. “It’s the whole family’s problem.”

Among other negative health effects, breathing high levels of nitrogen dioxide, or NO₂, over time can intensify asthma attacks and has been linked to decreased lung development in children and early deaths.

Although most exposure to NO₂ is caused by cars and trucks burning fossil fuels, the researchers estimate that the mix of pollutants coming from gas and propane stoves overall may be responsible for as many as 200,000 current childhood asthma cases. One quarter of these can be attributed to nitrogen dioxide alone, according to the paper’s authors, who include scientists from Central California Asthma Collaborative, PSE Healthy Energy, and the Harvard T.H. Chan School of Public Health.

“We found that just how much gas you burn in your stove is by far the biggest factor affecting how much you’re exposed. And then, after that, do you have an effective range hood — and do you use it?” said lead study author Yannai Kashtan, a PhD student in Earth system science.

Little room for additional exposure

Beyond asthma cases, the long-term exposure to NO₂ in American households with gas stoves is high enough to cause thousands of deaths each year — possibly as many as 19,000 or 40% of the number of deaths linked annually to secondhand smoke. This estimate is based on the researchers’ new measurements and calculations of how much nitrogen dioxide people breathe at home because of gas stoves and the best available data on deaths from long-term exposure to outdoor NO₂, which is regulated by the U.S. Environmental Protection Agency.

The death toll estimate is approximate in part because it does not factor in the harmful effects of repeated exposure to extremely high levels of nitrogen dioxide in short bursts, as occurs in homes with gas stoves. It also relies on past studies of health impacts from nitrogen dioxide encountered outdoors, where additional pollutants from vehicles and power plants are present.

The researchers used sensors to measure concentrations of NO₂ throughout more than 100 homes of various sizes, layouts, and ventilation methods, before, during, and after stove use. They incorporated these measurements and other data into a model powered by National Institutes for Standards and Technology (NIST) software known as CONTAM for simulating airflow, contaminant transport, and room-by-room occupant exposure in buildings. This allowed them to estimate nationwide averages and short-term exposures under a range of realistic conditions and behaviors, and cross-check model outputs against their home measurements.

The results show that nationwide, typical use of a gas or propane stove increases exposure to nitrogen dioxide by an estimated 4 parts per billion, averaged over a year. That’s three quarters of the way to the nitrogen dioxide exposure level that the World Health Organization recognizes as unsafe in outdoor air. “That’s excluding all outdoor sources combined, so it makes it much more likely you’re going to exceed the limit,” said Kashtan.

Understanding how gas stoves affect health

The study is the latest in a series from Jackson’s group at Stanford looking at indoor air pollution from gas stoves. Earlier studies documented the rate at which gas stoves emit other pollutants, including the greenhouse gas methane and the carcinogen benzene. But to understand the implications of stove emissions for human health, the researchers needed to find out how much pollutants spread through a home, build up, and eventually dissipate. “We’re moving from measuring how much pollution comes from stoves to how much pollution people actually breathe,” said Jackson, who is the Michelle and Kevin Douglas Provostial Professor in Earth System Science.

With any fuel source, particle pollution can rise from food cooking in a hot pan. The new research confirms that food emits little or no nitrogen dioxide as it cooks, however, and electric stoves produce no NO₂. “It’s the fuel, not the food,” said Jackson. “Electric stoves emit no nitrogen dioxide or benzene. If you own a gas or propane stove, you need to reduce pollutant exposures using ventilation.”

Home size matters

Even in larger homes, concentrations of nitrogen dioxide routinely spiked to unhealthy levels during and after cooking even if a range hood was on and venting air outdoors. But people who live in homes smaller than 800 square feet — about the size of a small two-bedroom apartment — are exposed to twice as much nitrogen dioxide over the course of a year compared to the national average, and four times more compared to those living in the largest homes, upwards of 3,000 square feet.

Because home size makes such a difference, there are also differences in exposure across racial, ethnic, and income groups. Compared to the national average, the researchers found long-term NO₂ exposure is 60% higher among American Indian and Alaska Native households, and 20% higher among Black and Hispanic or Latino households. This exposure to indoor air pollution from gas stoves compounds the fact that exposure to outdoor sources of nitrogen dioxide pollution, such as vehicle exhaust, is also typically higher among people in poorer, often minority, communities.

“People in poorer communities can’t always afford to change their appliances, or perhaps they rent and can’t replace appliances because they don’t own them,” Jackson said. “People in smaller homes are also breathing more pollution for the same stove use.”

This research was supported by HT, LLC.

The research team, led by Jeffrey Hartgerink, professor of chemistry and bioengineering, has developed peptide-based hydrogels that mimic the aligned structure of muscle and nerve tissues. Alignment is critical for the tissues’ functionality, but it is a challenging feature to reproduce in the lab, as it entails lining up individual cells.

For over ten years, the team has been designing multidomain peptides (MDPs) that self-assemble into nanofibers. These resemble the fibrous proteins found naturally in the body, much like a spiderweb at nanoscale.

In their latest study, published online and featured on the cover of the journal ACS Nano, the researchers discovered a new method to create aligned MDP nanofiber “noodles.” By first dissolving the peptides in water and then extruding them into a salty solution, they were able to create aligned peptide nanofibers — like twisted strands of rope smaller than a cell. By increasing the concentration of ions, or salt, in the solution and repeating the process, they achieved even greater alignment of the nanofibers.

“Our findings demonstrate that our method can produce aligned peptide nanofibers that effectively guide cell growth in a desired direction,” explained lead author Adam Farsheed, who recently received his Ph.D. in bioengineering from Rice. “This is a crucial step toward creating functional biological tissues for regenerative medicine applications.”

One of the key findings of the study was an unexpected discovery: When the alignment of the peptide nanofibers was too strong, the cells no longer aligned. Further investigation revealed that the cells needed to be able to “pull” on the peptide nanofibers to recognize the alignment. When the nanofibers were too rigid, the cells were unable to exert this force and failed to arrange themselves in the desired configuration.

“This insight into cell behavior could have broader implications for tissue engineering and biomaterial design,” said Hartgerink. “Understanding how cells interact with these materials at the nanoscale could lead to more effective strategies for building tissues.”

Additional study co-authors from Rice include chemistry department Ph.D. graduates Tracy Yu and Carson Cole, graduate student Joseph Swain, and undergraduate researcher Adam Thomas. Bioengineering undergraduate researcher Jonathan Makhoul, graduate student Eric Garcia Huitron, and Professor K. Jane Grande-Allen were also co-authors on the study. The team of researchers from the University of Houston includes Ph.D. student Christian Zevallos-Delgado, research assistant Sajede Saeidifard, research assistant professor Manmohan Singh and engineering professor Kirill Larin.

This work was supported in part by grants from the National Institutes of Health (R01DE021798, R01EY022362, R01HD095520, R01EY030063), the National Science Foundation (2129122), the National Science Foundation Graduate Research Fellowship Program, and the Welch Foundation (C-2141). The content in this news release is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations.

Scientists have been trying to figure out for decades how bacteria gain a foothold in otherwise healthy people, examining everything from how the microbes move inside and stick to the inside of the bladder to how they deploy their toxins to produce uncomfortable and often painful symptoms.

Research published in PNAS examines how the bacteria Escherichia coli, or E. coli — responsible for most UTIs — is able to use host nutrients to reproduce at an extraordinarily rapid pace during infection despite the near sterile environment of fresh urine.

Investigators working in the lab of Harry Mobley, Ph.D., at the University of Michigan Medical School began by looking at mutant strains that weren’t as good at replicating in mouse models to identify bacterial genes that may be important for establishing infection.

Doing so, they identified a group of genes controlling transport systems as critical.

“When bacteria need something to grow, say an amino acid, they can get it in two ways,” explained Mobley, who is the Frederick G. Novy Distinguishes Professor of Microbiology and Immunology.

“They can make it itself, or they can steal it from their host using what we call a transport system.”

Their previous gene expression screen revealed that nearly 25% of bacterial genes were dedicated to replication tactics including transport systems for specific amino acids, which E. coli use to bring in thousands of molecules per second, said Mobley.

First author Allyson Shea, Ph.D., a former member of Mobley’s lab and now assistant professor of Microbiology and Immunology at the University of South Alabama, cross referenced a library of transport proteins from E. coli against other species of UTI pathogens to see which were important for infection. She discovered that a type of transporter called ABC (for ATP-binding cassette) transporters appeared to be critical.

Then using organ agar made from the mouse urinary tract, she confirmed that ABC transporters were essential for infection. Many bacteria strains lacking these nutrient import systems were defective for growth on bladder and kidney organ agar.

“It appears bacteria make an investment into these energy expensive ATP transport systems in order to have a higher affinity for the energy sources they are interested in,” said Shea.

“These systems are very, very good at getting nutrients inside the cell.”

The findings, Mobley notes, open avenues for the development of new therapeutics — which is especially important in an era of increasing antibiotic resistance.

“If you inhibit these transport systems, maybe you can inhibit the rapid growth of these bacteria,” he said.

Doing so won’t be easy, notes Shea, as bacteria have evolved multiple backups systems for this important class of transporters.

“What’s nice about this ATP-binding family is they all have an ATP binding subunit which gives the transport system the energy it needs to get nutrients across the cell membrane.”

This subunit could potentially be a target to make the entire family of transporters dysfunctional.

While this wouldn’t necessarily replace antibiotics, she says, it could slow down growth so that antibiotics and the host immune system could do a better job at stopping the bugs.

Dr Margaret M. Brennan, Research Assistant, Department of Public Health and Primary Care, School of Medicine, Trinity College and first author, said:

“We hope this work can highlight the significant differences in vitamin D levels among different ethnic groups at northern latitudes and contribute to efforts to address the long-standing population health issue of vitamin D deficiency.”

The authors analysed data from half a million participants from the United Kingdom (UK,) and for each person, they calculated the individualized estimate of ambient ultraviolet-B (UVB) level, which is the wavelength of sunlight that induces vitamin D synthesis in the skin.

A comprehensive analysis of key determinants of vitamin D and their interactions revealed novel insights. The first key insight is that ambient UVB emerges as a critical predictor of vitamin D status, even in a place like the UK, which receives relatively little sunlight. The second is that age, sex, body mass index (BMI), cholesterol level, and vitamin D supplementation significantly influence how individuals respond to UVB. For example, as BMI and age increase, the amount of vitamin D produced in response to UVB decreases.

Professor Lina Zgaga, Associate Professor of Epidemiology, Department of Public Health and Primary Care, School of Medicine, Trinity College and the principal investigator, said:

“We believe our findings have significant implications for the development of tailored recommendations for vitamin D supplementation. Our study underscores the need to move away from a one-size-fits-all approach towards personalized strategies for optimizing vitamin D status.”

Rasha Shraim, PhD candidate, Department of Public Health and Primary Care, School of Medicine, Trinity College, and co-principal investigator on this study said:

“Our study also highlights the effect that natural environmental factors, like sunlight, can have on our health. We hope that our approach encourages future researchers and public health bodies to integrate these factors into their health and disease work.”

The authors hope that their manuscript will contribute to the ongoing discourse on vitamin D supplementation guidelines.

The tumor immune microenvironment (TIME) refers to the complex and dynamic interplay between tumor cells, various immune cells, and other cellular and non-cellular components within and surrounding the tumor.

T_RM cells are a unique type of immune cells that reside in peripheral tissues and many kinds of cancer types.

Because of the presence and functional properties of T_RM cells within the TIME in harnessing their potential for cancer immunotherapy, there has been much interest in studying T_RM cells and how they influence patient survival. Key to this understanding is to establish whether the presence and abundance of T_RM cells in cancer patients correlate with better patient prognosis. Previous studies conducted with melanoma patients have produced conflicting results. There has also been little effort to conduct a comprehensive study to evaluate the T_RM abundance and correlate immunomics data with patient survival outcomes.

The TIBI team sought to solve this problem by turning to data from single-cell RNA sequencing (scRNA-seq), a powerful technology that allows one to obtain a complete genetic profile of large numbers of individual cells. Instead of using a limited number of a cell’s identifying marker genes, utilizing the scRNA-seq technology provides a more comprehensive, accurate, and nuanced way of characterizing a cell’s type and function. From this profile, gene signatures can be generated- uniquely characteristic patterns of a specific immune cell type that can possibly be correlated with the presence of disease.

As described in their recent paper in iScience, the team used this approach on two independent cohorts of melanoma patients’ scRNA-seq data and were able to extract 11 distinct gene signatures that highly correlated with T_RM abundance in the patients. A solid association was also found between these gene signatures and patient survival outcomes.

Further studies revealed additional positive correlations between T_RM abundance and the presence of multiple anti-tumor immune cells in the melanoma TIME, as well as with immune pathways and regulatory genes, suggesting that T_RM cells have a crucial role in immunomodulation. The studies also indicated that an abundance of T_RM cells results in a more active melanoma TIME and better patient outcomes.

Finally, the TIBI researchers could use the data from their analysis to create a high-precision T_RM-derived risk scoring system to classify patients into high- and low-risk prognostic categories for melanoma patients.

“Our scientists’ analytical approach and discoveries about the role that T_RM cells play may help to refine and more accurately assess cancer patients’ response to immunotherapeutic drugs,” said Ali Khademhosseini, TIBI’s Director and CEO. “As treatments can have profoundly variable effects on individual cancer patients, this is an important step toward improving patient outcome.”

Authors: Chongming Jiang, Cheng-Chi Chao, Jianrong Li, Xin Ge, Aidan Shen, Vadim Jucaud, Chao Cheng, and Xiling Shen

Grant Information: This work is supported by the National Institutes of Health, USA (NIH) R01 DK119795 and R35 GM122465. This work is was also funded by the Cancer Prevention Research Institute of Texas (CPRIT) (RR180061).

In a study published recently in Cell Reports Physical Science, Fleeman showed that an antimicrobial peptide from cows has potential for treating incurable infections from the bacterium Klebsiella pneumoniae. The bacteria, commonly found in the intestines, is usually harmless. It becomes a health hazard when it enters other parts of the body and can cause pneumonia, urinary tract and wound infections. Those at highest risk include seniors and patients with other health problems such as diabetes, cancer, kidney failure and liver disease. However, younger adults and people without additional health problems can acquire urinary tract and wound infections from the bacteria that cannot be treated by antibiotics available today.

The CDC reports that antibiotic resistant bacteria are a growing global health threat. A 2019 study found that nearly 5 million people died worldwide that year from drug-resistant infections. A large portion of those deaths are attributable to K. pneumoniae because it has a 50% death rate without antibiotic therapy.

These bacteria are more resistant to drugs when they live in a biofilm — microorganisms that stick together and are embedded in a protective slime. Recent studies have shown that 60-80% of infections are associated with bacteria biofilms, which increase their drug resistance.

“It’s Iike a coat that bacteria put around itself,” Fleeman says.

Her research is examining ways to remove the protective coat and expose the bacteria so it can be killed by the body’s immune system or antibiotics that currently cannot pass through the biofilm. Through that research, Fleeman discovered how the peptides made by cows can quickly kill K. pneumoniae.

She determined that the peptides interact with sugar connections that keep the slime intact. She likened the process to cutting into a chain-linked fence. Once multiple chains are cut, the integrity of the slime structure is damaged, and the peptide can enter and destroy the bacteria that are no longer protected.

“Our research has shown polyproline peptide can penetrate and begin to break the slime barrier down in as little as an hour after treatment,” says Fleeman.

The peptide has another advantage — once it breaks through the protective slime barrier, tests showed it killed the bacteria better than antibiotics used as a last resort to treat incurable infections. Peptides kill the bacteria by punching holes in their cell membrane, causing death quickly compared to other antibiotics that inhibit growth from inside the cell.

The peptide could also be used as a topical treatment for a wide range of uses, especially for the military, to treat open wounds in the field. “Bacteria divide every 30 minutes, so you have to act fast,” Fleeman says.

The next phase of her research will seek to understand the biology behind the peptide’s efficacy and if combinations of other drugs would aid in its application.

Her research is funded through a three-year National Institutes of Health funding Pathway to Independence R00 grant and is in its second year. Her study initially started as a K99 award at University of Texas at Austin, where she worked before joining UCF in September of 2022.

Fleeman says research into resistant infections must continue because they pose such a threat to health.

“It is estimated that by 2050, antibiotic resistant bacterial infections will be the number one cause of human deaths,” she says. “Our work is focused on preparing for this post-antibiotic era battle, where common antibiotics that we take for granted will no longer be effective, jeopardizing cancer therapy, organ transplants, and any modern medical advancement that relies on effective antibiotic therapies.”

“The statistician inside me was excited — we don’t often see effect sizes this large in my area of psychology research because human behaviour is complicated and there’s lots of variability,” says Psychology Professor Jennifer Mills, co-author of the paper. “We hope this study can be used to help protect young people and influence social media companies to give users more agency in how they interact with these platforms.”

The paper, out this week in the journal Body Image, is thought to be the first to look specifically at social-media breaks and body image. Mills, whose lab has been on the forefront of this kind of research, collaborated on the paper with graduate researcher Lindsay Samson and undergraduate Olivia Smith, both students at York. They expected that there might be recruitment challenges, but it turns out there was enthusiasm for taking a social media pause among the 66 first-year female undergraduates who participated. Half were instructed to continue their social media as per usual, while the other half were given instructions to refrain from Instagram, Facebook, Twitter, and TikTok and other social media use for one week. They conducted baseline surveys before the experiment, and tested the participants again after the week was over.

“There’s natural variability in how people feel about their bodies and about themselves in general, so we took that into account statistically, and even after that there were still significant differences between the groups after one week,” says Mills, who is also the director of clinical training for the graduate psychology program.

The differences in the social media landscape are remarkable compared to when Mills started researching eating disorders and the effects of media, like magazines aimed at women.

“Back then, you could only spend so many minutes or hours looking at fashion and beauty magazines and they only came out once a month. There was a finite amount of content that you would be exposed to. With social media it’s infinite. It’s always new and novel, which triggers our brain’s reward system that makes us want more and more of something.”

Mills says the improvements found in this study might be explained both by women spending far less time engaging in behaviours known to have a detrimental effect, such as comparisons with others, but they may have also replaced social media with healthier behaviours.

“If we’re spending more time in real life, socializing with friends, getting sleep, getting outdoors, getting exercise, there could be secondary behaviours that fill the void left by social media. Future research will try to disentangle that.”

Land users rely on subsidies, but money is not everything

The researchers focused on the motivation and challenges driving decision-making among all land users engaged in low-intensity grazing practices. This was despite economic considerations becoming increasingly important as land users’ revenue-generating activities are no longer sufficient to cover the rising cost of equipment, rent, and taxes.

“Money is not everything. Many of the land users we interviewed practice this type of grazing management because they think it is good, not out of economic motivation,” says first author Dr Julia Rouet-Leduc. Rouet-Leduc led the project as a former doctoral researcher at iDiv and UL and is now a postdoctoral researcher at the Stockholm Resilience Centre. Caring for nature and, in some cases, also the desire to maintain traditional agricultural practices were important aspects of the land users’ motivation. For example, a land user working with wild ponies in Galicia (Spain) shared: “The main reason for the maintenance of this system is that people … love the ponies; they ‘have a fever’, and this tradition runs very deeply in their hearts.”

The researchers found that many land users struggle with rules and regulations that are incompatible with low-intensity grazing management. For example, rules to mark or tag livestock — an extremely challenging task when animals are allowed to graze freely in large areas — were perceived as limiting. Land users also felt that the policies in place, especially the Common Agricultural Policy of the European Commission (CAP), were holding back nature-friendly and sustainable practices. For example, a land user in Romania noted that farmers were required to remove scrubs from their pastures or they would otherwise not be eligible for subsidies or even have to pay penalties. However, scrubs have important ecosystem functions, such as providing shade in the summer and as an additional food resource in the winter. In general, the CAP was perceived as too restrictive, and many land users chose not to apply for subsidies at all. “By not applying for CAP support, we have the freedom to really see what suits the local ecosystem,” a Belgian land user stated.

Rural exodus is putting traditional labour at risk

The interviews also showed that many land users struggle with socio-economic changes in the countryside. The so-called ‘Rural Exodus’ is leading to a lack of workforce, while physical work is still very much needed, especially for work with cattle or horses. “The next generation does not want to farm because it is too hard, too much work,” a land user from Lithuania said. “They usually move abroad and choose easier career options’.’

“The CAP could support farmers in High Nature Value farming regions and put incentives in place to preserve or restore extensive grazing systems,” senior author Dr Guy Pe’er, a senior researcher at UFZ and iDiv, suggests. “It’s not a lack of budgets but rather the lack of ambition to support sustainable farming.”

More flexibility and improved market access needed

The researchers used the interviews to derive and suggest interventions to encourage better grazing practices. “What is needed is more flexibility for land users,” Rouet-Leduc says. “Current policies are, for the most part, not encouraging such practices, and particularly not offering a level playing field for land users.” While the EU’s CAP offers important economic support, it also drives counter-productive management due to problematic requirements, she adds. Additional financial incentives could improve the support for more sustainable grazing management, according to the study’s authors. Especially in areas where land has been abandoned, there can be opportunities for rewilding large herbivores, which ultimately provide multiple ecosystem services. However, such systems require flexibility since they differ from management approaches with domestic animals.

The researchers also call for better labelling and certification for environmentally friendly grazing practices to increase public support and to help develop markets for such products. Some of the interviewed land users felt that market access could be improved by supporting direct marketing, for example, via farm shops.

“There are clearly real challenges for farmers, and they are not easy to overcome,” Pe’er explains in light of ongoing farmers’ demonstrations in countries like Germany, Poland, and Italy. “But removing environmental standards will not help land users. They need a package that includes an ambitious CAP reform, providing real support for farmers who need it to be more sustainable; the Nature Restoration Law to improve the standards of good management; and a framework for sustainable food systems to improve the market options for sustainable farming.”

Postdoctoral researchers Artem Nemudryi and Anna Nemudraia conducted the research alongside Blake Wiedenheft, professor in the Department of Microbiology and Cell Biology in MSU’s College of Agriculture. The paper, titled “Repair of CRISPR-guided RNA breaks enables site-specific RNA excision in human cells,” was published online in the journal Science and constitutes the latest advance in the team’s ongoing exploration of CRISPR applications for programmable genetic engineering.

CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, is a type of immune system that bacteria use to recognize and fight off viruses. Wiedenheft, one of the nation’s leading CRISPR researchers, said that the system has been used for years to cut and edit DNA, but that applying similar technology to RNA is unprecedented. DNA editing uses a CRISPR-associated protein called Cas9, while editing RNA requires the use of a different CRISPR system, called type-III.

“In our previous work, we used type-III CRISPRs to edit viral RNA in a test tube,” said Nemudryi. “But we wondered, can we program manipulation of RNA in a living human cell?”

To explore that question, the team programmed type-III CRISPR proteins to cut RNA containing a mutation that causes cystic fibrosis, restoring cell function.

“We were confident that we could use these CRISPR systems to cut RNA in a programmable manner, but we were all surprised when we sequenced the RNA and realized that the cell had stitched the RNA back together in a way that removed the mutation,” said Wiedenheft.

Nemudryi noted that RNA is transient within the cell; it is constantly being destroyed and replaced.

“The general belief is that there’s not much point in repairing RNA,” he said. “We speculated that RNA would be repaired in living human cells, and it turned out to be true.”

Wiedenheft has mentored the two postdoctoral researchers since their arrival at MSU nearly six years ago, and said that the impact of their scientific contributions will lead to significant and continued advancements.

“The work done by Artem and Anna suggests that RNA repair might be a fundamental aspect of biology and that harnessing this activity may lead to new lifesaving cures,” said Wiedenheft. “Artem and Anna are two of the most brilliant scientists I have ever encountered, and I’m confident that their work is going to have a lasting impact on humanity.”

RNA editing has important applications in the search for treatments of genetic diseases, Nemudryi said. RNA is a temporary copy of a cell’s DNA, which serves as a template. Manipulating the template by editing DNA could cause unwanted and potentially irreversible collateral changes, but because RNA is a temporary copy, he said, edits made are essentially reversible and carry far less risk.

“People used Cas9 to break DNA and study how cells repair these breaks. Then, based on these patterns, they improved Cas9 editors,” said Nemudraia. “Here, we hope the same will happen with RNA editing. We created a tool that allows us to study how the cells repair their RNA, and we hope to use this knowledge to make RNA editors more efficient.”

In the new publication, the team shows that a mutation causing cystic fibrosis can be successfully removed from the RNA. But this is only one of thousands of known mutations that cause disease. The question of how many of them could be addressed with this new RNA editing technology will guide future work for Nemudryi and Nemudraia as they finish their postdoctoral training at MSU and prepare for faculty positions at the University of Florida this fall. Both credited Wiedenheft as a life-changing mentor.

“Blake taught us not to be afraid of testing any ideas,” said Nemudraia. “As a scientist, you should be brave and not be afraid to fail. RNA editing and repair is the terra incognita. It’s scary but also exciting. You feel you’re working on the edge of science, pushing the limits to where nobody has been before.”

“For the first time, the new enzyme cocktails not only remove the well-described A and B antigens, but also extended variants previously not recognized as problematic for transfusion safety. We are close to being able to produce universal blood from group B donors, while there is still work to be done to convert the more complex group A blood. Our focus is now to investigate in detail if there are additional obstacles and how we can improve our enzymes to reach the ultimate goal of universal blood production,” says Professor Maher Abou Hachem, who is the study leader at DTU and one of the senior scientists behind the discovery.

He states that the discovery is the result of combining the expertise of DTU researchers in enzymes from the human gut microbiota and Lund University researchers in carbohydrate-based blood groups and transfusion medicine.

High demand for donor blood

Human red blood cells carry specific complex sugars structures (antigens) that define the four ABO blood groups A, B, AB and O. These antigens control compatibility between donors and recipients for safe blood transfusion and organ transplantation. Donor blood is screened for disease markers and the main blood groups. It can then be stored refrigerated for up to 42 days.

The need for donor blood is high due to the elderly making up a larger proportion of the population and more patients undergoing blood-intensive medical procedures. Successfully converting A or B blood types into ABO universal donor blood can markedly reduce the logistics and costs currently associated with storing four different blood types. In addition, the development of universal donor blood will lead to an increased supply of donor blood by reducing the waste of blood approaching its expiry date.

The reason why it is necessary to remove the A and B antigens to create universal donor blood is because they can trigger life-threatening immune reactions when transfused into non-matched recipients.

The concept of using enzymes to generate universal donor blood was introduced more than 40 years ago. Since then, higher efficiency enzymes to remove the A and B antigens were discovered, but researchers are still not able to explain or abolish all immune reactions related to the blood, and therefore these enzymes are still not used in clinical practice.

Enzymes from the gut

The research groups from DTU and Lund University have gone new ways to find enzymes that can remove both the A and B blood antigens and the sugars that block them. The research teams discovered new mixtures of enzymes from the human gut bacterium Akkermansia muciniphila that feeds by breaking down the mucus, which covers the surface of the gut. It turns out that these enzymes are exceptionally efficient, as the complex sugars at the surface of the intestinal mucosa share chemical resemblance with those found at the surface of blood cells.

“What is special about the mucosa is that bacteria, which are able to live on this material, often have tailor-made enzymes to break down mucosal sugar structures, which include blood group ABO antigens. This hypothesis turned out to be correct,” says Maher Abou Hachem.

The researchers in this study tested 24 enzymes, which they used to process hundreds of blood samples.

“Universal blood will create a more efficient utilization of donor blood, and also avoid giving ABO-mismatched transfusions by mistake, which can otherwise lead to potentially fatal consequences in the recipient. When we can create ABO-universal donor blood, we will simplify the logistics of transporting and administering safe blood products, while at the same time minimizing blood waste” says Professor Martin L. Olsson, the leader of the study at Lund University.

The researchers from DTU and Lund University have applied for a patent on the new enzymes and the method for enzyme treatment and expect to make further progress on this in their new joint project over the next three and a half years. If successful, the concept needs to be tested in controlled patient trials before this can be considered for commercial production and clinical use.

The initial research project is funded by the Independent Research Fund Denmark (Technology and Production Sciences, FTP), the Swedish Research Council, ALF grants from the Swedish government and county councils as well as the Knut and Alice Wallenberg Foundation and Research Fund Denmark, Natural Sciences, FNU), while the new continued project is funded by the Novo Nordisk Foundation, Interdisciplinary Synergy Programme.

FACTS:

Donorblood

In Scandinavia, the four main blood types are distributed with approximately 40-45 percent blood type A, the majority of whom are so-called RhD positive and 10-15 percent RhD negative, followed by blood type O with about 40 percent, B with about 10 percent and AB with about 5 percent. Red blood cells from blood group O are the only type that can be used by all receiving patients regardless of ABO type.

Bacterium from the gut

Akkermansia muciniphila is a bacterium found abundantly in the guts of most healthy humans. This bacterium can break down mucus in the gut and produces beneficial compounds such as the short-chain fatty acid propionate, in addition to exerting beneficial effects on body weight and metabolic markers.

Kishore Kuchibhotla, a Johns Hopkins University neuroscientist who studies learning in humans and animals, and who has long worked with mice, wondered why rodents often performed poorly in tests when they knew how to perform well. With a simple experiment, and by acting as “a little bit of a mouse psychologist,” he and his team figured it out.

“It appears that a big part of this gap between knowledge and performance is that the animal is engaging in a form of exploration — what the animal is doing is very clever,” he said. “It’s hard to say animals are making hypotheses, but our view is that animals, like humans, can make hypotheses and they can test them and may use higher cognitive processes to do it.”

The work, which deepens our understanding of animal cognition, and could lead to identifying the neural basis for strategizing, published in Current Biology.

Kuchibhotla’s lab previously found that animals know a lot more about tasks than they demonstrate in tests. The team had two theories about what could be behind this gap. Either the mice were making mistakes because they were stressed, or they were doing something more purposeful: exploring and testing their knowledge.

To figure it out Kuchibhotla and Ziyi Zhu, a graduate student studying neuroscience, came up with a new experiment.

Mice heard two sounds. For one sound they were supposed to turn a wheel to the left. For the other sound, they’d turn the wheel to the right. When the mice performed correctly they were rewarded.

The researchers observed how upon hearing either sound over consecutive trials, the mice would turn the wheel left for a bit, then switch to turning it right, seemingly making mistakes but actually being purposeful.

“We find that when the animal is exploring, they engage in a really simple strategy, which is, ‘I’m going to go left for a while, figure things out, and then I’m going to switch and go right for a while,'” Kuchibhotla said. “Mice are more strategic than some might believe.”

Zhu added, “Errors during animal learning are often considered as mistakes. Our work brings new insight that not all errors are the same.”

The team learned even more about the rodents’ actions by taking the reward out of the equation.

When a mouse performed correctly and wasn’t rewarded, it immediately doubled down on the correct response when retested.

“If the animal has an internal model of the task, the lack of reward should violate its expectation. And if that’s the case, it should affect the behavior on subsequent trials. And that’s exactly what we found. On subsequent trials the animal just does a lot better,” Kuchibhotla said. “The animal is like, ‘Hey, I was expecting to be rewarded, I wasn’t, so let me test my knowledge, let me use the knowledge I have and see if it’s correct.'”

If the animal didn’t have an internal model of the task, there would be no expectations to violate and the mice would keep performing poorly.

“At a very early time in learning the animal has an expectation and when we violate it, it changes its strategy,” Kuchibhotla said. “It was surprisingly strategic.”

This mouse strategizing is comparable to how nonverbal human babies learn. Both are highly exploratory and both may test hypotheses in various ways, Kuchibhotla said.

During the experiments Kuchibhotla said he became “a little bit of a mouse psychologist” to interpret their behavior. Like working with a nonverbal infant, he and Zhu had to infer the underlying mental processes from the behavior alone.

“That’s what was really fun in this project, trying to figure out what the mouse is thinking,” he said. “You have to think about it from the perspective of the animal.”

Next the team hopes to determine the neural basis for strategic thinking, and how those strategies might compare across different animals.

From September to December 2020, the team, led by Ann Cheney, an associate professor of social medicine, population, and public health in the School of Medicine, conducted interviews in collaboration with María Pozar, a community investigator and CEO of Conchita Servicios de la Comunidad, with 36 Latinx and Indigenous Mexican caregivers of children with asthma or respiratory distress. The researchers found communities in the “colonias” (unincorporated areas in the borderlands) lack basic critical infrastructure including healthcare access.

The U.S.-Mexico borderland is home to nearly 2.7 million Hispanic or Latinx individuals. The immigrant population in the colonias has limited English proficiency, health literacy levels, and income, and lower levels of formal education. Many are undocumented.

“Our work shows the importance of geography in health and how geography acts as a structural determinant of health,” Cheney said. “For example, foreign-born caregivers who speak Spanish or Purépecha prefer to take their children across the U.S.-Mexico border for respiratory health care because physicians there provide them with a diagnosis and treatment plan that they perceive improves their children’s health.”

The study, published in the journal Social Science & Medicine, found the caregivers perceive U.S.-based physicians as not providing them with sufficient information since most physicians do not speak their language and do not adequately listen to or are dismissive of their concerns about their children’s respiratory health. The caregivers perceive Mexican-based physicians as providing them with a diagnosis and treatment plan, whereas U.S.-based physicians often prescribe medications and provide no concrete diagnosis.

“Further, only those with legal documentation status can cross the border, which contributes to disparities in children’s respiratory health,” Cheney said. “Thus, caregivers without legal status in the U.S. must access healthcare services in the U.S. for their children and receive, what these caregivers perceive, as suboptimal care.”

Cheney added she was surprised to learn that caregivers who did not have legal documentation status in the U.S. asked trusted family and friends to take their children across the border to receive healthcare services for childhood asthma and related conditions.

“Geography, meaning living in unincorporated communities, harms health,” she said. “Geography and the politics of place determines who can and cannot cross borders.”

Study participants discussed the distance they needed to travel to pediatric specialty care for the care and management of their children’s respiratory health problems. Some commented on the lack of interaction and communication with physicians during medical visits. Some participants commented on the lack of physicians’ knowledge about the connections between their children’s exposure to environmental hazards and poor respiratory health and allergic symptoms.

The research took place in four unincorporated rural communities — Mecca, Oasis, Thermal, and North Shore — in eastern Coachella Valley, along the northern section of the Salton Sea. People living in the colonias here are subject to the health effects of environmental hazards. Many are farmworkers living and working in the nearby agricultural fields. Most of the workforce lives in mobile parks and below the federal poverty line.

“In addition to toxic water and dust from the Salton Sea, other environmental health hazards, such as agriculture pesticide exposure, waste processing facilities, and unauthorized waste dumps, also contribute to this community’s high incidence of poor respiratory health,” said Gabriela Ortiz, the first author of the research paper and a graduate student in anthropology who works with Cheney. “These communities are vulnerable to the policies and governing decisions around exposure to environmental hazards and infrastructure development. The absence of infrastructure and lack of healthcare infrastructure limits their access to primary care and specialty care services.”

Ortiz explained that anthropologists and social scientists have long argued that environmental injustices are a product of structural violence.

“This is indirect violence caused by social structures and institutions that prevent individuals from meeting their basic needs because of political economic domination and class-based exploitation,” she said. “Understanding the complex interplay between geography, borderlands, and health is essential for coming up with effective public health policy and interventions.”

The title of the research paper is “Seeking care across the US-Mexico border: The experiences of Latinx and Indigenous Mexican caregivers of children with asthma or respiratory distress.”

Cheney, Ortiz, and Pozar were joined in the study by Ashley Moran and Sophia Rodriquez of UCR.

The study was funded by the National Institutes of Health/National Institute of Minority Health and Health Disparities.

The report documents the discovery, the first finding of HPAIV in a cetacean in North America, from the initial response by UF’s Marine Animal Rescue team to a report of a distressed dolphin in Dixie County, Florida, to the subsequent identification of the virus from brain and tissue samples obtained in a postmortem examination.

Analyses initially performed at UF’s zoological medicine diagnostic laboratory ruled out the presence of other potential agents at play in the dolphin’s disease, with the Bronson Animal Disease Diagnostic Laboratory in Kissimmee, Florida, verifying the presence of HPAI virus in both the lung and brain.

Those results were confirmed by the National Veterinary Services Laboratory in Ames, Iowa, which characterized the virus subtype and pathotype. The virus was confirmed to be HPAI A (H5N1) virus of HA clade 2.3.4.4b. Subsequent tissue analysis was performed at the Biosafety Level 3 enhanced laboratory at St. Jude Children’s Research Hospital in Memphis.

Allison Murawski, D.V.M., a former intern with UF’s aquatic animal medicine program, was first author on the study and developed a case report on the dolphin as part of her research project. She traveled to Memphis and worked closely with Richard Webby, Ph.D., who directs the World Health Organization Collaborating Center for Studies on the Ecology of Influenza in Animals and Birds at St. Jude’s and served as corresponding author on the paper

Webby’s laboratory investigates avian influenza cases in many species and was key in determining where the virus may have originated, what unique RNA characteristics or mutations were present that could suggest its ability to infect other mammals, and how the virus could be tracked from this source.

The researchers sequenced the genomes from local birds and looked at viruses isolated from Northeast seal populations.

“We still don’t know where the dolphin got the virus and more research needs to be done,” Webby said.

“This investigation was an important step in understanding this virus and is a great example where happenstance joins with curiosity, having to answer the ‘why’ and then seeing how the multiple groups and expertise took this to a fantastic representation of collaborative excellence,” said Mike Walsh, D.V.M., an associate professor of aquatic animal health, who served as Murawski’s faculty mentor.

Led by Dr. Jean Seely, this study published in the Canadian Association of Radiologists Journal reviewed breast cancer cases over 35 years to shed light on trends in breast cancer detection in Canada.

“Breast cancer in younger women tends to be diagnosed at later stages and is often more aggressive,” said Dr. Seely, Head of Breast Imaging at The Ottawa Hospital and Professor in the Department of Radiology at the University of Ottawa. “It’s alarming to see rising rates among women in their Twenties and Thirties because they are not regularly screened for breast cancer.”

Risk increases with age

Using data from the National Cancer Incidence Reporting System (1984-1991) and the Canadian Cancer Registry (1992-2019) at Statistics Canada, the research team, which included Larry Ellison from Statistics Canada and Dr. Anna Wilkinson, an Associate Professor in the Faculty of Medicine, looked at all women aged 20 to 54 who were diagnosed with breast cancer.

Their findings included:

• For women in their Twenties, there were 3.9 cases per 100,000 people between 1984 and 1988, compared to 5.7 cases per 100,000 between 2015 and 2019 for a 45.5% increase.
• For women in their Thirties, there were 37.7 cases per 100,000 people between 1984 and 1988, compared to 42.4 cases per 100,000 between 2015 and 2019 for a 12.5% increase.
• For women in their Forties, there were 127.8 cases per 100,000 people between 1984 and 1988, compared to 139.4 cases per 100,000 between 2015 and 2019 for a 9.1% increase.

The study’s results show the importance of targeting younger women in breast cancer awareness campaigns and screening programs. Most public health efforts focus on women over 50, but these findings suggest that younger women are increasingly at risk and may benefit from earlier and more frequent screenings.

Personal experience

Chelsea Bland is one of those women.

Hearing about a death from breast cancer at age 33 led Chelsea — then 28 — to conduct her own self-examination, where she discovered a lump. This led to screenings which ultimately led to a breast cancer diagnosis and subsequent treatment. While she is two years cancer free, she remains on hormone therapy today. The entire experience led Chelsea to help establish a local group that provides peer support for younger women — the average ages range between 28 to 40.

“I hope that by bringing awareness to this study it makes people think twice about saying that being in your twenties, thirties and forties is too young to have breast cancer. In my support group, I have heard the same story over and over again,” Chelsea says. “Young women are not being taken seriously after they find a lump because they are told they are too young for breast cancer. This has ultimately led to delays in being diagnosed and being diagnosed at a more advanced stage. We are not too young for this and this is happening to women who do not have any high-risk genetic markers for breast cancer, myself included.”

Improving awareness

The investigators say more research is needed to understand the root cause of rising breast cancer rates among younger women, information that could be used to develop targeted intervention strategies.

“We’re calling for increased awareness among health-care professionals and the public regarding the rising incidence of breast cancer in younger women,” said Dr. Seely, who alongside Dr. Wilkinson have long documented the benefits of early detection with screening for women in their forties. “We need to adapt our strategies and policies to reflect these changing trends, ensuring that all women, regardless of age, have access to the information and resources they need to detect and combat this disease.”

In their experiments, the researchers were able to use this automated robot to manipulate the genetics of multicellular organisms, including fruit fly and zebrafish embryos. The technology will save labs time and money while enabling them to more easily conduct new, large-scale genetic experiments that were not possible previously using manual techniques

The research is featured on the cover of the April 2024 issue of GENETICS, a peer-reviewed, open access, scientific journal. The work was co-led by two University of Minnesota mechanical engineering graduate students Andrew Alegria and Amey Joshi. The team is also working to commercialize this technology to make it widely available through the University of Minnesota start-up company, Objective Biotechnology.

Microinjection is a method for introducing cells, genetic material, or other agents directly into embryos, cells, or tissues using a very fine pipette. The researchers have trained the robot to detect embryos that are one-hundredth the size of a grain of rice. After detection, the machine can calculate a path and automate the process of the injections.

“This new process is more robust and reproducible than manual injections,” said Suhasa Kodandaramaiah, a University of Minnesota mechanical engineering associate professor and senior author of the study. “With this model, individual laboratories will be able to think of new experiments that you couldn’t do without this type of technology.”

Typically, this type of research requires highly skilled technicians to perform the microinjection, which many laboratories do not have. This new technology could expand the ability to perform large experiments in labs, while reducing time and costs.

“This is very exciting for the world of genetics. Writing and reading DNA have drastically improved in recent years, but having this technology will increase our ability to perform large-scale genetic experiments in a wide range of organisms,” said Daryl Gohl, a co-author of the study, the group leader of the University of Minnesota Genomics Center’s Innovation Lab and research assistant professor in the Department of Genetics, Cell Biology, and Development.

Not only can this technology be used in genetic experiments, but it can also help to preserve endangered species through cryopreservation, a preservation technique conducted at ultra-low temperatures.

“You can use this robot to inject nanoparticles into cells and tissues that helps in cryopreservation and in the process of rewarming afterwards,” Kodandaramaiah explained.

Other team members highlighted other applications for the technology that could have even more impact.

“We hope that this technology could eventually be used for in vitro fertilization, where you could detect those eggs on the microscale level,” said Andrew Alegria, co-lead author on the paper and University of Minnesota mechanical engineering graduate research assistant in the Biosensing and Biorobotics Lab.

Cardiovascular diseases are still among the top causes of death worldwide, and especially prevalent in developed countries. Myocardial infarctions, commonly known as “heart attacks,” are on the rise, resulting in a significant number of deaths each year.

Heart attacks typically kill millions of cardiac muscle cells, leaving the heart in a weakened state. Since mammals cannot regenerate cardiac muscle cells on their own, heart transplants are currently the only clinically viable option for patients suffering (or likely to suffer) heart failure. Given that full heart transplants are expensive and donors difficult to come by, it is no surprise that alternative therapies are highly sought after by the medical community.

One promising strategy that has been steadily gaining traction is using human induced pluripotent stem cells (HiPSCs) for regenerative heart therapy. Simply put, HiPSCs are cells derived from mature cells that can be effectively ‘reprogrammed’ into a completely different cell type, such as cardiac muscle cells (cardiomyocytes). By transplanting or injecting cardiomyocytes derived from HiPSCs into damaged areas of the heart, it is possible to recover some lost functionality. Unfortunately, studies have reported that this approach can increase the risk of arrythmias, posing a major hurdle to clinical trials.

In a recent study, a Japanese research team from Shinshu University and Keio University School of Medicine, tested a new strategy for regenerative heart therapy that involves injecting ‘cardiac spheroids’ derived from HiPSCs into monkeys with myocardial infarction. This study, published on April 26, 2024, in the journal Circulation, was led by Professor Yuji Shiba from the Department of Regenerative Science and Medicine, Shinshu University.

The team included Hideki Kobayashi, the first author, and Koichiro Kuwahara from the Department of Cardiovascular Medicine, Shinshu University School of Medicine, as well as Shugo Tohyama, and Keiichi Fukuda from the Department of Cardiology, Keio University School of Medicine, among others.

In their novel approach, the researchers cultivated HiPSCs in a medium that led to their differentiation into cardiomyocytes. After carefully extracting and purifying cardiac spheroids (three-dimensional clusters of cardiac cells) from the cultures, they injected approximately 6 × 10⁷ cells into the damaged hearts of crab-eating macaques (Macaca fascicularis). They monitored the condition of the animals for twelve weeks, taking regular measurements of cardiac function. Following this, they analyzed the monkeys’ hearts at the tissue level to assess whether cardiac spheroids could regenerate the damaged heart muscles.

First, the team verified the correct reprogramming of HiPSCs into cardiomyocytes. They observed, via cellular-level electrical measurements, that the cultured cells exhibited potential patterns typical of ventricular cells. The cells also responded as expected to various known drugs. Most importantly, they found that the cells abundantly expressed adhesive proteins such as connexin 43 and N-cadherin, which would promote their vascular integration into an existing heart.

Afterwards, the cells were transported from the production facility at Keio University to Shinshu University, located 230 km away. The cardiac spheroids, which were preserved at 4 °C in standard containers, withstood the four-hour journey without problem. This means that no extreme cryogenic measures would be needed when transporting the cells to clinics, which would make the proposed approach less expensive and easier to adopt.

Finally, the monkeys received injections of either cardiac spheroids or a placebo directly into the damaged heart ventricle. During the observation period, the researchers noted that arrythmias were very uncommon, with only two individuals experiencing transient tachycardia (fast pulse) in the first two weeks among the treatment group. Through echocardiography and computed tomography exams, the team confirmed that the hearts of monkeys that received treatment had better left ventricular ejection after four weeks compared to the control group, indicating a superior blood pumping capability.

Histological analysis ultimately revealed that the cardiac grafts were mature and properly connected to pre-existing existing tissue, cementing the results of previous observations. “HiPSC-derived cardiac spheroids could potentially serve as an optimal form of cardiomyocyte products for heart regeneration, given their straightforward generation process and effectiveness,” remarks Assistant Professor Kobayashi. “We believe that the results of this research will help solve the major issue of ventricular arrhythmia that occurs after cell transplantation and will greatly accelerate the realization of cardiac regenerative therapy,” he further adds.

Although tested in monkeys, it is worth noting that the cardiac spheroid production protocol used in this study was designed for clinical application in humans. “The favorable results obtained thus far are sufficient to provide a green light for our clinical trial, called the LAPiS trial. We are already employing the same cardiac spheroids on patients with ischemic cardiomyopathy,” comments Asst. Prof. Kobayashi.

Let us all hope for a resounding success in the LAPiS trial, paving the way for expanded and effective treatment avenues for people suffering from heart problems.

The drug, dapagliflozin, was initially approved for the treatment of Type 2 diabetes, but it since has been shown to reduce the risk of hospitalization for heart failure and death in patients with serious health problems that include heart and chronic kidney disease and heightened cardiovascular risk.

Reporting this month in the Journal of the American College of Cardiology, the researchers found that dapagliflozin also benefits patients after admission to the hospital for acute heart failure. The drug improves diuresis, the elimination of excess fluid from the lungs, thereby relieving congestion, and it can reduce hospital stays.

“We demonstrated safety and efficacy of initiating dapagliflozin within the first day of hospitalization for acute heart failure,” said the paper’s first author, Zachary Cox, PharmD, professor of Pharmacy Practice at Lipscomb University. This “will have international impact on the treatment of acute heart failure.”

Each year 800,000 patients with acute heart failure are admitted to U.S. hospitals from emergency rooms. These patients are at high risk for prolonged hospital stays and death. The annual cost of treating acute heart failure in the United States is estimated to exceed $34 billion.

Diuretics are administered to most patients with acute heart failure to improve symptoms and lung congestion caused by fluid buildup. However, the optimal approach to diuretic therapy in patients hospitalized for acute heart failure remains poorly defined and contributes to prolonged inpatient stays and high death and readmission rates.

Furthermore, many patients do not respond to diuretics, and about half of patients are discharged with persistent congestion. This can result in patients returning to the hospital soon after discharge and being readmitted for further heart failure therapy.

Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that acts on the kidneys to increase the removal of sodium and glucose from the body. In April 2020, VUMC began a randomized, clinical trial of the drug in patients hospitalized with acute heart failure.

The study was designed by VUMC’s JoAnn Lindenfeld, MD, and Sean Collins, MD, MSc, and by Cox, a member of VUMC’s heart failure research team.

Lindenfeld, professor of Medicine in the Division of Cardiology, is nationally known for her innovative contributions to the field of heart failure.

Collins, professor of Emergency Medicine, directs the Center for Emergency Care Research and Innovation (CERI), a national leader in emergency care research, co-directs the Vanderbilt Coordinating Center, which supports VUMC-led clinical research, and is associate director for clinical trials research in the Vanderbilt Institute for Medicine and Public Health.

Cox is a fellow of the Heart Failure Society of America who has published extensively in the field.

Despite the COVID-19 pandemic, which reached its crescendo in the middle of the study, the researchers were able to enroll 240 patients and complete the trial, “thanks to the diligent effort and collaboration between the CERI research team, and … the departments of emergency medicine and cardiology,” Cox said.

“This unique partnership allows VUMC to conduct trials in acute heart failure that are only possible in a small number of medical centers across the world,” he said.

The trial “really highlights the novelty of our Emergency Medicine infrastructure, and why we are a leader in designing and conducting highly impactful clinical trials such as this one,” Collins added.

Patients were enrolled at five sites in addition to VUMC: TriStar Centennial Medical Center and Ascension St. Thomas Hospital West in Nashville, the University of North Carolina at Chapel Hill, the University of Mississippi Medical Center in Jackson, and INTEGRIS Health Baptist Medical Center in Oklahoma City.

Within 24 hours of admission for acute heart failure, patients were randomized to receive either dapagliflozin or conventional diuretic treatment.

While early administration of dapagliflozin did not improve weight-based diuretic efficiency compared to conventional treatment, patients who received the drug experienced no increase in adverse events, required shorter periods of IV diuresis, and were discharged faster during the five-day study period.

The trial demonstrated the safety and efficacy of starting a drug during early hospitalization that will continue to be prescribed upon discharge to help achieve optimal outpatient therapy and reduce the likelihood of readmission.

“It is a way to both improve diuresis AND get a head start on implementing Guideline Directed Medical Therapy in patients with acute heart failure,” Lindenfeld said.

Other VUMC co-authors are Cathy Jenkins, MS, and Frank Harrell Jr., PhD, Department of Biostatistics, and Christina Kampe, MAcc, Karen Miller, RN, MPA, and William Stubblefield, MD, MPH, Department of Emergency Medicine.

The study was an investigator-initiated trial funded by AstraZeneca but independently conducted by VUMC investigators. Dapagliflozin is marketed under the brand name FARXIGA. Acute heart failure research at VUMC is supported in part by the National Heart, Lung and Blood Institute of the National Institutes of Health.

Frigid winters, food scarcity, intense competition for territories and the threat of becoming prey to large predators like the Canada lynx are just some of the trials they face.

Early-life struggles and trauma can literally get under their skin, affecting long-term survival, said Lauren Petrullo, a University of Arizona assistant professor in the Department of Ecology and Evolutionary Biology. Scientists want to know what factors, if any, can buffer young squirrels against these threats.

Petrullo is part of the Kluane Red Squirrel Project, a multi-university long-term field project involving the University of Alberta, University of Michigan, University of Colorado Boulder and University of Saskatchewan. The project has tracked and studied thousands of wild North American red squirrels in the southwestern part of Canada’s Yukon territory for over 30 years.

A new study — which Petrullo led with David Delaney, a postdoctoral fellow at the University of Colorado Boulder — finds that the more challenges young squirrels face in the year they are born, the shorter their adult lifespan.

Red squirrels who make it past their first year of life live about 3 1/2 years, on average, but early life adversity can cut life expectancy by at least 14%.

But there’s a big caveat.

“The ecosystem red squirrels inhabit in this region is unique,” Petrullo said. “Every three to seven years, their favorite food — seed from cones of white spruce trees — is produced in superabundance during what we call a food boom. We found that these booms, even though rare, can interrupt the biological embedding of early-life adversity. If a squirrel had a harsh first year of life, if they were lucky enough to experience a food boom in their second year of life, they lived just as long — if not longer — in spite of early-life adversity.”

The team replicated a food boom by offering wild squirrels in the Yukon peanut butter as a supplemental food source. The peanut butter didn’t have the same effect as the naturally occurring food boom did.

“This suggests that the buffering effect we see is not really just about an increase in available calories,” Petrullo said. “It’s probably about shifts in larger population-level dynamics, like competition.”

What squirrels can teach us about humans

Petrullo and her colleagues are eager to tease out the mechanisms that link squirrels’ early developmental conditions with later-life survival. What they learn could inform scientific understanding of human resilience, too.

“Our findings in red squirrels echo what we know about how early-life adversity can shorten adult lifespan in humans and other primates,” Petrullo said. “Humans vary widely in how vulnerable or resilient they are to challenges faced during early development. Our study demonstrates that future environmental quality might be an important factor that can explain why some individuals appear to be more, or less, susceptible to the consequences of early-life adversity.”

While it might be surprising that scientists can glean insights about human resilience from wild red squirrels, Petrullo pointed out that squirrels are rodents, and rodents are commonly used as models for humans in laboratory settings.

“Many lab experiments have limited relevance for broader dynamics between ecology and evolution, because it can be hard to really replicate the ecological challenges that animals have evolved to cope with in a lab setting,” she said.

Wild red squirrels, on the other hand, allow for such investigations and are an especially useful study group for questions regarding the early-life environment, Petrullo said. Although growing up as a young squirrel in the Yukon can be difficult, with lots of things making early development challenging, there are also things that can go right.

“Some red squirrels have the luck of being born into gentler early environments, akin to being born with a silver spoon,” Petrullo said. “Because of this, we’ve got this really nice individual variation in early-life environmental quality across a natural ecological environment.”

This environment, however, is expected to experience a great deal of change as global temperatures continue to rise.

“As food boom patterns begin to change,” Petrullo said, “the pathways that connect early-life experiences and lifespan may change as well, potentially offering important insight into how animals may adapt to increasingly challenging environments.”

In cancer, tumors often impair the body’s immune response. For example, they can prevent immune cells from perceiving cancer cells as a threat or render them inactive. Immunotherapies aim to overcome these mechanisms and stimulate the immune system, in particular the T cells. However, such therapies do not work for a large number of cancer patients. Researchers around the world are looking for the causes and new counter-strategies.

Messenger substance stops effector development of T cells in tumors

A team led by Dr. Jan Böttcher, research group leader at the Institute of Molecular Immunology at TUM, and Prof. Sebastian Kobold, Deputy Director of the Department of Clinical Pharmacology at LMU Klinikum München, has now discovered that tumors use a messenger substance to influence immune cells in an early phase of the immune response. Many cancer cells show increased secretion of the messenger substance prostaglandin E2. The researchers were able to show that prostaglandin E2 binds to EP2 and EP4, two receptors on the surface of certain immune cells.

These so-called stem-like T cells migrate from other areas of the body into the tumor. If the immune response is successful, they multiply in the tumor and develop into cytotoxic T cells that attack the cancer. “This whole process is strongly limited when tumors secrete prostaglandin E2 and this factor binds to EP2 and EP4 receptors,” says Jan Böttcher. “The T cell response collapses and the tumor can progress.” If the researchers prevented the interaction of messenger substance and receptor in tumor models, the immune system was able to fight tumors effectively.

Current therapies address a later point of the immune response

“We have discovered a mechanism that influences the body’s immune response in a crucial phase,” says Jan Böttcher. “Many tumors prevent the stem-like T cells from generating cytotoxic T cells in the tumor that could attack the cancer.”

Current immunotherapies aim to prevent the cancer from switching off immune responses at a later phase. Checkpoint inhibitor therapies, for example, aim to release the blockade of fully differentiated cytotoxic T cells and “switch them back on.” Before the dreaded T cell exhaustion sets in, which other researchers are trying to prevent, differentiated T cells must also be present.

Increase the effectiveness of existing therapies

“Current treatment approaches would probably be more effective if the effects of prostaglandin E2 on stem-like T cells is blocked to enable their unhindered differentiation within tumor tissue,” says Sebastian Kobold.

This similarly applies to recent approaches that rely on the protein IL-2 to stimulate T cells. The current study shows that as soon as the prostaglandin E2 binds to the two receptors, T cells can no longer respond to IL-2. “We suspect that even the body’s own IL-2 signals may be sufficient to enable T cells to successfully fight cancer once the effects of prostaglandin E2 have been stopped,” says Sebastian Kobold.

Second study in “Nature” confirms results

A second research publication in Nature investigates the effects of prostaglandin E2 on the immune system. For this study, the authors, researchers from the University Hospital of Lausanne, collaborated with the Munich team. In their laboratory, they among other things examined T cells from human tumor tissue. When they blocked the release of prostaglandin E2 in cancer tissue, the T cells showed better expansion and were thus able to fight human cancer cells more effectively.

Search for counter-strategies begins

“We now have a concrete starting point for significantly improving immunotherapies,” says Jan Böttcher. “Researchers around the world must now develop strategies to overcome the tumors’ defense. We need to stop the effects of prostaglandin E2 — either by preventing tumors from producing the molecule or by making immune cells resistant to it.”

In the study, published March 8 in Circulation Research, the researchers showed that boosting levels of a sphingolipid called S1P in artery-lining endothelial cells slows the development and progression of coronary artery disease in an animal model. The lead author was Dr. Onorina Laura Manzo, a postdoctoral researcher in the laboratory of Dr. Annarita Di Lorenzo, an associate professor of pathology and laboratory medicine at Weill Cornell Medicine.

Sphingolipids are named for the enigmatic sphinx of ancient mythology because their functions in biology traditionally have been somewhat mysterious. In recent years, there has been increasing evidence of their relevance in coronary artery disease; bloodstream levels of S1P, for example, are lower in patients with this condition. But the precise roles of these lipids have remained unclear.

In the new study, the researchers sought a better understanding of those roles — and of sphingolipids’ potential as therapeutic targets. Despite the availability of cholesterol-lowering drugs and other interventions, coronary artery disease — the underlying cause of most heart attacks and many strokes — continues to be the world’s leading cause of mortality, affecting more than 20 million people in the United States alone.

Using a novel mouse model developed by the same group, the researchers found that blood pressure-related stress on arteries — which eventually will induce coronary artery disease — triggers an increase in S1P production in endothelial cells, as part of a protective response. This response normally is only temporary, but deleting a protein called NOGO-B, which inhibits S1P production, allows the rise in endothelial S1P production to be sustained — and made the animals much more resistant to coronary artery disease and associated mortality.

Another key finding is related to a different group of sphingolipids called ceramides. Prior studies have linked coronary artery disease to high bloodstream levels of some ceramides, and their causative role in the disease has been widely assumed. In their model, however, the researchers observed that while ceramide levels were high in the bloodstream, levels in artery-lining endothelial cells remained about the same regardless of coronary artery disease status. This suggests that the current view of ceramides’ role in the disease should be revised.

All in all, the findings lay the foundation for the development of drugs that boost S1P to treat or prevent coronary artery disease, the researchers concluded.

The work reported in this story was supported by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health, through grant numbers R01HL126913 and R01HL152195 and a Harold S. Geneen Charitable Trust Award for Coronary Heart Disease Research.

Simple decisions like what local store is best to shop at to more complex ones like vaccinating a child are influenced by these behavior patterns and social discourse.

“We choose to be in networks, both offline and online, that are compatible with our own thinking,” explained Amin Rahimian, assistant professor of industrial engineering at the University of Pittsburgh Swanson School of Engineering. “The social contagion of behavior through networks can help us understand how and why new norms, products, and ideas are adopted.”

Initially, researchers thought highly clustered ties that are close together in networks created the perfect environment for the spread of complex behaviors that require significant social reinforcement. However, Rahimian, alongside a team of researchers from Massachusetts Institute of Technology (MIT) and Harvard University, counter these ideas. Long ties, which are created through randomly rewired edges that make them ‘longer,’ accelerate the spread of social contagions. For example, in the age of social media, long ties can facilitate broader reach across different demographics and heterogeneous populations. Rather than just communicating with one’s neighbor, one may also be connecting with someone in another state — even another country.

By using mathematical and statistical methods, the researchers were able to analyze the rate of spread over circular lattices with long ties and show that having a small probability of adoption below the contagion threshold is enough to ensure that random rewiring accelerates the spread of these contagions.

“Mechanisms that we identify for spread on circular lattices remain valid in higher dimensions,” explained Rahimian.

Similar network dynamics arise in the study of neural activity in the brain.

“We are interested in the implications of these results for a better understanding of network structures that facilitate the spread of bursting activity in various brain regions,” explained Jonathan Rubin, professor in Pitt’s Department of Mathematics.

This research suggests those wanting to achieve fast, total spread would benefit from implementing intervention points across network neighborhoods with long-tie connections to other network regions, explained Dean Eckles, associate professor of marketing at MIT.

“Further work could study such strategies for seeding complex behaviors,” Eckles continued.

Scientific research has shown that social relationships are important to human happiness, and that the greater the number and range of friendships that we engage with, the better our wellbeing. But once relationships are formed, some will naturally wax and wane, with many of us losing touch with friends and family that we were once close with.

As old friends who had reconnected themselves, Professor Lara Aknin from SFU and Dr. Gillian Sandstrom from the University of Sussex in Brighton (U.K.) were keen to find out what stops other people from doing the same.

Sandstrom, senior lecturer in the psychology of kindness and director of the Sussex Centre for Research on Kindness said: “We live in a time when people are more and more disconnected, and have fewer close friends than they used to in years past. And this is despite the multitude of modern-day communication channels available to us. With research finding that it takes more than 200 hours of contact to turn a new acquaintance into a close friend*, we wanted to find out if and why people were overlooking another pathway to meaningful connection: reviving pre-existing close friendships.”

Across seven studies, the psychologists examined the attitudes of almost 2,500 participants to reconnecting with lapsed friendships, the barriers and reasons for doing so, and whether targeted interventions could encourage them to send that first message to an old friend.

“We found that the majority of participants (90 per cent) in our first study had lost touch with a someone they still care about. Yet, a significant number (70 per cent) were neutral, or even negative, about the idea of getting back in touch in that moment, even when they felt warmly about the friendship,” says Aknin, director of the Helping and Happiness Lab at SFU and co-author of the paper.

Recognizing that people sometimes say one thing and do another, the psychologists designed a study to see how many people were willing to actually reach out to an old friend. Even when participants wanted to reconnect, thought the friend would be appreciative, had their contact information, and were given time to draft and send a message, only about a third actually sent it (28 per cent in one study and 37 per cent in another study).

The psychologists set out to benchmark this hesitance to reconnect by getting participants to rate their willingness to immediately carry out a range of activities, including calling or texting a friend they had lost touch with. They found that participants were as reluctant to reach out to an old friend as they were to strike up a conversation with a stranger — or even to pick up rubbish.

The top reported barriers included fears that one’s old friend might not want to hear from them, that it would be ‘too awkward after all this time’, and feeling ‘guilty’. A perception of being too busy — both the old friend and the participant — was the lowest cited reason for not reaching out.

Notably, the psychologists found that participants believed there were only a few legitimate reasons to get in touch, with the friend’s birthday reported as the most compelling. Reconnecting over the memory of a shared experience was the second most reported reason. Participants were least likely to consider getting in touch with an old friend to ask them a favour.

As part of the research, the psychologists tested targeted interventions, responding to the findings from four of the studies. Taking inspiration from a previous intervention conducted by Sandstrom on talking with strangers, they found that practising social connection with current networks by first sending a message to a warm friend, was the most successful strategy, boosting reach out rates by over two thirds.

Sandstrom explained: “Interestingly, despite people telling us that a key barrier to making contact with an old friend was concerns over how the message might be received, the intervention that we devised to help overcome this anxiety had little effect.

“Given that participants were as hesitant to reach out to a stranger as someone they had previously been close with, we drew inspiration from previous research I had conducted on talking to strangers, which found that practice made progress. When people were given time to practice in a situation that felt more comfortable, namely by sending messages to current friends, they were much more likely to make the leap to messaging someone they had lost touch with.”

Aknin adds: “We know from decades of research that social relationships are a key source of happiness and meaning in our lives.

“Gillian and I are old friends, dating back to our time as PhD students in Canada. We’ve been in touch on-and-off ever since, but most recently reconnected on New Year’s Day 2022 when I emailed her to say that I missed her and wanted to collaborate on a new project. We took inspiration from our period of disconnection and decided to study if and when people are willing to reach out to old friends.

“We hope these findings prompt other people to send that first message to someone that they miss in their lives.”

In the short term, working memory allows the brain to complete an immediate task, like loading the dishwasher. Long term, it helps the brain decide what to store for future use, such as whether more dishwasher soap will be needed.

University of Texas at Arlington researchers know that working memory varies greatly among individuals, but they aren’t sure exactly why. To better understand, Matthew Robison, assistant professor of psychology, and doctoral student Lauren D. Garner conducted an experiment to see if studying a person’s pupils (the centers of their eyes) was a good indicator of working memory.

Normally, a person’s pupils naturally widen (or dilate) in low-light environments to allow more light into the eye. However, in their new study published in the peer-reviewed journal Attention, Perception & Psychophysics, the researchers reported that a person’s pupils also dilate when they are concentrating on tasks. In particular, they found that the more a person’s eyes dilated during the task, the better they did on tests measuring their working memory.

“What we found was that the lowest performers on the tasks showed less pupil dilation,” Robison said. “For the highest-performing participants, their pupil dilations were both larger overall and the individuals were more discerning about the information they were asked to recall.”

For the study, he and Garner recruited 179 undergraduate students at UT Arlington. Participants completed several working memory tasks where they were presented with information and then asked to remember it for a few seconds. During the tasks, participants had their pupils continuously measured using an eye-tracker, similar to what optometrists use during eye exams.

“We found that people who more intensely and consistently paid attention, as measured by their pupils being dilated more, performed better on the memory tasks,” said Robison. “Importantly, we found high performers also showed more pupil sensitivity compared to low-performing participants. This is exciting research because it adds another valuable piece of the puzzle to our understanding of why working memory varies between individuals.”

This work was supported by funding from the U.S. Naval Research Laboratory (N00173-22-2-C006) and U.S. Army Research Institute (W911NF-23-1-0300).

Plants that contain these alkaloids have made it very clear they don’t want to be consumed, but that hasn’t deterred bella moths (Utetheisa ornatrix). These day-flying moths exclusively eat the alkaloid-laden leaves and seeds of rattlebox plants. They then use the toxin to guard their eggs and deter predators in later life stages. They even use it to make pheromones that attract mates.

Exactly how bella moths and related species evolved the ability to safely consume pyrrolizidine alkaloids remains unknown.

In a new study published in the journal PNAS, researchers sequence the bella moth genome, which they used to pinpoint specific genes that may confer immunity to these toxins. They also sequenced genomes from 150 museum specimens — some more than a century old — to determine where bella moths and their close relatives originated. Finally, they combed through genetic data looking for clues that could help explain how the intricate wing patterns of bella moths evolved over time — the first study on moths or butterflies that has done so using dry museum collection specimens.

“We’ve managed to show that you can use museum specimens to answer genetic questions that normally require complicated laboratory techniques,” said study co-author Andrei Sourakov, collections coordinator at the Florida Museum of Natural History’s McGuire Center for Lepidoptera and Biodiversity. “This opens a window for future research of this kind.”

Sourakov has been studying bella moths for 15 years and said sequencing the genome for this species was the natural next step in the research he’s conducted so far. Many of the insights he gained during that time came from his work with undergraduate and high school students, whom he helped conduct short experiments, analyze data for science fairs and interpret the results in peer-reviewed papers.

In one such project, a student set out to determine the average lifespan of bella moth adults and inadvertently stumbled across the Methuselah of the moth world. “To our great surprise, they can live for up to 50 days, which is four to five times longer than the average moth,” Sourakov said.

Longevity is not a critically important trait in most moth species. Many breed once, then die shortly after, either from senescence or predation. But bella moths aren’t limited by the latter, making it more likely that genes conferring increased longevity will be beneficial and passed down to the next generation.

“It makes sense for something that’s chemically defended to live longer, because even if they’re caught, the predator most often lets go, and the moth can continue flying around.”

Bella moths live throughout much of eastern North America, Central America and the Caribbean and are often active during the day. Rather than using darkness as a shroud to avoid predators, bella moths make a point of being seen. Their wings are garbed with radiant pink, pearl, onyx and sulfur yellow scales, which birds and carnivorous insects can easily spot from a distance. Any predator unlucky enough to catch a bella moth quickly corrects its mistake.

“Banana spiders will cut them out of their webs,” Sourakov said, adding that wolf spiders and birds will go out of their way to avoid them. “When caught, they produce foaming liquid that tastes bad made almost entirely out of alkaloids.”

When ready to mate, females release a plume of aerosolized alkaloids derived from the plants they ate as caterpillars. Males are attracted to this scent, which they follow to its source. There, they perform a short but elaborate ritual in which they gently touch the female’s head with two fluffy and retractable structures that bear a strong resemblance to dandelions. Each filament in these structures is laced with pyrrolizidine alkaloids.

If the female decides the male has a sufficient quantity and quality of alkaloids stored up, the pair will mate. When finished, the male leaves behind a parting gift called a spermataphore, which contains sperm and, yes, more alkaloids. The female will use this and alkaloids from her own reserve to infuse the resulting eggs with toxins. This sort of biparental egg protection in insects is rare. In fact, when it was first observed in 1989 among bella moth adults, it was the only known example of a male moth or butterfly that invested any chemical resources in its progeny.

Bella moths are able to avoid the ill effects of pyrrolizidine alkaloids by using a special enzyme that oxidizes the molecule, rendering it harmless. If a predator eats a moth, however, the process is reversed, and the alkaloid regains its potency.

Pyrrolizidine alkaloids likely first evolved as a defense mechanism in plants, which then became a commodity for moths. Sourakov and his colleagues wanted to know how bella moths acquired this detoxifying enzyme and how they maintained it through an arms race millions of years long between plant and moth.

The authors discovered bella moths have not one but two copies of the gene that codes for their unique detoxifying enzyme. They may have acquired the second through a process of gene duplication, whereby other species, including many plants, have evolved new traits.

They also found two copies of a gene partially involved in antioxidant production and defense. Sourakov suspects these genes may be related both to the ability of bella moths to detoxify alkaloids and to their remarkable longevity.

“Certain types of stress on biological systems result in a longer lifespan. It could be that the interaction bella moths have with alkaloids is not only the reason why it makes sense for them to live long lives, but also one of the mechanisms behind it.”

Irritable bowel syndrome (IBS) is a common diagnosis that causes abdominal pain, gas and abdominal bloating, diarrhea, and constipation, in various combinations and with varying degrees of severity.

Treatment often consists of dietary advice such as eating small and frequent meals and avoiding excessive intake of food triggers such as coffee, alcohol and fizzy drinks. Patients may also be given medications to improve specific symptoms, such as gas or constipation, diarrhea, bloating or abdominal pain. Antidepressants are sometimes used to improve symptoms in IBS.

The current study, published in The Lancet Gastroenterology & Hepatology, compared three treatments: two dietary and one based on use of medications. The participants were adult patients with severe or moderate IBS symptoms at Sahlgrenska University Hospital in Gothenburg.

More symptom relief after dietary adjustment

The first group was given traditional IBS dietary advice, focusing on eating behavior combined with low intake of fermentable carbohydrates, known as FODMAPs. These include e.g. products with lactose, legumes, onions, and grains, which ferment in the colon and can cause pain in IBS.

The second group received a dietary treatment low in carbohydrates and proportionally high in protein and fat. In the third group, the best possible medication was given based on the patient’s most troublesome IBS symptoms.

Each group included around 100 participants and the treatment periods lasted four weeks. When the researchers then examined how well the participants responded to the treatments, using an established IBS symptom scoring scale, the results were clear.

Of those who received traditional IBS dietary advice and low content of FODMAPs, 76% had significantly reduced symptoms. In the group receiving low carbohydrates and high protein and fat, the proportion was 71%, and in the medication group 58%.

All groups reported significantly better quality of life, less physical symptoms and less symptoms of anxiety and depression.

The importance of personalization

At a six-month follow-up, when participants in the dietary groups had partially returned to their previous eating habits, a large proportion still had clinically significant symptom relief; 68% in the traditional dietary advice and low FODMAP group, and 60% in the low-carbohydrate diet group.

The study was led by Sanna Nybacka, Researcher and Dietician, Stine Störsrud, Associate Professor, and Magnus Simrén, Professor and Senior Consultant, all at Sahlgrenska Academy, University of Gothenburg.

“With this study, we can show that diet plays a central role in the treatment of IBS, but that there are several alternative treatments that are effective,” says Sanna Nybacka.

“We need more knowledge about how to best personalize the treatment of IBS in the future and we will further investigate whether there are certain factors that can predict whether individuals will respond better to different treatment options,” she concludes.

In about 1 in 10 cases of MS, the body begins producing a distinctive set of antibodies against its own proteins years before symptoms emerge. These autoantibodies appear to bind to both human cells and common pathogens, possibly explaining the immune attacks on the brain and spinal cord that are the hallmark of MS.

The findings were published in Nature Medicine on April 19.

MS can lead to a devastating loss of motor control, although new treatments can slow the progress of the disease and, for example, preserve a patient’s ability to walk. The scientists hope the autoantibodies they have discovered will one day be detected with a simple blood test, giving patients a head start on receiving treatment.

“Over the last few decades, there’s been a move in the field to treat MS earlier and more aggressively with newer, more potent therapies,” said UCSF neurologist Michael Wilson, MD, a senior author of the paper. “A diagnostic result like this makes such early intervention more likely, giving patients hope for a better life.”

Linking infections with autoimmune disease

Autoimmune diseases like MS are believed to result, in part, from rare immune reactions to common infections.

In 2014, Wilson joined forces with Joe DeRisi, PhD, president of the Chan Zuckerberg Biohub SF and a senior author of the paper, to develop better tools for unmasking the culprits behind autoimmune disease. They took a technique in which viruses are engineered to display bits of proteins like flags on their surface, called phage display immunoprecipitation sequencing (PhIP-Seq), and further optimized it to screen human blood for autoantibodies.

PhIP-Seq detects autoantibodies against more than 10,000 human proteins, enough to investigate nearly any autoimmune disease. In 2019, they successfully used it to discover a rare autoimmune disease that seemed to arise from testicular cancer.

MS affects more than 900,000 people in the US. Its early symptoms, like dizziness, spasms, and fatigue, can resemble other conditions, and diagnosis requires careful analysis of brain MRI scans.

The phage display system, the scientists reasoned, could reveal the autoantibodies behind the immune attacks of MS and create new opportunities to understand and treat the disease.

The project was spearheaded by first co-authors Colin Zamecnik, PhD, a postdoctoral researcher in DeRisi’s and Wilson’s labs; and Gavin Sowa, MD, MS, former UCSF medical student and now internal medicine resident at Northwestern University.

They partnered with Mitch Wallin, MD, MPH, from the University of Maryland and a senior author of the paper, to search for autoantibodies in the blood of people with MS. These samples were obtained from the U.S. Department of Defense Serum Repository, which stores blood taken from armed service members when they apply to join the military.

The group analyzed blood from 250 MS patients collected after their diagnosis, plus samples taken five or more years earlier when they joined the military. The researchers also looked at comparable blood samples from 250 healthy veterans.

Between the large number of subjects and the before-and-after timing of the samples, it was “a phenomenal cohort of individuals to look at to see how this kind of autoimmunity develops over the course of clinical onset of this disease,” said Zamecnik.

A consistent signature of MS

Using a mere one-thousandth of a milliliter of blood from each time point, the scientists thought they would see a jump in autoantibodies as the first symptoms of MS appeared.

Instead, they found that 10% of the MS patients had a striking abundance of autoantibodies years before their diagnosis.

The dozen or so autoantibodies all stuck to a chemical pattern that resembled one found in common viruses, including Epstein-Barr Virus (EBV), which infects more than 85% of all people, yet has been flagged in previous studies as a contributing cause for MS.

Years before diagnosis, this subset of MS patients had other signs of an immune war in the brain. Ahmed Abdelhak, MD, co-author of the paper and a postdoctoral researcher in the UCSF laboratory of Ari Green, MD, found that patients with these autoantibodies had elevated levels of neurofilament light (Nfl), a protein that gets released as neurons break down.

Perhaps, the researchers speculated, the immune system was mistaking friendly human proteins for some viral foe, leading to a lifetime of MS.

“When we analyze healthy people using our technology, everybody looks unique, with their own fingerprint of immunological experience, like a snowflake,” DeRisi said. “It’s when the immunological signature of a person looks like someone else, and they stop looking like snowflakes that we begin to suspect something is wrong, and that’s what we found in these MS patients.”

A test to speed patients toward the right therapies

To confirm their findings, the team analyzed blood samples from patients in the UCSF ORIGINS study. These patients all had neurological symptoms and many, but not all, went on to be diagnosed with MS.

Once again, 10% of the patients in the ORIGINS study who were diagnosed with MS had the same autoantibody pattern. The pattern was 100% predictive of an MS diagnosis. Across both the Department of Defense group and the ORIGINS group, every patient with this autoantibody pattern had MS.

“Diagnosis is not always straightforward for MS, because we haven’t had disease specific biomarkers,” Wilson said. “We’re excited to have anything that can give more diagnostic certainty earlier on, to have a concrete discussion about whether to start treatment for each patient.”

Many questions remain about MS, ranging from what’s instigating the immune response in some MS patients to how the disease develops in the other 90% of patients. But the researchers believe they now have a definitive sign that MS is brewing.

“Imagine if we could diagnose MS before some patients reach the clinic,” said Stephen Hauser, MD, director of the UCSF Weill Institute for Neurosciences and a senior author of the paper. “It enhances our chances of moving from suppression to cure.”

Monkeypox virus (MPXV) is a double-stranded DNA virus that can infect animals and humans. MPXV causes a disease known as mpox, with symptoms that include fever, swollen lymph nodes, and a rash. Most cases are mild and tend to get better on their own; however, mpox can be very painful and may lead to permanent scarring. First encountered in 1958 in crab-eating macaque monkeys imported to Belgium, MPXV has caused sporadic human disease outbreaks since the 1970s in Central and Western Africa. In May 2022, multiple countries, including the United States, reported an increasing number of MPXV infections and associated disease, including clusters in cases potentially linked to super-spreading events in Belgium, Spain, and the United Kingdom. While the number of new cases associated with the 2022 spillover has decreased over time, cases of the disease are still occurring among unvaccinated individuals, including a current increase in Central Africa due to a new spillover. As the virus’s circulation in humans increases, the risk of emergence of a more transmissible variant capable of becoming endemic in the human population increases.

“Biopreparedness and virological surveillance involves studying the causes that favor zoonotic spillover and facilitates human-to-human transmission. When we observe significant changes in basic epidemiological features of a viral agent like monkeypox, it should reinvigorate our interest in understanding those transmission conditions. The increasing number of cases currently happening in Africa, and the 2022 epidemic, should be clear alert signals,” says Gustavo Palacios, PhD, Professor of Microbiology at the Icahn School of Medicine at Mount Sinai and a senior author of the study.

To carry out the study, researchers analyzed samples from 46 patients infected with MPXV whose diagnosis and sequencing were carried out at the ISCIII at the beginning of the 2022 mpox outbreak. The team performed high-quality sequencing of each study participant’s complete monkeypox virus genome to determine possible correlations between genomic variations in the different groups of sequences and epidemiological links associated with the virus’s ability to evolve, transmit, and infect.

According to the research team, recurrent observed genomic changes were located in areas of the genome that could be related to viral adaptation. Those specific locations would contribute to modulating the viral replication cycle, adaptability, and path of entry and egress. These alterations appear in areas known as low complexity genomic regions, which are particularly difficult to sequence and analyze, explaining why they were overlooked before. This highly sophisticated complete genome sequencing was made possible through the use of two advanced sequencing technologies: single-molecule long-read sequencing (to cover highly repetitive regions) and deep short sequencing reads (to provide accuracy and depth).

By detailing the genomic alterations within these repetitive genomic sequences and linking them to critical viral functions, researchers provide a plausible explanation for the heightened transmissibility observed during the 2022 mpox outbreak.

“These findings might be offering the first hints to help us understand the unique features of the strains associated with sustained human-to-human transmission, which has not ever been observed in these agents,” says Dr. Palacios. “Better understanding of the doors that facilitate transmission of viral agents and impact their clinical presentations will enable us to develop more effective prevention and treatment strategies.”

“The goal of this innovative insole technology is to mitigate the risk of diabetic foot ulcers by addressing one of their most significant causes: skin and soft tissue breakdown due to repetitive stress on the foot during walking,” said Muthu B.J. Wijesundara, principal research scientist at The University of Texas at Arlington Research Institute (UTARI).

Affecting about 39 million people in the U.S., diabetes can damage the small blood vessels that supply blood to the nerves, leading to poor circulation and foot sores, also called ulcers. About one-third of people with diabetes develop foot ulcers during their lifetime. In the U.S., more than 160,000 lower extremity amputations are performed annually due to complications from diabetic foot ulcers, costing the American health system about $30 billion a year. Those who have foot ulcers often die at younger ages than those without ulcers.

“Although many shoe insoles have been created over the years to try to alleviate the problem of foot ulcers, studies have shown that their success in preventing them is marginal,” Wijesundara said. “We took the research a step further by creating a pressure-alternating shoe insole that works by cyclically relieving pressure from different areas of the foot, thereby providing periods of rest to the soft tissues and improving blood flow. This approach aims to maintain the health of the skin and tissues, thereby reducing the risk of diabetic foot ulcers.”

In an article in the peer-reviewed International Journal of Lower Extremity Wounds, Wijesundara and UTA colleagues Veysel Erel, Aida Nasirian and Yixin Gu, along with Larry Lavery of UT Southwestern Medical Center, described their innovative insole technology. After this successful pilot project, the next step for the research team will be refining the technology to make it more accessible for users with varying weights and shoe sizes.

“Considering the impact of foot ulcers, it’s exciting that we may be able to make a real difference in the lives of so many people,” Wijesundara said.

This work was supported by a $229,480 grant from the National Institute of Aging of the National Institutes of Health, grant number 7R21AG061471.

The neocortex, a critical structure for human intelligence, is less than five millimeters thick. There, in the outermost layer of the brain, 20 billion neurons process countless sensory perceptions, plan actions, and form the basis of our consciousness. How do these neurons process all this complex information? That largely depends on how they are “wired” to each other.

More complex neocortex — different information processing

“Our previous understanding of neural architecture in the neocortex is based primarily on findings from animal models such as mice,” explains Prof. Jörg Geiger, Director of the Institute for Neurophysiology at Charité. In those models, the neighboring neurons frequently communicate with each other as if they are in dialogue. One neuron signals another, and then that one sends a signal back. That means the information often flows in recurrent loops.”

The human neocortex is much thicker and more complex than that of a mouse. Nonetheless, researchers had previously assumed — in part due to lack of data — that it follows the same basic principles of connectivity. A team of Charité researchers led by Geiger has now used exceptionally rare tissue samples and state-of-the-art technology to demonstrate that this is not the case.

A clever method of listening in on neuronal communication

For the study, the researchers examined brain tissue from 23 people who had undergone neurosurgery at Charité to treat drug-resistant epilepsy. During surgery, it was medically necessary to remove brain tissue in order to gain access to the diseased structures beneath it. The patients had consented to the use of this access tissue for research purposes.

To be able to observe the flows of signals between neighboring neurons in the outermost layer of the human neocortex, the team developed an improved version of what is known as the “multipatch” technique. This allowed the researchers to listen in on the communications taking place between as many as ten neurons at once (for details, see “About the method”). As a result, they were able to take the necessary number of measurements to map the network in the short time before the cells ceased their activity outside the body. In all, they analyzed the communication channels among nearly 1,170 neurons with about 7,200 possible connections.

Feed-forward instead of in cycles

They found that only a small fraction of the neurons engaged in reciprocal dialogue with each other. “In humans, the information tends to flow in one direction instead. It seldom returns to the starting point either directly or via cycles,” explains Dr. Yangfan Peng, first author of the publication. He worked on the study at the Institute for Neurophysiology and is now based at the Department of Neurology and the Neuroscience Research Center at Charité. The team used a computer simulation that they devised according to the same principles underlying the human network architecture to demonstrate that this forward-directed signal flow has benefits in terms of processing data.

The researchers gave the artificial neural network a typical machine learning task: recognizing the correct numbers from audio recordings of spoken digits. The network model that mimicked the human structures achieved more correct responses to this speech recognition task than the one modeled on mice. It was also more efficient, with the same performance requiring the equivalent of 380 neurons in the mouse model, but only 150 in the human one.

An economic role model for AI?

“The directed network architecture we see in humans is more powerful and conserves resources because more independent neurons can handle different tasks simultaneously,” Peng explains. “This means that the local network can store more information. It isn’t clear yet whether our findings within the outermost layer of the temporal cortex extend to other cortical regions, or how well they might explain the unique cognitive abilities of humans.”

In the past, AI developers have looked to biological models for inspiration in designing artificial neural networks, but have also optimized their algorithms independently of the biological models. “Many artificial neural networks already use some form of this forward-directed connectivity because it delivers better results for some tasks,” Geiger says. “It’s fascinating to see that the human brain also shows similar network principles. These insights into cost-efficient information processing in the human neocortex could provide further inspiration for refining AI networks.”

The study offers the first experimental evidence that chemicals present as additives in microplastics can leach into human sweat, and then be absorbed through the skin, into the bloodstream.

Many chemicals used as flame retardants and plasticisers have already been banned, due to evidence of adverse health effects including damage to the liver or nervous system, cancer, and risks to reproductive health. However, these chemicals are still present in the environment in older electronics, furniture, carpets, and building materials.

While the harm caused by microplastics is not fully understood, there is increasing concern over their role as conduits of human exposure to toxic chemicals.

The research team demonstrated in a study published last year, that chemicals were leached from microplastics into human sweat. The current study now shows that those chemicals can also be absorbed from sweat across the skin barrier into the body.

In their experiments, the team used innovative 3D human skin models as alternatives to laboratory animals and excised human tissues. The models were exposed over a 24-hour period to two common forms of microplastics containing polybrominated diphenyl ethers (PBDEs), a chemical group commonly used to flame retard plastics.