Biology subjects

Fang, X.

Publications and source records attributed to Fang, X..

At least 19 recordsLinked to original sources

bioRxiv2026

DNA methylation reveals molecular heterogeneity and urate excretion-associated subtypes of gout

Background: The molecular heterogeneity among gout patients remains largely unexplored, hindered the precise treatment for gout. Common indices for gout subtyping are cumbersome to measure, resulting in poor patient compliance. Methods: We elucidated the molecular heterogeneity of gout and developed a simple, reliable classification method for gout subtypes based on genome-wide DNA methylation, to facilitate individualized treatment. Genome-wide DNA methylation profiling was conducted in two independent cohorts, comprising a discovery cohort (n = 108) and a validation cohort (n = 100) representing four clinical gout subtypes. Results: We identified two gout subgroups associated with the fractional excretion of uric acid (FEUA) but not with 24-hour urinary uric acid levels (UUE) based on unsupervised clustering of whole-genome DNA methylation profiles, highlighting the contribution of epigenetic regulation to molecular heterogeneity in urate metabolism. Enrichment analysis links FEUA-associated subtypes to renal cell types, calcium related pathways and extended to the circulating immune compartment, with neutrophil- versus memory B cell-skewed leukocyte composition. A methylation-based classification model using 18 LASSO-selected CpGs with an XGBoost classifier effectively distinguished patients with high and low uric acid excretion, achieving excellent predictive performance (training cohort: AUC = 0.96, AP = 0.91; validation cohort: AUC = 0.86, AP = 0.85), outperforming the published model with clinical characteristics and SNPs. The signature site-associated genes NEK1 and TRPS1 display significant expression differences among urate-stratified patients and immune cells groups. TRPS1 may affect the AP-1/NF-{kappa}B inflammatory programme. Conclusions: These findings reveal distinct DNA methylation signatures underlying gout heterogeneity and demonstrate the feasibility of DNA methylation markers for gout subtype classification. The proposed methylation-based model provides a promising approach for personalized management of gout.

bioinformatics↗

bioRxiv2026

Domain-resolved epitope mapping of B7-H3-targeting VHH-Fcs defines isoform-selective binders for antibody-drug conjugate development

The immune checkpoint molecule B7-H3 has emerged as one of the most actively pursued therapeutic targets in solid tumors, and multiple B7-H3-targeting antibody-drug conjugates have entered clinical evaluation. B7-H3 occurs as a 2Ig isoform carrying a single IgV-IgC domain pair and a predominant 4Ig isoform carrying two tandem pairs of near-identical sequence in their extracellular domains. Resolving which pair an antibody engages, or how antibodies distinguish the two isoforms, requires epitope mapping at residue level. Here we generated a panel of six B7-H3-targeting VHH-Fcs and characterized them by surface plasmon resonance, epitope binning, domain-resolved deep mutational scanning and receptor internalization, benchmarked against the clinically advanced antibodies ifinatamab, mirzotamab and vobramitamab. Most VHH-Fcs bound the membrane-proximal pair more tightly than the distal pair, and 4Ig 10- to 100-fold more tightly than 2Ig, whereas the three clinical antibodies showed no such discrimination. Displaying each domain pair independently on yeast identified the residues that account for this selectivity. Internalization varied several-fold among binders, including between VHH-Fc 620 and 636, which have near-identical footprints and comparable affinities. VHH-Fc 620 internalized most efficiently, also compared to ifinatamab, and was conjugated to exatecan through a protease-cleavable linker. The conjugate showed B7-H3-dependent cytotoxicity that scaled with B7-H3 cell surface density, though it was less potent than ifinatamab-exatecan. Affinity, epitope and internalization therefore behaved as independent characteristics rather than integrating to predict antibody-drug conjugate potency. Together, these results define the molecular basis for isoform-selective recognition of B7-H3 and identify VHH-Fc 620 as a starting point for isoform-selective targeting.

cancer biology↗

bioRxiv2026

HSF1 inhibition potentiates the antifungal activity and proteome instability induced by the fungal Hsp110 inhibitor 2H

Fungal infections remain a major cause of morbidity and mortality worldwide; however, therapeutic options are limited and are increasingly compromised by antifungal resistance. Heat Shock Protein 110 kDa (Hsp110) is an essential molecular chaperone required for protein homeostasis (proteostasis) and fungal viability and has recently emerged as a promising antifungal target. We previously identified 2H, a first-in-class inhibitor of fungal Hsp110 proteins that exhibits broad-spectrum antifungal activity through disruption of proteostasis. Heat Shock Transcription Factor 1 (HSF1), the master regulator of cellular stress responses and chaperone expression, has also been proposed as a potential antifungal target, although direct pharmacological evidence supporting this strategy remains limited. Here, we investigated the effects of combining the HSF1 inhibitor DTHIB with the fungal Hsp110 inhibitor 2H in Cryptococcus neoformans and Candida albicans. Although DTHIB alone exhibited minimal antifungal activity, it significantly enhanced the growth-inhibitory and fungicidal effects of 2H. Notably, this potentiating effect was specific to 2H and was not observed with fluconazole. Consistent with the roles of Hsp110 and HSF1 in proteostasis, 2H induced extensive accumulation of detergent-insoluble protein aggregates in C. neoformans, whereas HSF1 inhibition further increased both the abundance and diversity of aggregated proteins. Quantitative proteomic analyses demonstrated that 2H induces proteome-wide protein aggregation, impacting proteins involved in a broad range of essential cellular processes, with high-molecular-weight proteins exhibiting particular susceptibility. Together, these findings provide pharmacological evidence supporting HSF1 as a promising antifungal sensitization target and demonstrate the utility of 2H as a chemical probe for studying Hsp110-dependent proteostasis. Simultaneous disruption of both HSF1-mediated stress responses and Hsp110-dependent proteostasis promotes extensive proteome instability and enhances antifungal activity, highlighting a potential new strategy for antifungal drug development.

microbiology↗

bioRxiv2026

Targeting ALCAT1 Ameliorates Cardiomyopathy in Barth Syndrome

Background: Barth syndrome (BTHS) is an X-linked mitochondrial disorder caused by loss-of-function mutations in TAFAZZIN (TAZ), resulting in defective cardiolipin (CL) remodeling, cardiomyopathy, and premature death. The mechanisms linking TAZ deficiency to impaired mitochondrial quality control remain incompletely understood, and there are no disease-modifying therapies available for BTHS. Here, we investigated the role of Acyl-CoA Lysocardiolipin Acyltransferase-1 (ALCAT1), a stress-inducible phospholipid-remodeling enzyme, in BTHS cardiomyopathy. Methods: Inducible TAZ knockdown (TAZKD) and cardiomyocyte-specific TAZ knockout (TAZcKO) mice were used to determine the effects of genetic ALCAT1 deletion or pharmacological inhibition with Juvenatin, a highly selective small molecule ALCAT1 inhibitor. Cardiac function, exercise capacity, mitochondrial function, lipid remodeling, lysosomal function, and mitophagic flux were assessed. Results: ALCAT1 was markedly upregulated in TAZ-deficient hearts. Genetic ALCAT1 deletion attenuated cardiac dysfunction in TAZKD mice. Juvenatin similarly improved cardiac function in TAZKD mice and reversed established cardiomyopathy in TAZcKO mice. Genetic or pharmacological ALCAT1 inhibition improved mitochondrial ultrastructure and respiration and reduced mitochondrial oxidative stress. These benefits occurred without correcting the characteristic CL abnormalities caused by TAZ deficiency. Instead, ALCAT1 deletion or inhibition corrected pathological phosphatidylinositol remodeling, normalized phosphoinositide signaling, and restored lysosomal function and mitophagic flux, leading to improved mitochondrial quality control in TAZ-deficient cells. Conclusions: ALCAT1 contributes to BTHS cardiomyopathy through a CL-independent pathway involving dysregulated phosphatidylinositol/phosphoinositide signaling, lysosomal dysfunction, and impaired mitophagy. Genetic and pharmacological targeting of ALCAT1 restores mitochondrial and cardiac function despite persistent CL abnormalities, establishing ALCAT1 as a promising disease-modifying therapeutic target for BTHS.

cell biology↗

bioRxiv2026

Structural basis for differential inhibition of THIK1 by chemically related inhibitors

TWIK-related halothane-inhibited potassium channel 1 (THIK1) is a two-pore domain potassium (K2P) channel highly expressed in microglia that contributes to microglial homeostasis and neuroinflammatory responses. Pharmacological inhibition of THIK1 suppresses tonic K+ currents and attenuates NLRP3-dependent IL-1{beta} release, highlighting THIK1 as a potential therapeutic target for neuroinflammatory disorders. However, the structural basis of THIK1 inhibition remains unclear. Here we report cryo-electron microscopy (cryo-EM) structures of full-length human THIK1 in complex with C101248, a commercially available tool compound, and CVN293, a clinical-stage inhibitor that has completed Phase I evaluation. The two inhibitors occupy a similar site within the inner vestibule formed by TM2 and TM4 beneath the selectivity filter. Consistent with their closely related chemical scaffolds and shared binding site, both inhibitors remodel the Y273 inner gate but differ in their effects on the C-terminal gate. Electrophysiological analyses further demonstrate that the C-terminal gate contributes differently to inhibition by the two compounds. Together, our findings show how chemically related inhibitors exert different effects on THIK1 despite engaging a common binding site.

biophysics↗

bioRxiv2026

EukaUTR: a foundation model for functional modelling and design of eukaryotic 3' UTRs

Eukaryotic mRNA 3' UTRs encode regulatory information that shapes post-transcriptional control, RNA fate and gene expression. However, a 3' UTR-specific foundation model that spans broad eukaryotic sequence diversity while supporting both functional prediction and sequence design is lacking. Here we present EukaUTR, a 3' UTR-specific foundation model trained on a large-scale eukaryotic 3' UTR sequence corpus spanning diverse evolutionary lineages. Across 13 prediction tasks spanning post-transcriptional regulation, RNA fate and expression output, EukaUTR models matched or exceeded the strongest external baselines on nearly all tasks, with relative improvements of up to 27.45%. EukaUTR also generated de novo 3' UTRs with natural-like sequence and regulatory properties. EukaUTR-Guide further derived stability-associated signals from small sequence sets to guide editing towards enhanced predicted stability. Together, EukaUTR provides a sequence-to-function-to-design framework for transferable 3' UTR modelling and design.

bioinformatics↗

bioRxiv2026

CodonMamba: a foundation model for programmable mRNA coding sequence design

Although mRNA codon language models provide a generalizable framework for biological sequence design, effective CDS design requires both a learned sequence design space that captures biological constraints and context-configurable design preferences. Here we present CodonMamba, a codon language model framework for mRNA prediction and programmable CDS design. Pretrained on large-scale coding-sequence corpora, CodonMamba achieved state-of-the-art performance across a comprehensive benchmark of 12 mRNA prediction tasks, ranking first on 10 of 12 tasks. Furthermore, CodonMamba establishes a programmable CDS design framework, transforming codon optimization from a process dependent on preferences embedded during model training into an inference-time steerable generation framework. By introducing user-specified codon usage priors during generation, CodonMamba enables inference-time steering toward host- or application-specific codon preferences without retraining. In design experiments, CodonMamba enabled coordinated optimization over multiple design-relevant sequence properties and demonstrated programmable cross-host CDS retargeting through inference-time prior switching, while preserving most model-derived codon choices. Together, these results establish CodonMamba as a programmable foundation model framework for CDS design, enabling context-specific mRNA sequence engineering and highlighting a promising direction for precise mRNA design using foundation models.

bioinformatics↗

bioRxiv2026

Plasma titration provides a physical ruler for cross-platform proteomics

Plasma proteomics is expanding across platforms and cohorts, and integrating these data for AI demands comparability at the protein level, not merely concordant associations1,2. Affinity and MS platforms use distinct probes (antibodies, aptamers, or peptides) and signal readouts, yielding contradictory cross-platform results3,4. Without a known quantitative truth, we cannot distinguish biology from measurement distortion, leaving no gold standard for integration. Here we introduce Plasmix--a plasma reference suite with predefined male:female ratios (M, 1:0; Y, 3:1; P, 1:1; X, 1:3; F, 0:1)--and show that preserving this quantitative titration gradient, not just technical repeatability, predicts cross-platform concordance and identifies protein measurements suitable for integration. Profiling Plasmix across five platforms (Olink, SomaScan, NULISA, AAgAtlas, and MS-DIA) and 12 protocols across 17 batches, we found discordance is dominated by signal generation, not sample identity, and platforms distort signals in a protein-specific manner. Crucially, proteins retaining the titration response showed stronger agreement in an independent cohort; anchoring to the Plasmix midpoint (P) via sample-to-reference ratios reduced distortions, extending harmonizable coverage by 10-20%. Plasmix thus provides a physical ruler to benchmark accuracy, identifying genuinely integrable measurements before pooling datasets or training AI models--a critical bottleneck for plasma proteomics.

molecular biology↗

bioRxiv2026

Mechanism of branched actin assembly at microtubule tips downstream of Adenomatous Polyposis Coli (APC) protein

During cell migration, branched actin filaments nucleated by the Arp2/3 complex induce leading edge protrusions, whereas directionality of cell migration is controlled by microtubules. We showed previously that Adenomatous Polyposis Coli (APC) initiates branched actin assembly at microtubule tips, which can explain how microtubules control directional protrusion. Here, we investigate a link from APC to Arp2/3 complex activity. We show that protrusion-generating activity of APC resides in its N-terminal region containing the Armadillo Repeat Domain (ARD). Furthermore, Asef1/ARHGEF4, a Cdc42 GEF known to be activated by the ARD of APC, as well as Cdc42 itself and its effector N-WASP, an Arp2/3 complex activator, are all required for the assembly of branched actin filaments in neuronal growth cones and neurite outgrowth. As downregulation of Asef1, Cdc42 or N-WASP produces phenotypes similar to APC knockdown, we propose that microtubules regulate directional cell migration and neuron navigation by inducing local membrane protrusion through the APC - Asef1 - Cdc42 - N-WASP - Arp2/3 pathway. These findings bridge a significant gap in our knowledge of cell migration.

cell biology↗

bioRxiv2026

Screening of Isolation and Culture Conditions of Lactic Acid Bacteria in Mongolian Horse Feces

ObjectiveThis study aimed to establish an efficient isolation, culture, and preservation system for lactic acid bacteria from Mongolian horse feces by systematically evaluating the effects of sampling methods, culture conditions, media types, and cryopreservation protocols. MethodsFecal samples were collected using rectal and natural defecation methods, and bacteria were isolated by the spread plate technique, with isolates subcultured and identified via 16S rRNA gene sequencing. The performance of five commercial media (A-E), aerobic versus anaerobic conditions, and different glycerol concentrations (10% and 30%), temperatures (-20 {degrees}C and -80 {degrees}C), and storage durations (7, 15, and 30 days) were compared. ResultsRectal sampling showed significantly higher lactic acid bacterial survival and greater species diversity (12 vs. 8). Anaerobic culture yielded substantially higher counts and diversity (707 strains, 12 species) compared to aerobic conditions (36 strains, 5 species). Medium C (M.R.S. AGAR) exhibited the best isolation performance, producing the highest number of strains (311) and species (11), with selective enrichment for both bacilli and cocci. Glycerol effectively improved strain survival during sample cryopreservation, with the optimal short-term storage ([≤]15 days) achieved at -20 {degrees}C with 30% glycerol. Functional screening of randomly selected strains from optimized conditions demonstrated promising growth, acid and bile salt tolerance, and antimicrobial activity. ConclusionRectal sampling combined with anaerobic incubation using Medium C is recommended for optimal isolation. For samples that cannot be processed immediately, short-term preservation at -20 {degrees}C with 30% glycerol prior to isolation is effective. This study provides practical technical references for the acquisition and preservation of equine intestinal lactic acid bacteria resources.

microbiology↗

bioRxiv2026

Health-associated gut bacteriocins target TLR4 to suppress intestinal inflammation

The human microbiome maintains host immune homeostasis by secreting bioactive metabolites. However, extending beyond well-characterized metabolites, the functions of most microbiome-encoded peptides remain poorly defined. In this study, we developed a multi-cohort metagenomic framework to profile protective class II bacteriocins--unmodified, ribosomally synthesized peptides--that are enriched in healthy individuals but depleted in patients with inflammatory bowel disease (IBD). We have designated these health-associated bacteriocins as gutcins. Two gutcins, which lack canonical antimicrobial activity, potently attenuate intestinal inflammation in murine models. Cryo-electron microscopy (cryo-EM) reveals that one gutcin, named gutcin 03, directly engages the C-terminus of TLR4, blocking its dimerization and downstream inflammatory signaling. Guided by this structural interface, we generated truncated variants with enhanced potency, demonstrating the amenability of these simple peptides to rational optimization. Collectively, our findings reposition class II bacteriocins from antimicrobial agents to endogenous immunomodulatory effectors and establish a structural and mechanistic foundation for their development as next-generation therapeutics for inflammatory intestinal disorders.

microbiology↗

bioRxiv2026

METTL1 regulates glioma proliferation through internal m7G methylation of EPHA2

BackgroundMethyltransferase-like 1 (METTL1) is highly expressed in organs like the pancreas but less so in the brain. The METTL1-WDR4 complex catalyzes N7-methylguanosine (m7G) methylation in tRNA, miRNA, mRNA, and rRNA, which impacts RNA stability and function. These modifications affect mRNA translation and tRNA functionality, influencing protein production and cellular activities. Such modifications can regulate tumor growth, invasion, and metabolism by selectively controlling protein expression. MethodGene expression data from public databases were analyzed to compare METTL1 expression in normal and tumor tissues. Western blot (WB) and immunohistochemistry (IHC) were used to quantify METTL1 levels in glioma samples and assess their prognostic significance. Cell viability, migration, invasion, and proliferation were evaluated using Cell Counting Kit-8 (CCK-8), wound healing, Transwell, cell cycle analysis, and colony formation assays. RNA immunoprecipitation PCR (RIP-PCR) identified m7G methylation sites on EPHA2 mRNA, and RNA stability was assessed with actinomycin D. ResultsBioinformatics analysis revealed that METTL1 is overexpressed in gliomas, correlating with poor prognosis. Knockdown of METTL1 significantly affected cell proliferation, migration, and invasion. RNA sequencing (RNA-seq) and m7G analysis identified EPHA2 as a downstream target, influencing the cell cycle via the AKT pathway. RIP and methylated RNA immunoprecipitation (MeRIP) confirmed two m7G sites on EPHA2 mRNA regulated by METTL1. Small interfering RNA (siRNA)-mediated METTL1 knockdown in EPHA2 mutants affected mRNA stability. Rescue experiments restored cell proliferation and AKT pathway gene expression. ConclusionMETTL1 methylates EPHA2 mRNA, enhancing its stability and expression, which activates the AKT signaling pathway and influences glioma cell proliferation. METTL1 could be a potential therapeutic target in glioma treatment.

cell biology↗

bioRxiv2026

UTRGen: A unified framework for full-spectrum design of mRNA 5' UTRs

AO_SCPLOWBSTRACTC_SCPLOWThe 5' untranslated region (5' UTR) is a key regulatory element that governs mRNA translation and protein output. However, existing computational methods typically address isolated tasks such as functional prediction or sequence optimization, limiting their ability to support rational design across the full 5' UTR engineering workflow. Here, we present UTRGen, a unified modeling framework for 5' UTRs that integrates sequence generation, multi-property prediction, and constrained function-guided design. UTRGen is pre-trained autoregressively on large-scale 5' UTR datasets from multiple species and subsequently adapted to diverse downstream regulatory tasks. Across systematic evaluations, UTRGen generates novel and diverse 5' UTRs while preserving sequence, structural, and functional characteristics of natural UTRs. After task-specific fine-tuning, UTRGen achieves state-of-the-art performance across 14 benchmark datasets, improving translation efficiency prediction by up to 11.1%, expression level prediction by up to 13.2%, and mean ribosome load prediction by up to 3.0% relative to the strongest baselines. It also achieved the best overall performance for internal ribosome entry site identification. To enable controllable design, we formulate function-guided 5' UTR design as a GRPO-based refinement process over a pre-trained autoregressive sequence prior, using composite rewards to encode functional objectives and biological constraints while regularizing toward the natural 5' UTR distribution. The resulting sequences show consistently improved predicted translation efficiency and expression levels across cellular contexts, and reveal interpretable sequence features associated with high activity, including reduced C content, fewer upstream AUGs, and depletion of inhibitory motifs. Together, our results establish a unified modeling strategy for 5' UTR design and lay a foundation for programmable control of translation.

bioinformatics↗

bioRxiv2026

Secreted ORF8 reprograms macrophages to enhance SARS-CoV-2 infection of lung epithelial cells

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily targets the respiratory epithelium, yet severe disease features diffuse lung injury and hyperinflammatory syndromes driven by dysregulated immune activation. Emerging evidence indicates that resident and infiltrating immune cells in the lung can encounter the virus early in infection and, under specific conditions, become infected (1, 2). This process amplifies local inflammation and facilitates viral propagation in the lower airways and distal lung regions (3, 4), where angiotensin converting enzyme 2 (ACE2) expression is limited (5, 6). However, how epithelial and immune cell compartments interact to produce the hallmark pulmonary pathology of SARS-CoV-2 infection remains unresolved. Here we show that secreted ORF8, a SARS-CoV-2 accessory protein, drives inflammatory lung pathology by increasing macrophage permissiveness to infection, triggering pyroptosis, and amplifying viral replication in alveolar epithelial cells. Co-culture of macrophages with human alveolar type II (AT2) cells overrides ORF8s previously reported inhibition of AT2 infection (7, 8), restoring productive viral replication. In vivo, IL-17RA blockade counteracts ORF8 activity, lowering viral burden and attenuating pulmonary inflammation and fibrosis. These findings reveal a paracrine role for ORF8 in reprogramming macrophages, thereby establishing a feedforward proviral circuit that accelerates lung pathology in COVID-19 and are clinically relevant given the recurrent emergence of SARS-CoV-2 variants with either intact or deleted ORF8 since the beginning of the pandemic.

microbiology↗

bioRxiv2026

Inhibition of Soluble Epoxide Hydrolase Rescues Cognitive Deficits by Preserving Neurovascular Integrity and Attenuating Glial- and Neuropathology in Diabetic-Related Dementia

Diabetes mellitus (DM) is a major risk factor contributing to the development of Alzheimers disease-related dementias (ADRD). While one of the early symptoms of both Alzheimers disease (AD) and DM-related ADRD is a reduction in cerebral blood flow, the underlying biological mechanisms driving this decline remain to be fully elucidated. Genome-wide association studies have linked AD/ADRD to single-nucleotide polymorphisms in the gene encoding soluble epoxide hydrolase (sEH), an enzyme we previously reported to be upregulated in the brains of an AD rat model. Our previous work also demonstrated that chronic inhibition of sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) preserves hippocampal-dependent spatial learning and memory and improves cerebral hemodynamics in both AD and DM-ADRD models. In the present study, we found that chronic TPPU treatment (1 mg/kg/day for 9 weeks) reduced brain sEH expression, improved cortical-based long-term non-spatial recognition memory involving both cortical and hippocampal networks, and reduced anxiety in DM-ADRD rats. TPPU improved brain perfusion and normalized impaired whisker-evoked functional hyperemia, an effect linked to upregulation of Kir2.1 expression in cerebral capillaries. Furthermore, TPPU restored tight junction proteins (ZO-1 and OCLN), mitigated capillary rarefaction, and suppressed astrocyte and microglial activation. At the cellular level, TPPU attenuated hippocampal neurodegeneration, restored the expression of synaptic proteins (PSD95 and SY38), and reduced levels of key pro-inflammatory chemokines, including MCP-1, RANTES, and MIP-1, in DM-ADRD. In conclusion, TPPU preserves cognitive function in DM-ADRD by mitigating cerebrovascular dysfunction, neuroinflammation, and gliosis while protecting synaptic integrity and neuronal survival, representing a promising therapeutic strategy for DM-ADRD.

neuroscience↗

bioRxiv2026

Dissociating volatility and stochasticity reveals transdiagnostic computational signatures of psychopathology

Adaptive learning requires distinguishing volatility, changes in the latent state of the environment, from moment-to-moment stochasticity of observations. The two demand opposite adjustments to the learning rate: volatility calls for faster updating, stochasticity for slower. Disentangling them is computationally difficult because both inflate experienced variance, leaving the inference prone to systematic individual differences with potential consequences for psychopathology. Three computational phenotypes capture this variation: intact learners; stochasticity-blind learners, who over-update by treating noise as change; and volatility-blind learners, who under-update by treating change as noise. In two large online samples and across three tasks, we found a double dissociation between these phenotypes and transdiagnostic psychiatric dimensions: stochasticity-blind learners scored higher on Internalizing (anxiety, depression), volatility-blind learners on Externalizing (behavioral addiction, compulsivity). Distinct symptom dimensions thus correspond to distinct failures of inference about uncertainty, supporting a selective rather than generalized account of learning-under-uncertainty deficits in psychopathology.

neuroscience↗

bioRxiv2026

Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function

Cardiolipin (CL) is a four-acyl chained, mitochondrial-specific phospholipid crucial for maintenance of inner mitochondrial membrane (IMM) structure and function. In healthy tissues, CL acyl chains are highly unsaturated and maintained by a conserved remodeling pathway. However, dysregulation of CL acyl chain composition can arise from mutations in the CL transacylase, Tafazzin (TAZ), resulting in Barth syndrome (BTHS), where patients exhibit heightened mitochondrial dysfunction. Cells lacking TAZ accumulate three-acyl chained monolysocardiolipin (MLCL) as well as CL species with saturated acyl chains (CLsat). While the presence of MLCL destabilizes electron transport chain (ETC) complexes and IMM-shaping proteins, the contributions of CLsat to mitochondrial dysfunction have not been elucidated. Here, we find that treatment of TAZ knockout cells with exogenous saturated fatty acids causes accumulation of CLsat and loss of IMM structure despite only minimal changes in MLCL composition. Imaging of cells with elevated CLsat showed reduced fluidity of the inner membrane. Biophysical measurements and molecular dynamics analyses showed that di-saturated (C16:0 18:1)2 CL species order and rigidify membranes, while also losing the intrinsic lipid curvature characteristic of tetra-unsaturated CL. These results implicate CLsat as a potential driver of mitochondrial dysfunction and an additional therapeutic target in mitigating BTHS pathology.

cell biology↗

bioRxiv2026

EthoClaw: An Integrated AI Workflow Platform for Automated Analysis in Neuroethology

Computational methods have advanced the analysis of animal behavior, yet significant challenges remain in data standardization, analytical reproducibility, and workflow integration. Existing computational solutions often demand extensive programming proficiency or compel users to navigate a highly fragmented ecosystem of disconnected tools for tracking, statistical analysis, and visualization. Here, we present EthoClaw, an open-source, artificial intelligence-driven workflow platform built upon the OpenClaw agentic framework, functioning as a locally deployable AI assistant for behavioral research. EthoClaw provides an integrated computational infrastructure that seamlessly bridges the gap between raw behavioral video acquisitions and publishable scientific results. In this study, we demonstrate the platforms capacity to natively ingest video data via a dual-mode tracking architecture: utilizing ultra-fast image processing for rapid object detection, and leveraging the SuperAnimal methods for precise, markerless postural tracking. To ensure maximal interoperability, EthoClaw automatically converts various tracking data formats into DeepLabCut-compatible formats, enabling high-throughput phenotyping by generating publication-quality visualizations alongside rigorous multidimensional statistical profiling. Furthermore, the platform incorporates a large language model (LLM)-driven reporting module that dynamically synthesizes analytical documents, ensuring methodological transparency. Through an open field test, we validate the practical usability of EthoClaw while accelerating computational throughput by localizing heavy video processing to circumvent cloud bandwidth bottlenecks. Operating via an omnichannel natural language interface that integrates seamlessly with ubiquitous instant messaging software, EthoClaw democratizes advanced computational behavioral analysis, offering a holistic, highly efficient ecosystem that enforces experimental reproducibility and open science principles.

animal behavior and cognition↗