Biology subjects

Chen, J.

Publications and source records attributed to Chen, J..

At least 163 records · Page 9Linked to original sources

bioRxiv2026

Sex-related structural alterations across common epilepsies: a worldwide ENIGMA study

Epilepsy is characterized by widespread structural brain alterations extending beyond the epileptic zone, involving both cortical and subcortical regions. Importantly, the clinical manifestation of epilepsy, including seizure types, psychiatric comorbidities, and treatment responses, has been shown to differ between sexes. However, sex differences in structural alterations in epilepsy have been seldomly reported in neuroimaging studies, partly due to limited sample sizes and single-center designs. Here, we systematically investigated sex differences in common epilepsies and their related clinical variables using structural neuroimaging biomarkers in an international multi-center cohort of 1,253 epilepsy patients and 1,077 healthy controls. We studied cortical thickness and subcortical volume in two types of epilepsy: temporal lobe epilepsy (TLE) and genetic generalized epilepsy (GGE). Both male and female patients with TLE showed widespread cortical and subcortical thinning compared with controls. In GGE, when compared separately to controls, male patients showed only subtle structural alterations, whereas female patients exhibited more widespread structural alterations. Sex-stratified analyses revealed some variation in the extent and distribution of cortical thickness and subcortical volume alterations between male and female patients in both epilepsy cohorts. Yet, we did not find significant sex-by-diagnosis interaction effects in TLE and GGE. Similarly, no significant interaction effects were observed between sex and age of onset or disease duration in either patient group. Overall, although we observed some differences in regional cortical thickness and subcortical volume between male and female patients with epilepsy, we did not find significant sex-by-diagnosis interactions. Our findings indicate that sex differences in behavioral and clinical outcomes of epilepsy may involve biological or functional processes that require further investigation.

neuroscience↗

bioRxiv2026

Loss of Arginase 2 Promotes Lung Metastasis in immune-competent hosts via Nitric Oxide Synthase 2-Dependent Th17 Response

Distant metastasis is the leading cause of mortality in many cancers. Although metabolic reprogramming is recognized as a hallmark of cancer, how tumor-intrinsic metabolic enzymes regulate tumor-immune crosstalk during metastatic progression remains poorly understood. Here, using a high-throughput functional CRISPR-Cas9 screen targeting metabolic genes in an orthotopic 4T1 murine mammary carcinoma model of spontaneous lung metastasis, we identify a selective enrichment of arginase 2 (ARG2)-deficient tumor cells in metastatic lungs of immunocompetent but not RAG1-deficient mice, indicating a lymphocyte-dependent mechanism. Loss of ARG2 enhances spontaneous lung metastasis without affecting primary tumor growth. Further, metastatic outgrowth in the lung is not affected when tumor cells are injected intravenously, indicating that ARG2 regulates an early stage of the metastatic cascade. Mechanistically, ARG2 deficiency upregulates nitric oxide synthase 2 (NOS2), resulting in increased nitric oxide production, accumulation of cytosolic DNA, and activation of the cGAS-STING-NF-{kappa}B pathway, leading to upregulation of inflammatory cytokines. ARG2-deficient tumors exhibit an immunosuppressive tumor microenvironment characterized by enrichment of Th17 cells and reduced anti-tumor immune populations. Functionally, Th17 cells enhance tumor cell migration in vitro and promote spontaneous lung metastasis in vivo. Genetic deletion of NOS2 attenuates cytosolic DNA accumulation, reduces STING-NF-{kappa}B activation, restores anti-tumor immunity, and suppresses ARG2 deficiency-driven metastatic burden in vivo. Collectively, these findings define a tumor cell-intrinsic ARG2-NOS2 axis that regulates inflammatory signaling and the tumor microenvironment to promote metastasis, highlighting a targetable vulnerability in metastatic breast cancer.

cancer biology↗

bioRxiv2026

Conserved TIR-only proteins drive transcriptional defense and basal immunity in dicot and monocot plants

Toll/interleukin-1/resistance (TIR) domain NADase enzymes signal in plant immunity by producing ribosylated nucleotide second messengers which activate EDS1 dimer-helper NLR pathways to restrict pathogen growth. Members of a small, distinctive group of TIR-only proteins are conserved between dicots and monocots, yet their functions remain poorly understood. Here, we show that conserved TIR-only proteins in Arabidopsis and barley share a fundamental enzymatic role in promoting basal defense against virulent filamentous pathogens, independently of NLR mediated effector-triggered immunity. Metabolite analysis of transiently expressed Arabidopsis and barley TIR-only proteins revealed their capacity to produce ribosylated cyclic nucleotides in vivo. By comparing phenotypes of tir-only and eds1 pad4 CRISPR mutants in the two species, as well as adr1 mutants in barley, we established that the TIR-only proteins promote PAMP-triggered transcriptional defenses associated with pathogen restriction. Barley possesses just one essential TIR-only enzyme and mutations of the two conserved TIR-only members in Arabidopsis were not compensated for by numerous other TIR-domain genes in the basal immune response. These findings suggest that conserved TIR-only proteins make a crucial contribution to TIR basal defense signaling networks of Arabidopsis and barley. We propose that a shared function in transcriptional defense regulation could explain the evolutionary retention of this discrete TIR-only group across monocot and dicot lineages.

plant biology↗

bioRxiv2026

Identification of highly immunogenic endogenous dsRNAs from cellular MDA5 filaments

ADAR1 converts adenosine to inosine in endogenous double-stranded RNAs (dsRNAs) to prevent excessive MDA5-driven interferon-stimulated gene expression. The source of endogenous immunogenic dsRNAs remains enigmatic because only a small fraction of ADAR1 substrates activate MDA5, and cellular MDA5 filaments have not been isolated. Here, we couple affinity purification of cellular MDA5 filaments with RNA sequencing to define immunogenic endogenous dsRNAs. Greater than 84% of dsRNAs suppressed by combined DDX3X RNA helicase and ADAR1 base-editing activities were present in MDA5 filaments, compared to less than 1% of dsRNA substrates acted on by ADAR1 alone. Dual substrate dsRNAs consisted of inverted repeats embedded in 3-UTRs with high base-pair complementarity and longer intervening sequences between repeats, with a minor contribution coming from intermolecular dsRNAs formed by sense and antisense transcripts. Moreover, the majority of dual substrate immunogenic dsRNAs were hyperedited in DDX3X mutant cancers. This reveals the identity of endogenous immunogenic dsRNAs and quality control mechanisms underlying their suppression.

cell biology↗

bioRxiv2026

Visibly Transparent, Near-Infrared Absorbing Nanofluids Enable High-Efficiency and Safe Laser Lithotripsy

Laser lithotripsy (LL) is the gold standard for urinary stone management yet maximizing ablation efficiency while maintaining procedural safety remains clinically challenging. Here, we present a visibly transparent, near-infrared (NIR)-absorbing ITO@SiO2 nanofluid irrigation strategy that significantly enhances LL efficiency without compromising endoscopic visibility. By spectrally matching the absorption profile of ITO@SiO2 with the clinical Holmium:YAG laser wavelength, ablation efficiency improved by >200% in the bench-top spot treatments and >100% in the hydrogel kidney model. Mechanistic investigations revealed that the enhanced optical absorption of the nanofluid modifies bubble dynamics and synergistically amplifies photothermal/microexplosion effects and cavitation damage. Importantly, both in-vitro hydrogel and in-vivo porcine kidney models demonstrated a substantial thermal safety margin (maximum temperatures <35 {degrees}C) and excellent acute biocompatibility, with no evidence of thermal tissue injury. Integrating seamlessly into established clinical workflows without requiring stone pretreatment, this strategy offers a highly translatable, safe, and efficient platform for next-generation endoscopic lithotripsy.

bioengineering↗

bioRxiv2026

A phage-encoded small RNA that mimics chimeric guide to inhibit CRISPR-Cas9

CRISPR-Cas9 relies on a dual crRNA-tracrRNA guide, yet whether RNA-based anti-CRISPRs exist for this system has remained unknown. Here we identify a phage-encoded small non-coding RNA, rAcrIIA1, that adopts an unexpected chimeric crRNA-tracrRNA architecture, faithfully recapitulating the entire single-guide RNA (sgRNA) of Cas9. Cryo-EM structures of the Cas9-rAcrIIA1 binary complex and the Cas9-rAcrIIA1-DNA ternary complex reveal that rAcrIIA1 engages Cas9 nearly identically to the native sgRNA, competitively blocking crRNA and tracrRNA loading and thereby abolishing DNA interference. Strikingly, beyond its natural inhibitory function, rAcrIIA1 is fully reprogrammable: with variable guide sequences, it directs Cas9 for sequence-specific DNA cleavage with efficiency comparable to the canonical sgRNA, and it activates trans-cleavage more potently. Thus, rAcrIIA1 provides the first experimentally validated, mechanistically resolved RNA-based inhibitor of CRISPR-Cas9, reveals a distinct anti-CRISPR mechanism through complete sgRNA mimicry, and serves as a versatile bifunctional scaffold for genome editing and diagnostics.

biochemistry↗

bioRxiv2026

Stimulus-response correlation analysis dissociates spatiotemporal cortical networks supporting speech production

IntroductionUnderstanding the spatiotemporal distribution of cortical activation during language production is a central question in cognitive neuroscience with broad clinical applications. High spatial/temporal resolution recording over multiple brain regions and specific psycholinguistic manipulations with testable behavioral predictions are necessary to separate neural variance attributable to processing stages. ObjectiveWe combine a delayed naming paradigm with intracranial electrophysiology to identify spatiotemporally dissociated cortical networks supporting stages of speech production. MethodsSubjects (20 healthy, 15 intracranial electrophysiology) are presented visual stimuli to name but are instructed to delay response until a go cue at 0/400/1000ms. Exploiting the temporal variance induced by delay, we calculate stimulus/response-locked correlation of high gamma (70-200Hz) activity at each contact. We compare shifts in stimulus-response correlation space to response time (RT) to validate separation of networks. ResultsBehaviorally, the factor delay modulated the effect of lexical selection on RT (p=0.021) but did not modulate the effect of phonological planning (p=0.4), confirming the paradigm separates processing stages. Stimulus-response correlation analyses revealed globally-invariant structure across subjects. Certain regions showed strong stimulus-locking (occipital lobe) or response-locking (motor cortex), but most regions were intermediate. Shifts in correlation space identified dissociated networks that predicted substantial variance in RT from lexical selection (R2=0.64) and phonological density (R2=0.75). Using a leave-one-subject-out cross validation approach, these shifts explained 31.4% of variance in RT at the trial level. ConclusionStimulus-response correlation space reveals stable spatiotemporal signatures of psycholinguistic processing that generalize across individuals. This approach permits hyperalignment of neurophysiological data and functional separation of cortical networks in speech production across subjects.

neuroscience↗

bioRxiv2026

Netrin-1 drives cell-type-specific plasticity of human dopaminergic neurons during circuit integration in a Parkinsonian model

The survival of transplanted ventral midbrain (vm) dopaminergic neurons (DAn) and their innervation of host striatal tissue are crucial for ameliorating motor symptoms in Parkinsons disease (PD). However, human pluripotent stem cells (hPSC) show inferior axonal plasticity compared to fetal donor tissue. While modulation of the host environment with trophic cues, such as glial cell-derived neurotrophic factor (GDNF), can improve graft outcomes, these cues lack specificity for DAn, resulting in plasticity of other neurons within the graft. Using single nuclei RNA sequencing, we identified axonal guidance pathways (Semaphorin, Netrin and Wnt) that were preferentially activated in DAn within the graft. Overexpression of Semaphorin3A/SEMA3A, Netrin1/NTN1 or WNT5A in the striatum of Parkinsonian mice following vm DA progenitor transplantation promoted A9-DA specification and selectively increased DA innervation of the host striatum, without off-target extrastriatal DA innervation observed in response to GDNF. In Parkinsonian rats, NTN1 overexpression promoted graft-induced motor recovery, selective DA plasticity and activation of postsynaptic striatal neurons without evidence of non-DAn plasticity. Further, snRNA-sequencing of NTN1 or GDNF-treated grafts confirmed the upregulation of DA-specific plasticity by NTN1, while GDNF promoted plasticity in both DA and non-DAn. These findings highlight the capacity to improve on-target integration of hPSC-derived DAn in grafts by selectively targeting DA-specific plasticity. Taken together, these results demonstrate the utility of DA-specific cues to promote functional recovery, improve graft predictability, and limit off-target innervation.

neuroscience↗

bioRxiv2026

Ultra-efficient High Resolution 3D Reconstruction of Spatial Omics Data with Neural Transcriptomic Field

Biological tissues are inherently three-dimensional (3D) ecosystems where spatial architecture dictates cellular function. While spatial omics technologies have revolutionized molecular profiling, they are largely restricted to isolated two-dimensional (2D) tissue sections. Existing computational methods attempting to reconstruct 3D volumes from sparse slices rely heavily on local slice-to-slice interpolation, struggling to balance high-fidelity reconstruction, noise reduction, and atlas-scale efficiency. Here, we present Neural Transcriptomic Field (NTF), a deep learning framework employing multi-resolution hash-grid encoding and implicit neural representations. Unlike interpolation-based approaches that merely bridge adjacent observations, NTF learns a global, continuous 3D representation of the tissue. By modeling the underlying latent biological patterns, NTF intrinsically decouples true molecular signals from technical artifacts, naturally enabling robust denoising and high-fidelity reconstructions. This global field paradigm shatters traditional scalability limits: NTF achieves up to a 1,000x speedup over existing methods, notably reconstructing a 100-million-cell scale 3D whole-mouse embryo atlas in under 15 minutes. Furthermore, NTF can generate super-resolved volumes from sparse input (e.g., utilizing only 10% of slices) and robustly extrapolating into unseen tissue regions. We demonstrate NTFs versatility across diverse transcriptomic and proteomic datasets, capturing complex spatiotemporal dynamics in Drosophila and mouse embryogenesis, and mapping intra-tumoral functional gradients in human breast cancer. Ultimately, NTF provides an unprecedentedly fast, scalable, and robust computational engine for constructing the next generation of comprehensive 3D tissue atlases.

bioinformatics↗

bioRxiv2026

MICAFlow: Fast and Robust MRI Preprocessing Bridging Research Neuroimaging and Clinical Practice

MICAFlow is a fully automated MRI preprocessing pipeline designed to translate advanced neuroimaging workflows from research into routine clinical practice. The pipeline emphasizes speed, robustness, and ease of use, focusing on structural and diffusion MRI. Key innovations include a Label-Augmented Modality-Agnostic Registration (LAMAReg) technique driven by deep learning segmentations for reliable cross-modal alignment, integration of state-of-the-art distortion corrections, and adherence to reproducible standards (Snakemake workflow, BIDSApp specifications). We describe the design of MICAFlow and evaluate its performance across heterogeneous datasets. First, accessibility: MICAFlow processes a multimodal MRI exam in minutes with clinically accessible hardware and without requiring GPU access, making it feasible for same-day clinical use. Second, registration accuracy: LAMAReg achieves cutting-edge multi-modal registration accuracy, yielding accurate alignment of diffusion MRI, FLAIR, and intra-subject T1-weighted images while remaining generally robust to common artifacts. Third, data reliability: Using identifiability, we show MICAFlow maintains consistent performance across diverse datasets, including subjects with pathology, and is closely comparable to contemporary pipelines. In sum, MICAFlows combination of machine learning and efficient workflows produces research-grade data quality with clinical-grade speed. This work demonstrates that advanced MRI preprocessing can be done fast and robustly, helping close the gap between research neuroimaging and broad clinical application of quantitative MRI techniques. The source code for MICAFlow is available here: https://github.com/MICA-MNI/micaflow, and for LAMAReg here: https://github.com/MICA-MNI/LAMAReg.

bioinformatics↗

bioRxiv2026

A lipid cue drives the subcellular localization of a self-inserting bacterial transmembrane protein

The correct subcellular localization of proteins is a critical step underlying myriad biological processes, but the cues that drive the specific localization of integral membrane proteins in bacteria remain largely undeciphered. During sporulation in Bacillus subtilis, a rod-shaped outer "mother cell" constructs an internal spherical "forespore" cell that eventually matures into the spore. The integral membrane protein ShfA is made in the mother cell cytosol and localizes to the surface of the forespore. Here, we report that, despite being a multi-pass transmembrane protein, ShfA spontaneously inserts into the lipid bilayer via its N-terminal "YabQ" domain without the apparent need for a pre-localized insertase. ShfA preferentially inserts into cell division septa in multiple bacterial species, indicating that a widely conserved septal cue drives ShfA localization. Structural modeling suggested that the YabQ domain harbors a specific intramembrane groove that can bind the universal lipid carrier undecaprenyl phosphate (UndP), and UndP depletion in vivo disrupted proper ShfA localization. We propose that ShfA localizes to sites of active cell wall synthesis by binding to UndP and/or molecules like lipid I and lipid II that contain UndP and speculate that the function of ShfA is to stabilize these precursors of cell wall biogenesis from the harsh cytosolic nanoenvironment that surrounds the forespore during sporulation.

microbiology↗

bioRxiv2026

HESTA: a curated and reusable database for the human early organogenesis spatiotemporal transcriptome atlas

BackgroundHuman organogenesis is orchestrated by precise spatiotemporal gene expression. Mapping these dynamic processes requires transcriptomic data that preserve native anatomical context across continuous developmental stages. FindingsWe present a spatiotemporal transcriptome database of human embryogenesis, profiling 77 sagittal sections from 13 euploid embryos (CS12-CS23) using Stereo-seq, yielding 14,708,858 bin50 spots. The atlas annotates 50 organs and maps 198 molecularly distinct substructures, complemented by 607,093 snRNA-seq cells. The database features a Spatial Exploration module for locating sections and visualizing spatial distributions of organs and substructures, and an Organ Atlas module for visualizing gene expression, regulon activities, and pathway enrichment at the single-organ level across stages. ConclusionsThis database provides an interactive resource to access spatial gene expression, substructures, and regulatory networks across 50 developing human organs, supporting further research into the mechanisms of human organogenesis.

bioinformatics↗

bioRxiv2026

rDNA breaks activate dsRNA pattern recognition through sense-antisense transcription

Myriad DNA damaging chemo- and radio- therapies interfere with ribosomal RNA (rRNA) transcription and processing, yet the biological consequences of these phenomena remain unclear. Here we show that aberrant transcripts emanating from rDNA breaks engage double-stranded RNA pattern recognition receptors, melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene I (RIG-I) to activate immune signaling. rDNA damage abolishes full-length rRNA synthesis while generating truncated sense-antisense rRNA transcripts, whose accumulation is restrained by ATM and ATR kinase activities. Purification of the endogenous MDA5-filament coupled with sequencing identified complementary sense and antisense rRNA transcripts that terminate and initiate near the break site, respectively. This implicates aberrant rRNA species as a major source of damage induced endogenous ligands for dsRNA pattern recognition and establishes a mechanism by which nucleolar stress is coupled to immune signaling.

cell biology↗

bioRxiv2026

An AI-agent-orchestrated grey-box Transformer framework for sparse pharmacokinetic curve reconstruction and pharmacometric model initialization

Clinical pharmacokinetic (PK) modelling is constrained by sparse sampling, limited general-isability of single-drug models, and labour-intensive workflows, making it difficult to infer complete drug exposure from limited concentration observations. We present the Pharmacokinetic Foundation Model (PKFM), a grey-box Transformer framework pre-trained across 32 drugs that reconstructs concentration-time profiles from sparse concentration observations, dosing events, molecular descriptors, and physiological covariates while preserving output interpretability. In representative oral PK curves, three sparse input points recovered the principal absorption-elimination trajectory, achieving coefficient of determination (R2) = 0.992 for Midazolam oral and R2 = 0.990 for Verapamil oral. Using reconstructed curves in NONMEM (nonlinear mixed-effects modelling) improved covariance stability and individual prediction accuracy. Contrastive-learning embeddings supported Top-10 physiologically based pharmacokinetic (PBPK) candidate retrieval, with 75.6% of observations within the 2-fold range. A pharmacometrics-informed AI Agent (PM Agent) outperformed general-purpose programming tools in stability and pairwise win rate on a standardised modelling benchmark, with each run requiring human pharmaco-metrician confirmation before downstream use. These results support cross-drug pre-trained PK models as an information-completion layer for sparse PK evidence and a structured scaffold for the modelling workflow; clinical or regulatory use requires prospective validation, broader external benchmarking, and independent expert assessment.

pharmacology and toxicology↗

bioRxiv2026

STID: A Standardized Spatial Transcriptomic Analysis Framework for Infectious Diseases

Spatial transcriptomic studies of infectious diseases still rely on fragmented data analysis processes. Here, we developed STID, a standardized framework for spatial transcriptomic analysis of infectious diseases that leverages the Seurat ecosystem and incorporates Python-based modules. STID provides an extensible infection-specific data structure and supports a full suite of analyses, such as pathogen background correction, infection-associated spot and niche identification, single-sample niche characterization, and multi-sample comparative and temporal analyses. Moreover, STID is broadly applicable to spatial transcriptomic data from infectious diseases caused by bacteria, viruses, and parasites, and enables systematic characterization of the structural features, cellular composition, molecular functions, and host-pathogen interactions within pathogen-infected and/or host-responsive niches. Overall, STID provides an accessible, reproducible, and extensible framework for analyzing infection-associated spatial transcriptomic data and for dissecting host-pathogen interactions in their native spatial microenvironments. MotivationSpatial transcriptomics technologies have emerged as powerful approaches for dissecting the structural and functional features of spatial microenvironments. However, the current general-purpose tools remain fundamentally inadequate for resolving the spatial heterogeneity of infectious disease samples, where the intricacies of host-pathogen interactions render spatial microenvironments both challenging to dissect and largely inaccessible. Tools tailored to infectious diseases are critically lacking, including those for reducing pathogen-derived background noise, identifying and isolating infection{square}associated spots or niches, dissecting host-pathogen interactions, and supporting systematic multi-sample analyses. We therefore developed STID, a unified framework that integrates standardized workflows and addresses the analytical bottlenecks in spatial transcriptomic analysis of infectious diseases. HighlightsO_LISTID standardizes spatial transcriptomic analysis in infectious diseases C_LIO_LISTID improves pathogen-infected spot detection by correcting pathogen background C_LIO_LISTID distinguishes pathogen-infected and host-responsive niches C_LIO_LISTID supports multi-sample comparative and temporal analyses of niches C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/727492v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@167d351org.highwire.dtl.DTLVardef@1628848org.highwire.dtl.DTLVardef@1e157aforg.highwire.dtl.DTLVardef@143ca1b_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2026

Polarity remodeling of ventricular cardiomyocyte precursors during heart morphogenesis is required for ventricular chamber formation

Vertebrate heart development requires precise regulation of morphogenetic movements and dysregulation causes congenital heart defects. However, cell polarity remodeling during early heart tube formation remains underexplored. Here, we show that zebrafish ventricular cardiomyocyte precursors (vCPCs) undergo striking polarity reorientation as they transition from a single-layered epithelium to a transient double-layered configuration by involution. During this process, vCPCs remove inner adherens components and re-establish polarity toward the ECM-attached outer surface, enabling proper directional extension to form the ventricle. We identify the junctional scaffold protein Afadin a (Afdna) as a critical regulator. Afdna localizes to the outer and lateral membrane to restrict Rap1 activity, facilitating Podocalyxin translocation and adhesion disassembly at the inner interface between vCPC double layers. afdna mutants exhibit a multilayered ventricle with impaired blood flow, phenocopying human congenital ventricular obliteration. Our findings uncover a polarity-based mechanism ensuring ventricular chamber formation and provide insight into ventricular obliteration.

developmental biology↗

bioRxiv2026

Decoding Immune Reconstitution Failure in People Living with HIV through Single-cell Genomics

Immune non-responders (INRs), a subset of people living with HIV (PLWH), fail to achieve full immune reconstitution and remain at increased risk of morbidity, mortality, and non-AIDS-related illnesses. As the mechanisms underlying this impaired immune recovery remain poorly understood, we performed single-cell multi-omics profiling on peripheral blood mononuclear cells from 43 INRs, 47 immune responders and 53 healthy donors. Our dataset comprises 2,744,009 transcriptomes and 1,226,658 chromatin-accessibility profiles across 58 identified immune cell types. INRs exhibited markedly elevated inflammatory signaling, increased apoptotic activity, and dysregulation of immune-activating ligand-receptor interactions. Additionally, we identified 2,996 interaction cis-eGenes and 5,938 cis-caPeaks, and validated key cell type-specific cis-xQTL effects associated with immune reconstitution failure. Furthermore, we identified 3,551 sc-eQTLs and 872 cell-state interaction eQTLs (ieQTLs) in CD4+ T cells. A genotype-specific upregulation of OAS3 in INRs, likely regulated by STAT1, was identified based on these results. We developed scPRISM (single cell Predictive Reconstitution Immune Status Model), a multi-modal framework that integrates scRNA-seq and scATAC-seq data to perform the dual tasks of differentiating disease states and predicting gene expression from chromatin accessibility, thereby deciphering the cell type-specific cis-regulatory basis of the disease. Our study delineates the transcriptional and epigenomic landscape of immune dysregulation in INRs and provides new genetic insights into HIV-associated immune reconstitution failure. These findings offer a foundation for developing biomarkers and precision therapies to restore immune function in PLWH.

genetics↗

bioRxiv2026

Loss of LanC-like proteins impairs post-injury regeneration of aging muscles

The adult skeletal muscle regenerates robustly upon injury, but this regenerative capacity rapidly declines with age. In this study, we identify the lanthionine synthetase C-Like (LanCL) proteins, mammalian homologs of the bacterial peptide cyclase LanC, as positive regulators of muscle regeneration in middle-aged mice. In a barium chloride-induced injury model, we found the protein levels of LanCL1 and LanCL2 to increase during an early phase of regeneration in middle-aged (12-month-old) but not young adult (4-month-old) mice. Utilizing a mouse line lacking all three LanCL proteins (LanCL triple KO or LTKO), we examined a potential role of LanCL in injury-induced muscle regeneration. Consistent with an age-dependent function of LanCL, we observed a delayed regeneration of the tibialis anterior (TA) muscle after injury, as reflected by reduced sizes of regenerating myofibers in middle-aged (but not young) LTKO compared to age-matched WT mice. Although the pool size of quiescent satellite cells (Pax7+) was comparable between 12-month-old LTKO and WT muscles without injury, the number of Pax7+ cells was significantly higher in regenerating LTKO muscles at day 5 after injury, accompanied by drastically decreased numbers of MyoD+ and MyoG+ cells, as well as increased numbers of proliferating cells. In addition, we detected elevated expression of pro-inflammatory cytokines in regenerating LTKO muscles, while the number of macrophages was similar comparing LTKO and WT muscles. Taken together, our observations suggest that in aging muscles LanCLs are important for proper timing of inflammation resolution and regeneration upon injury.

physiology↗