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Limited targeted agents are approved for pediatric sarcomas. Tyrosine kinase (TK) inhibitors have shown clinical efficacy in some, but not all, young sarcoma patients. A major obstacle preventing further advances and clinical implementation is the lack of predictive response biomarkers to guide TK-targeted treatments. TK-activating fusions or mutations are rare in these patients. RNA overexpression of TKs is a frequent feature. The unresolved question is when upregulated TK expression is associated with kinase activation and signaling dependence. We explored the TK molecular landscape of 107 sarcoma patients from the ZERO Childhood Cancer precision medicine program (ZERO) using whole genomic and transcriptomic sequencing. Phosphoproteomic analyses of tyrosine phosphorylation (pY) and functional in vitro and in vivo assays were performed in cell lines and patient-derived xenografts (PDXs). Our analysis shows that although novel genomic driver lesions are rare, when present they are therapeutically actionable as exemplified by a novel LSM1-FGFR1 fusion identified in an osteosarcoma patient. We further show that in certain contexts, TK RNA expression can indicate TK pathway activity and predict TK-inhibitor sensitivity. We highlight the utility of FGFR-inhibitors in PAX3-FOXO1 fusion-positive rhabdomyosarcomas (FP-RMS) characterized by high FGFR4 and FGF8 RNA expression levels, and FGFR4 activation (FGFR4_pY). We demonstrate marked tumor growth inhibition in all FP-RMS PDXs treated with single agent FGF401 (FGFR4-specific inhibitor) and single agent lenvatinib (multi-kinase FGFR-inhibitor), and report a clinical response to lenvatinib in a relapsed metastatic FP-RMS patient. Altogether, we identified new sarcoma patients who may benefit from FGFR-inhibitors, most notably FP-rhabdomyosarcoma via FGFR4/FGF8 co-expression. Show less

Psychiatric disorders, including bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ), share substantial genetic overlap. We conducted a cross-ancestry multivariate genome-wide association study (GWAS) integrating European and East Asian populations to uncover shared genetic underpinnings. Our analyses identified 403 loci associated with shared polygenic liability to psychiatric disorders, including 88 novel regions. Cross-ancestry fine-mapping highlighted robust shared signals, notably at VRK2 (rs7596038), consistently significant across ancestries. Gene prioritization revealed 90 high-confidence candidate genes enriched in neurodevelopmental pathways. Single-nucleus RNA sequencing implicated excitatory neurons and astrocytes as key cellular contexts, emphasizing NCAM1-FGFR1 and NEGR1-NEGR1 signaling pathways. Mendelian randomization analyses provided causal evidence linking shared genetic liability to structural brain alterations, particularly in regions crucial for emotion and cognition. Polygenic risk scores derived from shared genetic liability substantially enhanced predictive accuracy for BD and SCZ, demonstrating strong trans-ancestry validity. These results advance understanding of shared genetic architecture in psychiatric disorders, highlighting potential therapeutic targets and emphasizing the critical importance of diverse ancestry studies in precision psychiatry. Show less

Type 2 diabetes mellitus (T2DM) requires multi-target therapeutic approaches addressing both insulin resistance and insulin secretion deficits. Although natural compounds are promising multi-target candidates, systematic identification of their polypharmacological profiles remains challenging. The objective of this study was to establish a computational framework for identifying natural compounds with multi-target therapeutic potential against T2DM through integrated structure-activity analysis and experimental validation. We developed an SELFormer deep learning model to predict natural compound activities against six T2DM-related proteins including glucagon-like peptide-1 receptor (GLP1R), kinesin family member-11 (KIF11) for insulin secretion and insulin receptor (INSR), peroxisome proliferator-activated receptor-gamma (PPARG), fibroblast growth factor receptor-1 (FGFR1) and insulin-like growth factor-1 receptor (IGF1R) for insulin resistance. Uniform Manifold Approximation and Projection (UMAP) for dimension reduction clustering characterized chemical space distributions and molecular docking validated multi-target binding. Selected compounds were experimentally validated using 3T3-L1 adipocytes and mouse insulinoma (MIN6) pancreatic β-cells. The SELFormer model achieved Show less

Diet-based modulation of the gut microbiota has emerged as a promising strategy to alleviate obesity and its related complications. Our previous study demonstrated that polysaccharide derived from Cordyceps militaris (CMP) exerts anti-obesity effects, yet the specific mechanism linking gut microbiota to its metabolic impact remains unclear. Herein, we utilized murine models with distinct gut microbial profiles created via antibiotic cocktails to investigate these mechanisms. The protective effects of CMP against high-fat diet (HFD)-induced obesity and associated metabolic disturbances were substantially impaired in mice depleted of neomycin-sensitive gut bacteria. Metagenomic analyses further established that CMP required these bacteria to restore gut microbial homeostasis. Notably, we observed that CMP elevated hepatic levels of brassicasterol in a manner dependent on neomycin-sensitive gut bacteria. Brassicasterol treatment alone replicated the anti-obesity effects of CMP, as indicated by reduced body weight gain, improved lipid and glucose metabolism, and decreased inflammation. Through transcriptomic and functional analyses, we identified hepatic Apoa4 as a key downstream effector of brassicasterol. Our results indicated that brassicasterol upregulated Apoa4, facilitating lipid transport and suppressing inflammation both in vitro and in vivo. Collectively, our findings indicate that CMP exerts its anti-obesity effects through a neomycin-sensitive gut bacteria-brassicasterol-Apoa4 pathway. This work expands the mechanistic understanding of CMP and highlights a novel microbiota-metabolite-host regulatory axis for dietary intervention in metabolic disorders. Show less

Long-term alcohol consumption drives systemic damage through metabolites such as acetaldehyde, which trigger oxidative stress, inflammation, and gut dysbiosis. This study evaluated the protective effects of fermented red quinoa (FRQ) in an alcohol-exposed mouse model, with a focus on cognitive function. Male C57BL/6J mice were randomized into three groups for a 28-day study: a normal control, an alcohol-treated group gavaged with ethanol (1 mL/100 g·BW), and a group receiving the same ethanol dose co-administered with FRQ powder (human equivalent dose: 9 g/60 kg·BW). Our results demonstrated that fermentation with Lactobacillus kisonensis significantly increased the content of phenolic compounds (e.g., quercetin and veratric acid) in FRQ. FRQ intervention improved cognitive function, ameliorated synaptic structural impairment and blood-brain barrier disruption, and attenuated hepatic steatosis. The protective mechanisms involved three pathways: 1) The specific phenolic compounds in FRQ promoted alcohol metabolism by regulating ADH/ALDH activity, leading to reduced acetaldehyde levels. As a primary initiating pathway, this metabolic enhancement dominantly attenuated subsequent oxidative stress and inflammation, mitigating injury in the liver, brain, and colon. 2) It directly modulated AP-1 subunits (ΔFOSB/JUND), restored BDNF, and rebalanced the glutamate/GABA systems. 3) It regulated the gut-liver-brain axis by remodeling the gut microbiota (e.g., enriching butyrate-producing Butyricicoccus), reinforcing intestinal barrier integrity, and thereby suppressing systemic LPS translocation and inflammation. In conclusion, FRQ mitigates alcohol-induced cognitive and hepatic damage via multiple mechanisms, highlighting its promise as an integrative dietary intervention. Show less

West Nile virus (WNV), an arbovirus of emerging global interest, can cause neuroinvasive disease in humans. Currently, no protective vaccine or specific treatment is available for human WNV encephalitis. The virus induces neuronal cell death, while astrocytes and microglia cells are suspected to contribute to WNV pathology. Hence, understanding their role is crucial for future treatment approaches. In this study, we establish a WNV encephalitis model using human cerebral organoids, generated with male iPSCs. Infection results in heterogeneous kinetics with an early strong replication potentially leading to viral clearance, while a late peak was associated with more long-term infection. Viral foci are seen in cortical-like areas, rich in neurons and astrocytes, however void of microglia. Pro-inflammatory cytokines (IL-6, TNF-α, IL-18), chemokines (CXCL10, CCL17, CX3CL1, CCL2) and biomarkers (IL-1RA, sTREM-1, sRAGE, BDNF) are increasingly released. Conclusively, human cerebral organoids make suitable WNV encephalitis models with valuable properties to study acute and long-term infection. Show less

Snacktivity—brief, high-frequency bouts of moderate-to-vigorous physical activity (MVPA) integrated into daily routines—may interrupt prolonged sitting and help accumulate total activity. Step count is a practical proxy for this pattern, yet the cadence thresholds that map short-bout stepping to MVPA and the relevance of bout–cadence patterns to adiposity remain unclear. This study aimed to examine the associations between accelerometer-derived step metrics and adiposity and to identify pragmatic step-based thresholds in older women. We conducted a cross-sectional study of 1,109 community-dwelling older women in Yantai, Shandong Province, China, with a mean age of 64.93 years (SD = 2.82). Step-based metrics (daily steps, MVPA and light-intensity physical activity (LPA) steps, cadence, and bout patterns) were derived from a waist-worn triaxial accelerometer. adiposity was defined using body-fat-ratio (BFR) categories assessed by multi-frequency bioelectrical impedance analysis. Multiple linear regression estimated associations with progressive adjustment for sociodemographic, lifestyle, and health-related covariates, with additional adjustment for total sedentary time. Sensitivity analyses replaced BFR with BMI and examined visceral fat mass (VFM) using linear regression. Receiver operating characteristic (ROC) analyses identified pragmatic step and cadence cut-points. MVPA step counts and cadence were consistently and inversely associated with adiposity ( Among older women, MVPA-oriented step metrics—particularly ~ 1,846 MVPA steps/day and ~ 94.3 steps/min cadence—showed inverse associations with adiposity and outperformed LPA metrics. These thresholds may serve as pragmatic, low-barrier activity targets, but causal relationships require confirmation in longitudinal and experimental studies. The online version contains supplementary material available at 10.1186/s12889-026-26912-5. Show less

Alginate oligosaccharides (AOS) have recently shown promising activities in inhibiting tumour growth in osteosarcomas. It is, however, unknown if AOS is also effective against nasopharyngeal carcinoma (NPC). To this end, the antiproliferation activities of enzymatically derived AOS were investigated against the EBV-positive NPC cell line, C666-1. MTT cytotoxicity assays revealed an antiproliferation effect against the C666-1 cell line, albeit at concentrations above 10 mg/mL, but promoting growth at lower concentrations. As a potential heparin sulfate analog, which also demonstrates a similar biphasic effect on cell proliferation, it was hypothesized that AOS may act on fibroblast growth factors (FGFs) and their receptors (FGFR) like heparin. This hypothesis was supported by in silico molecular docking, which discovered a similar binding pattern between AOS pentasaccharide and heparin pentasaccharide on FGF2, FGFR1 and FGF2-FGFR1 complex. Furthermore, all-atomic molecular dynamics simulations revealed that only the AOS pentasaccharide can pre-form the FGFR1 dimer for binding by FGF2 when one AOS molecule per FGFR1 dimer was simulated, while other AOS models (DP2-DP4) deformed the FGFR1 dimer to disfavour FGF2 binding during the simulations. In contrast, all AOS models (DP2-DP5) deformed the FGFR1 dimer when two AOS molecules per FGFR1 dimer were simulated without FGF2. These results suggest that the observed biphasic effects on cell proliferation by the AOS mixture may be attributed to the binding of the AOS pentasaccharide to the FGFR1/FGF2 proteins, although further experiments to validate this in silico observation are warranted. Show less

Juvenile idiopathic arthritis (JIA) is the most common childhood chronic arthritis, and pain may persist despite controlled inflammation, potentially due to central sensitization. This study aimed to evaluate the effects of very early-onset arthritis on pain, behavior, and cognition using a collagen-induced arthritis model in juvenile rats. Thirty-six three-week-old male Wistar rats were divided into control, sham (saline), and arthritis (type II collagen with incomplete Freund's adjuvant) groups. Disease severity was monitored via joint thickness and VAS. Pain (hot plate, Randall-Selitto), behaviors (EPM, MFST), and cognition (PAT) were assessed. Locomotor activity was assessed. Joints were analyzed histologically (H&E); hippocampal BDNF and TNF-α were examined immunohistochemically. Arthritis severity progressed over six weeks, with increased joint thickness and VAS scores in the arthritis group (p < 0.05). Mechanical hyperalgesia showed a paw- and time-dependent pattern, with earlier changes in some paws and more consistent reductions during the late phase (weeks 4-6). Locomotor activity did not differ among groups, indicating no motor deficits. The arthritis group exhibited greater anxiety (EPM, p = 0.001) and depression-like behavior (FST, p = 0.004), while cognition (PAT) remained unaffected. Hippocampal TNF-α increased, whereas BDNF was unchanged. Very early-onset arthritis is associated with mechanical hyperalgesia and emotional disturbances, accompanied by hippocampal TNF-α alterations, and exhibits features consistent with central sensitization, without significant effects on cognition or hippocampal BDNF expression. Early juvenile arthritis showed mild severity with delayed mechanical hyperalgesia. Thermal hyperalgesia and locomotor deficits were not observed in arthritic rats. Hippocampal TNF-α increase was linked to anxiety and depression-like behaviors. Hippocampal BDNF levels remained stable, suggesting intact learning processes. Show less

To characterize whole-brain cortical thickness alteration in Kallmann syndrome (KS), assess its correlation with cognitive impairment, and explore the genetic association and extrapolated transcriptional underpinning. We prospectively recruited 100 patients with KS and 100 age- and sex-matched healthy controls. All participants underwent high-resolution structural MRI and a comprehensive neuropsychological assessment targeting global cognition (Montreal Cognitive Assessment, MoCA), executive function and inhibitory control (Stroop Color and Word Test, SCWT), cognitive flexibility (Trail Making Test, TMT), working memory (Digit Span Test, DST), and visuospatial memory (Visual Reproduction task, VR). Cortical thickness and subcortical volumes were quantified using FreeSurfer. In the KS cohort, we examined brain-cognition correlations, performed exploratory genetic association analysis using whole-exome sequencing, and conducted extrapolated neuroimaging-transcription analysis using the Allen Human Brain Atlas (http://human.brain-map.org/) to identify underlying biological pathways. Compared to the healthy controls, patients with KS exhibited significant cognitive deficits, with 36% MoCA scoring below the clinical cutoff for cognitive impairment. Domain-specific analysis revealed impairments in SCWT-C, DST-Backward, TMT-B, and VR (all P-value < .05). Structurally, patients showed bilateral increased cortical thickness predominantly in the fronto-limbic circuit (orbitofrontal and subgenual cingulate cortices) and default mode network (voxel P-value < .001, cluster random field theory corrected P-value < .05), alongside bilateral hippocampal enlargement (P-FDR = .048). Crucially, the cortical thickness in these fronto-limbic regions was negatively correlated with SCWT-C and DST. Exploratory genetic analysis linked variants in genes such as OTUD4 and FGFR1 to cognitive variability (TMT-A and VR). Furthermore, the spatial pattern of cortical thickening was significantly associated with extrapolated gene expression profiles enriched for neurodevelopment, neuronal migration, and synaptic function. This study identified cortical thickening involved in fronto-limbic and default mode network as key neuroanatomical signatures of the patients with KS, which was associated with cognitive impairment. Specific genetic variants may further modulate the structural alterations and cognitive functioning in patients with KS. Show less

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired communication, abnormal social interactions, and restricted, repetitive behaviors. Pathogenic mutations in UBE3B result in neurodevelopmental disease, including intellectual disability, lack of speech, and ASD. UBE3B is an E3 ubiquitin ligase that tags substrate proteins with ubiquitin, marking them for proteasomal degradation. The ubiquitin-proteasome system (UPS) regulates several signaling pathways critical for neurodevelopment, including neurogenesis and synaptogenesis, and mutations in various UPS genes have been identified in ASD and related neurodevelopmental disorders. To investigate the function of UBE3B in the brain and how its disruption gives rise to neurodevelopmental abnormalities, we generated a central nervous system-specific conditional Ube3b knockout (cKO) mouse model and evaluated the resulting neurobehavioral phenotypes. We found that Ube3b cKO mice exhibit severe deficits in vocalization, social behavior, learning and memory, and motor skills. Assessment of in vivo neuronal phenotypes revealed defects in dendritic morphogenesis, reduced excitatory synapse density, diminished spontaneous cortical circuit activity, decreased AMPA receptor surface expression, and hyperexcitability of excitatory cortical neurons. Using quantitative proteomics, we profiled the proteome and ubiquitome of neural stem cells and identified 116 proteins that exhibited increased protein levels and reduced ubiquitination following loss of UBE3B. These proteins were highly enriched for ones involved in synaptic processes, and we confirmed interaction of UBE3B with several key synaptic proteins, including ATP1A1, DOCK7, NLGN2, and STX12. Collectively, our findings identify a role for UBE3B in regulating social, cognitive, and motor functions, and neuronal morphogenesis and activity by fine-tuning the synaptic proteome. Show less

To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies. Twenty-four patients with concern for NS underwent clinical and central radiological review in this multi-institutional study. Whole-exome sequencing, RNA sequencing, and methylation analyses of peripheral blood and/or tumor specimens were performed. Nineteen (79%) of 24 participants had NS, 17/19 (89%) of which had a germline Show less

Schizophrenia is a severe mental disorder whose molecular mechanisms remain poorly understood. Investigating brain-derived neurotrophic factor (BDNF)-dependent signaling pathways and their contribution to schizophrenia pathogenesis is a promising research direction in schizophrenia research. BDNF activates multiple intracellular cascades, among which the MAPK/ERK pathway plays a central role. In this study, expression levels of key regulatory proteins of the MAPK/ERK signaling pathway (ERK1/2, STAT3, STAT5, NF-κB, IGF1R, IRS1, IR, TSC2, and CREB1) were examined in lysates of peripheral blood mononuclear cells (PBMCs) from schizophrenia patients using multiplex analysis. The study group included 58 patients diagnosed with schizophrenia (F20); the control group included 60 healthy individuals. The results revealed significantly increased expression of ERK1/2 and STAT3, along with decreased NF-κB levels, in PBMCs from schizophrenia patients compared to controls. Moreover, patients with leading positive symptoms exhibited elevated expression of CREB1 and ERK1/2. These findings suggest that dysregulation of the MAPK/ERK signaling may play a significant role in the pathogenesis schizophrenia. BDNF-dependent signaling pathways may therefore represent promising targets for diagnostics and therapy of this disorder. Show less

Lipoprotein(a) [Lp(a)] is a genetically determined, proatherogenic, and prothrombotic lipoprotein associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Elevated Lp(a) levels are associated with progressive ASCVD even when guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets are achieved under optimal lipid-lowering therapy. There is currently no approved pharmacological therapy specifically targeting Lp(a) reduction in routine clinical practice; therefore, current management strategies for patients with elevated Lp(a) primarily focus on aggressive control of modifiable cardiovascular risk factors and intensive LDL-C lowering. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide a modest reduction in Lp(a) levels and have been associated with greater cardiovascular benefit in patients with high baseline Lp(a); however, this degree of reduction is often insufficient in individuals with markedly elevated Lp(a) levels and progressive ASCVD. At present, lipoprotein apheresis remains the only therapeutic option capable of achieving substantial and sustained reductions in Lp(a) concentrations and is recommended in selected high-risk patients with progressive ASCVD despite optimal medical therapy. Meanwhile, Lp(a)-specific therapies, including antisense oligonucleotides and small interfering RNA agents, are in advanced clinical development and have shown marked reductions in Lp(a) levels in early phase trials. These emerging therapies are expected to significantly change future treatment strategies for patients with Lp(a)-driven residual cardiovascular risk. Show less

Short-chain fatty acids (SCFAs) are key microbial metabolites that support intestinal and skeletal development, yet their coordinated effects during early life remain poorly defined. In this study, neonatal mice were administered SCFAs for 28 days to evaluate their impacts on growth, intestinal barrier integrity, immune modulation, bone development, and gut microbiota composition. Valerate supplementation significantly increased body weight and intestinal length. It enhanced the villus structure, crypt depth, and goblet cell number, alongside upregulation of tight junction and mucin genes, indicating improved barrier function. Valerate and propionate also promoted the expression of interleukin-4 (IL-4) and interleukin-10 (IL-10) and reduced pro-inflammatory cytokines, suggesting an immunomodulatory shift. In the skeletal system, valerate improved the microarchitecture, increased bone mineral density (BMD), and upregulated osteogenic genes runt-related transcription factor 2 (Runx2), fibroblast growth factor receptor 1 (FGFR1), and growth hormone receptor (GHR). Microbiota profiling showed enrichment of several genera ( Show less

Overactive bladder (OAB) syndrome, characterised by urinary urgency, frequency, and nocturia can significantly impacts patients' quality of life. Current diagnosis is clinical, but complex cases often require invasive urodynamic studies (UDS), which are costly, subjective, and carry risks like discomfort and infection. Therefore, we hypothesise that urinary biomarkers could serve as noninvasive diagnostic tools for OAB. Establishing a reliable biomarker profile could ultimately lessen the reliance on invasive US, provided clinical validity is confirmed. Following PRISMA guidelines and registered under PROSPERO (ID: CRD420251026279), a comprehensive search across six major databases was conducted from their inception until September 2025, yielding 39 studies for qualitative analysis. This qualitative review identified several promising biomarkers for OAB diagnosis. Notably, NGF and BDNF consistently emerged as elevated in OAB patients and were responsive to treatment. Additionally, TNF-α, MIP-1β, Tie2, and CCL2 showed diagnostic potential, with TNF-α and MIP-1β particularly useful for differentiating OAB from interstitial cystitis/bladder pain syndrome (IC/BPS) and urinary tract infections (UTIs). However, limitations such as variability in measurement protocols and a lack of specificity for certain biomarkers (e.g. MMP-1, 8-OHdG) were noted. Urinary biomarkers offer a promising noninvasive approach to diagnosing OAB. Further validation of promising markers, particularly NGF, BDNF, TNF-α, MIP-1β, and CCL2, could lead to individualised therapies. While promising, the routine replacement of UDS remains an aspirational goal dependent on future large-scale validation. Show less

Since apolipoprotein E4 (ApoE4) is associated with therapy-related adverse effects of anti-amyloid-β monoclonal antibodies in Alzheimer's disease, such as amyloid-related imaging abnormalities, methods for determining the ApoE4 status are needed. The Lumipulse Plasma and serum obtained from a single blood draw from 157 patients were analyzed using ApoE4 and Pan-ApoE chemiluminescent enzyme immunoassays. The ApoE4, Pan-ApoE, and the resulting ApoE4/Pan-ApoE ratio showed minimal bias, strong positive correlation and linearity between plasma and serum. Using matrix-specific thresholds, plasma- and serum-derived ApoE4/Pan-ApoE ratios accurately classified the ApoE4 phenotypes in concordance with Using matrix-specific thresholds, the ApoE4/Pan-ApoE ratio in plasma and serum accurately classified the ApoE4 phenotype in concordance with Show less

Distressing dreams were previously reported to predict future all-cause dementia among predominantly white US participants aged 79-89 years, particularly in men. We investigated whether disturbing dreams (nightmares and bad dreams) were associated with all-cause and Alzheimer dementia (AD) among individuals aged 60-89 years from diverse international regions. Data were from six longitudinal cohort studies across Brazil, China, France, Italy, South Korea, and Taiwan (n = 10,238, 42.5% men). Cox regressions with a random effect for study investigated associations between disturbing dreams and incident dementia, with all participants and stratified separately by sex and baseline age. Analyses examined (i) any disturbing dreams and (ii) disturbing dreams at least once a week. Fully adjusted analyses included three studies with covariates for sleep problems, medications, mental and physical health, cognition, and APOE ε4 status. Disturbing dreams were reported by 24.2% overall and all-cause dementia, and AD incidence was 10.8 and 5.3 per 1000 person-years, respectively. In fully adjusted analyses, having any disturbing dreams was associated with increased incidence of all-cause dementia among 60-69-year-olds (hazard ratio [HR] 3.93, 95% confidence interval [CI] 1.32-11.67). There were no significant effects for older individuals. In fully adjusted sex-stratified analyses, having disturbing dreams at least once a week was associated with AD only among men (HR 3.59, 95% CI 1.44-8.96). We found some evidence for disturbing dreams being associated with incident all-cause dementia among individuals aged 60-69 years and with AD among men. The mechanisms potentially underlying these associations remain to be clarified. Show less

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic agents that lower blood glucose independently of insulin by inhibiting renal SGLT2 in the proximal tubule, thereby increasing urinary glucose and sodium excretion. Empagliflozin (Empa), an FDA-approved SGLT2 inhibitor, exhibits antioxidant, anti-inflammatory, and additional metabolic effects beyond glycemic control. Given the high expression of SGLT2 in the central nervous system and the established link between cognitive impairment, chronic hyperglycemia, oxidative stress, and inflammation, this study investigated Empa's neuroprotective potential on learning and memory deficits in streptozotocin-induced hyperglycemic male Wistar rats. Hyperglycemia was induced using streptozotocin (40 mg/kg/IP), followed by Empa treatment (10 mg/kg/day/PO). Cognitive performance was evaluated using the radial arm water maze, assessing learning and both short-term and long-term memory. Concurrently, hippocampal oxidative stress markers and key molecular mediators, including brain-derived neurotrophic factor (BDNF) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), were measured to elucidate possible underlying neuroprotective mechanisms. Hyperglycemic rats exhibited significant impairments in learning, short-term memory, and long-term memory compared to normoglycemic controls. Empa treatment significantly improved short-term memory, restoring performance to near-control levels. However, its impact on long-term memory was minimal. Unexpectedly, Empa induced only modest, non-statistically significant changes in hippocampal oxidative stress markers and BDNF and NF-κB levels. The findings underscore the complexity of oxidative stress and inflammatory pathways involved in hyperglycemia-associated cognitive impairment. The beneficial effects of Empa on short-term memory may involve alternative mechanisms unrelated to oxidative stress modulation. Further studies involving extended durations, higher dosages, or larger sample sizes are warranted to better elucidate the neuroprotective mechanisms of Empa. Show less

RNA G-quadruplexes (rG4s), formed through guanine self-recognition into stacked tetrads, serve as critical regulators of gene expression, yet their comprehensive mapping and dynamic regulation in physiological contexts remain technically challenging. Here, we develop Ultra-low-input rG4-seq (ULI-rG4-seq), enabling precise rG4 detection enabling precise rG4 detection with ∼140 bp resolution in samples as small as 100 oocytes, and reveal notable enrichment of rG4s near crucial regulatory regions, particularly transcription start sites and end sites. This technological advance, combined with Trim-away or oocyte-specific knockout of DHX36 (also known as G4R1 or RHAU), an rG4-specific helicase, reveals acute and chronic loss of DHX36 leads to opposing effects on rG4 levels. This observation extends beyond the traditional view of helicases as unwinding enzymes and suggests sophisticated cellular mechanisms maintaining RNA structural homeostasis. Through integrated analysis of rG4 landscapes and DHX36-binding profiles, we demonstrate coordination between cytoplasmic rG4 regulation and nuclear gene expression, revealing how RNA structure dynamics orchestrate RNA stability and translation, thereby influencing transcriptional elongation, genome stability, and alternative splicing. Finally, we show that deletion of DHX36 resulted in decreased oocyte quality, premature ovarian failure and complete female infertility due to transcriptional defects and genome instability related to R-loop accumulation. These technological and conceptual advances not only deepen our understanding of RNA-based regulation but also open new therapeutic possibilities for diseases involving RNA structure. Show less

Lipoprotein(a) (Lp(a)) is a proatherogenic lipoprotein associated with increased cardiovascular risk and is minimally responsive to statins or lifestyle changes. While Lp(a) is linked to adverse cardiovascular events, its role in predicting repeat revascularization after percutaneous coronary intervention (PCI) remains unclear. This review evaluates the relationship between Lp(a) levels and coronary revascularization outcomes. A systematic review and meta-analysis of studies from MEDLINE and EMBASE through June 18, 2025, evaluated the association between elevated Lp(a) and revascularization outcomes post-PCI. Random-effects models using the DerSimonian-Laird method were used to pool odds (ORs) and hazard ratios (HRs). Heterogeneity was assessed using the I Twenty studies were included in the systematic review, of which eighteen were included in the meta-analysis. Elevated Lp(a) levels were associated with a higher risk of any repeat revascularization, with pooled OR 1.33 (95% CI: 1.17-1.52) and HR 1.15 (95% CI: 1.05-1.25). High Lp(a) was also linked to increased risk of target vessel revascularization (TVR) (OR 1.42; 95% CI: 1.12-1.81). A non-significant trend towards increased target lesion revascularization (TLR) was observed (OR 1.25; 95% CI: 0.96-1.64). Elevated Lp(a) levels were associated with a higher risk of repeat revascularization and TVR, with a non-significant trend towards increased TLR. Further studies are warranted to confirm these findings and explore the potential benefit of Lp(a)-lowering strategies. Show less

Annotation of regulatory elements is essential for understanding mechanisms underlying gene regulation, particularly tissue-specific regulation in human and animals. Here, we characterize 274,682 enhancers and 25,975 promoters across 24 tissues from an adult female sheep using ChIP-seq, ATAC-seq, CAGE-seq, RRBS, WGBS, and RNA-seq. We identify seven neural development-related genes with over 10 enhancers in brain tissues, highlighting the role of tissue-specific regulation. Cis-regulatory enhancer-promoter combinations provide insights into tissue-specific enhancers, such as the cerebellum-specific enhancer (chr15: 57390520-57390685) regulating BDNF, which is expressed in both the cerebellum and cerebral cortex. Comparative analysis of enhancer-promoter combinations in human, mouse, pig, cattle, and sheep reveals ruminant-specific pathways, including pentose catabolism and long-chain fatty acid import regulation. A milk fat yield quantitative trait locus (QTL) identified within an enhancer interacts with the fat metabolism-related gene COMMD1, and a birth weight-associated QTL detected within a cerebellum-specific enhancer regulates XKR4. This study provides a robust framework for exploring cis-regulatory mechanisms and tissue-specific regulation, advancing the functional annotation of the sheep reference genome. Show less

Sodium perfluorononenoxybenzene sulfonate (OBS), a substitute for perfluorooctane sulfonate (PFOS), has been frequently detected in the environment and human blood. Although OBS exposure has been identified as a novel risk factor for atherosclerosis associated with endothelial dysfunction, the underlying molecular mechanisms remain unclear. In this study, in vitro experiments using human umbilical vein endothelial cells (HUVECs) demonstrated that OBS exposure induced oxidative stress, activated the PERK-eIF2α-ATF4 axis of endoplasmic reticulum stress (ERS) and triggered NF-κB signaling. Pharmacological inhibition with N-acetylcysteine (NAC, an antioxidant), 4-phenylbutyric acid (4-PBA, an ERS inhibitor), and BAY 11-7082 (an inhibitor for NF-κB signaling pathway) revealed a sequential pathogenic cascade, in which oxidative stress acts upstream to initiate ERS and compromise endothelial barrier function, leading to NF-κB activation, which drives inflammatory responses, monocyte adhesion, and impaired endothelial migration. Consistent with these findings, in vivo experiments in ApoE Show less

Myeloid/Lymphoid neoplasms with FGFR1 rearrangement (M/LN-FGFR1) are rare, heterogenous diseases due to fusion transcripts originated by translocations of FGFR1 with different partners, resulting in constitutive FGFR1-mediated signaling. Presentation varies from chronic myeloid neoplasms to acute leukemia or lymphoma and extramedullary localizations are common. Outside allogeneic stem cell transplantation (ASCT), survival with conventional therapy is dismal, representing an unmet clinical need. We summarize here the data that led to approval of pemigatinib, a FGFR1 inhibitor, showing unprecedented efficacy in M/LN-FGFR1. Show less

Lipoprotein(a) (Lp(a)) is a causal risk-factor for atherosclerotic cardiovascular disease including acute ischemic stroke (AIS). The underlying pathomechanisms mediating this risk are less well understood, especially in AIS caused by large artery atherosclerosis (LAA). In this observational cohort study, we evaluated the association of Lp(a) with markers of LAA, namely carotid intima media thickness (cIMT) and the presence of extra- or intracranial vessel narrowing plaques. Among participants of the BIOSIGNAL cohort study we determined Lp(a) levels within 24 h after symptom onset in 1161 AIS patients from the single center of Zurich. cIMT was determined using a semi-automated computerized edge tracking software, internal carotid artery (ICA) stenosis was graded according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria, intracranial ultrasound was performed by transcranial color-coded duplex (TCCD). Higher Lp(a) levels were not associated with an increased cIMT in univariable or multivariable regression models containing known cardiovascular risk factors. Higher Lp(a) levels were not associated with the presence of neither extracranial high-grade ICA-stenosis nor significant intracranial stenosis assessed by neurovascular ultrasound. In AIS patients higher Lp(a) levels were not associated with clinical markers of atherosclerotic burden despite its association with LAA-stroke etiology and an increased risk for stroke recurrence. Date of registration: 17–10-2014. Registration-URL: http://www.clinicaltrials.gov; Unique identifier: NCT-02274727. The online version contains supplementary material available at 10.1186/s12944-026-02913-6. Show less

Coronary artery disease (CAD) remains a leading cause of mortality worldwide, with substantial unmet therapeutic needs. This study aimed to identify and prioritize genetically supported therapeutic targets for CAD using Mendelian randomization (MR). We implemented a two-sample MR framework to infer the causal effects of blood druggable cis-expression quantitative trait loci (cis-eQTLs) on CAD. To consolidate MR findings, we applied Steiger filtering, Bayesian colocalization, and multiple sensitivity analyses. Mediation and phenomewide MR analyses were employed to investigate potential mechanisms and on-target effects of prioritized druggable genes. We identified 66 causal druggable genes associated with CAD in European populations (false discovery rate < 0.001). Among these, ERP29 (odds ratio [OR] = 1.311; 95% confidence interval [CI]: 1.176-1.460), MCL1 (OR = 0.877; 95% CI: 0.840-0.915), TNXB (OR = 1.183; 95% CI: 1.102-1.269), DAGLB, FES, and TRPM4 colocalized with CAD (posterior probability for colocalization > 0.8). The associations for ERP29, MCL1, and TNXB were replicated in an East Asian cohort. Protein-protein interaction network analysis highlighted MAPK3 and TNF as prioritized druggable targets at the protein level. Mediation analysis indicated that body mass index, triglycerides, blood pressure, and atrial fibrillation partially mediate the association between MAPK3 and CAD. Phenome-wide MR analysis further suggested additional beneficial effects of targeting MAPK3 and TNF on diabetes mellitus, obesity, hypertension, unstable angina, myocardial infarction, angina pectoris, coronary atherosclerosis, ischemic heart disease, and disorders of lipoid metabolism. This druggable genome-wide MR study not only corroborated the targets of FDA-approved CAD medications (e.g., FGFR1, MAPK3, NEU1) but also uncovered several novel genes, such as ERP29, MCL1, TNXB, DAGLB, FES, and TRPM4, implicating mechanisms related to blood pressure, lipid metabolism, and additional beneficial effects on endocrine/cardiometabolic traits and circulatory system disorders. Further exploration is imperative to explore their feasibility and generalizability. We identified circulating ERP29, MCL1, TNXB, DAGLB, FES, TRPM4, MAPK3, and TNF as promising, genetically supported druggable targets for CAD treatment. Notably, MAPK3 and TNF demonstrated strong protein-level interactions and close associations with cardiometabolic disorders. Show less

Nivolumab and nintedanib are both established agents for pre-treated NSCLC of adenocarcinoma histology. Hypothesizing that the combination of immune checkpoint inhibition (nivolumab) and anti-angiogenesis (nintedanib) increases efficacy, we intended to determine a safe and efficacious dose for the combination. Our multi-center, open-label, single arm, phase Ib/II study enrolled patients with histologically confirmed stage IIIB/IV adenocarcinoma NSCLC and one or two previous lines of systemic treatment with platinum-based chemotherapy +/- checkpoint inhibitors (CPI). A traditional 3 + 3 design was used to determine a recommended phase II dose (RP2D) for nintedanib combined with nivolumab. Primary endpoints were safety and tolerability together with 6- and 9-month rates of progression-free survival (PFS). The RP2D was determined as 200 mg nintedanib twice daily (bid) with 240 mg nivolumab biweekly (Q2W). No new safety signals were detected. PFS milestone rates at 6 and 9 months for the 52 patients who received this dose were 25% [95% CI 14.3-37.3%] and 11.5% [4.7-21.8%], respectively. Median overall survival (mOS) was 12.2 months [95% CI: 8.13-18.37]. Central biomarker analysis based on combined positive score (CPS) revealed that high PD-L1 and low PD-L1/low FGFR1 identified patients with prolonged OS at 36 months (70% and 40%, respectively), while low PD-L1/high FGFR1 was associated with shorter OS (p = 0.0195). CPI-rechallenged patients had better OS outcomes than those who were CPI-naïve (mOS 8.13 months [95% CI 2.03-15.2] vs. 14.7 months [95% CI 8.2-NR]; logrank p = 0.0493). Combination of nivolumab and nintedanib was shown to be safe and feasible. Despite missing synergistic effects on efficacy for the overall population, promising OS was observed for patients with high PD-L1 expression and for patients with previous immunotherapy. Therefore, CPI responsiveness may have been restored in some cases. Inhibition of FGFR-mediated tumor progression seems relevant in tumors with lower levels of both PD-L1 and FGFR1 expression and might be effectively inhibited by nintedanib. The combination nivolumab/nintedanib might warrant further exploration in selected patients. Show less

Mammalian genomes harbor hundreds of thousands of RNA polymerase II (RNA Pol II) landing pads, enhancers, and promoters from which transcription initiates bidirectionally. Nevertheless, processive transcription is largely restricted to the small gene-containing fraction of the genome. An essential metazoan complex, Restrictor, composed of WDR82 and ZC3H4, restrains processive RNA Pol II activity at extragenic transcription units, thus representing a critical enforcer of genome utilization. However, because of the widespread recruitment of Restrictor to both genic and non-genic transcription sites, the mechanistic basis for its selectivity for extragenic transcription is unclear. Here, we show that while WDR82 tethers Restrictor to transcription initiation sites, the C3H1-type zinc fingers of ZC3H4 make sequence-specific interactions with motifs enriched at the 5' end of extragenic transcripts, with such interactions being required for transcription termination. Hence, although Restrictor recruitment requires WDR82-dependent tethering to the initiating RNA Pol II, its selectivity mainly arises from sequence-specific RNA recognition. Show less