Biology subjects

Chen, M.

Publications and source records attributed to Chen, M..

At least 91 records · Page 5Linked to original sources

bioRxiv2026

Vitamin D3 attenuates nitrogen mustard-induced dermal toxicity by enhancing microbial butyrate production via the intestinal VDR-α-defensin signaling pathway

Nitrogen mustard (NM)-caused severe cutaneous damage lacks effective targeted therapies. Vitamin D3 (VD3) shows promise as a therapy for NM-induced dermal toxicity; however, the underlying mechanisms remain elusive. Herein, we initially confirmed that NM induced gut flora dysbiosis, characterized by a decrease of Akkermansia muciniphila (AKK) abundance, thereby leading to butyrate reduction. Antibiotics (ABX) significantly promoted NM-induced skin injury, whereas fecal microbiota transplantation of the controls feces (HC-FMT) or AKK administration attenuated NM-induced dermal toxicity. HC-FMT or AKK significantly increased butyrate levels in feces and serum of NM-treated mice. Butyrate notably attenuated ABX-caused acceleration of NM-induced skin injury. Meanwhile, NM markedly decreased the expression of -defensins, MMP7, and VDR. NM failed to further decrease AKK abundance and BA contents in intestinal MMP7-deficient mice, which was abolished by human alpha defensin 5 (HD5) overexpression. And intestinal MMP7 deficiency enhanced NM-caused skin injury, which was markedly attenuated by HD5 overexpression, AKK transplantation, or BA supplementation. Moreover, NM also failed to further reduce MMP7 and -defensin expression, AKK abundance, and butyrate levels in intestinal VDR-silenced mice. Finally, VD3 remodeled the gut microbiome particularly enriching AKK, increased butyrate contents and promoted the expression of -defensins, MMP7, and VDR, thereby attenuating NM-induced skin damage. The protective effect of VD3 against NM-caused dermal toxicity was abolished by either ABX or intestinal-specific knockdown of MMP7 or VDR in mice; however, this impairment was reversed by butyrate or AKK. In conclusion, VD3 attenuated NM-caused dermal toxicity by promoting BA production via remodeling the gut microbiota, and this effect was partially mediated by the intestinal VDR--defensin signaling pathway. These highlight that targeting the gut flora or supplementing with BA could be potential therapies for NM-induced dermal toxicity.

molecular biology↗

bioRxiv2026

Synergistic action of different molecular mechanisms causes striking levels of insecticide resistance in the malaria vector Anopheles gambiae

Intensifying insecticide resistance in the malaria vector Anopheles gambiae poses a serious threat to the hard-won gains in reducing malaria deaths in Africa. The genetic basis of insecticide resistance is often complex, involving multiple genes and mutations. However, we still lack a clear understanding of how each mechanism contributes to overall resistance and how highly resistant phenotypes arise. In this study we generated a suite of transgenic An. gambiae strains carrying either individual mechanisms or combinations that frequently co-occur in nature. We show that co-overexpression of different classes of detoxification enzymes (CYP6P3, CYP6M2, CYP9K1, ABCH2, GSTE2 and COEAE6G), as well as the overexpression of detoxification enzymes in the presence of target site resistance mutations, can lead to substantially greater levels of resistance. Our findings suggest that increased resistance strength is a primary driver for selection of multi-mechanism resistance and are transformative for the scientific insight required to design robust molecular diagnostics for timely and reliable resistance detection in the field. We further show that P450 based resistance can constitute an Achilles heel for highly resistant mosquitoes, making them more vulnerable to pro-insecticides; compounds that typically require P450 activation. Our results advance our understanding of the mechanistic basis of insecticide resistance and have important implications for the design and implementation of effective and evidence-based resistance management strategies.

genetics↗

bioRxiv2026

A Long-Context Generative Foundation Model Deciphers RNA Design Principles

Programmable design of RNA sequences with defined functions remains a central challenge in biology. Despite recent advances, existing RNA generative models lack robust controllable design capabilities and are constrained by short context windows, limiting their capacity to model the complex evolutionary manifold of full-length transcripts. Here, we introduce EVA (Evolutionary Versatile Architect), a long-context generative RNA foundation model trained on over 114 million full-length RNA sequences spanning the full breadth of evolutionary diversity. By integrating a Mixture-of-Experts architecture with an 8,192-token context window, EVA learns a unified, evolution-consistent representation of RNA sequence space that captures both global transcript structure and fine-grained functional elements. EVA establishes a unified framework for a broad spectrum of RNA design tasks within a single architecture, ranging from mutational fitness prediction to context-aware sequence engineering. We demonstrate EVAs versatility through the de novo design and targeted optimization of diverse RNA classes, including tRNAs, aptamers, and CRISPR guide RNAs, as well as mRNA and circular RNA therapeutics. In systematic evaluations, EVA achieves state-of-the-art performance across seven of nine established benchmarks, improving structural modeling accuracy by up to an order of magnitude compared to existing approaches. EVA is fully open-source at the following repository: https://github.com/GENTEL-lab/EVA.

molecular biology↗

bioRxiv2026

Quinone reductase 2 reads H3 serotonylation to support neuronal maturation

Histone H3 Gln5 serotonylation (H3Q5ser) is a recently described posttranslational modification1 that plays important roles in guiding transcriptional permissiveness in brain and peripheral systems2-5. H3Q5ser has been implicated in diverse physiological and pathological processes ranging from neural differentiation1 to sensory processing6, circadian rhythmicity7, stress responsivity8, placental gene regulation9, and tumorigenesis10-19. Since H3Q5ser can occur in combination with H3 Lys4 trimethylation (H3K4me3), most mechanistic studies to date have focused on H3Q5sers roles in modulating H3K4me3 reader interactions, where it has been shown to potentiate TAF3/TFIID binding to H3K4me31,20,21 and inhibit the recruitment of K4me3 demethylases21; however, whether H3 serotonylation functions as an autonomous chromatin signaling mark through dedicated reader proteins has remained unknown. Here, using a combination of proteomic-, structural-, molecular-, epigenomic-, and cellular-based approaches, we demonstrate that the Quinone reductase 2 (QR2) enzyme reads H3Q5ser independently of H3K4me3. CRISPR-Cas9-mediated disruption of H3 serotonylation or QR2s binding to the mark in human induced pluripotent stem cell-derived neurons impairs the establishment of neuronal transcriptional programs, alters synaptic connectivity, and disrupts electrophysiological maturation. These findings thus uncover an H3 serotonylation-dependent chromatin signaling axis that is essential for human neurodevelopment.

molecular biology↗

bioRxiv2026

HMA proteins produce 2',3'-cNMP signaling molecules and activate CNL-mediated immunity in rice

Plants deploy a sensor repertoire, usually NLRs, to perceive pathogen effectors and activate executor NLR-triggered immunity. Here we reveal that rice HMA proteins function as sensors detecting the Magnaporthe oryzae MAX effector AvrPigm to trigger broad-spectrum blast resistance mediated by the CNL PigmR. AvrPigm is conserved with multiple copies in blast genomes and targets HMA proteins, facilitating HMA translocation into the cytoplasm. Cryo-EM structure of the HPP04HMA reveals a filament-like oligomer with ssDNA/RNA bound inside the filament, which display cyclic nucleotide synthase activity to generate 2',3'-cNMP in a CNL-dependent manner. We further discovered that the LRR domains of the executor CNLs perceive 2',3'-cNMP to mount immunity. Our study thus establishes an unrecognized immunity mode with a distinct repertoire of sensor receptors that produce signaling molecules that are perceived by the LRR domains of executor NLRs to mediate immunity, shedding new light on the sensor-executor conception and immune activation in plants. HighlightsO_LIHMA proteins and CNL receptors form a new sensor-executor mode in plant immunity C_LIO_LICryo-EM reveals the filament-like structure of HMA-ssRNA/ssDNA C_LIO_LIHMA proteins are cyclic nucleotide synthetases to generate 2',3'-cNMP C_LIO_LILRR domains of CNLs perceive 2',3'-cNMP to mediate immunity C_LI

plant biology↗

bioRxiv2026

A nicotine biosensor derived from microbial screening

Physiologically relevant biosensors are in increasingly high demand, yet existing ones are severely limited in the number and type of biomarkers that are detected. The lack of biorecognition elements for most medically relevant biomarkers restricts the development of next generation single and continuous use monitors. Over billions of years, microbes have evolved a vast array of proteins to sense and metabolize small molecules, including those pertinent to human health. Of particular interest to us is the identification and subsequent integration of new microbial redox enzymes into electronic biosensors building off the established electrochemical technology of the continuous glucose monitor. Here we deploy genomic screening to identify analyte specific redox enzymes for biosensor development. As a proof of concept, we report the first electrochemical enzyme-based nicotine biosensor from a novel microbial enzyme, and use a variant with improved catalytic performance to enhance sensor performance. The biosensor detects nicotine over 0.4-100 M, a range relevant to nicotine concentrations present in active smoker sweat, saliva, gastric juice, and urine. This microbial mining approach for discovering redox enzymes expands the sensing parts toolbox available over conventional antibodies and aptamers.

bioengineering↗

bioRxiv2026

Loss of inwardly rectifying potassium channel Kir4.2 drives Parkinson's disease-like motor, cognitive and neuropathological features in mice

A critical barrier to therapeutic development in Parkinsons disease (PD) is the lack of endogenous genetic models that spontaneously recapitulate the diseases progressive, anatomically selective nigrostriatal pathology. Genetic studies have linked KCNJ15, encoding the inwardly rectifying potassium channel Kir4.2, to familial PD via a loss-of-function dominant-negative variant; however, its mechanistic role in neurodegeneration remains unexplored. Here, we demonstrate that Kcnj15-/- mice spontaneously develop a progressive PD-like phenotype, exhibiting a "coordination-first" motor syndrome, anxiety-like behavioural changes and spatial memory impairments. Crucially, neuropathology reveals selective degeneration of substantia nigra pars compacta neurons, sparing the ventral tegmental area, with marked microglial hyperactivation and phosphorylated -synuclein accumulation, faithfully recapitulating the topography of human PD. Striatal transcriptomics further reveals upregulation of oligodendrocyte- and myelin-associated genes, implicating compensatory glial remodeling. These findings identify Kir4.2 as a critical homeostatic regulator of nigrostriatal integrity and establish the Kcnj15-/- mouse as a new physiologically accurate and translatable model for PD research.

neuroscience↗

bioRxiv2026

Metabolic control of mitochondrial plasticity and extracellular vesicle biology drives Cryptococcus neoformans virulence

Metabolic adaptation to nutrient stress is a key but poorly understood driver of fungal virulence. Here, we show that a dominant East Asian lineage of Cryptococcus neoformans (VNIa-5), which disproportionately infects immunocompetent hosts, has undergone lineage-specific rewiring of glucose-responsive stress pathways. Integrating population genomics, transcriptomics, and experimental infection models, we demonstrate that VNIa-5s clinical dominance is not explained by environmental prevalence. Instead, selective activation of Snf1 signalling links glucose limitation to mitochondrial tubularisation, extracellular vesicle remodelling, and enhanced melanization. Under low-glucose conditions, VNIa-5 exhibits marked mitochondrial plasticity and extracellular vesicle compositional shifts resembling hypervirulent outbreak lineages of Cryptococcus gattii. Following experimental induction of dormancy, VNIa-5 shows significantly increased virulence in vivo compared with the closely related but clinically rare VNIa-31 subclade, with host survival tightly correlated with mitochondrial morphology. These findings identify metabolic stress integration as a central mechanism shaping cryptococcal virulence and disease in immunocompetent human hosts.

microbiology↗

bioRxiv2026

Diverse microbial metal resistance and novel metal cycling organisms in copper/nickel mine tailings

Mine tailings contribute to environmental heavy metal contamination through the formation of acid mine drainage (AMD). Microbially-mediated processes such as iron and sulfur redox cycling influence metal mobility. Here, we applied an integrated metagenomic and metaproteomic approach to profile microbial communities across vertical geochemical gradients in legacy copper/nickel tailings in Sudbury, Ontario, Canada. From 43 samples, we recovered 454 non-redundant metagenome-assembled genomes (MAGs), revealing diverse populations within the Actinobacteriota, Desulfobacterota, and uncultured lineages such as Candidatus Eremiobacterota and SZUA-79. Functional profiling identified 301 putative iron- and sulfur-cycling MAGs, including those within the Ca. Eremiobacterota and SZUA-79 phyla. Metal resistance genes were widespread and diverse, with abundances that did not correlate with measured metal concentrations. Proteomic data confirmed in situ expression of selected metal resistance genes and iron/sulfur metabolism genes, despite limited protein recovery from this challenging matrix. Our findings highlight both the depth of microbial diversity in metal resistance and metal biogeochemical cycling in mining waste, as well as the technical challenges that currently limit genomic and proteomic sequencing coverage in low-biomass, metal-rich matrices. This work also presents new protocols for multi-omics data capture and analysis from metal contaminated environments, including new protein extraction and bioinformatic gene annotation tools. HighlightsO_LIMetagenomics recovered 454 non-redundant MAGs from copper/nickel mine tailings, revealing high taxonomic novelty including uncultured Ca. Eremiobacterota and SZUA-79 lineages. C_LIO_LIA custom HMM-based pipeline targeting metal resistance genes uncovered a widespread and diverse set of metal resistance genes across MAGs in tailings, which did not correlate with metal concentrations. C_LIO_LIMetaproteomics validated in situ expression of both iron/sulfur cycling genes and metal resistance proteins, although low biomass and contamination limited proteomic sequencing coverage. C_LI

microbiology↗

bioRxiv2026

MMV687794 blocks Plasmodium falciparum invasion of red blood cells by targeting a Surface-associated Lipid-Interacting Rhoptry Protein, PfSLIRP

Invasion of red blood cells (RBCs) by the human malaria parasite, Plasmodium falciparum, drives disease. During invasion, the parasite pushes its way into the RBC while wrapping the RBC membrane around itself to establish the parasitophorous vacuole, a stable niche within the RBC where the parasite grows. To better understand invasion, we investigated the mechanism of action of an invasion-inhibitory compound, MMV687794 (MMV794). Lattice light-sheet microscopy revealed that MMV794 blocks parasite entry by preventing parasitophorous vacuole formation. In vitro drug resistance selection of parasites with MMV794 found mutations to the /{beta} hydrolase, PF3D7_0403800, and engineering one of these mutations (C36W) into parasites by CRISPR/Cas9 recapitulated the resistance phenotype. Expansion microscopy demonstrated that this protein is expressed in schizonts, localising to the surface of rhoptries, which are specialised apical secretory organelles that function during invasion. Lipidomics and proteomics analyses of C36W parasites uncovered widespread changes to lipid composition/homeostasis and altered abundance of proteins involved in invasion, indicating a role for PF3D7_0403800 in invasion-associated lipid metabolism. Finally, we used solvent-induced proteome profiling and reactivity assays to confirm drug-target engagement. Together, our findings identify a novel Surface-associated Lipid-Interacting Rhoptry Protein (PfSLIRP) that coordinates lipid metabolism at the rhoptries to enable RBC invasion.

microbiology↗

bioRxiv2026

Modulation of Intrauterine Adhesion Fibrosis by Lactobacillus delbrueckii: Insights from ERK1/2 Pathway Inhibition and Multi-omics Analyses

BackgroundIntrauterine adhesion (IUA) is an important cause of infertility and menstrual disorders, substantially reducing quality of life and increasing healthcare costs. Current treatments, including hysteroscopic adhesiolysis and hormonal therapy, show limited efficacy and high recurrence, highlighting the need for new therapeutic strategies. MethodsWe evaluated the antifibrotic effects of Lactobacillus delbrueckii in IUA, with a focus on ERK1/2 signaling inhibition. A multimodal framework integrating clinical outcomes, cellular and animal experiments, uterine microbiome profiling (16S rRNA sequencing), transcriptomics, and metabolomics was used to characterize host-microbe-metabolite interactions relevant to fibrosis. ResultsClinically, patients receiving L. delbrueckii showed lower adhesion formation scores(AFS) and reduced recurrence. Microbiome profiling demonstrated increased uterine microbial diversity and altered community composition in treated patients, accompanied by reduced expression of fibrosis-associated markers. In both cellular and mouse models, L. delbrueckii decreased fibrotic marker expression and reduced ERK1/2 phosphorylation. Metabolomics identified elevated 3-hydroxyanthranilic acid (3-HAA) in treated groups, suggesting a potential role in immune and inflammatory modulation. ConclusionL. delbrueckii attenuates IUA-associated fibrosis, at least in part, by suppressing ERK1/2 phosphorylation and increasing the abundance of the metabolite 3-HAA. These findings support the therapeutic potential of L. delbrueckii for improving uterine repair and reproductive outcomes. Future studies should validate efficacy and safety in larger, diverse cohorts and assess long-term outcomes.

microbiology↗

bioRxiv2026

Structural Rewiring of IL-7R Dimerization by an Oncogenic Transmembrane Mutation Can Be Reversed by Rational Design

Mutations within the transmembrane domains (TMDs) of single-pass transmembrane receptors often cause aberrant, ligand-independent receptor signaling associated with diverse malignancies, but their mechanism of action remain largely unknown. These TMD mutations are generally not targetable as they are buried in membrane. Here, we determined the mechanism of a gain-of-function (GOF) TMD mutation of interleukin-7 receptor (IL-7R) associated with T-cell acute lymphoblastic leukemia, and addressed the possibility of directly targeting the TMD mutation by using rationally designed transmembrane helices to restore order to uncontrolled signaling. We find that the GOF mutation of IL-7R severely shifts the TMD homodimerization interface, causing the receptor to homodimerize in a geometry that activates downstream signaling independent of ligand. Designed transmembrane helices that interfere with the new interface, delivered with mRNA technology, selectively block ligand-independent but not ligand-dependent signaling. Our study provides a conceptual framework for understanding and repairing disease-causing TMD mutations of single-pass cytokine receptors.

biophysics↗

bioRxiv2026

Zebrafish screen of schizophrenia risk genes reveals convergent dysregulation of cholesterol metabolism

Rare coding variants provide a tractable entry point for understanding the molecular mechanisms underlying schizophrenia risk. Here, we generated and characterized zebrafish lines with mutations in the orthologs of >20 human schizophrenia-associated genes, including eight of the top ten SCHEMA genes, genes disrupted in childhood-onset schizophrenia (COS), and genes located within recurrent copy number variants. Whole-brain phospho-Erk activity mapping and behavioral profiling identified phenotypes in multiple mutant lines. We prioritized a protein-truncating mutation in sp4, which encodes an activity-dependent transcription factor, and a COS-associated missense mutation in atp1a3a, which encodes a Na+/K+ ATPase pump, for additional characterization. Both knockout and point mutations in atp1a3a disrupted brain activity and behavior in larvae and impaired navigation of a Y-maze in juveniles. Bulk RNA sequencing data from adult sp4 and atp1a3a brains highlighted convergent upregulation of sterol biosynthesis pathways, including increased expression of srebf2 and msmo1. Analysis of previously published telencephalon single-cell data demonstrated that cholesterol synthesis genes are enriched in astrocyte-like cells and increase in expression during post-larval development. Consistent with transcriptomic findings, filipin staining indicated increased free cholesterol in juvenile sp4 and atp1a3a mutant brains. Our findings identify dysregulation of glial and sterol-associated programs as a shared molecular consequence of two distinct schizophrenia risk mutations. Although whether sterol pathway dysregulation represents a primary pathogenic mechanism or a secondary response to changes in neuronal activity requires further investigation, the convergence observed between genetic models and developmental stages suggests that disruptions to lipid homeostasis could represent a shared feature of schizophrenia disease biology.

genetics↗

bioRxiv2026

Mechanism of Gating and Isoform-Specific Inhibition in Renal CLC Chloride Channels

Hyponatremia is a prevalent disorder marked by excess water retention and substantial morbidity, motivating interest in the CLC-Ka chloride channel as a therapeutic target. Selectively inhibiting CLC-Ka without affecting the closely related CLC-Kb is essential for preventing serious side effects. However, developing isoform-selective inhibitors has been challenging because most small molecules do not distinguish between CLC-Ka and CLC-Kb, and the basis for selectivity in the few known exceptions remains unclear. The small molecule BIM1 preferentially inhibits CLC-Ka over CLC-Kb, providing an opportunity to dissect isoform-specific pharmacology. To investigate this mechanism, we determined cryo-EM structures of BIM1 and BIM15, a related nonselective analog, bound to a CLC-K variant engineered to match the human CLC-Ka binding pocket. Structural and computational analyses reveal that inhibition and isoform selectivity are anchored by interactions with a conserved lysine, with surrounding binding-site residues subtly tuning the local electrostatic environment to promote or disfavor these contacts. These analyses further identify a dynamic extracellular loop that intermittently occludes the shared pathway accessing the inhibitor-binding site and pore. Bound BIM15 engages this gating loop more extensively than BIM1, suggesting that differential loop engagement contributes to inhibitor selectivity, a prediction validated by mutagenesis. Because loop dynamics block the pore, we examined the structural impact of Ca{superscript 2}, which favors opening, and found the gating loop ordered and withdrawn from the pathway. Together, these findings define how binding-site microenvironments and gating-loop dynamics shape isoform-specific inhibition and pore access in CLC-K channels. Significance StatementHyponatremia is a major clinical problem with limited therapeutic options. The kidney chloride channel CLC-Ka is an attractive drug target, but its high sequence identity to CLC-Kb has hindered the development of isoform-selective inhibitors needed for safe therapy. A low-micromolar CLC-Ka-selective inhibitor had been identified, providing a foothold for drug development, but the structural basis of its selectivity was unknown. Here, by integrating cryo-EM structures with molecular dynamics simulations, we define the inhibitor-binding site and reveal the mechanism that enables preferential CLC-Ka inhibition. We further show that a dynamic extracellular loop functions as a gating element shaping inhibitor access and engagement. These findings establish a mechanistic foundation for developing improved treatments for hyponatremia.

biophysics↗

bioRxiv2026

Multi-agent reasoning enables predictive design of living materials

Artificial intelligence is increasingly used to accelerate scientific discovery, but most successful frameworks operate within well-defined molecular, protein or materials spaces. Living materials present a more formidable computational problem because functions emerge from context dependent coupling among cells, matrices, fabrication processes and evaluation conditions. Here we introduce LiveMat, a multi-agent reasoning framework that transforms unstructured literature into a computable design space for living materials. LiveMat standardizes 34,215 living material records, integrating 16,769 microorganism and 17,446 polymer entries into a knowledge graph linking living components, abiotic matrices, functional outputs, evaluation contexts and performance metrics. Benchmarking across five large language models shows that living material reasoning is limited mainly by cross-domain feature integration rather than coarse classification. LiveMat overcomes this limitation through constraint decomposition, provenance-aware extraction, consistency checking and expert-anchored ranking. In a prospective wound-healing task, it prioritizes a four-component design with state-of-the-art in vivo performance, establishing a scalable infrastructure for interpretable, evidence-grounded living material discovery.

biochemistry↗

bioRxiv2026

Mitigating CYP450-Mediated Insecticide Resistance in Malaria Vectors with Cannabis-Derived Synergists: The Potential of Cannabidiol

Insecticide resistance in mosquitoes, largely mediated by cytochrome P450 monooxygenases (CYPs), compromises the efficacy of vector control tools. In this study, chemically-wise selected natural extracts and compounds were screened for their CYP inhibition potential. Among 37 tested plant extracts and fractions, a decarboxylated acidic fraction of industrial hemp (Cannabis sativa Linnaeus var. Futura 75) emerged as a promising hit, and phytochemical profiling identified cannabidiol (CBD) as its major component (IC = 18.37 M for CYP9K1). CBD was used as a scaffold to generate semisynthetic analogues; of which a piperazinyl analogue outperformed the natural scaffold demonstrating significantly greater potency (IC = 2.50 M for CYP9K1). Docking studies using homology-derived CYP9K1 models also supported a stronger binding affinity of the piperazinyl analogue relative to CBD. Toxicity assays using pyrethroid-resistant Anopheles gambiae Giles adults confirmed that neither CBD nor the piperazinyl analogue had intrinsic toxicity, yet the semisynthetic analogue significantly enhanced deltamethrin efficacy, showing a threefold synergistic effect. The safety profile of the cannabis compounds for non-target organisms was evaluated through human cell line cytotoxicity tests and bee toxicity assays, suggesting low non-target organism toxicity. Our study describes the identification of a plant-derived synergist lead with strong potential as an insecticide additive to combat metabolic resistance in malaria-transmitting mosquitoes.

pharmacology and toxicology↗

bioRxiv2026

MAMBAxBrain: A Multi-task Neural Framework Linking Brain Functional Dynamics to Individual Fingerprints, Cognitive and Disease States

Functional magnetic resonance imaging (fMRI) contains rich individual, cognitive, and pathological information, yet no universal model exists for multi-task modeling of these dimensions. Here, we introduce MAMBAxBrain, a multi-task neural framework that integrates Mamba architecture with functional connectivity analysis to jointly model the temporal dynamics and spatial coordination of neural activity. MAMBAxBrain achieves high accuracy across four distinct fMRI objectives--brain fingerprinting, cognitive task decoding, reaction time prediction, and schizophrenia classification--consistently outperforming state-of-the-art methods with robust crosssession generalization. Interpretability analyses show that each task engages distinct, biologically plausible circuitry--from higher-order association cortex for identity to subcortical-motor loops for reaction time and disrupted control-sensory connectivity for schizophrenia. These findings inform a longstanding debate: rather than operating through wholly separate or entirely shared systems, the brain preferentially recruits task-specific circuits while retaining common representational structure across functions.

neuroscience↗

bioRxiv2026

Autoregressive forecasting of future single-cell state transitions

Predicting future cell state transitions from static transcriptomic snapshots is vital for understanding and steering cellular dynamics. Although existing trajectory and RNA velocity methods can infer local transitions within observed data, they are fundamentally limited in extrapolating long-range cellular dynamics. Here, we introduce CellTempo, an autoregressive generative framework that enables long-range forecasting of cell state trajectories directly from static transcriptomic snapshots. CellTempo is pretrained on scBaseTraj, a large-scale collection of multi-step cellular transition sequences constructed by integrating diverse experimental technologies and data sources. Across diverse biological systems, CellTempo accurately predicts long-range lineage progression and reconstructs unseen cellular potential landscapes. It further distinguishes transient perturbation responses from long-term cell-fate changes, enabling prioritization of candidate compounds for cell-fate engineering. These results demonstrate that long-range cellular dynamics are inferable from static observations, establishing a foundation for predictive and controllable modeling of cell fate.

bioinformatics↗