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PubMed2026

[Pathogenicity analysis and prenatal genetic counseling for five Chinese pedigrees harboring a hemizygous c.-32C>G variant of FGF13 gene].

OBJECTIVE: To explore the pathogenicity and prenatal counseling strategies for five Chinese pedigrees harboring a hemizygous c.-32C>G (NM_001139500.2) variant of fibroblast growth factor 13 (FGF13) gene. METHODS: Five Chinese pedigrees found to carry a hemizygous c.-32C>G variant of the FGF13 gene at the Prenatal Diagnosis Center of Henan Provincial People's Hospital between January 2024 and January 2025 were selected as study subjects. The pedigrees had undergone prenatal diagnosis for a family history of genetic disorders, abnormal fetal ultrasound findings, or advanced maternal age. A retrospective analysis was carried out, wherein clinical data for all members of the pedigrees were obtained through the medical records system and outpatient visit system. Peripheral blood samples were collected from all pedigree members, and amniotic fluid samples were obtained from the probands. Following extraction of genomic DNA, prenatal diagnosis was performed using chromosomal microarray analysis (CMA) and trio whole-exome sequencing (trio-WES). Sanger sequencing was used to determine the carrier status for the candidate variant, and Mini-Mental State Examination (MMSE) was used to assess the cognitive function of hemizygous individuals carrying the FGF13 gene c.-32C>G variant. Pathogenicity of candidate variant was assessed based on guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 2021-171). RESULTS: CMA and trio-WES revealed no pathogenic variants in all probands, whilst trio-WES and Sanger sequencing had identified 11 male individuals carrying a hemizygous c.-32C>G variant of the FGF13 gene from the five pedigrees, which included six adult males, a young boy, and four fetuses. One fetus had undergone termination of pregnancy due to hydrocephalus, one was born pre-term at 34+1 weeks of gestation owing to maternal hypertension, and other two were delivered at full term. Follow-up of the survived males revealed no phenotypic manifestations related to language or intellectual impairment. Among these, three adult males underwent the MMSE assessment, all of whom showed normal cognitive function. Search of the gnomAD database suggested the carrier frequency of FGF13 c.-32C>G variant in the East Asian population to be 0.125%, with 11 hemizygous males documented. Three male patients harboring the variant showed severe intellectual disability. Both in vitro and in vivo studies suggested that it could reduce the translation levels of FGF13 protein. Based on the ACMG guidelines, it was classified as variant of uncertain significance (BS4+PS3_Supporting). CONCLUSION: There is insufficient evidence to classify the FGF13 c.-32C>G as a pathogenic variant in clinical practice, and its presence should not be considered an indication for pregnancy termination due to major birth defects.

Adult↗
PubMed2026

Valproate vs levetiracetam in juvenile myoclonic epilepsy: systematic review and meta-analysis.

INTRODUCTION: Juvenile myoclonic epilepsy (JME) is a genetic generalized epilepsy syndrome with onset typically in adolescence and a chronic course requiring long-term antiseizure medications (ASMs). Valproate (VPA) is the most effective treatment for seizure control in JME but use is limited by metabolic, cognitive, and teratogenic adverse effects (AEs). Levetiracetam (LEV) is an alternative ASM when VPA is contraindicated or not tolerated. Comparisons of the efficacy and long-term tolerability of VPA and LEV remain limited. METHODS: We conducted a systematic review and meta-analysis using PRISMA guidelines and the Cochrane Handbook. We searched PubMed, Embase, and the Cochrane Library from inception through January 2026 for studies in JME patients comparing LEV and VPA, and included randomized controlled trials and comparative observational studies with ≥ 6 months of follow-up. Primary outcomes were seizure remission and ASM failure or treatment discontinuation. Secondary outcomes included, memory impairment, weight gain or obesity, dizziness, and overall AEs. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Heterogeneity was assessed using the I2 statistic. RESULTS: Seven studies encompassing 1,009 patients were included. VPA was associated with higher pooled seizure remission rates compared with LEV (344 of 574 vs. 169 of 390; RR 1.44, 95% CI 1.27-1.63); however, substantial heterogeneity (I2 = 88.4%) limits confidence in this finding. VPA was associated with a lower risk of drug failure or treatment discontinuation (RR 0.68, 95% CI 0.54-0.86), with no heterogeneity (I2 = 0.0%). VPA was also associated with a higher risk of memory impairment (RR 5.37, 95% CI 2.05-14.04; I2 = 74.5%) and weight gain or obesity (RR 6.40, 95% CI 3.64-11.26; I2 = 35.9%). No significant differences were observed between treatments regarding dizziness (RR 0.91, 95% CI 0.61-1.37; I2 = 21.2%). Sensitivity analyses confirmed the robustness of the pooled estimates. CONCLUSION: VPA was associated with higher seizure remission rates and lower treatment discontinuation compared with LEV; however, these findings must be interpreted with caution given the substantial heterogeneity, the predominance of observational studies, and the serious risk of bias identified in most included studies VPA also demonstrated lower rates of treatment discontinuation, despite a higher burden of cognitive impairment and weight gain. No relevant differences were observed regarding dizziness. Large-scale randomized trials with standardized outcome definitions and longer follow-up are needed to define the comparative risk-benefit profiles of LEV and VPA in JME.

Humans↗
PubMed2026

ER proteostasis failure in HYOU1 deficiency alters B cells, neutrophils, and interferon signalling.

Hypoxia upregulated 1 (HYOU1) is a stress-inducible ER chaperone. We investigated 2 unrelated patients carrying biallelic HYOU1 variants and presenting with primary immunodeficiency. Patient 1, homozygous for p.Pro444His, displayed failure to thrive, hypoglycemia, B cell lymphopenia, and neutropenia. Patient 2, compound heterozygous for p.Arg262Gln and p.Pro757_Glu758insAla, exhibited recurrent infections, enteropathy, and hypogammaglobulinemia. In Patient 1, while HYOU1 transcription was preserved, the protein was severely reduced. Tunicamycin treatment of dermal fibroblasts showed a blunted unfolded protein response and defective induction of ER stress-responsive genes. Immunophenotyping showed near-absence of circulating B cells, and single-cell RNA sequencing of bone marrow identified an arrest at the pro-B cell stage. Neutrophils displayed hypogranulation and dysregulated IFN- and apoptosis-associated transcriptional signatures, unresponsive to G-CSF. HYOU1 deficiency hence results in ER stress-induced proteostasis failure that simultaneously impairs adaptive immunity through B cell developmental arrest and innate immunity through neutrophil dysfunction and IFN pathway imbalance. This work expands the spectrum of HYOU1 deficiency and further identifies ER proteostasis as a central determinant of immune homeostasis.

Journal Article↗
PubMed2026

The cold case of state transition 7 (stt7) mutants of Chlamydomonas reinhardtii, solved by whole-genome sequencing.

The process of State Transitions (ST) corresponds to an STT7 kinase-driven redistribution of the transmembrane LHCII antenna proteins between Photosystem II (PSII) and Photosystem I (PSI), which results from changes in their phosphorylation state. For the past two decades, two LHCII-kinase mutants, stt7-1 and stt7-9, have been instrumental in the study of STs in Chlamydomonas reinhardtii, the former being a null mutant for the kinase but quasi-sterile in crosses, while the latter, although fertile, has a leaky phenotype. Using long-read sequencing, this study further characterized the genetic lesions of the stt7 mutant strains through whole-genome reconstruction and de novo chromosome assembly. In addition, two new stt7 null mutants were generated, one derived by crosses from the original stt7-1 and one obtained by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (Cas9) technology. This work provides a comprehensive genomic characterization of the original stt7-1 null mutant, revealing extensive chromosomal rearrangements and high levels of aneuploidy, associated with increased cell size and meiotic dysfunction. Reassessment of their physiology and genetic backgrounds highlights the need for caution in interpreting genetic information. We thus produced more reliable null mutants for the LHCII-kinase, amenable to genetic crosses for the study of STs in a variety of genetic backgrounds.

Chlamydomonas reinhardtii↗
PubMed2026

Single-nucleus transcriptomics reveals cell type-specific remodeling and epilepsy-associated microglia.

Temporal lobe epilepsy (TLE) is the most common acquired epilepsy, causing refractory seizures and cognitive deficits. We performed single-nucleus RNA sequencing on hippocampal tissue from mice 3 and 6 weeks following pilocarpine-induced status epilepticus, a robust model of TLE. Epilepsy samples showed reductions in Cck and Lamp5-Lhx6 interneuron subclusters, alongside increases in Cajal-Retzius cells, dentate granule (DG) cell precursors, and a mature DG cell subcluster. Among glia, an astrocyte subcluster and a markedly expanded microglia sublcuster were increased. We term this microglia population epilepsy-associated microglia (EAM). The transcriptomic profile of EAM overlaps with microglia described in models of Alzheimer's disease and traumatic brain injury, including enrichment of Myo1e and Igf1. EAM display amoeboid morphology, can be found in clumps around pyramidal and granule cell body layers, and exhibit enlarged vesicles and mitochondria. Cell-cell interaction analysis predicts DG cells as their primary interaction partners. This dataset defines transcriptomic programs underlying key cellular alterations in TLE, enabling mechanistic dissection of epileptogenesis.

TLE↗
PubMed2026

Epigenetic Gene Networks Governing Immune State Transitions Across the Lifespan.

Immune function across development, tissue repair, aging, and disease depends not only on signaling pathways but also on epigenetic architectures that determine whether coordinated transcriptional programs can be accessed and resolved. Increasing evidence indicates that epigenetic gene networks regulate the accessibility and reversibility of semi-stable immune states, shaping plastic, homeostatic, reparative, and degenerative configurations. We propose the concept of epigenetic transition windows, defined as temporally and contextually restricted intervals during which epigenetic constraints are relaxed, permitting coordinated and reversible transitions between immune states. During development, these windows are broad and support immune tolerance and adaptive plasticity. In adulthood they become spatially and temporally restricted, preserving stability while enabling conditional adaptation. With aging, they progressively narrow, contributing to chronic inflammation, impaired repair, and increased vulnerability to neurodegeneration. Conversely, pathological persistence of regulatory permissiveness may underlie immune evasion and sustained plasticity in cancer. We outline operational genomic readouts for quantifying transition windows, including chromatin accessibility variance, enhancer switching dynamics, reversibility metrics, and cross-cell coordination indices, and derive experimentally testable predictions that distinguish this model from pathway-centric or damage-centric explanations. By reframing immune dysfunction as a failure of regulated state transition rather than excessive signaling alone, this framework integrates inflammaging, trained immunity, immune resolution failure, and tumor immune escape within a unified regulatory architecture and provides a systems-level perspective on immune adaptability across the lifespan.

Epigenesis, Genetic↗
PubMed2026

Beyond risk factors: A capacity framework for cancer survivorship research.

Cancer survivorship research has identified numerous biological, behavioral, psychosocial, health care, and structural factors that influence recovery. However, these factors are typically studied as separate determinants rather than interacting influences. This commentary proposes available survivorship capacity as a unifying framework that explains how these diverse determinants collectively shape recovery and survivorship outcomes. Concepts from geroscience, health care delivery, rehabilitation, occupational therapy, and human factors science were synthesized to develop a conceptual framework of available survivorship capacity. The framework conceptualizes recovery as a function of the capacity remaining after competing health care and life demands draw upon survivors' finite physical, cognitive, emotional, social, financial, temporal, and health care resources. It generates testable propositions for measurement, intervention research, health care delivery, and implementation science while positioning available survivorship capacity as a common mechanism linking diverse determinants of recovery and identifying actionable targets for intervention. Available capacity offers a unifying conceptual framework for understanding heterogeneity in survivorship outcomes and intervention effectiveness while generating a research agenda for future survivorship science. Measuring and strengthening survivors' available capacity, while reducing unnecessary demands, may improve engagement in care, health behaviors, and long-term recovery.

Humans↗
PubMed2026

Urban Design Quality and Clinical Mental Health: A Systematic Review.

ObjectivesThis systematic review synthesizes empirical evidence on core urban design dimensions that affect clinical mental health outcomes and examines how environmental exposures mediate or moderate these relationships.BackgroundUrban design has increasingly been recognized as a determinant of psychological well-being, yet a standardized framework to evaluate its mental health impact remains underdeveloped.MethodsFollowing PRISMA 2020 guidelines, we systematically reviewed 19 quantitative empirical studies published through January 2025, examining relationships between outdoor urban design features and validated clinical mental health indicators across four major databases.ResultsFindings reveal that urban design influences clinical mental health outcomes (depression, anxiety, stress, cognitive decline) through two objective spatial scales: street-level features (imageability, enclosure, human scale, complexity) and neighborhood environments (land use mix, density, green infrastructure). Environmental exposures (traffic, noise, air pollution) operate as perceptual and experiential mechanisms that mediate or moderate the mental health effects of these spatial design features.ConclusionsWe propose an integrated three-domain conceptual framework distinguishing objective spatial design scales from subjective exposure mechanisms. This framework provides evidence-based guidance for urban planners and policymakers toward creating mentally healthier urban environments.

Humans↗
PubMed2026

How the microbiome shapes epigenetic trained memory in neuroinflammation: Implications for neurodegenerative diseases.

Neurodegenerative diseases are increasingly recognized as disorders involving immune dysregulation. However, the mechanisms underlying this dysfunction remain poorly characterized. Trained immunity has recently emerged as a potential contributor to immune dysregulation, particularly in neuroinflammation and neurodegenerative diseases, where trained immunity is the epigenetic reprogramming of innate immune responses following an initial inflammatory stimulus, which increases responses to subsequent exposures. In parallel, although the brain has traditionally been viewed as an immune-privileged organ, growing evidence indicates that peripheral immune activity exerts significant influence on neuroinflammation in the brain. A major driver of peripheral immunity is the microbiome. Therefore, this perspective aims to present a conceptual framework for a relationship between the microbiome, trained immunity, and neurodegenerative diseases. We first summarize evidence of trained immunity in the brain and its role in neurodegeneration. Next, we highlight the role of the microbiome in peripheral immune modulation and in trained immunity. Finally, we propose potential mechanisms through which the microbiome may induce or modulate trained immunity in the brain. These include: 1) immunogenic microbial metabolites that cross the blood-brain barrier and alter host cell epigenetics; 2) migration of peripherally trained myeloid cells into the brain; 3) viral infection-induced trained immunity that may predispose to neurodegeneration. Together, this perspective suggests that microbiome-induced trained immunity offers a novel mechanism linking peripheral immune regulation with neuroinflammation and neurodegeneration with implications for therapeutic targeting of epigenetic modification as a molecular prevention strategy for progression of neurodegeneration.

Humans↗
PubMed2026

Cross-tissue multi-omics integration highlights BPHL and mitochondrial targets in Alzheimer's disease.

BACKGROUND: Mitochondrial dysfunction is a hallmark of Alzheimer's disease (AD), yet specific molecular targets remain to be fully characterized. METHODS: A summary-data-based Mendelian randomization (SMR) framework integrated AD genome-wide association study (GWAS) statistics (39,918 cases) with blood DNA methylation quantitative trait loci (mQTL), gene expression (eQTL), and protein (pQTL) data for 1136 mitochondria-related genes. Associations were assessed using Bayesian colocalization and HEIDI testing. Tissue relevance was evaluated in four brain regions (hippocampus, amygdala, cortex, frontal cortex) using GTEx and external transcriptomic datasets. RESULTS: Screening identified eight candidates supported across blood mQTL and eQTL layers. Stepwise central nervous system (CNS) evaluation singled out biphenyl hydrolase-like (BPHL) as the consistent candidate. Higher genetically predicted BPHL expression was associated with reduced AD risk across the hippocampus (OR=0.920, 95% CI 0.873-0.970), amygdala (OR=0.925, 95%CI 0.880-0.973), cortex (OR=0.943, 95% CI 0.908-0.978), and frontal cortex (OR=0.938, 95%CI 0.901-0.976). These findings aligned with protein-protein interactions connecting BPHL to respiratory complexes and lower BPHL expression in independent AD brains. Functional enrichment converged on oxidative phosphorylation pathways. CONCLUSIONS: By integrating multi-omics data with tissue-specific validation, this study nominates BPHL as a consistent protective candidate in the brain. These findings provide genetic support for mitochondrial molecular perturbations in AD, offering insights for future validation.

Alzheimer Disease↗
PubMed2026

Hippocampal teneurin-4 knockdown promotes depression-like behavioral phenotypes by disrupting oligodendrocyte differentiation in mice.

Depression is one of the most prevalent mental disorders worldwide. The limited clinical efficacy of current antidepressants highlights identifying new therapeutic targets. Emerging evidence suggests that dysfunction of oligodendrocyte lineage cells contributes to the pathophysiology of depression. Teneurin-4 (Tenm4), a transmembrane protein that promotes oligodendrocyte differentiation and myelination, has been implicated in psychiatric disorders in genome-wide association studies; however, its causal role remains unclear. To determine whether Tenm4 contributes to depressive-like behavioral phenotypes, we examined Tenm4 protein expression in mice exposed to repeated forced swimming stress and generated hippocampal Tenm4 knockdown (Tenm4KD) mice. Chronic stress reduced Tenm4 expression levels in the hippocampus. Mice with hippocampus-specific Tenm4KD exhibited depressive-like behaviors, accompanied by reduced hippocampal myelin basic protein. Importantly, administration of clemastine, a myelin formation promoter, inhibited the reduction of myelin and attenuated depression-like behavioral phenotypes. Immunohistochemical analysis showed that Tenm4KD significantly decreased the number of mature oligodendrocyte cells and increased in the number of oligodendrocyte precursor cells, without changes in the total number of oligodendrocyte lineage cells. This study provides the first evidence that hippocampal Tenm4 deficiency induces depression-like behavior phenotypes through impaired oligodendrocyte differentiation and promoting demyelination. Our results identify Tenm4 as a molecular regulator of stress-induced behavioral phenotypes and suggest that it might represent a potential therapeutic target for mood disorders associated with demyelination.

Animals↗
PubMed2026

Evaluation of Physical and Mental Workload and Transfusion Time in Trauma Resuscitation.

BACKGROUND: Trauma resuscitation is time sensitive and complex. Whole blood (WB) and blood components are standard treatments for trauma related hemorrhage, yet their nursing workload and transfusion time have not been well evaluated. PURPOSE: To assess feasibility of a simulation-based crossover trial and obtain preliminary estimates comparing nursing workload and transfusion completion time between WB and blood component administration. METHODS: A randomized crossover pilot study using in situ simulation was conducted with experienced trauma nurses. Time-motion analysis measured transfusion completion time, and the National Aeronautical and Space Administration Task Load Index assessed workload domains. RESULTS: Strong feasibility was demonstrated across recruitment, retention, adherence, and completion. WB was associated with significantly shorter transfusion time, lower overall workload and mental demand, less effort, and better perceived performance. CONCLUSIONS: These findings support the feasibility and justify a fully powered trial. WB may improve resuscitation efficiency and reduce cognitive burden, with potential implications for patient outcomes and nursing workflow.

Humans↗
PubMed2026

Biliary Cirrhosis in Myhre Syndrome: The First Case Report of Liver Transplantation and a Review of Reported Hepatic Findings.

Myhre syndrome is a rare autosomal-dominant disorder caused by gain-of-function pathogenic variants in SMAD4 and is now recognized as a progressive multisystem fibrotic disease. Although transforming growth factor-β (TGF-β) signaling plays a central role in hepatic fibrogenesis, hepatobiliary involvement in Myhre syndrome has not been systematically evaluated. We report the first case of Myhre syndrome complicated by rapidly progressive biliary cirrhosis requiring liver transplantation in a 15-year-old male with a confirmed SMAD4 p.Ile500Val variant. Following an infectious episode, the patient developed severe cholestasis with imaging and histopathologic findings consistent with fibro-obliterative cholangiopathy, ultimately necessitating living donor liver transplantation. A systematic review of 55 published reports comprising 217 patients with Myhre syndrome revealed that hepatic evaluation was rarely performed and that previously reported liver abnormalities were mild and secondary, most commonly related to right heart dysfunction or metabolic disease, with no prior cases of progressive biliary fibrosis. This case suggests that dysregulated SMAD4-TGF-β signaling may predispose selected organs to fibro-obliterative injury and that infection-driven inflammation may act as a critical trigger for hepatic fibrosis in Myhre syndrome, expanding the recognized spectrum of organ involvement in this disorder.

Humans↗
PubMed2026

Decoding tumor immune microenvironment heterogeneity by single-cell and spatial multi-omics: From immunotherapy resistance to translational biomarkers.

Immune checkpoint blockade has transformed cancer therapy, yet primary and acquired resistance remain major clinical challenges. Increasing evidence indicates that immunotherapy resistance cannot be fully explained by tumor-intrinsic alterations or conventional biomarkers such as PD-L1 expression, tumor mutational burden, or microsatellite instability. Instead, therapeutic response is shaped by the tumor immune microenvironment (TIME) as a heterogeneous, spatially organized, and dynamically evolving ecosystem. Single-cell omics has revealed diverse immune and stromal cell states, including progenitor and terminally exhausted T cells, suppressive myeloid programs, B-cell/TLS-associated immune-reactive states, and CAF-mediated exclusion phenotypes. Spatial transcriptomics, spatial proteomics, and imaging-based approaches further demonstrate that these cell states assemble into distinct immune niches, including immune-inflamed, T-cell-excluded, myeloid-suppressive, metabolic/hypoxic, and TLS-associated niches. These spatial ecosystems determine whether antitumor immune cells can access malignant cells, receive antigen-presenting support, or become restrained by stromal, vascular, metabolic, and myeloid barriers. In this review, we summarize how single-cell and spatial multi-omics redefine TIME heterogeneity in immunotherapy resistance, highlight ligand-receptor communication networks linking cell states to spatial immune dysfunction, and discuss emerging translational biomarkers for patient stratification. We further propose that future immunotherapy biomarkers should evolve from static single-marker assays toward longitudinal, spatially resolved, and interpretable multi-omics models that guide precision combination immunotherapy.

Humans↗
PubMed2026

Maternal transfer of nonylphenol drives oxidative, immune, and epigenetic dysregulation in zebrafish offspring.

Nonylphenol (NP), a widespread surfactant and endocrine-disrupting pollutant, poses significant ecological and public health risks globally; however, its transgenerational effects remain poorly understood. Using zebrafish (Danio rerio), we compared chronic maternal NP exposure (50 and 100 µg/L, 28 days) with acute embryonic exposure (0.22 µmol/L) during 0-3 days post-fertilization (dpf) to delineate mechanistic differences in toxicity. Maternal NP exposure produced severe developmental defects in offspring, including edema, axial curvature, impaired swim bladder inflation, reduced growth, cardiac dysfunction, and decreased viability. These phenotypes were accompanied by systemic molecular disruptions including oxidative stress, altered estrogen receptor (ER) expression, dysregulated mitogen-activated protein kinase (MAPK) signaling, and suppressed innate immune response characterized by attenuated neutrophil/macrophage density, reduced CD68 and complement protein C3 expression, diminished nitrite load, and downregulation of pro-inflammatory mediators at both transcript and protein levels. Maternal exposure further induced apoptosis and persistent epigenetic reprogramming (alterations in DNA methylation and histone-modifying enzymes), hallmarks of transgenerational toxicity. In contrast, direct embryonic NP exposure elicited morphological abnormalities without significant lethality, accompanied by induction of pro-inflammatory cytokines, nitric oxide (NO) synthesis, and MAPK activation, reflecting an augmented inflammatory response. These mechanistic contrasts reveal that maternal NP exposure is a potent driver of systemic, heritable molecular reprogramming, whereas embryonic exposure triggers acute inflammatory pathways. Together, our findings underscore the global relevance of NP as a transgenerational toxicant, advocating for its urgent inclusion in ecotoxicological risk assessments and regulatory frameworks.

Animals↗
PubMed2026

Bacteroides cellulosilyticus-derived 2-hydroxyphenylacetic acid rectifies hepatic lipid homeostasis in MASLD by targeting the PPARγ-CD36 axis.

The gut microbiota plays an important role in the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD), but the specific molecular mechanisms involved have not been fully elucidated. In this study, human cohort studies were performed to identify that the relative abundance of Bacteroides cellulosilyticus (B. cellulosilyticus) was significantly decreased in patients with MASLD. Through the integration of metagenomic and metabolomic analyses, it was confirmed that B. cellulosilyticus and its metabolite 2-hydroxyphenylacetic acid (2HPAA) are key factors regulating the occurrence and development of MASLD. Single-cell sequencing and lipidomic analyses revealed that 2HPAA can enter the liver through the enterohepatic circulation to exert regulatory effects. Specifically, 2HPAA inhibits the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, thereby suppressing the expression of the fatty acid transporter CD36. Meanwhile, 2HPAA regulates lipid metabolism in hepatocytes by significantly enhancing palmitate conversion efficiency and inhibiting CD36 palmitoylation. This dual regulatory effect on CD36 expression and palmitoylation can reduce lipid accumulation in hepatocytes and ultimately alleviate MASLD progression. These findings reveal the mechanism by which B. cellulosilyticus and 2HPAA alleviate MASLD by targeting the PPARγ-CD36 pathway. This work provides a new perspective for the study of gut microbiota-host interactions in regulating liver diseases.

PPAR gamma↗
PubMed2026

Measurable Residual Disease and the Unresolved Biology of Leukemic Stem Cells.

Measurable residual disease (MRD) testing has transformed the management of hematologic cancers by enabling detection of residual malignant cells after therapy. Current approaches rely on qPCR and next-generation sequencing to monitor leukemia-associated somatic mutations, while multiparameter flow cytometry identifies aberrant leukemic immunophenotypes. Although these methods provide valuable prognostic and therapeutic information, MRD negativity remains an imperfect surrogate for cure. Most MRD platforms evaluate CD45+, rapidly dividing leukemic populations and fail to detect quiescent cells that may survive cytotoxic therapies which efficiently target proliferating hematopoietic cells. Relapse frequently occurs despite deep molecular remission, suggesting persistence of rare leukemic stem cells (LSCs) that are intrinsically resistant to chemotherapy and targeted therapies. The paradox of relapse despite molecular remission could be explained by the presence of very small embryonic-like stem cells (VSELs) which are pluripotent, quiescent stem cells sitting at the top of cellular hierarchy in multiple adult tissues including bone marrow. A pluripotent VSEL divides through asymmetrical cell division to give rise to two cells of different sizes and fates, smaller cell is to self-renew while the bigger is lineage-restricted and tissue-committed progenitor which undergoes extensive epigenetic changes, divides rapidly and undergoes clonal expansion before further differentiation. Dysfunctions of VSELs initiate both solid and hematologic cancers. Based on this view, somatic mutations monitored during MRD assessment possibly represent downstream consequences of clonal expansion rather than the initiating drivers of disease persistence. Thus, exclusive monitoring of somatic mutations and CD45 + leukemic populations possibly overlook rare, small-sized, CD45- VSELs that contribute to therapeutic resistance and relapse.

Humans↗
PubMed2026

A systematic review of macaque brain stimulation: Trends and future directions.

Neurostimulation techniques can powerfully modulate neural circuit activity and provide causal insights into the relationship between brain function and behavior. Macaque monkeys have long been a key animal model for brain stimulation studies. While stimulating the macaque brain with one or a few electrodes has already taught us much about brain function and dysfunction, recent technological advances promise a future with more precise stimulation using many more electrodes. However, such possibilities also increase the number of choices an experimenter has when designing their study. We can learn from a rich past, but a comprehensive overview of which brain regions have been studied and with what stimulation parameters is lacking. Here, we present a PRISMA-compliant systematic review of 734 macaque brain stimulation studies using electrical and/or optogenetic stimulation. We find a striking bias in which brain areas have traditionally been stimulated: a mere 10 brain regions account for half of all studies, with the remainder of studies investigating approximately 150 other areas. Across studies, stimulation frequency robustly predicted direct behavioral effects independent of brain region, while amplitude did not. Future studies could more systematically explore less studied regions through lower stimulation frequencies (e.g., 20-50 Hz) alongside established ranges (∼200 Hz). Tools such as fMRI or optical imaging can capture neural circuit engagement evoked by these frequencies, even when behavioral effects are absent or remain subtle. Our synthesis offers a guide towards the next steps in high-channel-count, high-precision stimulation approaches.

Animals↗