Tag: Academic research

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Early Genomic Indicators of Praziquantel Resistance in Schistosoma mansoni

The warning signs are subtle—genetic variants scattered across a vast parasite genome—but together they sketch a picture that disease‑control and elimination programs can’t afford to ignore. A new study published in Science Advances, “Extensive parasite transmission and variation in a functional receptor associated with drug resistance in endemic Schistosoma mansoni,” reveals genomic changes in the parasite that cause schistosomiasis, which may reduce its sensitivity to praziquantel, the only drug currently available to treat the disease.

The international team, led by researchers at the Wellcome Sanger Institute, the Royal Veterinary College, and the Medical College of Wisconsin, analyzed whole‑genome sequence data from 570 Schistosoma mansoni parasites collected across Africa and the Caribbean. As the paper noted, “Mass drug administration (MDA) with praziquantel is the cornerstone of schistosomiasis control and elimination efforts.” Yet after two decades of large‑scale treatment campaigns, the parasite’s genome is beginning to show signs of drug resistance.

The study uncovered extensive long‑distance transmission of S. mansoni and a striking degree of genetic diversity across endemic regions. But the most consequential finding lies in Sm.TRPMpzQ, a transient receptor potential (TRP) melastatin ion channel recently identified as praziquantel’s molecular target. Researchers found four naturally occurring variants in this receptor with reduced praziquantel sensitivity.

In some cases, parasites persisted even after treatment. As the paper reports, “Analyses of parasite infrapopulations collected from people pre‑ and post‑praziquantel treatment further identified instances of treatment failure, supporting the potential for praziquantel resistance.”

For global health programs that rely entirely on praziquantel, these findings represent an early but important signal.

Stephen Doyle, PhD, co‑senior author and group leader and UKRI Future Leaders Fellow at the Wellcome Sanger Institute, emphasized the shift this genomic insight enables: “Whole‑genome sequencing gives us an unprecedented window into how schistosome populations are structured and evolving across Africa, and by characterizing variation in the drug’s molecular target at scale, we can move from reactive surveillance to proactive monitoring.”

Professor Joanne Webster, DPhil, of the Royal Veterinary College and director of the Global Centre for Neglected Tropical Disease Research, underscored the stakes: “While praziquantel remains largely highly effective, our findings provide a sobering warning about the reliance on a single drug for schistosomiasis control and highlight the need for comprehensive surveillance to monitor the potential emergence of drug resistance.”

Schistosomiasis affects more than 250 million people worldwide, with 90% of infections occurring in sub‑Saharan Africa. With elimination targets set for 2030, the emergence of resistance could jeopardize decades of progress.

The authors argue that genomic surveillance should become a routine part of schistosomiasis control. Their dataset, the largest genomic analysis of S. mansoni from human infections to date, provides a baseline for tracking resistance‑linked variants as MDA programs continue.

The post Early Genomic Indicators of Praziquantel Resistance in <i>Schistosoma mansoni</i> appeared first on GEN – Genetic Engineering and Biotechnology News.

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Flu Virus Interaction with Host Cell Machinery Mapped Inside Infected Cells

Researchers at EMBL Hamburg and collaborators at the Leibniz Research Institute for Molecular Pharmacology (FMP) have mapped in unprecedented detail how the influenza A virus (AIV) rewires infected human cells. The researchers developed a customized experimental workflow that used in-cell cross-linking mass spectrometry (XL-MS), combined with AlphaFold-based structural modeling and functional assays, to directly map protein-protein interactions (PPIs) in IAV-infected human cells.

They claim that the study marks the first time that scientists have mapped direct virus-host protein contacts at scale inside intact influenza-infected cells, with enough structural detail to model how the proteins fit together. “Our work provides a new way to study flu-host interactions in their native context and with structural insight,” said Jan Kosinski, PhD, group leader at EMBL Hamburg and the Centre for Structural Systems Biology (CSSB). “The current results are a snapshot of a moment during infection, and it opens the door to studying flu-host interactions across the entire infection cycle.”

Kosinski is co-senior and co-corresponding author of the team’s published paper in Nature Microbiology, titled “Mapping in-cell protein contact sites reveals hijacking of paraspeckles during influenza A virus infection,” stating that their findings “… uncover mechanisms by which IAV exploits and remodels host compartments during infection.”

Every year, seasonal influenza kills up to 650,000 people globally and causes serious illness for 3–5 million individuals. When IAV infects cells, it releases RNA that contains the blueprints for a handful of proteins that spread throughout the host cell and repurpose its molecular machinery to make more viruses. “Its replication relies on protein–protein interactions (PPIs) between up to 14 viral proteins and host factors, often confined to cellular compartments and organelles,” the team stated.

Scientists want to understand this process in detail, as it would help in designing better drug therapies and vaccines against the flu virus. “Understanding these host–IAV PPIs in context is essential for elucidating viral strategies and therapeutic targets,” they added.

Studying protein-protein interactions in action during infection is challenging. Most previous studies relied on biochemical methods that required the cell to be broken open before the interactions could be measured. Once the cell’s compartments were gone, proteins that were never in contact inside the cell could meet in the test tube, and fragile or location-specific contacts could be lost. It was then hard to know which interactions actually happened inside an infected cell.

“This is when we learned that our collaborators—Boris Bogdanow and Fan Liu—at FMP Berlin had developed a specialized version of cross-linking mass spectrometry (XL-MS), a long-established technique for mapping protein contacts, tailored specifically to virus-infected cells,” said Kosinski. This was the critical breakthrough. It allowed researchers to do what previous methods couldn’t, including capturing short-lived and location-specific interactions.

“XL-MS allows us to capture protein-protein interactions directly in infected intact cells, while also providing structural information about how these interactions are happening,” explained Bogdanow, who is now a junior research group leader at the Institute of Virology, Charité—Universitätsmedizin Berlin. “This gives us insight into the interface between the virus and the human cell and may, through structural modelling, help identify actionable targets for future pharmaceutical interventions.”

By combining the results obtained through XL-MS with computational structural modeling, the researchers could identify which viral and human proteins interact and also predict how they physically fit together. For this, they used a modified version of the protein structure prediction algorithm AlphaFold.

“The key advantage of the modified AlphaFold approach is that it allowed us to feed our experimental cross-linking data directly into the structural modeling,” explained Kosinski. “This tells the model which parts of the viral and host proteins are close to each other inside infected cells. This was especially useful for virus-host complexes, which are often difficult to predict reliably.”

The study findings revealed two important ways in which the virus hijacks the cell. One involves hemagglutinin, a protein on the virus’s surface that it uses to bind and enter host cells. Tracing how hemagglutinin moves through the cell’s internal transport and processing system revealed how host proteins, some with previously unknown functions, helped the virus correctly fold and modify hemagglutinin during infection.

The other involves paraspeckles, small droplet-like compartments in the nucleus. The researchers found that infection by the influenza A virus causes these organelles to dissolve, releasing the RNA-binding proteins bound within them, which the virus can then use to replicate. “We identified host factors linked to the maturation of distinct glycoforms of the viral surface glycoprotein haemagglutinin through the membrane-bound endoplasmic reticulum–Golgi system,” the scientists wrote in summary. “In the nucleus, we observed the progressive disassembly of paraspeckles (phase-separated membraneless compartments) across multiple cell lines.”

First author Iuliia Kotova, PhD, former predoctoral fellow at the Kosinski group at EMBL Hamburg, and currently at ETH, said, “What surprised us most was the paraspeckles. Watching these tiny organelles in the nucleus dissolve, consistently across every cell line and every flu strain we tested, told us this isn’t a side effect of infection—it might be a strategy.”

Kosinski added, “There may also be a second benefit for the virus: some evidence suggests paraspeckles contribute to cellular stress responses and antiviral gene regulation, so disrupting them could also weaken parts of the cell’s defense response.”

The researchers believe that their “mapping in context” approach can be used to understand the mechanism of action of other viruses that act similarly. “While the exact host factors and mechanisms often differ from virus to virus, we think our overall approach—combining in-cell cross-linking, structural modeling, and targeted cell-biology follow-up to map native virus-host interactions at specific stages of infection—remains broadly applicable,” Kosinski said.

Bogdanow further commented, “Although this study has focused on a lab-adapted strain, this study lays the groundwork to apply the methodology to viruses of potential pandemic relevance, such as H5N1, and for uncovering the interaction networks that support their multiplication in human cells.”

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A 3-Tier AI Model for COVID-19 Triage Using Pharyngeal Images: Algorithm Development and Validation

Background: SARS-CoV-2 remains a common cause of acute respiratory illness; however, symptom-based triage poorly discriminates it from other febrile conditions. A recently developed artificial intelligence (AI)–powered pharyngeal camera acquires pharyngeal images and clinical data to assist in influenza diagnosis; leveraging this workflow, we evaluated an adjunct AI algorithm (COVID-19-AI) that reports high, medium, or low suspicion to guide whether SARS-CoV-2 testing should subsequently be performed. Objective: This study aimed to report diagnostic accuracy outcomes and clinical utility of the COVID-19-AI as a triage support tool. Methods: We conducted a performance evaluation using a prospectively collected multicenter dataset from 26 Japanese institutions between December 2023 and March 2024. Patients with suspected influenza or COVID-19 were eligible. The COVID-19-AI algorithm, a stacked ensemble of a Swin Transformer and boosting models, was developed using pharyngeal images combined with routine clinical variables from 2133 patients, and it produced a 3-tier output. Classification thresholds were predefined to optimize clinical rule-out and rule-in utilities. Diagnostic performance was assessed in 696 independent patients against centralized reverse transcription polymerase chain reaction–confirmed SARS-CoV-2 infection under 2 prespecified operating criteria: inclusive (high or medium=positive and low=negative) and strict (high=positive and medium or low=negative). A subanalysis stratified accuracy by time from symptom onset (12-hour bins to 72 hours). Results: Among 696 analyzed participants (all Asian), 247 (35.5%) had reverse transcription polymerase chain reaction–confirmed SARS-CoV-2 infection. The COVID-19-AI categorized 12.4% (n=86), 72.8% (n=507), and 14.8% (n=103) patients as high, medium, and low suspicion, respectively. Under the inclusive criteria, sensitivity of COVID-19-AI was 93.9% (95% CI 90.4%‐96.4%), specificity was 19.6% (95% CI 16.1%‐23.5%), and negative predictive value was 85.4% (95% CI 77.6%‐91.3%). Under the strict criteria, sensitivity was 24.7% (95% CI 19.6%‐30.4%), specificity was 94.4% (95% CI 92.0%‐96.3%), and positive predictive value was 70.9% (95% CI 60.7%‐79.8%). Across 12-hour onset strata, sensitivity under the inclusive criteria remained ≥92.0% and specificity under the strict criteria remained ≥83.3%; no pronounced temporal trend was observed. Additionally, an integrated model using both pharyngeal images and clinical variables (area under the receiver operating characteristic curve [AUROC] 0.78) outperformed models using only clinical variables (AUROC 0.75) or images alone (AUROC 0.71); feature importance analysis further confirmed that pharyngeal image information was the most influential individual predictor, providing greater predictive value than any single clinical variable. Conclusions: Embedded within AI-powered pharyngeal camera workflows, a 3-tier AI suspicion output enables complementary operating behaviors—high sensitivity to rule out COVID-19 (inclusive criteria) and high specificity to support immediate infection control measures (strict criteria), although these criteria involve inherent trade-offs with low specificity and low sensitivity, respectively. Performance stability across onset times suggests robustness to symptom chronology, offering a standardized tool for clinical triage. Trial Registration: UMIN Clinical Trials Registry UMIN000052896; https://tinyurl.com/3b7et428
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High-Risk Multiple Myeloma Redefined in Era of Modern Quadruplet Therapy

Advances in frontline treatment for multiple myeloma may prompt clinicians to rethink how they identify patients with the poorest prognosis, according to a study published in Cancer. Researchers report that patients whose disease progresses within 36 months—not the longstanding 18-month benchmark—should now be considered to have functional high-risk (FHR) multiple myeloma.

Functional high-risk disease has traditionally been defined as myeloma that progresses within 18 months of starting therapy, a group historically associated with survival of less than two years after relapse. However, widespread adoption of quadruplet therapy—combining an anti-CD38 antibody, a proteasome inhibitor, an immunomodulatory agent, and dexamethasone—followed by autologous stem cell transplantation (ASCT) has substantially prolonged remission for many patients.

To determine whether the historical definition remains appropriate, investigators from the University of Alabama at Birmingham and the CoMMiT consortium analyzed outcomes in 310 patients with newly diagnosed multiple myeloma treated with quadruplet therapy plus ASCT. Patients were followed for a median of 41.8 months (3.5 years), during which 66 experienced disease progression.

The researchers evaluated several definitions of FHR disease based on progression occurring within 12, 18, 24, or 36 months after treatment initiation. Their analysis found that progression within 36 months most accurately identified patients whose survival after relapse remained approximately two years or less despite current frontline therapy.

“The current analysis provides validation of FHR36 as the optimal classification for FHR multiple myeloma in the era of QUAD + ASCT, providing a benchmark for future therapies to be explored in this setting,” the authors conclude.

Using the new definition, 16.4% of patients were classified as having FHR36 disease. Many would not have been identified as high risk using conventional staging systems: more than one-third had lower-stage disease according to the second revised International Staging System, and more than half met standard-risk criteria under current International Myeloma Society guidelines.

The study also suggests that T-cell redirecting therapies (TCRTs), including CAR T-cell therapies and bispecific antibodies, may improve outcomes in this population. Although only 11 patients received TCRTs as second-line treatment, outcomes were markedly better than with conventional therapies.

The 12-month second progression-free survival rate was 80% for patients treated with TCRTs, compared with 23% for those receiving other therapies. Overall response rates were 91% versus 47%, respectively. Multivariable analysis showed that TCRT remained associated with improved progression-free survival after adjustment for FHR status.

The authors caution that these findings require confirmation because relatively few patients received TCRTs. Still, they argue that patients meeting the FHR36 definition should be prioritized for early T-cell redirecting therapy and enrollment in clinical trials evaluating novel agents.

“We believe FHR36 should be a standard definition for FHR going forward and that the safety and efficacy of experimental agents should be reported in this important subset of patients or dedicated trials should be designed and conducted for this special population,” the authors write.

 

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Defining and Assessing Empathic Communication in Patient Portal Secure Messages: Adapted Coding Framework Development Study

Background: Empathic communication in the clinical setting has been associated with improved clinical outcomes, decreased anxiety, and increased patient satisfaction, treatment adherence, and trust. Despite the recent growth in patient portal use, the expression of empathic communication through patient portal secure messages is not well understood. Objective: This study aimed to construct a coding schema to define and assess empathic opportunities initiated by patients and primary care clinicians’ responses to these opportunities within a patient portal messaging environment. Methods: Data for this study included adult patient secure messages and responding messages from clinicians working in family practice clinics within a regional health care system serving central and northeast Pennsylvania between January 2018 and December 2023. We conducted a manual review of messages using the Empathic Communication Coding System as a guiding framework, which defines empathic opportunities created by patients and corresponding empathic responses by clinicians. We double-coded 500 patient messages for 3 empathic opportunity types: statements of emotion, progress, and challenge. Coding definitions were iteratively updated to describe specific textual cues unique to the patient portal context. This procedure was repeated to code for empathy in clinician responses to empathic opportunities. An additional 100 patient messages were double-coded for interrater reliability testing, and 500 patient messages were single-coded using the finalized coding schema. Results: Among 1100 patient messages coded, 576 (52.4%) included an empathic opportunity. Of these messages, 100 (17.3%) included a statement of emotion, 85 (14.7%) included a statement of progress, and 539 (93.6%) included a statement of challenge. Statements of challenge were primarily characterized by patients explicitly describing physical or mental health issues, a barrier in care, or difficulties in their personal lives. Among the 576 patient messages with empathic opportunities, 446 (77.4%) received at least 1 response from a clinician. Clinicians sent 483 response messages, of which 64 (13.2%) expressed empathy. Conclusions: While patients created empathic opportunities in over half of patient portal secure messages, primary care clinicians infrequently responded with empathy. The findings of this study provide initial evidence of gaps in empathic communication within patient portal secure messages and lay the groundwork for using artificial intelligence models to systematically measure and improve this communication across the patient portal messaging system.
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Protein Protects Against Tau Tangles, Synaptic Loss in Mouse Model of Tauopathy

Alzheimer’s disease (AD) and many other forms of neurodegeneration share a common culprit. In these diseases, tau proteins that normally stabilize neuronal microtubule filaments within nervous system networks instead form noxious knots and gradually disrupt the circuits they would otherwise preserve.

Scientists at Sanford Burnham Prebys have now shown that a different protein known as SORLA offers protection against the effects of these lethal loops. The results of the researcher’s’ study in mice suggests that future research may yield new treatments capable of boosting this protein’s ability to defend the brain.

Timothy Huang, PhD, assistant professor in the Center for Neurologic Diseases at Sanford Burnham Prebys, is senior and corresponding author of the team’s published paper in Science Advances, titled “SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain,” in which they concluded “These findings reveal a protective role for SORLA in multiple aspects of tauopathy pathogenesis and highlight its potential as a  therapeutic target.”

Normally, tau proteins are found throughout the brain and nervous system, helping to maintain the shape and structure of our neuronal wiring. But in certain diseases, including Alzheimer’s disease, tau proteins clump together inside nerve cells, forming what are known as tau tangles. These toxic tangles are linked to cognitive impairment and nerve cell death in diseases known as tauopathies. “In AD, amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) comprising hyperphosphorylated tau accumulate in brain,” the authors explained.

The new study focused on the safeguarding capabilities of protein known as SORLA. “A role for the trafficking receptor SORLA (Sortilin-related receptor containing LDLR class A repeats) in reducing Aβ levels has been well established,” the investigators continued. “… however, relatively little is known with respect to whether and how SORLA can potentially affect tau pathology in vivo.”

Timothy Huang added, “In the last 15 or 20 years, considerable data has come out from our lab and other groups showing that SORLA can suppress one of the hallmarks of Alzheimer’s disease—amyloid-beta generation and accumulation. Very little was known, however, about whether SORLA affected the tau tangles reflected on the other side of the coin in Alzheimer’s disease.”

SORLA is expressed in both neurons and glia in mouse and human brain, the authors noted. For their newly reported study the team began by crossbreeding mice that produce extra human SORLA protein, with PS19 (P301S) mice that develop tau tangles, brain atrophy and cognitive deficits. This new mouse model enabled experiments to determine SORLA’s effects on tau protein buildup and its resulting harms.

Their studies showed that an overabundance of SORLA protein protected against a number of biological processes linked to the formation of tau tangles and progression of neurodegeneration. These include reducing the addition of too many phosphate groups to tau—known as hyperphosphorylation—and the ability of misshapen tau to serve as “seeds” that attract more tau and form clumps. This protection also extended to preservation of the synapses at the junction between neurons and the brain’s ability to adjust these connection points—which is called synaptic plasticity. “Using complementary approaches, we show that SORLA overexpression attenuates ventricular enlargement, tau phosphorylation and seeding, synaptic loss, impaired synaptic plasticity, and glial hyperactivation in the PS19 mouse brains,” the team wrote in summary.

An overabundance of SORLA protein protects against a number of biological processes linked to the formation of tau tangles and progression of neurodegeneration. These include reducing the addition of too many phosphate groups to tau, known as hyperphosphorylation. In these biopsy images, less phosphorylated tau—stained to appear green—has accumulated in the bottom sample overexpressing SORLA. [Tim Huang, Huijie Huang, Sanford Burnham Prebys]
An overabundance of SORLA protein protects against a number of biological processes linked to the formation of tau tangles and progression of neurodegeneration. These include reducing the addition of too many phosphate groups to tau, known as hyperphosphorylation. In these biopsy images, less phosphorylated tau—stained to appear green—has accumulated in the bottom sample overexpressing SORLA. [Tim Huang, Huijie Huang, Sanford Burnham Prebys]

“When you upregulate SORLA, you can suppress the negative effects found in tauopathies,” said first author Huijie Huang, PhD, a staff scientist in the Huang lab at Sanford Burnham Prebys. “We found there was less brain atrophy and less tau accumulation, which was very exciting to see.”

Because some people have mutations that disable the gene carrying the code for SORLA, Sorl1, the scientists wanted to compare the outcome of having extra SORLA to having none of it at all. Tests of mice genetically modified to lack Sorl1 told a very different story. “The opposite turned out to be true when we deleted the ability to produce SORLA proteins,” said Timothy Huang. “A lack of SORLA exacerbated the harmful effects observed in tauopathies.”

To address how extra SORLA or a lack of SORLA were either ameliorating or aggravating diseases featuring tau tangles, the research team used a combination of sequencing techniques capturing the levels of all proteins and gene expression in each cell, as well as mapping the spatial relationship of RNA and proteins within brain tissue. The scientists found that upregulated SORLA prevented problematic protein production changes in the synapses between neurons while also suppressing other drivers of tauopathy disease progression. They also observed that extra SORLA tamped down on disease-related gene expression patterns in brain cells known as glial cells that support and protect neurons in many ways. “One particularly notable finding that we can build on is the upregulation of a member of the plexin-B family of receptors in the absence of SORLA,” said Huijie Huang.

“There are unique drugs that can target this class of receptors that we may be able to apply to tau-related dementia disorders,” suggested Tim Huang. “One potential future direction is to repurpose these drugs to target overactivation of glial cells and perhaps reverse some of the phenotypes in tauopathies.”

The scientists also want to better understand what happens in each individual cell type when they upregulate or downregulate SORLA. “While it is not possible to specifically determine how cell-specific modulation of SORLA can affect tau using the global transgenic overexpression/deletion models used here, we are interested in further characterizing specific effects of SORLA on tau in neurons, and the extent of SORLA modulation on glia in influencing overall tau pathology,” they stated. The team plans to graft human neurons or glial cells into the mouse brain to study the effects of different SORLA mutations.

“Mouse cells and human cells are different,” said Tim Huang. “Because we’re looking at human disease, it’s more informative if we can observe the modulation and dysfunction of SORLA in the context of a human cell inside of a diseased brain environment.”

This continued research will reveal more knowledge about the ability of SORLA to safeguard against the toxic effects of tau tangles, and how to develop new treatments or repurpose existing therapies to benefit patients suffering from Alzheimer’s disease and other tau-related dementia disorders.

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Patient-Derived Tumor Organoids Show Promise for Personalizing Cancer Treatment

The development of patient-derived tumor organoids for preclinical research will undoubtedly advance precision medicine research. Now, researchers have developed a pan-cancer patient-derived organoid (PDO) platform comprising 220 PDOs from 191 patients across 15 cancer types. This advance points to an increase in the use of tumor organoids as models for evaluating and optimizing cancer treatments.

This work is published in Science Advances in the paper, “Patient-derived organoids across cancers reveal conserved tumor heterogeneity and actionable therapeutic vulnerabilities.”

The team characterized the organoids extensively, showing that they retained key characteristics of the parent tumors over extended periods and showed promise in screens to identify unrecognized treatment candidates. The organoids had similarity to their parent tumors in terms of microscopic appearance, driver DNA mutations, gene expression patterns and other features.

More specifically, the comprehensive characterization demonstrated “high fidelity to parent tumors, with 93% histopathology concordance, 80% median genomic concordance for driver mutations, and a 0.85 median gene expression correlation.” Expression profiles remained largely stable over 10 passages, ensuring reproducibility for long-term screening. And clonality analysis, the authors note, showed that 85% of dominant tumor clones were preserved, with genomic concordance directly reflecting clonal similarity.

“Essentially, these organoids appear to be very good preclinical models of the parent tumor, and are practical models because they can be used long-term,” said Andrea Sboner, PhD, associate professor of pathology and laboratory medicine, director of informatics and computational biology in the Englander Institute for Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell.

The team selected a subset representing patient tumors that, based on standard clinical criteria, had been deemed ineligible for treatment with a new class of drugs—PARP inhibitors. They then tested a PARP inhibitor, talazoparib, on the organoids, and found that more than half—58%—showed substantial sensitivity, implying that the current clinical criteria are excluding patients who could benefit from such drugs. The team characterized the mutational and other features that made these organoids susceptible—offering clues to how the clinical criteria might be expanded—and identified drugs that synergistically enhance talazoparib’s effects.

“You can use these organoids as patient ‘avatars’ during clinical trials of experimental therapies, for example, to get an early picture of treatment effects and side effects,” notes Juan Miguel Mosquera, MD, a professor of pathology and laboratory medicine and director of research pathology at the Englander Institute.

The scientists also envision the future use of tumor organoid technology in selecting treatments for individual patients—growing an organoid from a sample of the patient’s tumor and then testing it rapidly with different treatment regimens.

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Memory Shaped by Brain Remodeling During Adolescence in Mice

The human brain continues developing beyond the teenage years, with crucial changes involving decision-making and emotional regulation extending into the mid-to-late 20s. Researchers at Albert Einstein College of Medicine have identified a biological process in mice that offers new insight into how memory circuits mature during this period of brain development. 

The study published in PLOS Biology titled, “Retrosplenial cortical reorganization during late adolescence introduces instability of contextual memory circuits,” found that a key memory region of the mouse brain undergoes a period of remodeling during late adolescence, causing memories formed earlier in life to become temporarily more difficult to retrieve before resurfacing with less precise detail. The findings identify a biological mechanism that may explain how access to memories changes during development. 

The study focused on the retrosplenial cortex (RSP) and discovered that protective mesh-like structures, called perineuronal nets, stabilize memory circuits and unexpectedly diminish during late adolescence before rebuilding in adulthood. The changes were confined to the RSP and were not observed in the nearby hippocampus, another brain region essential for memory. 

“We’ve known for years that the brain continues developing through adolescence and young adulthood,” said senior author Jelena Radulovic, MD, PhD, professor of neuroscience, psychiatry, and behavioral sciences at Einstein. “Our findings begin to explain what that developmental process looks like in one of the brain’s memory circuits and how it can influence the way earlier experiences are recalled. 

Previous studies suggested that the memory circuits reached maturity during early adolescence. Instead, results showed that an important stabilizing system temporarily weakened during late adolescence before recovering in adulthood. 

The timing is notable because it corresponds to a period now recognized as one of continued brain maturation in humans. According to the National Institutes of Health, the brain continues developing and maturing into the mid-to-late 20s. 

“The behavior matched the biology,” said lead author Hui Zhang, PhD, a research fellow at Einstein. “The retrosplenial cortex is responsible for older, more established memories. As its stabilizing structures declined, access to memories formed earlier in life became less reliable.” 

To determine how these brain changes affected behavior, the researchers trained mice to associate a specific environment with a mild foot shock. The mice remembered the experience and froze when returned to the same chamber. Weeks later, many of the mice trained during early adolescence no longer showed that fear response, while mice trained during adulthood retained stable memories over the same period. 

When the adolescent mice later experienced another test in a different environment, they once again responded to the original setting, demonstrating that the memories had become temporarily inaccessible rather than erased. 

The researchers traced these changes to a decline in key structural proteins that help build and maintain perineuronal nets, along with reduced activity of growth factor, TGFβ2. When TGFβ2 activity was restored, the mice regained their ability to retrieve memories formed earlier in life. 

By mid-adulthood, many of those memories resurfaced spontaneously, although they had become less precise. Rather than responding only to the original environment, the mice generalized their fear to unfamiliar settings. The researchers note that this pattern resembles the “reminiscence bump,” a well-known phenomenon in which adults disproportionately recall memories from adolescence and early adulthood while often remembering the emotional significance of an experience more readily than its specific details.  

The findings may also have implications beyond memory. Schizophrenia and major depression often emerge in humans during late adolescence. The authors suggest that changes in this developmental process could contribute to vulnerability to psychiatric disorders in genetically susceptible individuals. Additional research is needed to evaluate whether similar mechanisms occur in humans. 

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New CVD Risk Tool Boosts Women’s Risk, Lowers Risk for Some Black Adults

A change in the guidelines used to judge a person’s cardiovascular risk in the U.S. means who is classed as ‘at risk’ or not depending on their lipid levels and other factors will change.

Men, non‑Hispanic Black adults, and current smokers are more often moved down, whereas women and people with diabetes would see their risk category upgraded with the new tool suggests research led by Allison Peng, MD, Johns Hopkins University School of Medicine, and colleagues.

The research is published in JAMA and compares risk classification with the new PREVENT-atherosclerotic cardiovascular disease (ASCVD) tool and the 2013 pooled cohort equations, which have been the standard tools for estimating 10-year atherosclerotic cardiovascular disease risk for a long time.

The team used data from the National Health and Nutrition Examination Survey, a large ongoing study that interviews and examines a sample of the U.S. population every year and focused on 24,403 adults aged 40 to 79 years who did not already have cardiovascular disease and did not have very high levels of low‑density lipoprotein (LDL) cholesterol.

For each person, the investigators estimated the chance of a heart attack or stroke in the next 10 years using both the old and new calculators, grouped them as low, borderline, intermediate, or high risk under each system, and then asked who moved up or down. They also examined whether this reshuffling would change who is advised to take cholesterol‑lowering medicines such as statins.

The new tool removes race as an input, adds more risk factors such as body mass index and markers of glycemia and kidney disease, and predicts both 10‑ and 30‑year cardiovascular risk, whereas the old tool focused on 10‑year ASCVD and treated race as Black vs. White.

The results show 22% of study participants changed risk category with the new calculator. Around 14% of all adults were placed into a lower‑risk group, while about 7% were moved up. Around 50% of the population continued to be classed as low risk, but the borderline group grew from about 13% to 18%, while the intermediate group shrank from about 25% to 20%, while the high‑risk group did not change much from about 12% to 11% with the new tool.

Key changes show women’s risk increasing and men’s decreasing, factors such as diabetes playing a bigger role in risk estimation and Black adults being generally classed as lower risk.

In the older framework, an intermediate or high risk often directly triggered a statin recommendation. With the new tool, more patients sit in the enlarged borderline group and would be offered additional tests like coronary artery calcium scoring and allowed shared decision‑making about medications and preventive treatment. Despite these shifts, the proportion of adults for whom statins would be recommended was almost unchanged at around 50% before and after.

“Overall, cardiovascular risk reclassification with the 2026…Dyslipidemia Guideline may result in opportunities for consideration of more personalized cardiovascular risk assessment with risk enhancers and coronary artery calcium scoring to guide lipid-lowering therapy and cardiovascular disease prevention,” write the authors.

In an accompanying editorial in the same journal, Philip Greenland, MD, Northwestern University Feinberg School of Medicine, and Karen Lasser, MD, Boston Medical Center, Boston University, note that despite improving risk assessments, many people who are at risk still do not get treatment or reach suggested goals for healthy cholesterol levels.

“A large percentage of U.S. adults aged 30 years or older are candidates for guideline-directed lipid lowering therapy, and many who are currently taking lipid lowering therapy are not reaching new (or previous) low density lipoprotein cholesterol goals. This is a huge public health burden for the U.S. population for a medical condition that should be highly treatable.”

They conclude: “Given the large numbers of people who would be recommended for treatment following a risk-based discussion, these reports signify a major challenge, and so far, a missed opportunity, for the U.S. health care system.”

The post New CVD Risk Tool Boosts Women’s Risk, Lowers Risk for Some Black Adults appeared first on Inside Precision Medicine.

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