Researchers discover a new neural biomarker for OCD

A recent study from Baylor College of Medicine and Texas Children’s Hospital has identified a specific neural activity pattern as a novel biomarker to accurately predict and monitor the clinical status of individuals with obsessive-compulsive disorder (OCD) who have undergone deep brain stimulation (DBS), a rapidly emerging therapeutic approach for severe psychiatric disorders. The study, led by led by Drs. Sameer Sheth and Wayne Goodman along with co-lead authors, Drs. Nicole Provenza, Sandy Reddy, and Anthony Allam, was published in Nature Medicine.

“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.

Groundbreaking study reveals insights into Alzheimer’s disease mechanisms through novel hydrogel matrix

Researchers at the Terasaki Institute for Biomedical Innovation (TIBI) have unveiled a pioneering study shedding light on the intricate mechanisms underlying Alzheimer’s disease (AD). The study, titled “Effects of amyloid-β-mimicking peptide hydrogel matrix on neuronal progenitor cell phenotype,” represents a significant leap forward in understanding the interplay between amyloid-like structures and neuronal cells.

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.

New ways to study spinal cord malformations in embryos

A group of scientists at UCL have successfully created mechanical force sensors directly in the developing brains and spinal cords of chicken embryos, which they hope will improve understanding and prevention of birth malformations such as spina bifida.

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.”

User control of autoplay can alter awareness of online video ‘rabbit holes’

The rabbit hole contains madness, according to author Lewis Carroll. Online, that madness manifests in the form of increasingly extreme content, often without users realizing it. A new study by Penn State researchers suggests that giving users control over the interface feature of autoplay can help them realize that they are going down a rabbit hole.

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.

Researchers uncover brain region’s role in hearing and learning

Have you ever noticed how you can suddenly hear your refrigerator humming in the background when you focus on it? Or how the sound of your name instantly catches your attention even in a noisy crowd?

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).

Uncovering late-onset combined immune deficiency in chromosome 18q deletion syndrome

Chromosome 18q deletion (18q del) syndromeis a rare genetic condition disorder, affecting approximately 1 in 40,000 to 55,000 individuals, caused by the deletion of genetic material on the long arm of chromosome 18. This genetic anomaly disrupts normal growth and development, and critically, can impair the immune system’s functionality. Patients with 18q del syndrome often exhibit humoral immunodeficiency or a common variable immunodeficiency (CVID)-like phenotype, characterized by low levels of immunoglobulins (antibodies) in the blood, compromising the body’s ability to effectively combat infections.

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.

Prime editing efficiently corrects cystic fibrosis mutation in human lung cells

Cystic fibrosis is one of the most common genetic disorders, causing thick mucus build-up in the lungs and other parts of the body, breathing problems, and infection. A three-drug cocktail known as Trikafta has greatly improved patient quality of life since its development in 2019, but can cause cataracts and liver damage and must be taken daily at a cost of about $300,000 per year.

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.

Cirrhosis affects twice as many transgender adults as cisgender adults, study finds

Cirrhosis is chronic, progressive end-stage liver disease that occurs when scar tissue prevents the liver from functioning normally. Studies have shown that two of the leading causes of cirrhosis — alcohol use disorder and viral hepatitis — occur more frequently in transgender individuals, but there has been little research examining if these risk factors translate into greater incidences of cirrhosis among transgender patients.

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.

Stem cell-derived therapy shows promise against treatment-resistant liver cancer

Researchers at University of California San Diego have found that the most common form of liver cancer — one with a high mortality rate — can be better targeted and treated using an innovative new stem cell-derived therapy, according to a recently published study in Cell Stem Cell.

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.

Run screaming or slow retreat? New study advances understanding of brain responses to emotionally-charged scenes

The ability to recognise and respond to emotionally-charged situations is essential to a species’ evolutionary success. A new study published today [July 9th] in Nature Communications advances our understanding of how the brain responds to emotionally charged objects and scenes.

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.