Publisher Health

A recent imaging study led by a scientist at The University of Texas at Dallas has identified early risk factors linked to children’s temperament and a neural process that could foretell whether an individual might develop depression and anxiety in adolescence and early adulthood.
The study, published Oct. 26 in JAMA Psychiatry, tracked a cohort of 165 individuals from 4 months old, between 1989 and 1993, through age 26.
Dr. Alva Tang, assistant professor of psychology in the School of Behavioral and Brain Sciences and corresponding author of the study, found that people who are more inhibited in early childhood and who also don’t respond typically to potential rewards as adolescents are vulnerable to developing depression later in life, more so than anxiety.
“The findings highlight different mechanisms in the brain and relate them to who is at greater risk for developing different mental health issues,” said Tang, who conducted the research at the University of Maryland, College Park, before joining UT Dallas in August. “These results could inform the development of prevention-oriented treatments tailored to the individual.”
When babies are exposed to novel objects, people or situations, some react positively and approach them without fear, whereas others respond with wariness or avoidance. This differentiation defines uninhibited versus inhibited behavior.
“We know that inhibited children are more likely to have anxiety disorders later, particularly social anxiety, that begins in late childhood to adolescence,” Tang said. “Less has been known about depression, which generally has a later onset, in young adulthood. But we do know that people who have had an anxiety disorder are 50% to 60% more likely to have depression later in life, so inhibited children should have higher risk for depression as well.”
Tang’s research is unique for its characterization of the subjects’ early temperamental risks and the protracted length of time they were studied.

A new study from the Centers for Disease Control and Prevention’s VISION Network presents and analyzes some of the first real-world data on mRNA COVID vaccine effectiveness during Omicron BA.4 and BA.5 predominance for immunocompromised adults. The large, geographically diverse study confirms that overall protection provided by vaccination — even with one, or later two, boosters — for this population was lower than vaccine effectiveness for adults without immunocompromising conditions. Vaccine effectiveness was lowest among individuals with solid organ or stem cell transplants or hematologic malignancies such as leukemia, lymphoma, or multiple myeloma. BA.4 and BA.5 are the strains that are currently dominant and spreading.
The multistate study includes data from spring and summer 2022 when BA.4 and BA.5 Omicron subvariants became dominant and a total of four vaccine doses (two primary and two booster doses) was available to adults with immunocompromising conditions. The determination of lower vaccine effectiveness among individuals in this high-risk group suggests that non-pharmaceutical interventions, including masks, prophylactic antibody treatment, and anti-viral treatment after acquisition of the virus are important tools to consider for additional protection against severe COVID-19 in immunocompromised adults.
A review of the medical records of 30,000 immunocompromised adults found protection against COVID-19 associated hospitalizations was 34 percent after two vaccine doses, increasing to 71 percent during days 7 to 89 after a third dose, then declining to 41 percent 90 days or more after that dose. Although immunocompromised adults received increased protection after a third dose of the vaccine, this study found that vaccine effectiveness in this population remains lower than in the larger population of all adults.
“This study confirms that even with boosters, immunocompromised adults, because of their weakened immune systems, are still at high risk of moderate to severe COVID. While vaccines in the general adult population have been found to be 70 to 90 percent effective, for the immunocompromised we’re looking at a much lower range — 34 to 71 percent effective,” said study co-author Brian Dixon, PhD, MPA, of the Regenstrief Institute and Indiana University Richard M. Fairbanks School of Public Health. “Those with healthy immune systems should keep in mind that we are a community with a responsibility to keep fellow community members, who are immunocompromised or have other conditions that place them at higher risk for COVID, even with vaccination, protected by taking precautions like hand hygiene and mask wearing, especially when transmission rates are high. We need to look out for one another.”
“This higher risk group has been taking precautions and should continue to work with their providers to access needed tools to protect themselves. Immunocompromised individuals should consult their physician with any questions regarding remaining up-to-date with COVID vaccinations to optimize their protection,” said Shaun Grannis, M.D., M.S., of the Regenstrief Institute and Indiana University School of Medicine. “Adults with immunocompromising conditions and other populations have specific questions about the pandemic and vaccine effectiveness. Our findings in this study are a step forward in helping to answer these questions.”
“Effectiveness of COVID-19 mRNA Vaccines Against COVID-19-Associated Hospitalizations Among Immunocompromised Adults During SARS-CoV-2 Omicron Predominance — VISION Network, 10 States, December 2021 — August 2022” is published in the CDC’s Morbidity and Mortality Weekly Report and was funded by the CDC.
The CDC collaborated with seven U.S. healthcare systems plus the Regenstrief Institute to create the VISION Network to assess COVID-19 vaccine effectiveness. In addition to Regenstrief, other members are Columbia University Irving Medical Center, HealthPartners, Intermountain Healthcare, Kaiser Permanente Northern California, Kaiser Permanente Northwest, University of Colorado and Paso Del Norte Health Information Exchange (PHIX). Regenstrief contributes data and scientific expertise to the VISION Network.
Regenstrief Institute authors of this VISION Network study, in addition to Drs. Dixon and Grannis, are William F. Fadel, PhD, Nimish Ramesh Valvi, DrPH, MBBS, and former Institute president and current affiliate scientist Peter Embi, M.D.
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Actin filaments are protein fibers that make up the internal skeleton of the cell. As active elements of our cells, actin filaments support the cell’s fusion, movement and are involved in many other cellular processes. Importantly, they are also a major constituent of muscle cells. The structural complexity of these filaments has fascinated scientists since its discovery in the 1940s — and has opened a sea of unanswered questions behind their ability to facilitate many processes of the cell.
For the first time, researchers at the Max Planck Institute of Molecular Physiology in Dortmund, Germany, have been successfully able to visualize hundreds of water molecules in the actin filament, representing a quantum leap in actin research. Using the technique of electron cryo microscopy (cryo-EM), the group of Stefan Raunser reveals in unprecedented detail how actin proteins are arranged together in a filament, how ATP — the cell’s energy source — sits in the protein pocket, and where individual water molecules position themselves and react with ATP.
“We are answering fundamental questions of life that scientists have been trying to answer for several decades,” remarks Raunser. In eukaryotic cells, actin proteins are abundant and tend to join together (polymerize) into filaments. These filaments make up the network that constitutes the cytoskeleton of the cell and controls various cell processes through movement. Immune cells, for example, use actin filaments to move and hunt bacteria and viruses. Researchers knew already that the filaments’ dynamics is regulated by ATP hydrolysis — the reaction of ATP with water that cleaves a phosphate group and generates energy. What previously remained unanswered, however, was the exact molecular details behind this process.
Too flexible, too big? — not for cryo-EM
As actin filaments are too flexible or too big for X-ray crystallization and nuclear magnetic resonance, cryo-EM has been the only technique viable for obtaining detailed images. In 2015, Raunser’s team used cryo-EM to picture a novel three-dimensional atomic model of the filaments, with a resolution of 0.37 nanometres. In 2018, his group described the three different states that actin proteins acquire in the filament: bound to ATP, bound to ADP in the presence of the cleaved phosphate, bound to ADP after release of the phosphate.
How water molecules move
In their current study, Raunser and his colleagues were able to set a new resolution record: they obtained all three actin-states with a resolution of about 0.2 nanometers, making previously invisible details visible. The three-dimensional maps not only display all amino-acid sidechains of the proteins but alsoreveal where hundreds of water molecules are placed. Through comparison between these new structures and those of isolated actin, they were able to infer how water molecules move. Upon polymerization, water molecules relocate in the ATP pocket in such a way, that only a single water molecule remains in front of ATP, ready to attack one phosphate and initiate hydrolysis. The accuracy obtained through this approach can help further research in the field: “Our high-resolution model can propel scientists in designing small molecules for light microscopy research on tissues, and ultimately in therapeutic applications,” Raunser says.
A door opener
The authors also cast light on the final fate of the phosphate. Previously, scientists believed there to be a back door in the ATP pocket that remains open after ATP hydrolysis to facilitate the exit of the phosphate. However, the new cryo-EM structures show no trace of open backdoors. Hence, the release mechanism remains a mystery. “We believe there to be a door, but it likely opens momentarily,” comments Raunser, who now wants to use mathematical simulations and time-resolved cryo-EM methods to demonstrate just how the phosphate exits. Evidently, these exciting discoveries have opened the door for scientists to dig deeper in the hopes of discovering even more details behind the processes by which actin filaments contribute to the cell’s motion.
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In a recent study that represents the largest to date to examine the severity of the SARS-CoV-2 Omicron BA.2 subvariant (the strain making a re-emergence this fall), a team led by investigators at Massachusetts General Hospital (MGH) determined that the BA.2 subvariant is less severe than the previous Delta variant and less severe to an even greater extent than the original Omicron variant.
This pattern revealed in the JAMA Network Open study suggests that the severity of SARS-Cov-2 may be diminishing.
To provide an accurate assessment of the severity of SARS-Cov-2 variants above and beyond previous studies, the researchers used a method called entropy balancing to account for potential confounding factors such as prior infections, vaccinations, treatments, and comorbidities. The team applied this method to data leveraged from the Mass General Brigham’s electronic health record system that’s linked to a COVID-19 vaccine registry.
Of 102,315 confirmed COVID-19 cases from March 3, 2020 to June 20, 2022, there were 20,770 labeled as Delta variants, 52,605 labeled as Omicron B.1.1.529 variants (the original Omicron variant), and 28,940 labeled as Omicron BA.2 subvariants.
Mortality rates were 0.7% for Delta, 0.4% for the original Omicron variant, and 0.3% for Omicron BA.2. After adjustments, the odds of death were more than 2-times higher for the Delta and the original Omicron variant compared with Omicron BA.2. Patients with Delta and original Omicron variants were also more likely to need hospitalizations, invasive ventilation, and intensive care admissions.
“While the SARS-CoV-2 virus always has the potential to mutate to a more deadly form, when you look at the recent trajectory of Delta, Omicron BA.1, to Omicron BA.2, the virus seems to be getting intrinsically less severe. Hopefully this trend will continue,” says lead author Zachary Strasser, MD, MBA, an academic physician in the Laboratory of Computer Science at MGH and an Instructor of Medicine at Harvard Medical School. “We can continue to use our analytics system and method to assess many other questions such as which vaccinations have the most impact on preventing long COVID, or whether certain treatments reduce the likelihood of long COVID.
Additional co-authors include Noah Greifer, PhD, Aboozar Hadavand, PhD, Shawn N. Murphy, MD, PhD, and Hossein Estiri, PhD.
This work was supported in part by the National Institute of Allergy and Infectious Disease and the National Human Genome Research Institute.
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Researchers at University of California San Diego have identified a new signaling process involving G protein-coupled receptors (GPCRs), a cellular target already exploited by hundreds of diverse drugs. The discovery, published in the October 26, 2022 issue of Nature, opens the possibility of new therapies, including for multiple forms of cancer.
GPCRs are the largest and most diverse group of membrane receptors in eukaryotes — cells containing a nucleus and other organelles. Residing on the cell’s surface, they act as an inbox for messages arriving in the form of sugars, proteins, lipids and peptides, and play myriad roles in body functions, including fundamentally in regulating communications between cells.
As a result, they have become an important therapeutic target for treating everything from high blood pressure to asthma to acid reflux, with ongoing investigations of their potential in moderating conditions like diabetes, obesity and Alzheimer’s disease. It is estimated that more than one-third of all current Food and Drug Administration-approved drugs target one or more members of the GPCR family.
“We believe these new findings may change the textbook model of GPCR-mediated signaling,” said senior study author Jin Zhang, PhD, professor of Pharmacology at UC San Diego School of Medicine, professor of Chemistry and Biochemistry, and professor of Bioengineering at UC San Diego Jacobs of Engineering, “and that could have profound implications for future drug development.”
The canonical view of GPCRs is that they sit on the cell membrane where they activate a variety of reactions, including an enzyme called extracellular-signal-regulated kinase (ERK), which triggers a cascade of signals to control cell growth and survival.
But Zhang’s team found that there is essentially no ERK signaling at the cell plasma membrane. Rather, GPCR-mediated ERK signaling originates at the endosomes — organelles within the cell that sort and help deliver material from the surface to internal destinations or help degrade, recycle and export unneeded material. GPCRs are known to be transported through endosomes.

When the world shut down in March of 2020 because of the COVID-19 pandemic, people the world over experienced profound psychological stress to varying degrees. Now, a new study takes advantage of the unique situation and longitudinally studied the demographic, neurobiological, and psychological factors that contributed to individuals’ risk or resilience to mental health disruptions related to the stress.
The study appears in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier.
While “resilience” is a broad term with many connotations, the authors describe it as the ability of an individual to resist the negative impacts of illness, stress, or trauma, in line with a recently proposed definition. Psychological factors, such as coping abilities, help people protect themselves from harmful experiences and are associated with resilience to trauma.
The researchers assessed data from over 2,000 participants collected as part of the Barcelona Brain Health Initiative. They analyzed the change in participants’ anxiety and depression symptoms from two years before to during the first year of the pandemic. The researchers analyzed the data to identify participants with resilience, which they defined here as the lack of development of anxiety or depression over the pandemic.
Before the pandemic, all participants reported normal or mild symptoms, and in terms of measures of resilience, reported medium-high coping skills and low-to-moderate stress levels. Across the sample, scores reflecting depressive and anxiety symptoms increased, particularly in women, but the changes were mediated by individual differences in coping skills and perceived stress.
Resilience has also been linked in previous studies to structural and functional characteristics of specific brain areas and circuits, including the default mode network (DMN), which is associated with mind-wandering activity. To examine these influences, the researchers made use of brain imaging data that had been collected on over 400 participants before the pandemic. The data showed that brain connectivity within the DMN explained much of the individual resilience and the psychological influences on mental health.
David Bartrés-Faz, PhD, from the University of Barcelona and a senior author of the study, said, “Our findings show that psychological aspects such as coping strategies should be considered within the context of each individual biological complexity. We found evidence of how the specific configurations of brain networks (such as the DMN) were meaningful to understand responses to stress — even years later — in the context of the COVID-19 pandemic. Therefore, the combination of individual psychological factors and specific biological substrates can predict the risk of vulnerability to anxiety and depression symptoms during a prolonged stress factor.”
Cameron Carter, MD, Editor of Biological Psychiatry:Cognitive Neuroscience and Neuroimaging, said of the study, “While we are in the early stages of being able to characterize brain network function and relate it to individual differences, the results of this study strikingly suggest that the state of the DMN, known to be associated with social and emotional processing as well as self-referential memory, may provide contextual support during stressful experiences that may contribute to healthy coping and better mental health outcomes.”
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Colorectal cancer remains a disease with high mortality rates in advanced stages. In recent years, numerous research findings have improved early diagnosis and therapy, although unfortunately not all patients respond adequately to novel therapeutic approaches. Current research suggests that one characteristic of tumour diseases is immune dysfunction: immune cells that are supposed to fight the tumour are systematically suppressed by the tissue surrounding the tumour, the tumour microenvironment. As a result, T cells, which are our body’s natural immune response against cancer, are restricted in their function, allowing the tumour to grow and spread uncontrollably.
The research team led by Professor Florian Greten, Institute for Tumour Biology and Experimental Therapy and Goethe University Frankfurt, has now come a significant step closer to a possible solution to the problem. The researchers showed that urolithin A induces a biological pathway that recycles and renews mitochondria, the “powerhouse” of the cell in T cells, through a process known as mitophagy. Aged and damaged mitochondria in the T cells are removed and replaced by new, functional ones. This changes the genetic programme of the T cells, which are thus more able to fight the tumour. The researchers demonstrated the therapeutic potential of urolithin A in two ways: on the one hand, urolithin A can be used as a food in the preclinical model, which limits tumour growth and even acts synergistically with existing immunotherapy. On the other hand, the benefits of urolithin A were also observed in human T cells. In vitro treatment with urolithin A “rejuvenates” human T cells, producing memory T memory stem cells in the laboratory.
Dominic Denk, MD, physician at Frankfurt University Hospital and first author of the study, explains: “Our findings are particularly exciting because the focus is not on the tumour cell but on the immune system, the natural defence against cancer. This is where reliable therapeutic approaches are still lacking in the reality of colorectal cancer patients. By possibly improving the combination therapy with existing immunotherapies, the study opens up meaningful possibilities for further application in the clinic. We hope to use this to sustainably improve the therapy of colorectal cancer, but also of other cancers.”
Building on these findings, the researchers plan to continue the successful collaboration: in future clinical trials, the application of urolithin A will be investigated in individuals with colorectal cancer.
Professor Greten, director of the Georg-Speyer-Haus and spokesperson of the Frankfurt Cancer Institute, emphasizes the necessary teamwork: “This work proves once again how successful the interdisciplinary concepts of the FCI are. We are very pleased that we can now quickly transfer our results to the clinic and look forward with great excitement to the upcoming clinical trials.”
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People with opioid-use disorder who enter treatment are at risk for relapse, overdose or death if they engage in less than two outpatient visits in their first month of care, according to a study coauthored by Rutgers researchers.
The study, published in The American Journal of Psychiatry, examined the likelihood of patients continuing treatment for opioid-use disorder during their first month in care based on how often they engaged in outpatient visits or other professional services.
“Engagement in outpatient visits or professional services appears to be a necessary condition for adequate care retention,” said study coauthor Stephen Crystal, the director of the Center for Health Services Research at the Rutgers Institute for Health, Health Care Policy and Aging Research and Distinguished Research Professor at the Rutgers School of Social Work. “Monitoring this engagement may help identify and address barriers and disparities in outcomes.”
Starting an individual on medication for opioid-use disorder and then retaining them in professional care are two evidence-based interventions for reducing overdoses, according to the National Academies of Sciences, Engineering and Medicine. Researchers said patients participating in outpatient visits during treatment can be a measure of success for care retention, but there is a need to assess how this measure applies specifically to individuals with opioid-use disorder who are receiving medication, such as buprenorphine, as part of treatment.
Using data reported between 2011 and 2019 from a multisite buprenorphine clinic throughout eight states, researchers examined the relationship between participating in outpatient visits and care retention in nearly 20,000 individuals. The patients were predominately male and non-Hispanic, which is broadly representative of people nationwide who are using buprenorphine for opioid use disorder treatment, according to prior research from study authors.
Researchers found that nearly half of patients who participated in multiple outpatient visits in their first month of care remained in treatment for a minimum of six months, whereas 2.9 percent of patients who didn’t participate in multiple visits remained in treatment after six months.
“This finding is critically meaningful and could guide intervention development to prioritize stabilization of high-risk patients early in treatment,” said Arthur Robin Williams, lead author of the study and an assistant professor at Columbia University Department of Psychiatry. “Without early engagement, the great majority of patients will be lost to relapse and possible death.”
The study’s findings align with the priorities of organizations such as the Substance Abuse and Mental Health Services Administration, which support care coordination and peer navigation services early in treatment to help stabilize patients who otherwise might be lost to follow up.
“Many of these services are not currently reimbursable by payers, so insurance plans need to create bundled rates to be more innovative,” Williams said.
More research is needed to identify patients at the greatest risk for overdose, said the researchers, adding that further research can demonstrate the importance of milestones in opioid-use treatment to develop care-performance measures.
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Materials provided by Rutgers University. Original written by Nicole Swenarton. Note: Content may be edited for style and length.

Hemophilia A is the most common severe form of hemophilia. It affects almost exclusively males. The disease can usually be treated well, but not for all sufferers. A study at the University of Bonn has now elucidated an important mechanism that is crucial for making the therapy effective. The results could help better tailor treatment to patients. They have already been published online in a preliminary version; the final version will soon be published in the “Journal of Clinical Investigation.”
Hemophilia A patients have a defect in a protein that is important for blood clotting: factor VIII. Most patients therefore receive an intravenous injection of the functional clotting factor every few days as treatment. But frequently, and especially at the start of treatment, the immune system recognizes the injected agent as foreign to the body and attacks it. This is the most serious complication of hemophilia treatment because factor VIII can then no longer work.
In these cases, immune tolerance therapy, which was also developed at the University Hospital Bonn (UKB) more than 40 years ago, often helps. This involves regularly injecting the hemophiliacs with a high dose of factor VIII over several months. The immune system thereby gets used to the injected protein and tolerates it. The underlying immune mechanisms are unknown. “However, this doesn’t always work,” explains Prof. Dr Johannes Oldenburg, Director of the Institute for Experimental Haematology and Transfusion Medicine at the UKB. “In about 30 percent of patients, tolerance induction does not lead to success. So your body’s own defenses continue to attack and destroy the factor VIII protein, which means that factor VIII cannot be used for treatment. We wanted to know the reason for this.”
To this end, the team looked at two cell types in the immune system, B cells and regulatory T cells. B cells recognize foreign molecules in the body and produce antibodies against them, which switch off the function of the molecule. For factor VIII, this means that it is no longer effective in hemophilia treatment.
Brake in the immune system
Regulatory T cells prevent an immune response from being too strong or lasting too long. The researchers have now found a new type among them that can act specifically against certain B cells rather than just non-specifically against all immune responses. “We were able to show that immunotolerance therapy results in the generation of regulatory T cells that exclusively induce B cells against factor VIII to commit suicide,” says Dr. Janine Becker-Gotot of the Institute of Molecular Medicine and Experimental Immunology (IMMEI) at UKB. “These T cells have a sensor that allows them to recognize and attach to the corresponding B cells. In addition, they have the ability to push the self-destruct button on the surface of B cells.”
This button is a molecule called PD-1. By activating it, it starts a program in the B cell that results in its death. Every active B cell has this button. “Our experiments enabled us for the first time to detect regulatory T cells that can activate this self-destruct button only in very specific B cells, in order to specifically prevent unwanted immune responses,” explains IMMEI Director Prof. Dr. Christian Kurts.

A study led by researchers at Columbia University Mailman School of Public Health uses contract tracing data to produce a detailed map to date of SARS-CoV-2 spread in New York City. They found that the city’s contact tracing program was efficient and produced data that can inform neighborhood-level interventions like vaccination and reactive restriction on business capacity.
The study is published in the journal Nature Communications.
The researchers analyzed contact tracing and testing records for 644,029 cases and their contacts in New York City during the second pandemic wave between October 1, 2020 and May 10, 2021. Data was collected by the NYC Test & Trace Corps and the Department of Health and Mental Hygiene.
They found it was not possible to establish transmission chains at the individual level because more than 90 percent of self-reported close contacts were predominately household members and data on contacts outside home was incomplete. Instead, the researchers focused on how SARS-CoV-2 spread across communities and what the effects of control measures and vaccination on its spread. They also examined the operational performance of contact tracing.
By reconstructing transmission chains, the authors found large heterogeneity in the number of reported close contacts and secondary infections. The transmission networks also reveal the spatial pattern of SARS-CoV-2 transmission across neighborhoods. The combination of vaccination and reactive, neighborhood-based interventions likely reduced the spread of COVID-19 during the second wave.
Neighborhoods with many visitors, such those with a high density of businesses, were associated with elevated transmission levels within those areas and to other neighborhoods.