Biology subjects

Zhang, M.

Publications and source records attributed to Zhang, M..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

LARP4 is a B cell-specific metabolic checkpoint for plasma cell differentiation and a therapeutic target in systemic lupus erythematosus

RNA-binding protein LARP4 plays an important role in T cell activation and differentiation, but its role in B cell biology and the pathogenesis of systemic lupus erythematosus (SLE) remains unclear. This study found that LARP4 was specifically highly expressed in B cells of SLE patients and was positively correlated with disease activity. By constructing T cell-specific and B cell-specific conditional knockout mice, we found that deletion of LARP4 in B cells, but not in T cells, significantly alleviated pristane-induced and Bm12-induced lupus nephritis. Further analysis showed that LARP4 deletion selectively inhibited B cell differentiation into plasma cells, but did not affect germinal center B cell formation. Integrated transcriptomic and metabolomics analyses revealed that this effect is due to reduced phosphatidic acid synthesis and decreased mTORC1 activity caused by mitochondrial oxidative phosphorylation dysfunction. Furthermore, we used LIPEP, a LARP4 inhibitory peptide that effectively mimicked the therapeutic effects of LARP4 gene knockout in the MRL/lpr spontaneous lupus model and outperformed cyclophosphamide in reducing glomerular immune complex deposition and improving extrarenal dermatitis. These results indicates that LARP4 is a key metabolic checkpoint regulating B cell differentiation into Plasma cells and suggest that it may be a potential therapeutic target for SLE.

immunology↗

bioRxiv2026

PFOS aggravates atherosclerosis via Bacteroides caecimuris expansion-driven bile acid remodeling and subsequent intestinal FXR-TLR3 signaling cascade

BACKGROUNDPerfluorooctane sulfonate (PFOS) is a widely distributed persistent organic pollutant in the environment and has been associated with an increased risk of atherosclerosis. However, the underlying pathogenic mechanisms remain largely unclear. This study aimed to investigate the effects of PFOS on atherosclerosis and its associated gut-vascular axis. METHODSPseudo-germ-free mouse models and fecal microbiota transplantation (FMT) were used to determine the role of the gut microbiota in PFOS-induced atherosclerosis. Metagenomic sequencing was performed to characterize alterations in gut microbial composition following PFOS exposure, and targeted metabolomics was used to assess bile acid profiles in the ileum and plasma. Transcriptomic analysis of Bacteroides caecimuris (B.caecimuris) was conducted to explore the reasons for the increased abundance of B.caecimuris after PFOS exposure. In addition, intestinal transcriptomics and ChIP-qPCR were performed to validate transcriptional regulation within the FXR-TLR3 signaling axis. RESULTSAmong 127 participants with paired serum and fecal samples, including 82 patients undergoing coronary angiography with Gensini scores (GS score), fecal PFOS levels were significantly associated with lipid profiles and GS score, whereas serum PFOS showed no such association.Mechanistically, PFOS exposure promotes intestinal enrichment of B.caecimuris by upregulating its tolC gene, thereby enhancing efflux capacity.This microbial shift was accompanied by reduced levels of tauro-ursodeoxycholic acid (TUDCA) and aberrant activation of intestinal FXR signaling.Further analyses demonstrated that FXR activation upregulated TLR3 expression and promoted inflammatory responses and atherosclerosis progression via the TLR3-NF-{kappa}B signaling axis. Both intestinal epithelial-specific FXR deficiency (Fxr{Delta}IE) and TUDCA supplementation significantly suppressed pathway activation and alleviated disease phenotypes.Functional experiments identified TLR3 as a key downstream effector of FXR. Overexpression of TLR3 abolished the protective effects observed in Fxr{Delta}IE mice. Moreover, pharmacological inhibition of TLR3 using CU CPT-4a significantly improved established atherosclerotic lesions in vivo. CONCLUSIONSThis study identifies a gut microbiota-driven FXR-TLR3 signaling axis that mediates PFOS-induced atherosclerosis. These findings provide new mechanistic insights into environmentally induced cardiovascular disease and suggest potential targets for risk assessment and therapeutic intervention.

pathology↗

bioRxiv2026

Topological data analysis captures complex behavioral dynamics during naturalistic social interaction between domestic ferrets

Capturing naturalistic behavioral dynamics is essential for understanding social interaction in ecologically valid settings. Existing investigations of naturalistic social interaction rely on time-aggregated analysis methods better suited for task-based experiments, which lose the complex, moment-to-moment dynamics exhibited in naturalistic settings. The emerging field of topological data analysis (TDA) provides new tools to characterize fine-grained dynamics in time-series data that cannot be captured by time-averaged methods. The present work utilizes Temporal Mapper, a recently developed TDA specifically tailored to analyzing dynamical systems. Temporal Mapper characterizes complex temporal dynamics as transition networks, where nodes are stable states and edges are transitions between states. Originally designed for human neural time series analysis, here we demonstrate the utility of Temporal Mapper to capture rich animal postural dynamics during naturalistic social interaction. We utilized an existing dataset with 12 video recording sessions of two domestic ferrets (Mustela putorius furo) during naturalistic interaction and tracked the postures of animals during social interaction. Ferrets were chosen due to their strong social-cognitive skills and rich postural dynamics for investigating social behavior via posture estimation. Temporal Mapper was then used to represent the postural dynamics as transition networks for each recording session. Here, we found that posture states are significantly smaller and more widespread during active social interaction compared to non-social activities. Additionally, the number of sequential postural states before transitioning to new behaviors is more consistent during active social interaction than non-social activities. Together, our findings suggest that social activity has a broad range of unstable postural states arranged in consistent sequences. Our method, Temporal Mapper, allows for network structure analysis of complex naturalistic data, applicable for characterizing rich dynamics in different species, scales, and paradigms.

neuroscience↗

bioRxiv2026

Multimodal computational framework identifies B cell convergence in autoimmunity and ageing

Identification of the origin of pathogenic immune cells is crucial for therapeutic interventions and diagnosis but pseudotime methods struggle to trace immune cells accurately. Current trajectory inference methods for B cell development and response in health and disease either ignore or underutilize antigen receptor sequence information, limiting their ability to resolve developmental pathways, particularly for pathogenic populations. Widely used methods such as Monocle 3 reconstruct developmental paths from transcriptomic similarity alone, discarding the features from immune receptors. Dandelion has combined the immune receptor features with transcriptomics but it struggles to simulate the trajectory path of B cells. Here we present ClonoTrace, a computational framework that integrates BCR sequence features with transcriptomic trajectory inference through gated fusion of multimodal embeddings. In fetal B cell development and germinal centre development, ClonoTrace achieves higher trajectory inference accuracy than Monocle 3 and Dandelion. Applied to systemic lupus erythematosus, ClonoTrace identifies memory B cell extrafollicular maturation pathway in addition to naive B cell, accompanied by induction of ZEB2 with a concomitant decline of BACH2 along the trajectory, as the alternative origin of pathogenic double negative 2 B cells (DN2) in systemic lupus erythematosus (SLE) patients. In healthy ageing, ClonoTrace identified three pathways from naive, IgM+ memory B cells and switched-memory B cells mature through a DN2-associated transcriptional state that precedes age-associated B cells. ClonoTraces fate probability algorithm indicated that IgM+memory B cell to ABC transition emerged as the leading candidate age-associated transition, that is a process distinct from SLE DN2 maturation. ClonoTrace provides a generalizable framework for receptor-informed trajectory inference, revealing the developmental pathways of pathogenic B cell populations that are untraceable to single modality approaches in autoimmunity and aging.

bioinformatics↗

bioRxiv2026

A CSF Proteomic Clock Reveals Opposing Brain-Aging Programs and Predicts Neurological Disease Progression

Aging is the risk factor for neurological disease, yet the molecular architecture of human brain aging remains poorly defined. Here, we analyzed more than 10,000 cerebrospinal fluid (CSF) proteomes across multiple cohorts and proteomic platforms to developed a 249-protein CSF aging clock that accurately predicts age and generalizes across independent datasets. CSF brain-age acceleration was increased across diverse neurological diseases, associated with blood-brain barrier (BBB) dysfunction, and predictive of longitudinal cognitive decline, neuroimaging progression, and dementia conversion. A simplified 30-protein panel retained similar prognostic performance. Biologically, clock proteins resolved two opposing programs: pro-aging activation of immune, vascular/BBB, ECM and coagulation pathways marked by CHI3L1, CD14, VWF, LRG1 and LTBP2, and anti-aging collapse of neuronal, synaptic, axonal and structural-maintenance programs marked by NPTX2, COL1A2, NID1, CDH8 and PENK. Brain-wide single-cell and regional mapping linked these programs to disease-vulnerable compartments. These findings establish a molecular framework for biological brain aging and neurological disease vulnerability.

neuroscience↗

bioRxiv2026

The contribution of recent and historical demographic histories to genomic diversity and conservation status in plant species

Demographic factors are intrinsically crucial to evaluate species extinction risk. However, measuring them remains difficult and time-consuming and the use of genomic summary statistics has been advocated to assess the conservation status of a species. In the present study, we estimated (i) the census number (Nc), (ii) effective population size (Ne) over three different time periods, recent, historical and ancient, (iii) neutral genetic diversity ({pi}4), and (iv) a measure of the efficacy of purifying selection ({pi}0/{pi}4) for 101 plant species using population genomic sequencing data. Twenty-one species are from the Plant Species with Extremely Small Populations (PSESP) program of SW China. Threatened species exhibited significantly lower Ne, Nc,{pi} 4, and weaker purifying selection, but had a higher Ne/Nc ratio than non-threatened ones. Nc was the main determinant in identifying conservation status, and contemporary neutral genetic diversity was predominantly influenced by historical Ne. In the absence of demographic information, genetic parameters are a good proxy of conservation status, likely because currently threatened species also had a low historical population size. In summary, our findings suggest that direct estimates of Nc are more useful than{pi} 4, although the latter remains a valuable conservation indicator. Hence, efforts such as the PSESP should be extended. Significance StatementExtinction is essentially a demographic process. However, evaluating the risk of extinction of species based only on demographic parameters remains a difficult task, and today only 18% of plant species are included in the International Union for Conservation of Nature (IUCN) Red List of Threatened Species. Here, we use demographic data and whole genomic data from 101 plant species to show that while census number remains the best predictor of extinction risk, genomic based parameters provide good alternatives. More specifically, current neutral nucleotide diversity and historical effective population size are good predictors of the extinction risk of plant species.

evolutionary biology↗

bioRxiv2026

A Spectrum of Free Energy Landscape Topologies Encodes Chromatin Polymorphism and Phase Separation

Chromatin exhibits structural polymorphism, yet how such substantial structural heterogeneity is encoded in its underlying free-energy landscape remains unknown. Here we map the folding landscapes of tetra-nucleosome arrays using adaptive Markov state models constructed from near-atomistic coarse-grained simulations. We find that chromatin is not governed by a single folding funnel analogous to those of many globular proteins. Instead, it spans a continuum of free-energy landscape topologies, ranging from funnelled to rugged to flat. Remarkably, phase separation reshapes chromatins free-energy landscape by stabilising conformations that maximise intermolecular connectivity, demonstrating that the landscape is determined not only by intrinsic molecular parameters but also by the environment and intermolecular interactions. Linker DNA geometry selects among landscape regimes through geometric frustration of zig-zag nucleosome stacking. At short and intermediate linker lengths, canonical 10N bp linkers produce funnelled landscapes dominated by compact zig-zag structures, whereas 10N +5 bp linkers generate rugged landscapes with multiple competing minima. Long linkers relieve frustration and flatten the landscape into a broad entropic basin. This control operates with single-base-pair precision, such that changing linker length by one base pair is sufficient to reorganise both the thermodynamics and kinetics of chromatin folding. DNA sequence provides a second level of control by modulating linker deformability, but only when zig-zag geometric frustration is present. These results establish free-energy landscapes as a framework for understanding the physical origin of chromatin polymorphism and its coupling to phase separation.

biophysics↗

bioRxiv2026

Systemic viral vector vaccination induces brain resident memory T cells to drive anti-glioblastoma immunity

Glioblastoma is a lethal brain tumor that is unresponsive to current cancer immunotherapeutic approaches, including immune checkpoint blockade (ICB). This suggests that initial priming of T cells, rather than their expansion and licensing as effectors, is a restricting feature in this tumor setting. To overcome the limited initiation of CD8+ T cell responses, we employed a strong heterologous prime-boost vaccination with the simian adenovirus ChAdOx1 and poxvirus modified vaccinia Ankara (MVA). Vaccination conferred therapeutic efficacy against orthotopic, immune checkpoint-blockade (ICB)-refractory SB28 murine glioblastoma. Vaccination was effective against both the murine tumor antigen, P1A, and a newly identified glioblastoma-associated antigen, Gpr149. Additional treatment with ICB provided no additional benefit. Systemic ChAdOx1/MVA vaccination induced robust infiltration of antigen-specific T cells in tumor-challenged brains, the majority of which exhibited a CD103+CD69+CD8+ tissue-resident memory (TRM)-like phenotype. These cells were polyfunctional, durable in brains with sustained tumor control, and mediated tissue-specific immunological memory. Moreover, intracranial adoptive transfer of glioblastoma-derived antigen-specific TRM-like cells was sufficient to protect naive recipients from subsequent orthotopic tumor challenge. Together, these findings establish that viral vector vaccination can generate tumor-specific TRM-like cells that mediate effective anti-glioblastoma immunity, providing a rationale for clinical evaluation of ChAdOx1/MVA-based strategies in glioblastoma.

immunology↗

bioRxiv2026

A Tripartite Map of the Ventromedial Prefrontal Cortex

The ventromedial prefrontal cortex (VMPFC) has been repeatedly implicated in affect, valuation, and social cognition, yet how these diverse functions are organized within a single cortical territory has remained unresolved. Here, we integrate large-scale meta-analysis, individual-level task fMRI, artificial neural-network encoding models, and multimodal connectivity analyses to reveal the internal functional architecture of the human VMPFC. Across four complementary studies, we identify a robust tripartite organization along the anterior-posterior axis, comprising posterior affective, middle valuation, and anterior social functional motifs. Connectivity fingerprinting demonstrates that each motif is preferentially embedded within distinct large-scale brain networks, providing a mechanistic account of VMPFC functional specialization. This organization is reproducible at the level of individual subjects, generalizes to naturalistic stimuli, extends across development, and shows cross-species correspondence with non-human primates and multiple neurobiological markers. Together, these findings resolve a long-standing organizational question and establish a biologically grounded framework for interpreting VMPFC function.

neuroscience↗

bioRxiv2026

Vascular and synaptic proteomes reveal blood-brain barrier disruption and postsynaptic remodeling in human temporal lobe epilepsy

Blood-brain barrier (BBB) dysfunction and mesial temporal lobe epilepsy (MTLE) are considered to be engaged in a pathological feedback loop, with the consequent worsening of both conditions. However, the molecular landscape of the disruptions at the synapse and the blood-brain barrier during MTLE remains poorly characterized. Here, we perform quantitative proteomics on paired brain microvessel and vessel-depleted postsynaptic density (PSD) enriched fractions isolated from the epileptic hippocampus and ipsilateral temporal pole of patients with drug-resistant MTLE. The microvessel fraction (1,541 proteins; 439 differentially expressed proteins (DEPs)) reveals loss of tight-junction and endothelial adhesion proteins together with pericyte markers, concurrent with a significant increase of fibrinogen, plasminogen, complement C3, GFAP, and enrichment for complement and coagulation cascades. The PSD enriched fraction (7,450 proteins; 1,881 DEPs) shows the consequences of BBB leakage with an increase of protein infiltration, alongside inflammatory and extracellular-matrix proteins, together with disruption of the pre- and postsynaptic signaling machinery and loss of GABAergic interneurons. Cross-referencing healthy-brain expression confirms that the dysregulation of the processes reflects disease-associated changes rather than regional differences. Immunohistochemistry confirms microvascular remodeling, pericyte loss, parenchymal fibrinogen extravasation, microglial activation and presynaptic marker depletion in the epileptic hippocampus. Ligand-receptor mapping reveals dysregulation of the neurovascular ECM-adhesion interface, with upregulated parenchymal ECM ligands and downregulated vascular integrin receptors. Network-proximity analyses nominate candidate disease-modifying compounds for reversing the combined vascular and synaptic MTLE signature. Together, these findings establish a molecular map of vascular and synaptic dysfunction in human MTLE.

neuroscience↗

bioRxiv2026

SCD1 inhibition synergizes with TMZ to improve IDH1 MUT glioma survival of mice via lipotoxic stress

Mutations in the isocitrate dehydrogenase enzyme (IDH1) are prevalent in low-grade gliomas, such as oligodendrogliomas. Other than surgery, radiation, and chemotherapy, few options for treatment exist. The standard of care for patients currently consists of maximal safe resection, as well as the potential use of radiation and chemotherapy, typically followed by radiographic surveillance. Although significant advances have been achieved, these have not translated into meaningful improvements in overall survival, warranting the development of novel therapies. Herein, we demonstrate that the inhibition of SCD1 in vitro leads to decreased colony formation and is more specific to IDH1MUT glioma than the IDH1WT cells, We further identified MF-438 as an active inhibitor of this enzyme and showed that this inhibitor is linked with iron transport and ferroptosis. MF438 depleted oleic (C18:1) and palmitoleic acid (C16:1) levels, driving saturated phosphatidylcholine (PC) accumulation and ER stress (INSIG1, SEL1L upregulation). TS603 exhibited selective polyunsaturated phosphatidylcholine reduction with downregulation of GPX4, FTH1, and KEAP1, and upregulation of NCOA4, SLC11A2, ALDH7A1, and DPP4, consistent with ferroptosis priming via ferritinophagy-driven expansion of the labile iron pool, as confirmed by FerroOrange flow cytometry. Neutral lipid metabolism genes (LPIN1, LDLR, PNPLA3, ACSL1), intracellular lipid transport genes (TMEM41B, OSBP, STARD4), and lipid droplet organization genes (SQLE, CHKA, AUP1) were coordinately upregulated in TS603 after treatment with MF-438. MF438+TMZ activated the integrated stress response (ATF3, DDIT3, IRF1, CDKN1A, GADD45B) and synergistically suppressed TS603 neurosphere growth (p=0.0326). In vivo combination between MF-438 and TMZ showed improved survival versus the TMZ-alone group, in an IDH1-mutant oligodendroglioma model. Tissue analyses showed significant reduced Ki67 expression, a marker of cellular proliferation, in the combination treatment. Collectively, these findings suggest that targeting lipid metabolism may enhance the efficacy of standard-of-care therapy in IDH1-mutant oligodendroglioma.

Cancer Biology↗

bioRxiv2026

A multi-agent system for spine MRI report generation from multi-sequence imaging

Spinal pathology is a leading cause of pain and disability worldwide. Spine magnetic resonance imaging (MRI) is central to clinical evaluation, yet its interpretation remains complex and time-consuming, requiring integration of information across multiple imaging sequences and anatomical regions. Despite recent advances in automated MRI analysis, effectively combining multi-sequence data while preserving sequence-specific diagnostic information remains an open challenge. Here we present SpineAgent, a multi-agent framework for spine MRI report generation built upon a multi-sequence foundation model trained on routine clinical data from 32,047 patients and 453,683 MRI series, comprising a total of 13,441,191 MRI slices. To accommodate diverse modalities of sequences, we first pre-train two DINOv3-based encoders separately on T1- and T2-weighted sequences. We then introduce a continual training strategy that learns a synthesizer to embed images of other sequences using the T1 and T2 encoders, producing patient-level embedding that integrates various signals across MRI sequences. Using these embeddings, SpineAgent achieves state-of-the-art performance, with mean 10.8% AUROC improvement across 17 spinal condition-prediction tasks compared to the best competing method, and demonstrates strong generalizability under cross-manufacturer and cross-cohort evaluation. Beyond classification, SpineAgent enables pathology localization by identifying findings-relevant slices and segmenting pathological regions. It also supports multimodal image-report retrieval, providing a solid foundation for scalable and explainable MRI report generation. We further integrate these validated capabilities of SpineAgent into 37 specialized agents for condition diagnosis, pathological-region localization, and clinically-similar-cases retrieval. Finally, we incorporate their outputs as structured tokens within a Medical Report Agent trained end-to-end for report generation. Through both automated metrics and expert evaluation by five radiologists, SpineAgent achieves leading performance in spine MRI report generation. Together, SpineAgent introduces a continual training approach for multi-sequence spine MRI understanding. By decomposing report generation into clinically grounded subtasks addressed by specialized agents, the SpineAgent framework enables accurate, interpretable and generalizable spine MRI reporting across diverse imaging sequences and anatomical regions.

bioinformatics↗

bioRxiv2026

Bone Morphogenetic Protein Pathway Modulates Parkinson's Disease Genetic Risk and Promotes Motor Recovery

Progress toward disease-modifying Parkinsons disease (PD) therapies is hindered by limited understanding of pathogenic drivers and lack of therapies that restore the damaged dopaminergic (DA) neurons driving motor deficits. We investigated the role of the bone morphogenetic protein (BMP) pathway in PD using common and rare genetic variants across large-scale datasets. Single-variant analyses identified nominal associations with PD risk and onset age. A BMP polygenic risk score (PRS) was significantly associated with PD risk (OR = 1.21, empirical P = 1.0 x 10-), a result replicated in proxy-case analyses (OR = 1.14, empirical P = 1.0 x 10-) and remained significant after sensitivity testing. To test the results functional relevance, we genetically and pharmacologically inhibited BMP signaling in mice, which induced motor deficits and PD-like neuropathology. In a -synuclein preformed fibril (PFF) mouse model, BMP5 and BMP7 (BMP5/7) demonstrated neuroprotective effects when administered concurrently with -synuclein PFFs. Importantly, when delivered after PFFs-induced motor symptoms onset, BMP5/7 demonstrated neurorestorative effects, ameliorating both motor impairments and neuropathology. These findings provide first evidence that BMP signaling variations contribute to polygenic PD risk, identify a physiological role for this pathway in safeguarding against PD-related pathology, and demonstrate BMPs therapeutic potential for disease modification.

neuroscience↗

bioRxiv2026

β-Catenin Drives Apical-Basal Polarization to facilitate TE lineage commitment In Vitro and In Vivo

Embryo polarization is critical for the first cell fate segregation. While mechanisms underlying its initiation have been described, the intrinsic signaling pathways that regulate this process remain poorly understood. Here, we show that mouse embryonic stem cells, when aggregated under defined conditions, recapitulate the first lineage segregation to generate trophectoderm (TE)-like cell populations and undergo self-organized morphogenesis into blastocyst-like structures. In the blastoid-forming medium, we identify CHIR99021 is essential for the generation of blastoids from both ESCs and totipotent-like cells. CHIR99021 promotes cell polarization and TE differentiation by activating the WNT/{beta}-catenin pathway and upregulating associated genes. Consistent with this, genetic ablation of {beta}-catenin abolished the cell polarization and disrupted blastoid formation from ESCs, a defect that was restored by {beta}-catenin overexpression. Moreover, {beta}-catenin depletion compromised cell polarization in natural embryos. Collectively, this study establishes the Wnt/{beta}-catenin as a critical regulator initiating polarization in vitro and in mouse early embryo development.

developmental biology↗

bioRxiv2026

Cross-presentation of citrullinated antigens drives cytotoxic CD8+ T cell responses in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune synovitis marked by anti-citrullinated protein antibodies (ACPAs) and infiltration of the synovium by activated immune cells. In ACPA-positive RA, CD8 T cells are elevated in both the blood and synovium, and can be activated by MHC class I-restricted citrullinated autoantigens to mediate cytotoxic effector function. However, the mechanisms underlying the activation of cytotoxic CD8 T cells in RA remain poorly understood. Here, single-cell transcriptomic and T cell receptor repertoire analysis of RA blood and synovial T cells revealed shared clonally expanded cytotoxic CD8 T cell programs, with synovial enrichment of activated effector and proliferating populations and increased frequencies of GZMBIFNG CD8 T cells. We demonstrated that RA-associated oral bacteria stimulate neutrophil extracellular trap (NET) formation, leading to the peptidyl arginine deiminases (PAD)-dependent generation of extracellular citrullinated bacterial and host proteins. We further demonstrated that these antigens can be cross-presented to CD8 T cells via HLA class I molecules expressed by monocyte-derived dendritic cells (MoDCs) and autoreactive ACPA-expressing B cells. Toll-like receptor (TLR) signaling, particularly TLR4 activation by citrullinated antigens, enhanced cross-presentation of citrullinated antigens and promoted CD8 T cell activation and clonal expansion. In turn, citrullinated antigens stimulated autoreactive B cells to produce IL-8, which recruited CXCR1/2 cytotoxic CD8 T cells and amplified B cell-CD8 T cell interactions. These findings reveal a mechanistic pathway linking microbial triggers, antigen presentation, and cytotoxic CD8 T cell responses that may drive joint destruction in RA. One Sentence SummaryTLR4-driven cross-presentation of citrullinated antigens by dendritic cells and autoreactive B cells promotes activation of CD8+ T cells in rheumatoid arthritis.

immunology↗

bioRxiv2026

The Laminar Organization of a Decision Circuit in Orbitofrontal Cortex is Agnostic to the Variable Encoding Scheme

Economic choices are believed to depend on the orbitofrontal cortex (OFC). Work in primates and rodents indicates that neurons in OFC participate in computing and comparing subjective values, suggesting that different groups of cells constitute the building blocks of a decision circuit. In a recent study (Livi et al., 2025), we examined the laminar organization of this circuit in mice. We found that different decision variables were differentially represented in layer 2/3 (L2/3) and layer 5 (L5). Furthermore, the temporal dynamics of decision signals indicated a combination of feed-forward and feed-back across layers, and pointed to L5 as the locus for winner-take-all value comparison. Importantly, these results were obtained under the constraint that each neuron encoded a single variable. Here, we tested whether our results on laminar organization depended on the categorical framework. We applied LASSO regression to identify a minimal set of variables explaining each neurons activity. Even with approximately half of all neurons representing two or more variables, the layer specificity of decision variables was preserved. In addition, Granger Causality Analysis and activity profiles reached similar conclusions as for analyses conducted under the single-variable constraint. We conclude that the decision circuit in OFC exhibits a laminar architecture, independently of whether the representation of decision variables in this area is categorical or mixed.

neuroscience↗

bioRxiv2026

Amino Acid Stress Induces Non-AUG Initiation of c-myc Translation

Initiation of translation at non-AUG start codons can generate novel isoforms of important cellular regulators, with activities or localization distinct from their AUG-initiated counterparts. Ribosomes scanning the 5UTR upstream of canonical AUG starts recognize near-cognate starts inefficiently, however, and the mechanisms by which non-canonical starts might be regulated physiologically are poorly understood. We show here that the restriction of utilization of individual amino acid induces a switch in expression of c-myc from its AUG-initiated isoform, c-myc-2, to an upstream CUG-initiated isoform, c-myc-1. This switch is enhanced in cells lacking GCN2, the protein kinase linking amino acid stress to phosphorylation and inhibition of eif2. Induction of upstream CUG start site usage in c-myc by restriction of proline utilization depends on the proximity of proline codons downstream of the canonical AUG start site. These observations support a model in which the stalling of an elongating ribosome near a canonical start leads to the accumulation of a ribosome queue that facilitates initiation at an upstream non-canonical start site. We find similar effects associated with deprivation of amino acids other than proline, and isoform changes with ATF-3 as well as c-myc. These findings suggest a broad mechanism by which amino acid stress can regulate translation initiation site use to modify the N-terminal proteome.

cell biology↗

bioRxiv2026

Ultrasensitive voltage imaging reveals distinct electrical microdomains in neurons

For the brain to compute, electrical signals must propagate over the membranes of individual neurons, connecting synaptic inputs to synaptic outputs1. Complex neuronal morphologies coupled with the spatial organization of synaptic inputs and outputs enable diverse voltage transformations that underlie cell-type specific computations2,3. However, measuring these transformations in vivo has remained challenging, leaving a crucial gap in our mechanistic understanding of single neuron computation. Here, we develop ASAP7y, a genetically encoded voltage indicator with unprecedented subthreshold sensitivity and expanded excitation compatibility in both mice and flies. We leveraged ASAP7y combined with two-photon random-access microscopy to record sensory stimulus-evoked voltage dynamics with millisecond, subcellular, and subthreshold resolution along the neurites of individual neurons in Drosophila. We found remarkable heterogeneity in voltage propagation across cell-types, delineating a fundamental axis of electrical diversity. Leveraging a nanoscale EM reconstruction of the visual system4, we modeled the electrotonic properties of single neurons spanning 717 cell types, revealing how morphology shapes voltage transformations. Finally, we demonstrate that confined voltage propagation creates substrates for local computation, producing subcellular domains with distinct feature selectivity across multiple cell types. These results provide mechanistic insight into how critical single neuron computations arise and reveal parallel processing in single neurons.

neuroscience↗