A new study shows a growing number of people are regularly using cannabis, while frequent alcohol consumption has remained stable.For the first time on record, cannabis has outpaced alcohol as the daily drug of choice for Americans.In 2022 there were 17.7 million people who reported using cannabis either every day or nearly every day, compared with 14.7 million who reported using alcohol with the same frequency, according to a study, published on Wednesday in the journal Addiction that analyzed data from the U.S. National Survey on Drug Use and Health.While far more people drink than use cannabis, drinking frequently has become slightly less common than it was around 15 years ago, the study found. But the proportion of people in the U.S. who use cannabis frequently has increased 15-fold in the three decades since 1992, when daily cannabis use hit a low point.Cannabis legalization has also rapidly accelerated since the ’90s. The drug is now legal for recreational use in 24 states and Washington, D.C., and for medical use in 38 states and D.C.The sharp increase in the prevalence of high-frequency cannabis use over the last three decades might partly be attributed to a growing acceptance of the drug, said Jonathan P. Caulkins, a professor of public policy at Heinz College at Carnegie Mellon University. And because the survey data was self-reported, people may now feel more comfortable disclosing how often they use it.Even so, “I don’t think that for most daily or near-daily users it is a health-promoting activity,” he added. “For some, it’s truly harmful.”We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

15 minutes agoBBCA 17-year-old has been rejected by the Army, despite passing all the selection tests, because two members of her family have had breast cancer.

The Guardant Health Shield test, one committee member said, “is better than nothing for patients who are getting nothing, but it is not better than a colonoscopy.”A committee of experts that advises the Food and Drug Administration voted by large majorities on Thursday that a new blood test to screen people for colon and rectal cancers was safe and effective, and that its risks outweighed its benefits.But the group cautioned that the blood test had limitations and added that they were endorsing it with the hope that it would increase the abysmally low number of people who are regularly screened for this cancer.The F.D.A. usually follows the advice of its expert committees.In the United States, about 150,000 people are diagnosed with colon and rectal cancers annually, and about 53,000 are expected to die this year. Most who are screened for the disease receive a colonoscopy or a fecal test. The F.D.A. approved these methods long ago, and research has demonstrated that they are more accurate than the new blood test, Shield, made by Guardant Health of Palo Alto, Calif.But for people with average risk of the disease, a blood test would offer convenience — no difficult preparation, fasting or anesthesia needed as is the case for a colonoscopy, no ick factor of a self-administered fecal test. It still must be followed by a colonoscopy if cancers or pre-cancers are detected.The biggest issue with the blood tests is that, unlike colonoscopies, they miss most of the precancerous growths on the colon that, if detected and removed, would prevent a person from developing cancer. That, said Dr. Stephen M. Hewitt, a committee member from the National Cancer Institute, “really undermines the concept of cancer prevention.”The test, said Charity J. Morgan, a committee member who is a biostatistics professor at the University of Alabama, Birmingham, “is better than nothing for patients who are getting nothing, but it is not better than a colonoscopy.”We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Published23 minutes agoShareclose panelShare pageCopy linkAbout sharingBy Joe Pike and Charlotte RowlesBBC NewsnightA man discovered a medical specimen bag had been left inside his stomach after his hernia surgery, the BBC has found.The surgeon who carried out the procedure, at the Royal Sussex County Hospital in Brighton in 2016, also left behind part of Tom Hadrys’s bowel that had been cut out during the operation. According to a hospital incident report seen by BBC Newsnight, the surgeon realised his mistakes while driving home from work. Sussex Police are investigating at least 105 cases of alleged medical negligence by two surgery teams at the University Hospitals Sussex NHS Foundation Trust.The trust said the work of its surgery teams “are continuously and closely monitored”, and “whenever our care falls short of our high standards, we take immediate action”.Coming round in a recovery ward bed as the effects of his general anaesthetic were wearing off, retired engineer Tom Hadrys, 63, remembers being approached by a doctor.”I was conscious,” Mr Hadrys says, “and I heard what must have been the surgeon whispering in my ear. He said, ‘I’m terribly sorry’, and I think he said, ‘We made a mistake, and I’ve got to take you back to surgery’.”Mr Hadrys later learned the surgeon had been running through the operation in his mind while driving home and realised what he had done. “He turned his car around and drove back to the hospital,” Mr Hadrys says.The same surgeon subsequently performed a second surgical procedure to remove both the specimen bag and the section of bowel mistakenly left behind during the initial operation.Classed by hospital managers as a “never event” – something that should not have happened – it led to a serious incident investigation.The hospital trust conceded the surgical errors inflicted on Mr Hadrys meant his recovery was prolonged. In 2020, it apologised and awarded him a settlement of £15,000.But the surgeon – who the BBC is not naming for legal reasons – continued to operate and still works at the trust. He was subsequently appointed to a consultants’ rota against the advice of some colleagues who did not think he was sufficiently qualified.Culture of fear exists at Sussex hospital – reportHospital boss concedes not all staff feel supportedNHS trust downgraded as staff blow whistleGang culture at neurosurgery department, doctor allegesFurther “concerns about the competence” of the surgeon were highlighted in emails between senior staff. And in 2019, the General Medical Council (GMC), which regulates doctors in the UK, contacted the hospital trust in response to a complaint it had received relating to the same surgeon. The trust says the GMC inquiry was not related to patient safety and that it concluded there was “no case to answer, and no action required”.In 2022, the Care Quality Commission (CQC) – the independent healthcare regulator – contacted the hospital trust with concerns about operations carried out by the same surgeon. “Details supplied by the trust assured us that no further action was required from CQC on that occasion,” the CQC told the BBC.Junior doctors at the hospital had also raised a number of general patient safety concerns – including about this surgeon – with the chief executive and chief medical officer. The trainees’ wider concerns – including about an “apparent increase in death rates over a period of years” – were cited in an independent report from Health Education England.Professor Katie Urch, Chief Medical Officer at University Hospitals Sussex NHS Foundation Trust, said: “Our surgery staff are committed to delivering the best, safest care to our patients, often in challenging situations. “Surgeons do not work as individuals, they work collaboratively in teams. Those teams are highly skilled, performing complex surgery that is never without some risk. “Their outcomes are continuously and closely monitored – both internally and externally – and whenever our care falls short of our high standards, we take immediate action to learn and improve.” The BBC has been investigating patient safety concerns at University Hospitals Sussex NHS Foundation Trust for ten months.In 2023, four whistleblowers told the BBC patients had died unnecessarily while others were “effectively maimed”. The whistleblowers also complained of a “mafia-like” management culture.The trust previously said its main priority was delivering “safe and effective care”, that data does not reflect allegations of unnecessary deaths, and that there was no evidence of a top-down toxic culture. Some eight years on from his own hernia operation, Mr Hadrys told Newsnight of the lasting negative impact on his health. “There’s no doubt whatsoever that I’m suffering,” he says. “It’s affected me. I have a weak abdomen now, I can’t really lift anything heavy.”More on this storyCulture of fear exists at Sussex hospital – reportPublished6 FebruaryNHS trust downgraded as staff blow whistlePublished12 May 2023

The Epstein-Barr virus can cause a spectrum of diseases, including a range of cancers. Emerging data now show that inhibition of a specific metabolic pathway in infected cells can diminish latent infection and therefore the risk of downstream disease, as reported by researchers from the University of Basel and the University Hospital Basel in the journal Science.
Exactly 60 years ago, pathologist Anthony Epstein and virologist Yvonne Barr announced the discovery of a virus that has carried their names ever since. The Epstein-Barr virus (EBV) made scientific history as the first virus proven to cause cancer in humans. Epstein and Barr isolated the pathogen, which is part of the herpesvirus family, from tumor tissue and demonstrated its cancer-causing potential in subsequent experiments.
Most people are carriers of EBV: 90% of the adult population are infected with the virus, usually experiencing no symptoms and no resulting illness. Around 50% become infected before the age of five, but many people don’t catch it until adolescence. Acute infection with the virus can cause glandular fever — also known as “kissing disease” — and can put infected individuals out of action for several months. In addition to its cancerogenic properties, the pathogen is also suspected to be involved in the development of autoimmune diseases such as multiple sclerosis.
As yet, no drug or approved vaccination can specifically thwart EBV within the body. Now, a research group from the University of Basel and the University Hospital Basel has reported a promising starting point for putting the brakes on EBV. Their results have been published in the journal Science.
EBV hijacks the metabolism of infected cells
Researchers led by Professor Christoph Hess have deciphered how the immune cells infected with EBV — the so-called B cells — are reprogrammed. Known as “transformation,” this process is necessary for the infection to become chronic and cause subsequent diseases such as cancer. Specifically, the team discovered that the virus triggers the infected cell to ramp up the production of an enzyme known as IDO1. This ultimately leads to greater energy production by the power plants of infected cells: the mitochondria. In turn, this additional energy is needed for the increased metabolism and the rapid proliferation of B cells reprogrammed by EBV in this way.
Clinically, the researchers focused on a group of patients who had developed EBV-triggered blood cancer following organ transplantation. To prevent a transplanted organ from being rejected, it is necessary to weaken the immune system using medications. This, in turn, makes it easier for EBV to gain the upper hand and cause blood cancer, referred to as post-transplant lymphoma.

In the paper, which has now been published, the researchers were able to show that EBV upregulates the enzyme IDO1 already months before post-transplant lymphoma is diagnosed. This finding may help to develop biomarkers for the disease.
Second chance for a failed drug
“Previously, IDO1 inhibitors have been developed in the hope that they could help to treat established cancer — which has unfortunately turned out not to be the case. In other words, there are already clinically tested inhibitors against this enzyme,” explains Christoph Hess. Accordingly, this class of drugs might now receive a second chance in applications aimed at dampening EBV infection and thereby tackling EBV-associated diseases. Indeed, in experiments with mice, IDO1 inhibition with these drugs reduced the transformation of B cells and therefore the viral load and the development of lymphoma.
“In transplant patients, it’s standard practice to use drugs against various viruses. Until now, there’s been nothing specific for preventing or treating Epstein-Barr virus associated disease,” says Hess.

A new study shows that the use of psilocybin, a compound found in the widely known “magic mushrooms,” initiates a pattern of hyperconnectivity in the brain linked to the ego-modifying effects and feelings of oceanic boundlessness. The findings, appearing in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier, help explain the so-called mystical experiences people report during the use of psychedelics and are pertinent to the psychotherapeutic applications of psychedelic drugs to treat psychiatric disorders such as depression.
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.”

Although the Human Genome Project announced the completed sequencing of 20,000 human genes more than 20 years ago, scientists are still working to grasp how fully formed beings emerge from basic genetic instructions.
Biomedical efforts to learn how disorders can take hold in the earliest stages of development would benefit from knowing specifically how complex organisms arise from a single fertilized cell. Researchers from the University of California San Diego have captured a new understanding of how embryonic development unfolds through the lens of a simple model organism.
The comprehensive report led by School of Biological Sciences scientist Rebecca Green and Professor Karen Oegema provides a play-by-play of how genes function during embryonic development in Caenorhabditis elegans (C. elegans), a millimeter-long roundworm known to biologists as “the worm.” Despite its tiny size, C. elegans has been a workhorse for scientists because so much of its biology, including early developmental stages, resembles that of higher organisms, including humans. The research, which forges a decade’s worth of work by a collaborative multidisciplinary team into a “genetic atlas,” is published in the journal Cell.
“By characterizing many of these poorly understood genes in a simple model organism, we can learn about what they are doing in more complex systems like humans,” said Green, a bioinformatics scientist and first author of the paper. “While the work is done using C. elegans, the majority of genes analyzed are present in humans and mutations in many of them are associated with human developmental disorders.”
The researchers developed an automated system for profiling the function of genes required for embryogenesis, the process by which a fertilized egg, which starts as a single cell, develops into an organism with different tissues, such as skin, digestive tract, neurons and muscles. They used time-lapse 4-D imaging to methodically track the function of each gene throughout all embryonic stages, including when cell identity is determined and when the tissues in the organism take shape. The researchers monitored this process using an approach known as “computer vision” to track specific aspects of development, including the number of cells in each tissue. They also tracked the mass, position and shape of the tissues within the developing organism.
To fully understand the function of nearly 500 genes that are important in embryonic development, they blocked the function of each gene, one at a time. This allowed the researchers to group genes into common clusters that revealed the role of each gene through “guilt by association.” Green likens the process to automated facial recognition, in which images with features that appear similar are grouped together. By using this meticulous process to analyze a collection of nearly 7,000 4-D embryogenesis movies, the team was able to create “fingerprints” for individual genes, such as those required for cells to become muscle or skin. This helped them understand the physiological roles that the genes play in embryogenesis, such as controlling the formation of tissues like the intestine or nervous system.
“We show that our approach correctly classifies the functions of previously characterized genes, identifies functions for poorly characterized genes and describes new gene and pathway relationships,” said Oegema, a faculty member in the Department of Cell and Developmental Biology and the paper’s senior author. “A lot of genes that we thought served mundane functions were found to have important roles that were underappreciated.”
In conjunction with the Cell paper, the abundance of data from the research led to the launch of a new online resource that houses all of the information. PhenoBank now offers a portal to the genetic atlas developed during the research.

“The approach yielded surprising insights into how metabolic pathways are specialized during embryogenesis and revealed interesting new connections between different molecular machines involved in gene regulation,” said Professor Arshad Desai, a paper coauthor.
Beyond the 500 genes covered in the Cell study, the researchers are now working to finish the entire set of 2,000 C. elegans genes that have been implicated in embryogenesis.
“The broad interest lies in the approach developed to tackle arguably the most challenging problem in biology: how a single cell with a genome that contains approximately 20,000 genes (similar to the number of genes in humans) is able to build an entire organism,” he said.
Authors of the paper included: Rebecca Green, Renat Khaliullin, Zhiling Zhao, Stacy Ochoa, Jeffrey Hendel, Tiffany-Lynn Chow, HongKee Moon, Ronald Biggs, Arshad Desai and Karen Oegema. The researchers also thank Tony Hyman and the Scientific Computing group at Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) for facilitating the PhenoBank build.

Humans have been long fascinated by bird song and the cacophony of other avian sounds — from coos and honks to quacks and peeps. But little is known about how the unique vocal organ of birds — the syrinx — varies from species to species or its deeper evolutionary origins.
A trio of recent studies led by researchers from The University of Texas at Austin is changing that.
The studies include high-resolution anatomical scans of syrinxes from hummingbirds and ostriches — the world’s smallest and largest bird species — and the discovery that the syrinx and larynx, the vocal organ of reptiles and mammals, including humans, share the same developmental programming.
According to Julia Clarke, a professor at UT’s Jackson School of Geosciences, this genetic connection between the vocal organs is an exciting new example of “deep homology,” a term that describes how different tissues or organs can share a common genetic link.
“To me, this is as big as the flippers-to-limbs transition,” said Clarke, who co-led or co-authored the studies. “In some ways, it’s even bigger because the syrinx is not a modified organ with a new function but a completely new one with an ancient and common function.”
The three studies are built on a foundation of collaborative and interdisciplinary syrinx research with physiologists and developmental biologists that Clarke has been leading for over a decade. The research got its start in 2013 when Clarke, a paleontologist, discovered a syrinx in a fossil of a duck-like bird that lived in what is now Antarctica during the Late Cretaceous. The specimen is the oldest syrinx to be discovered. But when she tried to compare the fossil syrinx to the syrinxes of modern birds, she found the scientific literature lacking. Many of the studies dated back to the 19th century, before the advent of modern scientific imaging, or cited claims from those older studies made without double-checking them.
This set Clarke on a mission to modernize — and maximize — syrinx data collection.

“We had this new three-dimensional structure, but we had nothing to compare it to,” said Clarke, describing CT imaging data of the fossil syrinx. “So, we started generating data that did not previously exist on syrinx structure across many different groups of birds.”
Over the years, Clarke and members of her lab have developed new methods for dissecting, preserving and CT-scanning syrinxes that have helped reveal the syrinx in more detail. These enhanced views of the ostrich and hummingbird vocal organ have shown that bird behavior may be just as important as the syrinx when it comes to the repertoire of sounds these birds produce.
For example, in the study of the ostrich syrinx, the researchers found no significant differences in syrinx anatomy between adult male and female birds (previous studies focused only on male ostriches.) However, even though both sexes have the same vocal equipment, male ostriches tended to make a wider variety of sounds than female ostriches, with the sounds often associated with aggressive behaviors between rowdy males. On a visit to a Texas ostrich farm, the researchers recorded 11 types of calls, ranging from high frequency peeps and gurgles in baby ostriches to low frequency boos and booms in adult males. These included a few call types that had never been recorded before. The only sounds definitively recorded from adult female ostriches were hisses. What the females lacked in range, they made up for in attitude said Michael Chiappone, who became involved with the ostrich research as an undergraduate student at the Jackson School and is the lead author of the study.
“They were quite prolific hissers,” said Chiappone, who is now a doctoral student at the University of Minnesota.
For the hummingbird study, the researchers compared the hummingbird syrinx to the syrinx of swifts and nightjars, two close relatives, and found that all three birds have similar vocal folds in their syrinx despite having different ways of learning their calls. Swifts and nightjars work with a limited repertoire of instinctive calls while hummingbirds are able to elaborate on calls by learning complex songs from each other, a trait called vocal learning.
According to Lucas Legendre, a Jackson School research associate who led the hummingbird research, the findings suggest that the common ancestor of all three birds also had a similar vocal fold structure — and that it may have helped lay the groundwork for the evolution in vocal learning in hummingbirds.

“Having all of the [vocal fold] structures already present before vocal learning was acquired by hummingbirds probably made it easier for them to acquire vocal production learning,” he said.
Before the study, it was uncertain if swifts even had vocal folds. As part of the research, Legendre created a 3D digital model of the swift vocal track that takes viewers down the windpipe to the syrinx and to the vocal folds that rest near the top of each branch of the syrinx. The model — dubbed the “magical mystery voyage” by Clarke — shows the advances in anatomical knowledge of syrinx that her lab is leading.
“This is a structure that wasn’t known to exist outside of hummingbirds, but our CT scans revealed that swifts have these vocal folds in the same position,” Clarke said. “This is the kind of voyage we needed to go on to get these answers.”
At the same time Clarke and her team were developing methods to preserve and capture syrinx anatomy across bird species, they were collaborating with Clifford Tabin, a developmental biologist at Harvard University, on investigating the evolutionary origins of the syrinx by tracking the gene expression that accompanied vocal organ development in the embryos of birds, mammals and reptiles.
The research published in Current Biology is a culmination of that collaboration. The study details how scientists discovered the deep connection between the larynx and the syrinx tissues by observing that the same genes were controlling the development of the vocal organs in mice and chicken embryos, respectively, even though the organs arose from different embryological layers.
“They form under the influence of the same genetic pathways, ultimately giving the vocal tissue similar cellular structure and vibratory properties in birds and mammals,” said Tabin, a co-lead on the study.
The study also analyzed syrinx development across bird species — which involved observing gene expression in embryos from 14 different species, from penguins to budgies — and found that the common ancestor of modern birds probably had a syrinx with two sound sources, or two independently functioning vocal folds. This trait is found in songbirds today, allowing many to create two distinct sounds at the same time. The research suggests that that the common ancestor of birds may have been making similarly diverse calls.
These results may shed light on the syrinx’s origins but it’s still unknown when the syrinx first developed and whether non-avian dinosaurs — the ancestors of today’s birds — had the vocal organ, said Clarke. No one has yet found a fossil syrinx from a non-avian dinosaur.
According to Clarke, the best way to understand the possibilities for ancient dinosaur sounds is to continue studying vocalization as it exists today in birds, the dinosaurs that are still with us, and other reptile cousins.
“We can’t start talking about sound production in dinosaurs until we truly understand the system in living species,” she said.
This research was supported by the Gordon and Betty Moore Foundation, Howard Hughes Medical InstituteProfessors Program and the Jackson School of Geosciences. Chad Eliason, a senior research scientist at the Field Museum of Natural History and former postdoctoral scholar at the Jackson School, was also a major contributor to these syrinx projects and others.

A comprehensive approach that examines the intersection of multiple biological processes is necessary to elucidate the development of stress-related disorders. In a new study, investigators from McLean Hospital, a member of the Mass General Brigham healthcare system, working with colleagues at The University of Texas at Austin and Lieber Institute for Brain Development, uncovered both shared and distinct molecular changes across brain regions, genomic layers, cell types, and blood in individuals with posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). These results, published May 24th in Science, could provide potential avenues for novel therapeutics and biomarkers.
“PTSD is a complex pathological condition. We had to extract information across multiple brain regions and molecular processes to capture the biological networks at play,” said first author Nikolaos P. Daskalakis, MD, PhD, director of the Neurogenomics and Translational Bioinformatics Laboratory at McLean Hospital, and an associate professor of psychiatry at Harvard Medical School.
Stress-related disorders develop over time, stemming from epigenetic modifications caused by the interplay between genetic susceptibility and traumatic stress exposure. Previous studies have uncovered hormonal, immune, methylomic (epigenetics) and transcriptomic (RNA) factors mostly in peripheral samples contributing to these diseases, but limited access to postmortem brain tissues from diseased PTSD patients has restricted characterization of brain-based molecular changes at the appropriate scale.
“Our primary goals for this study were to interpret and integrate differential gene and protein expression, epigenetic alterations and pathway activity across our postmortem brain cohorts in PTSD, depression and neurotypical controls,” said senior author Kerry Ressler, MD, PhD, chief scientific officer and director of Division of Depression and Anxiety Disorders and Neurobiology of Fear Laboratory at McLean Hospital, and a professor of psychiatry at Harvard Medical School. “We essentially combined circuit biology with powerful multi-omics tools to delve into the molecular pathology behind these disorders.”
For this, the team analyzed multi-omic data from 231 PTSD, MDD and neurotypical control subjects, along with 114 individuals from replication cohorts for differences in three brain regions — the medial prefrontal cortex (mPFC), hippocampal dentate gyrus (DG) and central nucleus of the amygdala (CeA). They also performed single-nucleus RNA sequencing (snRNA-seq) of 118 PFC samples to study cell-type-specific patterns and evaluated blood-based proteins in more than 50,000 UK Biobank participants to isolate key biomarkers associated with stress-related disorders. Finally, the overlap of these key brain-based disease process genes was compared with genome-wide association studies (GWAS)-based risk genes to identify PTSD and MDD risk.
PTSD and MDD individuals both shared altered gene expression and exons in the mPFC, but differed in the localization of epigenetic changes. Further analysis revealed that history of childhood trauma and suicide were strong drivers of molecular variations in both disorders. The authors noted that MDD disease signals were more strongly associated with male-specific results, suggesting that sex differences may underlie disease risk.
Top disease-associated genes and pathways across regions, omics, and/or traits implicated biological processes in both neuronal and non-neuronal cells. These included molecular regulators and transcription factors, and pathways involved in immune function, metabolism, mitochondria function and stress hormone signaling.

“Understanding why some people develop PTSD and depression and others don’t is a major challenge,” said investigator Charles B. Nemeroff, M.D., PhD, chair of the Department of Psychiatry and Behavioral Sciences at Dell Medical School of UT Austin. “We found that the brains of people with these disorders have molecular differences, especially in the prefrontal cortex. These changes seem to affect things like our immune system, how our nerves work, and even how our stress hormones behave..”
The genetic components of the work built on a study published last month by researchers including Ressler and Daskalakis in Nature Genetics, in which they identified 95 locations, or loci in the genome (including 80 new) associated with PTSD. Their multi-omic analyses found 43 potential causal genes for the disorder.
The researchers now could reveal only limited overlap between the top genes and those implicated in GWAS studies, underscoring the gap in current understanding between disease risk and underlying disease processes. In contrast, they discovered greater correlations between brain multi-omics and blood markers.
“Our findings support the development of brain-informed blood biomarkers for real-time profiling,” said Daskalakis.
Ressler added, “These biomarkers could help overcome current challenges in obtaining brain biopsies for advancing new treatments.”
Limitations of the study include the inherent biases in postmortem brain research, including population selection, clinical assessment, comorbidities, and end-of-life state. The authors also caution that they did not fully characterize all cell-subtypes and cell states, and that future studies are required to understand contrasting molecular signals across omics or brain regions.
The team plans on using this database as groundwork for future analysis of how genetic factors interact with environmental variables to create downstream disease effects.
“Learning more about the molecular basis of these conditions, PTSD and MDD, in the brain paves the way for discoveries that will lead to more effective therapeutic and diagnostic tools. This work was possible because of the brain donations to the Lieber Institute Brain Repository from families whose loved ones died of these conditions,” said Joel Kleinman, MD, PhD, associate director of Clinical Sciences at the Lieber Institute for Brain Development. “We hope our research will one day bring relief to individuals who struggle with these disorders and their loved ones.”

Schizophrenia is a complex disease with variable presentations, and the diverse nature of this mental health disorder has made understanding the mechanisms that cause the disease, and subsequently developing effective treatments, especially challenging. In a new study, published May 23 is Science, a team led by McLean Hospital researchers used comprehensive genetic and cellular analyses to shed new light on the intricate molecular mechanisms underlying schizophrenia. Their new work provides a map for how the genes known to increase risk of schizophrenia affect specific cells within the brain.
“We discovered which cell types express genes associated with schizophrenia risk differently, which biological functions are impacted within those cells, and which transcription factors are important for these changes,” explained lead and co-corresponding author, W. Brad Ruzicka MD, PhD, director of the Laboratory for Epigenomics in Human Psychopathology at McLean Hospital. “This understanding will allow future treatments to be tailored to specific genes and cell types, as well as individuals with schizophrenia.”
Schizophrenia affects approximately 24 million people, or 1 in 300 people, worldwide, according to the World Health Organization.
For the new study, a multi-center team of researchers conducted a comprehensive single-cell analysis of transcriptomic changes in human prefrontal cortex, examining postmortem brain tissue from 140 individuals across two independent cohorts. Their analyses included more than 468,000 cells.
They uncovered unprecedented insights into the cellular basis of schizophrenia, linking genetic risk factors to specific neuronal populations. Specifically, the researchers found that excitatory neurons emerged as the most affected cell group, with transcriptional changes implicating neurodevelopment and synapse-related pathways. Additionally, they found that known genetic risk factors for schizophrenia converge on alterations in specific neuronal populations, highlighting the interplay between rare and common genomic variants. Through transcriptomic analysis, two distinct subpopulations of individuals with schizophrenia were identified, marked by the expression of specific excitatory and inhibitory neuronal cell states.
The new study suggests potential links between schizophrenia pathology and processes such as neurodevelopment, synaptic signaling, and transcriptional regulation, implicating key transcriptional regulators associated with both schizophrenia and neurodevelopmental disorders.
The study’s authors anticipate that insights gleaned from this research could pave the way for targeted interventions and personalized treatments for schizophrenia, potentially improving clinical outcomes for individuals affected by this debilitating and often disabling disorder.
The research team is now working to expand on these findings by investigating other regions of the brain and the molecular impact of other psychiatric diseases such as bipolar disorder. They are also pursuing another dimension of complexity in this system by investigating isoform expression of implicated genes and how these cell type-specific gene expression changes lead to functional and potentially druggable changes in the protein space.
“This work advances understanding of schizophrenia pathophysiology at greater detail across both the complex landscape of cells within the brain, and the diverse experiences of people with this disease,” said Ruzicka, who is also associate medical director of Harvard Brain Tissue Resource Center at McLean, and an assistant professor of Psychiatry at Harvard Medical School. “Our increased mechanistic understanding of schizophrenia provides avenues for future research to unravel the genetic and environmental underpinnings of this complex disease so we can provide our patients better care.”