The human brain is a fascinating and complex organ that supports numerous sophisticated behaviors and abilities that are observed in no other animal species. For centuries, scientists have been trying to understand what is so unique about the human brain and how it develops over the human lifespan.

Recent technological and experimental advances have opened new avenues for neuroscience research, which in turn has led to the creation of increasingly detailed descriptions of the brain and its underlying processes. Collectively, these efforts are helping to shed new light on the underpinnings of various neuropsychiatric and neurodevelopmental disorders.

Researchers at Beijing Normal University, the Changping Laboratory and other institutes have recently set out to study both the human and macaque brain, comparing their development over time using various genetic and molecular analysis tools. Their paper, published in Nature Neuroscience, highlights some key differences between the two species, with the human pre-frontal cortex (PFC) developing slower than the macaque PFC.

“Unraveling the cellular and molecular characteristics of human prefrontal cortex (PFC) development is crucial for understanding human cognitive abilities and vulnerability to neurological and neuropsychiatric disorders,” wrote Jiyao Zhang, Mayuqing Li, and their colleagues in their paper. “We created a comparative repository for gene expression, chromatin accessibility and spatial transcriptomics of human and macaque postnatal PFC development at single-cell resolution.”

Mapping brain development at a single-cell level

The researchers collected several samples of brain tissue that was surgically removed from the PFC of macaques and humans at different stages after birth. The human subjects were children with epilepsy who were undergoing surgical procedures as part of their treatment plan.

The researchers analyzed the expression of genes in single cells taken from the tissues they collected, as well as chromatin accessibility (i.e., how open DNA is within individual cells). They also mapped the expression of genes across the entire brain tissues, using a technique known as spatial transcriptomics, and looked at the types of cells that were present.

“Integrative analyses outlined species-specific dynamic trajectories of different cell types, highlighting key windows and gene regulatory networks for processes such as synaptogenesis, synaptic pruning and gliogenesis,” wrote the authors.

The researchers’ analyses revealed that the human PFC takes longer to develop than that of macaques. They also observed that glial progenitors (i.e., stem-like cells that later divide and develop into specific types of glial cells) proliferate more in humans.

“We identified regulatory correlates of the prolonged development of human PFC relative to macaques,” wrote the researchers. “Glial progenitors showed higher proliferation capability in humans compared to macaques, associated with distinct gene expression profiles. Furthermore, we uncovered cell types and lineages most susceptible to neurodevelopmental and neuropsychiatric disorders, focusing on transcription factors with human-specific expression features.”

Insight that could deepen our understanding of the brain

Zhang, Li and their colleagues gathered new valuable observations that could explain in greater detail known differences between the brain functions of humans and other primates. Notably, the researchers also identified transcription factors that modulate the development of the human brain but not of macaques, while also pinpointing types of cells in human tissues that are known to be affected in the brains of patients with specific disorders.

“Our discoveries shed light on human-specific regulatory programs extending postnatal cortical maturation through coordinated neuronal and glial development, with implications for cognition and neurodevelopmental disorders,” wrote the team.

In the future, the results of this recent study could help to better understand how the human brain develops and the molecular processes that are disrupted in the brains of individuals with specific neurodevelopmental or neuropsychiatric disorders. This could in turn pave the way for the introduction of new strategies to prevent or treat these disorders.

A pioneering study has found that an individualized approach to breast cancer screening that assesses patients’ risk, rather than annual mammograms, can lower the chance of more advanced cancers, while still safely match people to the amount of screening they need.

The results—which come from 46,000 U.S. women enrolled in the first phase of the WISDOM study—support shifting our approach to screening from one that is based on age alone, to one that starts with comprehensive risk assessment to determine each woman’s optimal screening schedule. UCSF was the coordinating center for this study.

“These findings should transform clinical guidelines for breast cancer screening and alter clinical practice,” said Laura J. Esserman, MD, MBA, director of the UCSF Breast Care Center. Esserman is the first author of the study, published in JAMA and presented at the San Antonio Breast Cancer Symposium.

“The personalized approach begins with risk assessment, incorporating genetic, biological, and lifestyle factors, which can then guide effective prevention strategies.”

How risk-based screening was implemented

Breast cancer is the most common cancer in women in the U.S. except for skin cancers. For decades, screening assumed all women have the same risk, and guidelines were based largely on age, despite strong evidence that individual risk varies widely.

WISDOM compared the standard annual mammogram with an approach based on individual risk. Women were stratified into four groups, based on their age, genetics, lifestyle, health history, and breast density, using well-validated risk models.

Those in the lowest risk category—26% of the participants—were told not to screen until they reached age 50 or when an algorithm predicted their risk would meet the level of a 50-year-old.

Those with average risk, who made up 62%, were told to screen every two years. Annual screening was recommended for the 8% of women with elevated risk. The 2% of women in the highest risk category received two screenings a year, alternating between mammography and MRI, regardless of their age.

Those with either elevated or highest risk got personalized recommendations for how to reduce their risk of getting breast cancer. This included an online tool to make breast health decisions and direct outreach from a breast health specialist. The recommendations included ways to improve diet and exercise, as well as considerations for risk-reducing medications.

Study outcomes and participant preferences

This risk-based screening approach did not result in an increase in the frequency of higher-stage cancers. Participants who did not want to be randomized could still enroll in an observational group, where they could choose their own screening approach. Of these participants, 89% chose risk-based screening, showing that it was preferred by women.

“Shifting resources from lower-risk women to higher-risk women is an efficient, effective approach to screening for and preventing breast cancer,” said co-author Jeffrey A. Tice, MD, a professor of Medicine at UCSF who develops and evaluates risk assessment tools for breast cancer.

Since its inception in 2016, WISDOM has enrolled more than 80,000 women. In recent years, researchers enrolled women as young as 30 to identify those who could be at risk of developing aggressive early cancers because of the pathogenic variants they carry.

The role of genetics in risk assessment

Importantly, the study found that 30% of the women who tested positive for a genetic variant that increased their risk of breast cancer did not report a family history of breast cancer. Under current clinical guidelines, these people would not normally be offered genetic testing.

In addition to the more widely known pathogenic variants that increase risk for breast cancer—such as BRCA1 and BRCA2—WISDOM also looked at other smaller changes in DNA that, when taken together with a polygenic risk score, can better predict risk. This made the prediction algorithm even more precise, shifting between 12% and 14% of the participants to a different level of risk.

“This is one of the first studies to offer genetic testing to all women, regardless of family history,” said co-author Allison S. Fiscalini, MPH, of UCSF, director of the Athena Breast Health Network and the WISDOM study.

“When used as part of a comprehensive risk assessment, these results could have a real impact on improving the safety and effectiveness of screening and prevention.”

Next steps for the WISDOM study

WISDOM is continuing to advance risk assessment through the WISDOM 2.0 study, which is now actively enrolling participants. The goal is to identify women at higher risk of developing more aggressive breast cancers, so they can be offered personalized screening and prevention options that may better support their long-term health.

Gastric (stomach) cancer remains one of the most common and deadly cancers in East Asia, including Korea. Yet despite its high prevalence, it has received far less molecular attention than colorectal cancer, which is more common in Western countries. As a result, many of today’s models of gastric cancer biology are still based on assumptions borrowed from colorectal cancer research—often with limited success when applied to patients.

One of the biggest unanswered questions concerned the very first steps of gastric cancer development: how do early cancer cells survive and grow when they should not?

Under normal conditions, cells lining the stomach cannot grow independently. They rely on constant signals from their surrounding tissue—known as the microenvironment—to tell them when to divide, when to rest, and when to die. Losing this dependence is one of the defining features of cancer. But in gastric cancer, researchers have long struggled to explain how this transition occurs.

This problem has been tackled by a joint international research team led by Dr. Lee Ji-Hyun, Dr. Koo Bon-Kyoung, and Dr. Lee Heetak at the Center for Genome Engineering within the Institute for Basic Science (IBS), in partnership with the laboratories of Prof. Cheong Jae-Ho and Prof. Kim Hyunki (Yonsei University College of Medicine) and Prof. Daniel E. Stange (TU Dresden / University Hospital Carl Gustav Carus).

The team has identified a previously unknown mechanism that allows early gastric cancer cells to become self-sufficient. The findings, published in Molecular Cancer, provide a new framework for understanding how stomach cancer begins—and point to potential new targets for treatment.

The role of WNT and MAPK signaling

The inner lining of the stomach is one of the most dynamic tissues in the human body. It is continuously exposed to acid, food, and mechanical stress, and must constantly regenerate. To maintain this balance, stomach cells depend on tightly regulated molecular signals that control growth and repair.

One of the most important of these signals is called WNT signaling. In healthy tissue, WNT molecules are supplied by neighboring “niche” cells that act like caretakers, allowing stomach cells to survive and divide only when appropriate. Without these external signals, gastric epithelial cells simply cannot grow.

In colorectal cancer, this system breaks down in a well-known way. Mutations in genes such as APC or CTNNB1 permanently activate the WNT pathway, allowing cancer cells to grow uncontrollably without outside help. Surprisingly, these classic mutations are rare in gastric cancer, leaving researchers puzzled for decades about how WNT signaling becomes activated in the stomach.

The new study shows that gastric cancer cells solve this problem in a very different way. Instead of waiting for WNT signals from their environment, early gastric cancer cells begin producing the signals themselves. In effect, they stop listening—and start talking.

The researchers discovered that activation of another major pathway, known as MAPK signaling, triggers this switch. MAPK is a signaling system that normally helps cells respond to growth cues and stress. In gastric cancer, it is frequently activated by mutations in genes such as KRAS or HER2, which together are found in roughly one-third of patients.

When MAPK signaling is turned on, the cancer cells begin producing a specific WNT molecule called WNT7B. By secreting this molecule, the cells create a self-sustaining loop: they supply their own growth signal, activate WNT signaling internally, and continue to proliferate even in the absence of normal tissue support.

“This is a fundamental change in how these cells behave,” explained Dr. Lee Ji-Hyun. “They effectively become independent of their environment at a very early stage.”

The study reveals an unexpected functional link between the MAPK and WNT pathways—two of the most important signaling systems in cancer biology—and shows how their interaction drives early tumor growth in the stomach.

Validation in organoids and patient samples

Crucially, the team demonstrated that this mechanism is not an artifact of laboratory models.

The findings were first identified using genetically engineered mouse models, but were then validated in gastric cancer patient-derived organoids—three-dimensional mini-tumors grown directly from human cancer tissue. These organoids closely mimic the structure and behavior of real tumors, making them a powerful bridge between animal studies and human disease.

To build this resource, the researchers conducted long-term domestic and international collaborations with Yonsei University College of Medicine and University Hospital Carl Gustav Carus Dresden, collecting gastric cancer samples from diverse patient groups. The consistency of the results across species and platforms confirms that the newly identified mechanism is directly relevant to human gastric cancer.

Implications for treatment and research

Beyond answering a long-standing biological question, the findings open new therapeutic possibilities. Gastric cancers by this MAPK-driven WNT self-activation currently lack effective targeted treatments. By identifying how these tumors sustain their own growth, the study highlights vulnerabilities that could be exploited to block tumor initiation at its earliest stages—before the disease becomes advanced or resistant.

Building on this work, the research team is now actively exploring strategies to selectively disrupt this signaling program while sparing normal gastric tissue.

More broadly, the study reflects a growing shift in biomedical research toward human-relevant experimental systems. As the limitations of animal-only models become increasingly clear, regulatory agencies such as the FDA, have emphasized the importance of patient-derived platforms, including organoids.

By combining mechanistic insights from mouse genetics with direct validation in human tumors, this work exemplifies a modern translational research pipeline aligned with global research priorities.

Researchers at the Johns Hopkins Kimmel Cancer Center’s Ludwig Center developed a new treatment that selectively targets TRBC2-positive T-cell cancers, expanding a precision approach they established in 2024 for TRBC1-positive tumors.

The therapy, an antibody-drug conjugate, targets a protein expressed on the surface of T-cell cancers to deliver a cancer cell-killing drug.

The work, published in Nature Cancer, provides a long-sought therapeutic option for half of T-cell lymphomas and leukemias that express the TRBC2 variant of the T-cell receptor.

Challenges in treating T-cell cancers

T-cell lymphomas and leukemias affect roughly 100,000 people worldwide each year. These T-cell malignancies, rare and scientifically complex, have received far less pharmaceutical investment than B-cell leukemias and lymphomas and have fewer treatment options. As a result, adults with relapsed T-cell cancers have five-year survival rates of 7% to 38%.

“There is a challenging situation,” says senior author Suman Paul, M.B.B.S., Ph.D., assistant professor of oncology, “because unlike B-cell therapies—where eliminating both cancerous and healthy B cells is tolerable—therapies targeting T cells must preserve enough normal T cells for patients to survive infections.”

“The tricky part is that if the drug kills both the T-cell lymphoma and the normal T cells, then it’s very hard for that person to survive,” Paul explains. “We have to be mindful that it has to get rid of the cancer, but it cannot completely get rid of the normal T cells.”

Targeting TRBC variants for precision therapy

One way to achieve this balance is to target TRBC1 or TRBC2, two mutually exclusive genetic variants of the T-cell receptor. Normal T cells are a mix of TRBC1-positive (~40%) and TRBC2-positive (~60%) populations, but each T-cell cancer expresses only one of the two variants. Selectively targeting the cancer-associated TRBC variant preserves approximately 40%–60% of normal T cells.

In 2024, the team published findings on the first TRBC1-targeting therapeutic antibody. However, until now, no TRBC2-specific therapeutic antibody existed, leaving half of the patients without an equivalent approach.

Development and testing of the new antibody

In the new study, the researchers used a phage-displayed antibody library, a powerful tool used to discover new antibodies, to create JX1.1, a new antibody that recognizes only the TRBC2 protein target and not the similar TRBC1 protein.

“Our antibody was developed using SLISY, a next-generation sequencing-based platform for rapid identification of antibody candidates from a phage library,” says Ken Kinzler, Ph.D., Barry Family Professor in Oncology, and director of the Ludwig Center.

Researchers then linked the new JX1.1 antibody to the cancer-cell killing drug pyrrolobenzodiazepine to generate an antibody-drug conjugate (ADC). In laboratory studies using cancer cell lines and animal models, they found the new ADC to be highly specific to TRBC2 cancers, clearly distinguishing between TRBC2-positive and TRBC1-positive normal T cells.

The ADC killed TRBC2-positive cancer cells, leading to robust tumor regression in animal models with minimal toxicity. All JX1.1-treated mice sustained elimination of detectable cancer throughout the entire follow-up period of 150 days.

“The development of TRBC1 and TRBC2 antibodies together now provides a conceptual ‘matched set’ of precision tools for the great majority of patients with T-cell cancers,” says Paul.

The secret to a healthier and “younger” heart lies in the vagus nerve. A recent study coordinated by the Sant’Anna School of Advanced Studies in Pisa and published in Science Translational Medicine has shown that preserving bilateral cardiac vagal innervation is an anti-aging factor. In particular, the right cardiac vagus nerve emerges as a true guardian of cardiomyocyte health, helping to preserve the longevity of the heart independently of heart rate.

The study is characterized by a strongly multidisciplinary approach, integrating experimental medicine and bioengineering applied to cardiovascular research. Specifically, the research was led by the Translational Critical Care Unit (TrancriLab) of the Interdisciplinary Research Center Health Science, under the responsibility of Professor Vincenzo Lionetti, and by the laboratory of the Biorobotics Institute led by Professor Silvestro Micera, which contributed to the development of the bioabsorbable nerve conduit used to facilitate vagal regeneration.

The study involved a broad network of Italian and international institutions of excellence, including the Scuola Normale Superiore, the University of Pisa, the Fondazione Toscana G. Monasterio, the Institute of Clinical Physiology of the CNR, the University of Udine, GVM Care & Research, Al-Farabi Kazakh National University, the Leibniz Institute on Ageing in Jena and the École Polytechnique Fédérale de Lausanne.

“When the integrity of the connection to the vagus nerve is lost, the heart ages more rapidly,” explains Professor Lionetti.

“Even partial restoration of the connection between the right vagus nerve and the heart is sufficient to counteract the mechanisms of remodeling and preserve effective cardiac contractility,” adds Anar Dushpanova, cardiologist at TrancriLab.

The contribution of bioengineering was decisive. “We have developed an implantable bioabsorbable nerve conduit designed to promote and guide the spontaneous regeneration of the thoracic vagus nerve at the cardiac level,” explains Eugenio Redolfi Riva, co-author of the neuroprosthesis patent at Biorobotics Institute

“Taken together, these results open new perspectives for cardiothoracic and transplant surgery, suggesting that restoring cardiac vagal innervation at the time of surgery may represent an innovative strategy for long-term heart protection, shifting the clinical paradigm from managing late complications associated with premature cardiac aging to their prevention,” concludes Professor Lionetti.

A new study published in Science Translational Medicine by researchers at The University of Texas MD Anderson Cancer Center details a therapeutic vulnerability in patients with an aggressive subtype of triple-negative breast cancer.

Led by Khandan Keyomarsi, Ph.D., professor of Experimental Radiation Oncology, the study shows that simultaneous inhibition of ATR and PKMYT1 triggers a type of cell death in Rb1-deficient breast cancer models.

Using genomic profiling, proteomics and patient-derived xenografts, the researchers found that loss of Rb1—a gene important for normal cell division—disrupts DNA repair processes and forces tumor cells to rely on ATR and PKMYT1 dependent pathways for survival, creating a vulnerability that can be selectively targeted.

“This is a breakthrough discovery,” Keyomarsi said. “Rb1-deficient tumors do not respond to CDK4/6 inhibitors because they depend on Rb1 to regulate cell division. But that same deficiency makes them vulnerable to ATR and PKMYT1 inhibition. We can now identify patients who may benefit from an entirely different therapeutic strategy.”

ATR and PKMYT1 co-inhibition

The study demonstrates that simultaneously inhibiting ATR and PKMYT1—two proteins required for maintaining genomic stability during cell division—induces cell death in Rb1-deficient breast cancers. By blocking both repair pathways, the treatment overwhelms the cancer cell’s ability to correct DNA errors, leading to catastrophic DNA damage, apoptosis, tumor shrinkage and improved survival in preclinical models.

How does Rb1 deficiency create a vulnerability if it also indicates resistance?

Rb1 normally prevents uncontrolled cell division and helps maintain genomic integrity. When Rb1 is lost, cells accumulate DNA errors more rapidly and become prone to malignant transformation. These tumors also resist CDK4/6 inhibitors because the therapy depends on an intact Rb1 pathway to halt the cell cycle.

The same mechanism that allows mutations to more easily occur also creates the vulnerability. While DNA mutations can lead to cancer development, cancer cells also need to replicate, and if they build too many mutations as they replicate, they can no longer function. Using an inhibitor to intentionally cause this to happen is what’s known as synthetic lethality.

By inhibiting ATR and PKMYT1—two proteins that are also important for repairing mutations in DNA—this strategy causes an overload of mutations, leading to cell death and ultimately tumor shrinkage. In this study, targeting these pathways led to tumor shrinkage and increased overall survival in preclinical models.

Next steps for bringing this discovery to the clinic

One of the most noteworthy aspects of this study is its near-term clinical relevancy. Several ATR and PKMYT1 inhibitors already are in clinical trials and have received fast-track designation from the FDA.

The Phase I MYTHIC Trial, which is also being led by MD Anderson researchers, is one example of a trial already testing the combination for certain mutations in solid tumors. The current findings could directly inform the development of Rb1-based biomarker strategies to identify patients most likely to benefit from dual ATR/PKMYT1 inhibition.

“Beyond this combination strategy, our study also shows that Rb1 deficiency predicts sensitivity to other DNA-damaging therapies, such as chemotherapy and radiation,” Keyomarsi said.

“Incorporating Rb1 status into clinical decision-making could help tailor more effective, personalized treatment plans for these patients.”

Bipolar disorder (BD) is a psychiatric disorder characterized by extreme mood changes. Individuals diagnosed with BD typically alternate between periods of high energy, euphoria, irritability and/or impulsivity (i.e., manic episodes) and others marked by feelings of sadness, low energy, and hopelessness (i.e., depression).

While there are now several medications that can help patients to manage the disorder and stabilize their mood, many of these drugs have side effects and dosages often need to be periodically adjusted. Recent studies suggest that the bacteria and microorganisms living in the digestive system, also known as gut microbiota, play a key role in mental health and might also contribute to some symptoms of BD.

Researchers at Zhejiang University, the Nanhu Brain-Computer Interface Institute and other institutes recently carried out a study investigating the possible connection between gut microbiota and the depressive episodes experienced by people diagnosed with BD. Their findings, published in Molecular Psychiatry, suggest that the microorganisms in the digestive system can directly influence connections between specific brain regions known to be affected by BD depression.

“Adequate evidence has shown that gut microbial dysbiosis is an emerging disease phenotype of BD and is closely related to clinical symptoms of this intractable disease,” wrote Anying Tang, Yiwen Chen and their colleagues in their paper.

“However, how gut microbiota affects the nervous system in BD remains largely unclear. In this study, we constructed a BD depression-like mouse model via fecal microbiota transplantation, and explored the changes of synaptic plasticity and connectivity in the medial prefrontal cortex (mPFC) of BD mice.”

Modeling BD depression and its underlying gut bacteria

To explore the link between gut microbiota and BD depression, the researchers collected gut bacteria from individuals diagnosed with BD who were going through a depressive phase. They then transplanted these bacteria into the digestive system of healthy mice.

“We found that bipolar depression-like mice presented with a decrease in the density of dendritic spines in medial prefrontal neurons, and translation post-synapse as a key contributor to the changes in synaptic plasticity,” wrote the authors.

“In addition, analysis of synaptic connectivity in the mPFC revealed that compared to control mice, fewer connections were observed between ventral tegmental area and mPFC glutamate neurons and dopamine response was decreased in BD mice.”

Notably, the researchers found that after they received the microbiota taken from individuals who were experiencing BD depression, the mice also started exhibiting depression-like behaviors. In addition, neurons in two brain regions known to be implicated in mood regulation, namely the ventral tegmental area (VTA) and the medial prefrontal cortex (mPFC), appeared to be less connected with each other.

The team also observed disruptions in the production of proteins and reduced dopamine signaling. Dopamine signaling (i.e., the release of dopamine) is essential for maintaining motivation and emotional regulation.

Improving the future treatment of BD

The results of this study confirm that microorganisms and bacteria in the gut can influence the connections between neurons in different brain regions. These altered connections could in turn have an impact on motivation, mood regulation and the processing of emotions.

“These findings suggest that gut microbiota from BD depression patients induces the development of bipolar depression possibly by modulating aberrant synaptic connectivity and dopamine transmission in the VTA-mPFC pathway, which sheds light on the microbiota-gut-brain mechanisms underlying BD,” wrote Tang, Chen and their colleagues.

The team’s findings will need to be validated in humans before they can be reliably translated into psychiatric and medical insight. In the future, however, they could potentially help to identify promising pathways for the treatment of depression in patients diagnosed with BD, which are designed to alter their gut microbiota.

Human immunodeficiency virus (HIV) infections are still fairly common and an estimated 40 million people worldwide are currently living with this condition. The HIV virus attacks the body’s immune system and thus makes those who contract it more vulnerable to a wide range of infections.

While there is still no known cure for HIV, there are now various treatment options that allow affected patients to live long and healthy lives. When treated with antiretroviral therapy (ART), the virus is known to remain in a latent state, essentially ‘hiding’ inside cells and forming a reservoir of dormant virus. If the medication is stopped, however, the virus can be re-awoken, causing severe immune deficiencies again.

Researchers at the New York Medical College, Valhalla, NY, Southwest National Primate Research Center, San Antonio, TX, and University of Iowa, Iowa City, IA, have recently been investigating how the brain, particularly tiny molecules and protein-carrying packages released by cells, influence the persistence of HIV. In a new paper, published in Molecular Psychiatry, they presented new findings that shed new light on molecular mechanisms that can either re-ignite or suppress latent HIV.

“Our team has been working on extracellular particles for several years and have made pivotal discoveries about their composition and roles in host health and disease,” Chioma M. Okeoma and Mahesh Mohan, co-senior authors of the paper, told Medical Xpress.

“The inspiration for this recent paper came from reviewers’ critique of our NIH grant application. Specifically, a reviewer, while excited about data on condensates, suggested we focus on the role that the condensates play on HIV reservoirs in the brain. The findings we reported are thus the product of that constructive criticism.”

The extensive analysis of macaque extracellular condensates

As part of their study, Okeoma, Mohan and their colleagues collected extracellular particles from the brain of macaques that were either uninfected or infected with a primate equivalent of HIV, known as SIV (simian immunodeficiency virus). These are small molecule-packed particles that cells release in their surroundings, which can either be enclosed by a membrane (i.e., extracellular vesicles or EVs) or not enclosed by a membrane (extracellular condensates or ECs).

“Isolating EPs is challenging because there is no unified isolation method in the field,” explained Okeoma and Mohan. “The separation of EVs from ECs is even more challenging because of the overlap in their physicochemical properties, but nevertheless very necessary so as to correctly ascribe biological functions to the appropriate particle type—EVs or ECs.”

To effectively isolate EPs in the brains of macaques, the researchers developed a new method known as purification liquid chromatography (PPLC). This method allowed them to isolate the particles more reliably, greatly reducing, if not entirely eliminating, common procedural problems.

“We used PPLC to isolate ECs from the basal ganglia (a part of the brain) tissues of rhesus monkeys from three groups,” said Okeoma and Mohan. “Group 1 were chronic SIV-infected and vehicle treated monkeys. Group 2 were chronic SIV-infected and D⁹-THC treated monkeys. Group 3 were uninfected and vehicle-treated control monkeys.”

The team stored the ECs they collected at -80 degrees Celsius and subsequently used them to carry out different experiments and analyses. These included a first set of tests aimed at exploring the functions of the isolated ECs and a second round of experiments assessing the effects of the particles on host cells.

“We first performed cell-based experiments to assess the functions of ECs,” said the authors. “Primary human PBMCs and various cell lines (TZM-GFP, HIV-1 Infected U937 Cells (U1), J-Lat GFP, J-Lat Tat-GFP, human microglia, Huglia (HC69), CEMx174, Raji, and Akata) were treated with ECs and used to assess various host cells responses.”

To study the functions of ECs, the researchers used various laboratory tests that measured different things. These included a test to check whether cells actually absorb ECs, analyses assessing whether they harm or kill cells and an assay exploring whether large multinucleated cells (syncytia) were formed, which is a sign that HIV is active and spreading.

They also performed a test that measured how efficiently HIV passed from one cell to another, which can help to determine whether they can contribute to the transmission of a virus. Finally, they looked at whether ECs reactivated latent reservoirs of the virus in immune cells extracted from HIV-positive patients.

“We then carried out molecular experiments to assess the effects of ECs on host cells at the molecular level,” said Okeoma and Mohan. “Total RNA, total protein, and clarified culture supernatants from cells were subjected to the following assays: secretome analysis using cytokine array/immunoassay, flow cytometry, ELISA, western blot analysis, real-time quantitative PCR (RT-qPCR), and RNA-Seq.”

In this second round of tests, the team collected specific materials from the cells that were hosting ECs, to explore how the particles affected gene activity, the production of proteins and immune signaling. Finally, the researchers used statistical techniques to analyze all the data they collected, identify features in their datasets and derive meaningful insights.

Key findings and possible implications for HIV treatment

Okeoma, Mohan and their colleagues found that ECs collected from the brains of SIV-infected but untreated macaques strongly re-activated latent virus reservoirs increasing the activity of viral genes, the production of proteins and causing the virus to spread between cells. Interestingly, however, particles extracted from the brains of infected macaques who were treated with cannabinoids were found to suppress the re-activation of the virus.

“Cannabinoids have been shown to inhibit neuroinflammation,” said the authors. “Earlier, we showed that cannabinoids exert similar anti-inflammatory effects via EVs and in the current study on ECs, we report that ECs isolated from brains (basal ganglia) of rhesus monkeys have this anti-inflammatory effect and that cannabinoids modulate the cargos of the ECs, with resultant effects on latent HIV reservoirs.”

Overall, the findings gathered by these researchers suggest that the brain’s chemistry, particularly ECs, do play a key role in the reactivation or suppression of dormant HIV. In the future, their work could pave the way for the development of new drugs and therapeutic interventions aimed at better managing, or perhaps even curing, HIV infections.

“Now that we know that ECs regulate HIV reservoirs in the brain, we are investigating the mechanisms involved in these observed effects,” added Okeoma and Mohan. “We are also interested in the role of EPs on brain aging and neurodegeneration, as well as developing a system whereby ECs may be used as a drug delivery platform.”

A new study analyzing the immune response to COVID-19 in a Catalan cohort of health workers sheds light on an important question: does it matter whether a person was first infected or first vaccinated?

According to the results, the order of the events does alter the outcome, at least when it comes to long-term protection against omicron.

The study, published in Nature Communications, was led by the Barcelona Institute for Global Health (ISGlobal) in collaboration with the Catalan Health Institute (ICS) and the Jordi Gol Institute (IDIAP JG), and with support from the Daniel Bravo Andreu Private Foundation (FPDBA).

Since the start of the pandemic, scientists have studied how the body responds to SARS-CoV-2, focusing on antibodies and on T-cell responses. Today, most people have what is known as hybrid immunity, meaning a combination of vaccination and infection.

“Previous studies have shown that hybrid immunity provides stronger protection than either vaccination or infection alone,” says ISGlobal researcher Carlota Dobaño, “but whether the order of these exposures affected the outcome remained an open question.”

A unique four-year dataset

The study was conducted among health care professionals from ICS Central Catalonia, a group that was particularly exposed to SARS-CoV-2 throughout the different waves of the pandemic.

The team led by Dobaño analyzed blood samples collected repeatedly between 2020 and 2023 from 357 health care professionals in the COVIDCatCentral cohort. Of these, 160 were vaccinated before becoming infected, while 197 were infected first. Among the latter, almost all (98%) were infected with the original Wuhan variant.

“This long-term follow-up has made it possible to build a solid and highly relevant database to analyze the immune response to COVID-19 over time,” says Anna Ruiz-Comellas, a researcher at ICS–IDIAP Jordi Gol who led the fieldwork.

Thanks to regular serological testing, it was possible to detect both symptomatic and asymptomatic infections. The team assessed antibody and T-cell responses to five different viral antigens.

Stronger antibodies to omicron in those vaccinated first

The study found that, compared to those initially infected, people who were first exposed to SARS-CoV-2 through vaccination developed higher levels of IgG and IgA antibodies against six omicron lineages (particularly, to the receptor binding domain of the spike protein). This difference became smaller as individuals accumulated more exposures to the virus.

“In contrast, those infected first mounted a somewhat stronger T-cell response, which may result from being exposed to a wider repertoire of antigens or higher viral loads,” says ISGlobal researcher and senior co-author Gemma Moncunill . However, the authors note that the number of participants evaluated for T-cell immunity was limited, so these results should be interpreted with caution.

Antibody dynamics reflect clinical protection

These antibody differences were reflected in clinical protection over time. People infected first were better protected early in the pandemic, when variants were closer to the original strain. But with the arrival of omicron, the advantage shifted: those vaccinated first were better protected from breakthrough infections.

“Our results provide new evidence that first exposure to SARS-CoV-2 antigens via vaccination strengthens the long-term protective effect of hybrid immunity,” says Otavio Ranzani, first author of the study.

Overall, the study highlights the role of the vaccination campaigns against SARS-CoV-2 by helping shape a strong immune response as new variants emerge.

This study is part of the END-VOC project, which aims to support the response to COVID-19 and other pandemics.

Using marijuana just once or twice a month was associated with worse school performance and emotional distress for teens, according to a large national study of adolescents led by Ryan Sultán, an assistant professor of clinical psychiatry at Columbia University Vagelos College of Physicians and Surgeons. The more frequently teens used cannabis, the more likely they were to report emotional distress and other social and academic problems.

“While previous studies have focused on the effects of frequent cannabis use among teens, our study found that any amount of cannabis use at all may put kids at risk of falling behind in school, and the kids using most often may have the greatest risk,” says Sultán, who studies adolescent substance use.

“A few ‘harmless’ joints can snowball into real academic consequences. Teens using it regularly often struggle to focus, miss school, and may lose interest in their future plans.”

Shifting trends in teen drug use

The new study arrives amid a national backdrop of shifting trends in teen drug use. While use of many substances is at record lows among US youths, cannabis remains an exception. About 1 in 5 high school students currently use cannabis, and approximately 6% of 12th graders use it daily—a rate that has increased in the past decade.

“The real-world impact can be dramatic,” Sultán says. “It’s not uncommon for a young teen to smoke marijuana only a few times before showing signs of withdrawal and worsening mood.”

Scientists are especially concerned because today’s cannabis products contain two to three times more THC (the ingredient that causes a high) than in the past, making them more potent. And previous studies have shown that using cannabis during adolescence, when the brain is still developing critical neural connections, may have lasting effects on cognitive functions that are critical to academic performance.

“A teenager’s brain is still developing the circuits for learning, self-control, and emotional regulation,” says Tim Becker, a child & adolescent psychiatrist at Weill Cornell Medicine and study co-author. “Using cannabis, even casually, during these critical growth periods interferes with those processes and can derail normal development.”

Study details

The new study analyzed data from a nationally representative survey of over 160,000 U.S. 8th, 10th, and 12th grade students conducted from 2018 to 2022. Over one-quarter of the respondents reported cannabis use; less than 20% reported monthly or less frequent use; and much smaller percentages said they used cannabis weekly or almost every day.

In the study, adolescents who used cannabis once or twice a month reported higher rates of depression-like symptoms, anxiety, and impulsive behavior than those who abstained. Near-daily users were almost four times as likely to have poor grades and were frequently disengaged from school activities. These associations were even stronger for younger cannabis users.

What should parents and caregivers do?

Experts recommend having frank, nonjudgmental conversations with teens about cannabis early and often.

“Make sure they understand that “natural” doesn’t mean “safe,” Sultán says. “Parents also need to keep an eye out for warning signs like declining grades, mood changes, or loss of interest in hobbies—and consider that cannabis could be a factor.”

“Cannabis Use Among US Adolescents” was published online in Pediatrics on Dec. 23.