Biology subjects

Patel, N.

Publications and source records attributed to Patel, N..

At least 19 recordsLinked to original sources

bioRxiv2026

Rapid, reversible RNA/DNA precipitation using rare earth ion coordination

Efficient recovery and removal of nucleic acids remain major challenges in molecular biology, diagnostics, and viral-vector manufacturing. Conventional precipitation methods often require organic solvents, low temperatures, and extended centrifugation, while nuclease-based contaminant removal can be incomplete and/or is incompatible with downstream workflows. Here, we evaluate NADA, a trivalent rare earth-based reagent, for rapid, solvent-free precipitation of RNA and DNA, and ALGO-mediated recovery of the full range of properties of unmodified RNA. Using hepatitis B virus pre-genomic RNA, lambda bacteriophage DNA, and the HBV nucleocapsid as model systems, we show that NADA rapidly sequesters both ssRNA and dsDNA from solution, reducing Midori Green nucleic acid fluorescence and UV absorption to baseline levels. The NADA complex prevents HBV core protein binding to the HBV pgRNA, and therefore triggering of nucleocapsid formation, even when added simultaneously with core protein, suggesting that lanthanide ion coordination, out-competes the cognate Cp for viral RNA-binding interactions. Recovery with ALGO restores pgRNA integrity and functionality, enabling subsequent assembly of the expected T=4/T=3 nucleocapsids. In contrast, pre-assembled nucleocapsids resist NADA-ALGO treatment, demonstrating coat protein capsid-mediated protection of encapsidated pgRNA. Similar outcomes for lambda dsDNA establish NADA/ALGO as a rapid, reversible, and selective alternative platform for nucleic acid precipitation, with potential applications in viral particle purification, contaminant removal, and RNA handling workflows.

biochemistry↗

bioRxiv2026

Systematic exploration of predicted quaternary structures within pandemic-relevant viral proteomes

Mechanistic understanding of viral protein-protein interactions enables global health security and pandemic preparedness, yet experimental characterisation remains difficult, costly, and often restricted to specialised laboratories. Here, we describe an in silico campaign using AlphaFold2 and AlphaFold-Multimer to predict monomers and dimer structures within 2,812 viral proteomes from 23 viral families relevant to human health. We report high-confidence predicted structures of 5,279 hetero-, and 2,749 homo-dimers. Structural clustering of interfaces reduces the set fivefold to 1,598 consolidated by form and function, of which 471 (29.5%) lacked detectable similarity to experimentally determined interfaces in the PDB. These clusters yielded two notable findings: new data on vaccinology-relevant glycoproteins, and accurate prediction of the specificity and cleavage-site recognition of viral proteases, which are targets for anti-viral development. Viral monomers and high-confidence dimers are available for interactive browsing in the Pandemic Preparedness Portal of the AlphaFold Database (https://alphafold.ebi.ac.uk/), and the full dataset is available for bulk download.

bioinformatics↗

bioRxiv2026

Integrated Patient-Derived Xenograft and Patient-Derived Cell Models Reveal Therapeutic Vulnerabilities Beyond Standard-of-Care Therapy in Endometrial Cancer

Endometrial cancer (EC), the most common gynecologic malignancy in the USA, has seen limited improvement in patient outcomes over recent decades, underscoring the need for relevant preclinical models. To address EC heterogeneity, we established an integrated platform of patient-derived xenografts (PDXs) and matched patient-derived primary cancer cells (PDCs) for disease modeling and systematic drug sensitivity testing. Fresh tumor specimens (n=103) were collected from EC patients to generate PDXs in immunodeficient mice and corresponding PDCs. Fifty-three PDX models were successfully established (52% engraftment rate), with higher success observed in high-grade, recurrent, metastatic tumors (70%), compared with their low-grade counterparts (56%). Histopathologic and immunohistochemical analyses confirmed that PDX tumors faithfully preserved morphology, hormone receptor status, and intertumoral heterogeneity across multiple passages. Using 13 PDC models, we performed an unbiased screening of 179 FDA-approved oncology drugs, revealing marked intertumoral variability in drug response. Almost all PDC models exhibited limited sensitivity to NCCN-recommended therapies, highlighting the need for alternative treatment strategies. In contrast, multiple FDA-approved agents including epigenetic modulators, dual PI3-kinase/HDAC inhibitors, topoisomerase II inhibitors, and proteasome inhibitors demonstrated potent antitumor activity. Importantly, a low-dose combination of the DNA methyltransferase inhibitor 5-azacytidine and the histone deacetylase inhibitor romidepsin significantly suppressed tumor growth across six independent PDX models. Together, these findings establish a comprehensive PDX and PDC platform as a robust translational resource. By capturing the histopathologic and molecular diversity of EC and identifying clinically actionable therapeutic advantages, including an epigenetic combination regimen, this study offers a translational resource for preclinical drug evaluation.

cancer biology↗

bioRxiv2026

Post-infection immune response in adults with COVID-19 with and without nirmatrelvir-ritonavir treatment and virologic rebound

BackgroundNirmatrelvir-ritonavir (N-R) reduces morbidity and mortality from COVID-19 in high-risk individuals; however, N-R use has been associated with risk of SARS-CoV-2 virologic rebound. The mechanisms contributing to virologic rebound after N-R treatment are currently unknown. One plausible mechanism is that antiviral treatment may alter the development of immune responses to SARS-CoV-2 infection, thereby contributing to rebound after cessation of therapy. MethodsWe profiled immune responses in a case-ascertained, longitudinal, prospective cohort of ambulatory individuals with COVID-19. Participants were grouped according to whether virological rebound occurred and whether they had received N-R treatment. We assessed antibody, T-cell, and innate responses. ResultsWe observed no differences in the binding or neutralizing antibody, T-cell, and innate immune responses between participants with virologic rebound compared to participants without virologic rebound. N-R use was associated with slightly weaker antibody responses overall, even after adjustment for immunosuppression. ConclusionVirologic rebound after N-R treatment is likely driven by non-immune mechanisms. FundingThe project was supported by the National Institutes of Health (R01 AI 138801) and the Massachusetts Consortium on Pathogen Readiness. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

immunology↗

bioRxiv2026

Pandemic Coronavirus Genome Packaging Relies on Multiple Dispersed Packaging Signals

Packaging of viral genomes into progeny virions is a critical step in the viral life cycle. Coronaviruses such as SARS-CoV-2 possess unusually large RNA genomes ([~]30 kb), yet the mechanism by which these genomes are selectively condensed and incorporated into virions remains poorly understood. Here, we demonstrate that the SARS-CoV-2 genome contains multiple dispersed RNA structures, termed packaging signals (PSs), which cooperate with a dominant central PS to direct genomic RNA incorporation into infectious particles. We identify the dominant PS within the coding region of the nsp15 gene, downstream of a packaging signal previously described in Embecoviruses. Using virus-like particles (VLPs), we investigate its role in virion assembly and selective genomic RNA packaging, and show that it promotes the formation of ribonucleoprotein (RNP) complexes with the viral nucleocapsid protein (N), as revealed by mass photometry. Notably, we uncover a unique N-induced conformational rearrangement of the PS RNA, from an extended structure to a double stem-loop architecture. This dominant PS acts together with a nearby stem-loop element to assemble a higher-order RNP complex containing 12 N-protein dimers. Using a SARS-CoV-2 replicon system, we further demonstrate functional cooperativity between the dominant PS, its proximal partner stem-loop, and additional packaging elements located approximately 10 kb upstream. Collectively, our findings support a highly dynamic and cooperative mechanism of SARS-CoV-2 genome packaging that relies on multiple dispersed packaging signals organized around a dominant central PS. These insights provide a mechanistic framework for understanding coronavirus genome packaging and reveal new opportunities for antiviral intervention through disruption of this process. They also have important implications for vaccine development and may enable the design of membrane-based vector systems capable of efficiently delivering large nucleic acid cargoes, expanding the potential of bionanotechnology and genetic medicine.

microbiology↗

bioRxiv2026

System xc- imaging maps ferroptosis-linked redox remodeling in cancer

Ferroptosis is a regulated non-apoptotic form of programmed cell death that is implicated in tumor suppression and the normal tissue damage response. While the link between redox stress and ferroptosis is well established, no non-invasive methods exist to assess ferroptosis in vivo. Here, we demonstrate that the redox-sensitive positron emission tomography radiotracer and system xc-substrate, 18F-(S)-4-(3-fluoropropyl)-L-glutamic acid ([18F]FSPG), serves as a non-invasive marker of tumor ferroptosis. Global changes in amino acids, glutathione, and system xc- activity occurred before loss of membrane integrity in cells sensitive to ferroptosis, but not in resistant cells. Resistant cells sensitized to ferroptosis through nuclear factor erythroid 2-related factor 2 (NRF2) knockout had reduced glutathione and [18F]FSPG retention, which were rescued by ferroptosis inhibitors. In vivo, immune checkpoint blockade decreased ferroptosis-specific [18F]FSPG tumor retention prior to immune cell infiltration. Together, our data demonstrate that [18F]FSPG can identify early redox changes that precede ferroptosis and enabled real-time monitoring of immunotherapeutic efficacy.

cancer biology↗

bioRxiv2026

scFAIR Consortium: a decentralized hub for single-cell RNA-Seq data standardization and unification

The rapid accumulation of single-cell RNA-Seq (scRNA-seq) data across multiple repositories presents major challenges for data accessibility, integration, and reproducibility. While primary repositories provide raw data, they rarely include structured cell-type annotations or descriptions of analytical workflows, limiting the ability to reuse and integrate datasets in a FAIR (Findable, Accessible, Interoperable, Reusable) manner. Here we present scFAIR, a consortium of single-cell data resources that has developed a unified metadata schema and common curation framework to improve the FAIRness of scRNA-seq data. Building on and extending the CZ CELLxGENE Discover metadata schema, the scFAIR consortium has been instrumental in driving key schema improvements, including the expansion of supported organisms, richer biological context, and structured reporting of computational workflows. To provide unified access to decentralized datasets, the consortium developed the sc-fair.org portal, which currently aggregates 2,346 datasets across partner resources through ontology-aware semantic search. We demonstrate the practical value of FAIR-compliant datasets through a cross-species validation between human and mouse Allen Brain Atlases, showing that standardized ontology annotations enable reliable annotation transfer across species, with 90% of neuronal clusters receiving an exact or equivalent label. Together, the scFAIR schema, validator, and portal constitute a community-driven framework that advances single-cell data standardization and lays the foundation for reproducible, large-scale integration of single-cell datasets.

bioinformatics↗

bioRxiv2026

Occurrence of Biased mTOR Signaling in Hepatocellular Carcinoma

BackgroundmTOR signaling promotes cell growth and anabolic processes in all eukaryotes. Hyperactivation of mTOR signaling is associated with various cancers along with hepatocellular carcinoma (HCC). HCC is a highly lethal malignancy with multiple aetiologies such as viral infection, alcohol abuse, and metabolic dysfunction. Therapeutic options for HCC remain limited due to an incomplete understanding of oncogenic drivers and poorly characterized mechanisms of disease progression. MethodsVarious regimens of DEN and CCl4 carcinogen dosage were investigated on C57BL/6J mice to induce HCC. The histological analysis for fibrosis and serum markers for liver function were performed. Molecular analyses of oncogenic drivers were performed in the HCC tissues obtained from mice and HCC patients. The impact of inhibition of mTOR signaling was assessed on HCC progression. ResultsWe established a rapid DEN+CCl4 induced (DCI) HCC model in C57BL/6 mice to study disease progression longitudinally. The molecular analysis revealed upregulation of MAPK and downregulation of mTORC1-S6K-S6 signaling in HCC. However, other branches of mTOR such as mTORC1-ULK1, mTORC1-4EBP1, and mTORC2-PKC were upregulated due to the increased expression. Similar observations were found in tissues derived from HCC patients. Furthermore, inhibition of mTORC1 alone by Rapamycin did not reduce HCC progression but Torin 1 mediated inhibition of both mTORC1 and mTORC2 significantly reduced HCC progression. ConclusionsWe propose this biased mTOR signaling modulates mTOR activity towards specific downstream processes that are crucial for cancer cell growth and targeting both the mTOR complexes has better therapeutic potential in HCC. Impact and ImplicationsThis study provides a rapid pre-clinical model for understanding HCC progression and to explore various intervention strategies. The study reports a novel phenomenon of biased mTOR signaling where deregulation of downstream substrate levels modulates the mTOR activity towards the specific branches, the master regulator of cell growth and metabolism. Furthermore, the study suggests that the clinical investigations exploring the rapalogs against HCC should be cautiously considered depending on the aetiology and signaling status of HCC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/727188v2_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@ef3714org.highwire.dtl.DTLVardef@1091b25org.highwire.dtl.DTLVardef@d52f2forg.highwire.dtl.DTLVardef@cc158_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDEN and CCl4 treatment generated a well-established HCC within 4 months. C_LIO_LILiver fibrosis and serum markers correlated with HCC progression. C_LIO_LIUpregulation of mTOR pathway substrates create biased mTOR signaling. C_LIO_LIDual inhibition of mTORC1 and mTORC2 reduced HCC progression significantly. C_LI

cancer biology↗

bioRxiv2026

BK Channels Orchestrate Cardiac Homeostasis Through Mitochondrial Uncoupling Proteins

BK channels, coded by the Kcnma1 gene, integrate voltage and intracellular Ca2+ signals and are recognized for their roles in smooth muscle and neuronal excitability. However, their contribution to baseline cardiac physiology remains poorly defined. Here we uncover a fundamental function for BK channels in maintaining normal cardiac performance, independent of pathological stress. Using non-invasive echocardiography, transcriptional profiling, and mechanistic analyses, we demonstrate that Kcnma1 deletion disrupts ventricular function, and remodels metabolic and stress-response pathways. Transcriptomic profiling revealed selective downregulation of mitochondrial uncoupling proteins (UCPs) and suppression of the PGC-1/FOXO3a axis, without broad loss of oxidative phosphorylation components. Enhancing UCP expression restored cardiac performance, indicating that mitochondrial uncoupling and redox control constitute key downstream effectors of BK signaling. Together, these results identify a physiological role for BK channels in maintaining myocardial function and define a mitochondrial BK-UCP axis, critical for cardiac homeostasis.

cell biology↗

bioRxiv2026

Characterization of long non-coding RNAs during compatible and incompatible pollination in Arabidopsis thaliana

Long non-coding RNAs (lncRNAs) have emerged as critical players in plant development and stress responses, yet their involvement in pollination responses is largely unknown. To address this gap, we identified and characterized lncRNAs and their cis-acting, trans-acting, and miRNA-mediated regulatory interactions during both compatible and incompatible pollination in Arabidopsis thaliana. Leveraging publicly available datasets, we analyzed expression profiles at 10 and 60 minutes post-pollination. We identified 1,073 novel and 3,422 annotated lncRNAs, with 1,002 novel and 985 annotated, respectively, showing detectable expression after filtering. Differential expression analysis identified 12 lncRNAs at 10 min and 32 lncRNAs at 60 min post-pollination. Further investigation revealed 9 cis-targets, 112 trans-targets, and 144 miRNA-mediated regulatory interactions, many of which were enriched in pathways related to stress, defense, and self-incompatibility. Notably, the regulatory landscape is more active at 60 minutes than at 10 minutes post-pollination. These findings provide a robust framework and resource to facilitate future functional studies of lncRNAs during pollination.

plant biology↗

bioRxiv2026

AlphaFold Database expands to proteome-scale quaternary structures

Protein function is governed by molecular interactions, yet structural coverage of these interactions remains sparse. The AlphaFold Protein Structure Database (AFDB) transformed access to accurate monomeric protein structures at scale. Here, we expand the AFDB to quaternary structures by predicting 31M candidate homo- and heterodimeric protein complexes, compiled from 4,777 proteomes, including model- and global health organisms. We established confidence criteria via analysis of experimentally determined structures, resulting in 1.81M high-confidence predictions. These models enabled the discovery of emergent structures and topologies not present in monomeric predictions. Additionally, the top 1% of structural clusters accounted for [~]44% of all complexes, and [~]8.3% of clusters were conserved across multiple domains of life, pointing to a substantial fraction of ancient, universally retained assemblies. Structural search highlighted that high-confidence predictions are anchored in experimental multimer space, yet 31.3% extend beyond detectable PDB coverage. These freely accessible proteome-scale predictions facilitate functional and mechanistic hypothesis generation across biology.

synthetic biology↗

bioRxiv2025

Transcriptomic module fingerprint reveals heterogeneity of whole blood transcriptome in type 1 diabetic patients

BackgroundType 1 diabetes (T1D) is a complex autoimmune disease resulting from {beta}-cell destruction in the pancreas. Yet, no gene signature derived from whole blood samples has been established to differentiate T1D patients from healthy donors, likely because of the high heterogeneity of the underlying pathophysiological mechanisms. MethodsWe analysed whole blood transcriptomic profiles from 39 patients and 43 healthy donors, collected as part of our observational clinical trial, using a multi-step multivariate statistical analysis. This approach combined classical differential analysis, random forest and support vector machine classifications, gene set functional enrichment analysis to construct the most stable and reliable gene signature. ResultsClassical differential analysis did not separate clearly samples into healthy and T1D clusters, but rather spread samples into three clusters. On the contrary, we show that our approach, which combined molecular signatures independently constructed, adds robustness to the analysis without compromising the specificity. This efficiency was demonstrated by the clear separation of the samples according to their diagnosis group. Also, the functional annotation of the gene modules that we obtained was more associated with T1D-related pathways compared to the classical statistical analysis. ImpactsThese results emphasize that single differential analyses are not able to capture immune continuums involved in such a complex pathophysiological process. We hypothesize that T1D patients can have different molecular pathways involved in their pathology or/and can display unsynchronized -omics profiles. These findings call for further investigations to identify the molecular pathways involved in T1D patients, and for revising the nosology of autoimmune diseases.

bioinformatics↗

bioRxiv2025

Decorin promotes nascent proteoglycan retention in cartilage matrix by strengthening collagen II-aggrecan integration

Cartilage extracellular matrix (ECM), a hydrated collagen II-aggrecan composite, undergoes dynamic turnover during both normal homeostasis and disease-associated remodeling. This study elucidates a crucial role for decorin in promoting the retention and stability of nascent aggrecan within this matrix. By applying bio-orthogonal click-labeling, we demonstrate that loss of decorin accelerates the release of nascent aggrecan under both physiological and inflammatory conditions, without affecting its preferred localization to the pericellular matrix. Conversely, supplementation with exogenous decorin mitigates inflammation-induced loss of nascent aggrecan, supporting its potential as a therapeutic target. At the molecular level, decorin exhibits strong binding affinity for aggrecan, and enhances aggrecan-aggrecan and aggrecan-collagen II interactions, reinforcing its direct role in integrating cartilage matrix constituents. Also, by binding to collagen II, decorin stiffens the collagen II fibril network, thereby strengthening the confinement effect that limits the diffusive loss of entrapped aggrecan. Notably, decorin does not alter chondrocyte transcriptomic profiles in vivo, emphasizing its primary role in maintaining matrix integrity through biophysical mechanisms rather than cell signaling. Together, these findings provide a mechanistic foundation for developing decorin-based biomaterials or gene therapies aimed at preserving or regenerating the cartilage matrix for improved outcomes in osteoarthritis.

biophysics↗

bioRxiv2025

REPTRA: Mapping Immune T Cell Receptor Activity from Full Sequences with a Debiased Contrastive Loss

Contrastive learning is amenable to representing the vast space of interaction between highly specific T cell receptors (TCRs) and the epitopes to which they bind, potentially enabling diverse applications in immune engineering. However, progress in mapping TCR-epitope recognition has been limited by skewed datasets and training approaches that may exacerbate biases and obfuscate model performance. Furthermore, most TCR-epitope models represent only one of three complementaritydetermining regions (CDRs) of the TCR, potentially limiting performance. Here, we present a CLIP-style contrastive-learning model for representation of epitopes and T cell receptor activity (REPTRA), incorporating full TCR sequences and trained using a debiased InfoNCE loss. We trained this model on a dataset with over fivefold more epitope diversity than previous reports, collected using the DECODE platform (Repertoire Immune Medicines). We demonstrate resulting improvements in model performance, and ablate the modified loss and TCR representation to demonstrate the contributions of this approach. Furthermore, we apply an interpretability analysis to the REPTRA attention-pooling projection heads to reveal that CDR1 and CDR2, in addition to CDR3, are important for learning TCR-epitope recognition. In doing so, we develop a performant model for contrastive mapping of T cell receptor activity.

immunology↗

bioRxiv2025

Continuous evolution of a halogenase enzyme with improved solubility and activity for sustainable bioproduction

Halogenation enhances the stability and function of pharmaceuticals, biomaterials, and industrial compounds. However, chemical halogenation lacks stereoselectivity and requires the use of toxic or expensive chemicals. Although enzymatic halogenation can improve selectivity and reduce environmental impact, current halogenases are inefficient and insoluble, leading to low yields that limit their applications. Here, we develop RebHEvo4, a soluble and highly active tryptophan halogenase, containing 12 mutations that confer 37-fold and 44-fold increases in 7-chloro and 7-bromotryptophan production respectively, in vivo. To create RebHEvo4, we devised an aminoacyl tRNA synthetase based halogenase biosensor and conducted over 500 hours of phage-assisted continuous evolution (PACE). Use of RebHEvo4 in a bioreactor resulted in the production of 2.7 g/L of halogenated tryptophan. When coupled with a downstream enzyme, RebHEvo4 allowed 36-fold increased yields of halogenated tryptamines compared to the wild-type enzyme. Additionally, RebHEvo4 enabled efficient production of genetically encoded antimicrobial halogenated peptides. The efficient, site-specific halogenation by our evolved halogenase will accelerate sustainable biomanufacturing of halogenated drugs.

biochemistry↗

bioRxiv2025

Age-Related Decline in NCKX4-Mediated Calcium Clearance Accelerates Aortic Remodeling and Drives Early Vascular Aging

Aging is the primary nonmodifiable risk factor for cardiovascular diseases (CVDs), with older women facing a greater risk of CVDs than age-matched men. Vascular smooth muscle cells (VSMCs) dysfunction and impaired calcium (Ca2+) handling are recognized as central contributors to arterial stiffening and calcification. However, the molecular and functional determinants of Ca2+ clearance in vascular aging remains a topic of ongoing research. We identify the (Na+)-sodium/Ca2+-calcium (K+)-potassium-dependent exchanger 4 (NCKX4) as a critical functional regulator of VSMCs Ca{superscript 2} clearance and vascular integrity. We demonstrate that NCKX4 (coded by Slc24A4) expression is markedly reduced in aorta of aged (72-78 weeks) mice, with a pronounced decline in females. Functional assays revealed impaired Ca2+ clearance in both aged and Nckx4-/- VSMCs, which was accompanied by increased calcification. Histomorphometric analyses of young Nckx4-/- mice revealed fragmentation of elastic fibers, collagen accumulation, wall thickening, and extracellular matrix (ECM) remodeling, all hallmarks of vascular aging that closely resembled those of aged wild-type mice. Transcriptomic profiling of VSMCs showed that loss of NCKX4 alters pathways linked to Ca2+-integrin signaling, ECM turnover, and mineralization, including dysregulation of protective anchorage integrins, microfibril-stabilizing, osteogenic drivers and pro-fibrotic integrins. These findings support a model in which impaired Ca2+ clearance promotes maladaptive inside-out integrin signaling, disrupting VSMCs anchorage, ECM homeostasis, and mineralization processes. Collectively, our results establish NCKX4 as a previously unrecognized determinant of vascular aging, whose decline accelerates premature arterial remodeling and calcification. This study positions NCKX4 as a potential mechanistic link between age, sex-dependent vulnerability, and vascular stiffening, with implications for novel therapeutic strategies targeting Ca2+ handling in CVDs prevention.

cell biology↗

bioRxiv2025

Patient-derived Cellular Models of Polygenic Scores: Application to Long QT Syndrome

Polygenic scores (PGS) have emerged as important modifiers of disease risk, drug response, and rare variant penetrance, but the biological mechanisms underlying these associations remain poorly understood. To experimentally investigate these relationships, we derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from individuals at the 1st, 50th, and 99th percentiles of a genome-wide QT interval polygenic score (QT-PGS). We examined baseline repolarization, drug response to the hERG inhibitor E4031, and penetrance of two KCNH2 variants (p.Arg148Trp and p.Arg823Trp) in these cellular models. While baseline field potential durations (FPDs) did not differ across PGS levels, high-PGS iPSC-CMs showed exaggerated prolongation in response to E4031 and increased phenotypic expression of both KCNH2 variants. These findings provide the first experimental demonstration that polygenic background can shape cardiac electrophysiologic phenotypes and modulate the functional impact of both pharmacologic and genetic perturbations. This work establishes a scalable platform for mechanistic studies of polygenic risk.

genetics↗

bioRxiv2025

Medial preoptic area FoxO1 controls metabolic adaptation in a sexually dimorphic manner

The medial preoptic area (MPOA) of the hypothalamus is essential for metabolic adaptation to environmental challenges, though the molecular mechanisms underlying this process remain poorly understood. Here, we investigate the role of Forkhead transcription factor O1 (FoxO1), a key mediator of stress adaptation, in MPOA-dependent metabolic responses to temperature and nutritional changes. Our findings reveal sex-specific responses to both nutritional and temperature challenges. In female mice, but not males, a high-fat diet (HFD) challenge decreased FoxO1 expression in the MPOA. Specific deletion of FoxO1 in MPOA neurons (FoxO1-KOMPOA) had no effect on body weight under normal chow-fed conditions but protected females from HFD-induced obesity (DIO). These protected females exhibited increased lean mass, decreased fat mass, enhanced thermogenesis, increased energy expenditure, and reduced food intake under HFD conditions. They also showed enhanced cold-induced heat production at 6{degrees}C, though this effect vanished at thermoneutrality (30{degrees}C). The protection against DIO was abolished by ovariectomy (OVX) and was not restored by 17{beta}-estradiol supplementation, suggesting an estrogen-independent mechanism. Conversely, constitutive activation of FoxO1 in MPOA neurons (FoxO1-CAMPOA) increased DIO susceptibility in both sexes. Together, these findings demonstrate that FoxO1MPOA plays a crucial role in coordinating metabolic adaptation to nutritional and temperature challenges specifically in female mice.

physiology↗