Biology subjects

Li, J.

Publications and source records attributed to Li, J..

At least 271 records · Page 15Linked to original sources

bioRxiv2026

Mechanistic Basis for the Selective Recognition of the Fcγ Receptor IIa by Monoclonal Antibody IV.3

The monoclonal antibody IV.3 selectively binds the platelet Fc{gamma} receptor IIa (Fc{gamma}RIIa), potently blocking immune complex engagement without cross-reacting with the closely-related Fc{gamma}RIIb. This specificity has made IV.3 invaluable for dissecting Fc{gamma}RIIa-mediated activation in diverse conditions, including infection, autoimmunity, thromboinflammation, and platelet-mediated thrombosis. We combined cryogenic electron microscopy, surface plasmon resonance, alchemical free energy calculations, and molecular dynamics simulations to elucidate IV.3s binding sites on Fc{gamma}RIIa and the mechanistic basis of IV.3 specificity. We find that IV.3 engages a broader Fc{gamma}RIIa epitope than previously recognized, extending beyond residues H/R134 and L135 (R and S in Fc{gamma}RIIb). Simulations of Fc{gamma}IIa-R134 variants bearing either L135 or S135 reveal that IV.3 specificity arises from hydrophobic stabilization mediated by L135 and disruption of an R134-specific interaction network in the presence of S135. These findings provide a mechanistic framework for rational design of Fc{gamma}RIIa-targeted therapeutics.

biophysics↗

bioRxiv2026

Linking cross-species trajectories of cerebrovascular remodeling in aging and Alzheimer's disease to brain vessel transcriptome

Cerebrovascular remodeling driven by subtle molecular changes starts early in the asymptomatic stage of Alzheimers disease (AD). Despite progress in human vascular imaging and postmortem tissue analysis, there is limited data on the early features of small vessel reorganization, particularly in the context of cell-specific molecular drivers. This is largely because of the invasive nature of the tools for direct cellular observation and analysis. Since early detection is key, histopathology falls short with end-point data from people that died in late stages of the disease. This is a critical knowledge gap, because the early vascular processes are thought to be strongly correlated with health outcomes, tipping the scales from mild cognitive impairment to AD. To meet these translational challenges, we performed near life-span in vivo two-photon imaging and MRI of the cerebrovascular tree in a mouse model of amyloidosis. We identified precisely when subtle abnormalities in vessel tortuosity and red blood cell velocity first emerge in the context of differential amyloid accumulation in vessels walls and tissues. We then isolated the brain vessels for transcriptional analysis at this flagship timepoint and performed cross-species analysis linking changes in vascular cells to genes and pathways common to both mice and humans. Importantly, using 7T MRI of aging humans, we directly associated vascular remodeling trajectories of mice and humans and identified a remarkably analogous tortuosity course in the smallest brain vessels. Our integrated framework across scales and species advances neuroimaging biomarker understanding and uncovers early mechanistic routs of dysfunctional angiogenesis and actin-mediated contractility.

neuroscience↗

bioRxiv2026

Noninvasive Laser SCOS Monitoring of Rat Brain Hemodynamics During Intracerebral Injection

Cerebral blood volume (CBV) and blood flow (CBF) constitute key metrics for cerebrovascular monitoring, enabling assessment of stroke severity and risk-prediction, aging-related changes, and neurological diseases. CBF and CBV monitoring are key aspects in diagnosis, treatment triage, and clinical outcome of ischemic and hemorrhagic strokes. In recent years, there have been ongoing efforts toward the development of optical devices for noninvasive monitoring of CBV and CBF. Speckle contrast optical spectroscopy (SCOS) has recently emerged as a strong candidate for clinical translation in monitoring CBF and CBV, due to its affordability, compact and wearable design, and noninvasive nature. However, experimental demonstrations that SCOS can effectively monitor brain hemodynamics remain sparse. This is primarily due to challenges in design experiments that isolate cerebral blood dynamics from those in the scalp and skull. In this paper, we report experiments using SCOS to monitor cerebral hemodynamics in rats during intracerebral blood flow modulation. To modify cerebral blood dynamics, a surgical procedure was performed to insert a catheter for direct injection of flow modulation fluids into the brain. Using the SCOS device, we monitored changes in CBV during deliberate CBF interventions into the brains of five rats. A saline solution was also injected as a sham control of the flow intervention. The results show a significant decrease in CBV during injection, followed by a return to baseline. This behavior is consistent with physiological expectations, as the injected fluids dilute the blood, leading to a transient reduction in blood volume. Notably, the CBV decrease induced by the flow modulation fluid solution required more than twice as long to recover to baseline compared with the saline solution, which is consistent with the delayed clearance of the flow modulation fluid by design. These experimental results demonstrate the effectiveness of SCOS for monitoring cerebral hemodynamics in animal models and highlight its potential for translation to human studies. Moreover, this work paves the way for the testing and characterization of cerebral therapeutic agents intended for blood flow modulation in animal models.

biophysics↗

bioRxiv2026

Wiz regulates clustered protocadherin genes by restricting CTCF/cohesin loop extrusion in a genomic-distance biased manner

Zinc finger (ZF) proteins (ZFPs) constitute the largest family of transcription factors in mammals; however, their regulatory mechanism remains largely elusive. Here we propose COP (C2H2-ZFP occupancy predictor), a deep learning framework that integrates DNA sequence information with protein primary and secondary features to systematically predict ZFP genomic enrichments. Applying COP to the mouse clustered protocadherin (cPcdh) gene locus, we identified dozens of C2H2-ZFPs potentially involved in CTCF-mediated gene regulation with Wiz having the highest number of 12 ZFs. We confirmed Wiz enrichments at all of the CBS (CTCF-binding site) elements across the Pcdh clusters by Myc-tagging the endogenous Wiz gene. Genetic experiments revealed significant increases of expression levels of the cPcdh genes upon Wiz deletion in both neuronal cells in vitro and in mouse brain in vivo. Finally, integrated ChIP-seq, RNA-seq, and 4C-seq analyses demonstrated that Wiz regulates CTCF/cohesin occupancy and long-range enhancer-promoter contacts in a genomic-distance biased manner. Together, these findings have interesting implications regarding molecular mechanism of C2H2-ZFPs in cPcdh gene regulation.

cell biology↗

bioRxiv2026

Progressive Backmapping of Highly Coarse-Grained Protein Models

Reconstructing all-atom (AA) structures from highly coarse-grained (HCG) models remains a significant challenge in multiscale molecular dynamics (MD) simulations, particularly for mesoscale biomolecular assemblies that are beyond the reach of conventional MD methods. Building upon ProNet Backmapping, a neural-network-based thermodynamically consistent approach, we introduce a progressive backmapping framework that reconstructs AA models in a stepwise manner across neighboring resolutions, for example, from a 3-residue-per-site HCG model to a 1-residue-per-site model, then to an AA model. This progressive backmapping method achieves high accuracy across a wide range of proteins and effectively reconstructs flexible linkers in multidomain architectures. Moreover, it supports hierarchical reconstruction of complex protein assemblies, including multiple virus-like particles spanning tens of nanometers and containing hundreds of subunits. Using this framework, we demonstrate--for the first time--the ability to hierarchically backmap entire viral assemblies from HCG to full AA resolution, covering at least three different resolutions. Overall, our method provides a scalable framework for incorporating atomistic detail into mesoscale simulations of complex systems across many applications in chemistry and biology. Table of contents figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=70 SRC="FIGDIR/small/709104v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@4af423org.highwire.dtl.DTLVardef@e2669borg.highwire.dtl.DTLVardef@1be80eforg.highwire.dtl.DTLVardef@2e679_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2026

Dissociable frequency regimes in human temporal cortex integrate facial and acoustic cues during natural speech

Face-to-face communication relies on the seamless integration of visual and acoustic cues, yet the spatiotemporal principles governing how the human brain dynamically represents and combines these multisensory streams remain largely unresolved. To address this, we recorded high-density electrocorticography (ECoG) from eight participants perceiving matched audiovisual, audio-only, and video-only continuous natural Mandarin speech. Using time-frequency-resolved encoding models, we reveal complementary, frequency-dependent integration regimes across the temporal lobe. We show that the superior temporal gyrus (STG) implements a feature-selective, auditory-dominant strategy, utilizing visual input to selectively strengthen low-frequency representations of lip-reading kinematics. Conversely, the middle temporal gyrus (MTG) acts as a higher-order multisensory hub, employing a frequency-selective strategy to broadly integrate diverse facial and articulatory features. Crucially, we demonstrate that access to visual information during perception significantly improves the acoustic and lexical accuracy of neural speech decoding and re-synthesis, with the MTG driving the largest gains in linguistic intelligibility. These findings uncover the dissociable neural architectures supporting robust multisensory perception, providing critical mechanistic insights for the development of next-generation, multimodal brain-computer interfaces.

neuroscience↗

bioRxiv2026

A vagal gut-brain axis for feeding induced gastric secretion

Feeding begins with food-seeking and ends with nutrient absorption and waste elimination. Although meal-related sensory cues are known to shape feeding behavior, how they engage neural circuits to control digestion remains unclear. We dissected vagal gut-brain-gut pathways that mediate meal-induced gastric secretion. Vagal afferent neurons innervating the stomach were necessary and sufficient for secretion. Among those, Glp1r and Sst neurons robustly drove acid, pepsin, and gastrin secretion, whereas Oxtr and Vip neurons had little effect. Piezo2 was expressed in Glp1r mechanosensory afferents, and conditional deletion of Piezo channels attenuated distension-evoked secretion. On the efferent limb, genetically defined vagal motor neuron subsets differentially recruited secretory outputs: Cck neurons broadly increased acid, pepsin, and gastrin, whereas Grp neurons preferentially drove acid secretion. Finally, enteric circuit dissection revealed modular output control: Calb2 enteric neurons potently drove secretion with minimal motility effects, Grp enteric neurons coupled secretion to motility, and Cysltr2 enteric neurons selectively modulated acid output. Together, these results define a cell-type resolved vagal-enteric architecture for gastric control and show that secretory and motor programs can be segregated across dedicated enteric neuron subtypes.

neuroscience↗

bioRxiv2026

Single-cell Analysis of Paired FFPE Placentas Reveals Trophoblast Reprogramming and Immune Dysregulation in Chronic Villitis of Unknown Etiology

Villitis of unknown etiology (VUE) is a common placental inflammatory lesion associated with adverse pregnancy outcomes, yet its mechanisms remain unclear. Mechanistic studies are hindered by reliance on archived formalin-fixed paraffin-embedded (FFPE) tissues, which are incompatible with standard single-cell methods. Here, we develop an FFPE-compatible single-nucleus RNA sequencing strategy and apply it to paired placentas from sequential pregnancies. VUE placentas exhibit pronounced immune expansion and disrupted trophoblast differentiation. A distinct extravillous trophoblast population and a subset of syncytiotrophoblasts aberrantly express classical MHC class I molecules, promoting natural killer cell engagement and indicating loss of trophoblast immune privilege. Pro-inflammatory maternal macrophages infiltrate, while fetal Hofbauer cells are reduced and transcriptionally reprogrammed. Increased intracellular viral burden and JAK-STAT signaling correlate with aberrant MHC class I expression, suggesting stress-induced local alloimmune activation. These findings define a cellular basis for disrupted maternal-fetal immune tolerance in VUE and demonstrate the utility of FFPE-based single-cell transcriptomics in placental disease.

cell biology↗

bioRxiv2026

mSWI/SNF complex inhibition sensitizes KRAS-mutant lung cancers to targeted therapies via epithelial-mesenchymal subversion

Targeted therapies for KRAS-mutant non-small lung cancer (NSCLC) have shown promising clinical results, however, incomplete tumoral responses and the inevitable emergence of therapeutic resistance remain critical challenges. Here we identify mSWI/SNF chromatin remodeling complexes as critical determinants of (EMT)-mediated KRAS inhibitor inefficacy and resistance in KRAS G12C lung cancers. Treatment with the clinical-grade SMARCA4/2 inhibitor, FHD-286, dampens EMT-mediated acquired resistance in drug-responsive models and similarly resensitizes drug-refractory models by rewiring mSWI/SNF chromatin localization and activities that modulate epithelial transcriptional programs and cell state. Further, synergistic mSWI/SNF and KRAS inhibitor combination treatment sensitizes non-G12C KRAS-mutant NSCLC cells to pan-RAS and G12D-specific inhibitors. Finally, FHD-286 and sotorasib combination treatment results in potent anti-tumor efficacy in both G12Ci-resistant and - sensitive organoid models and in vivo patient-derived xenograft (PDX) systems. These data nominate mSWI/SNF inhibition as a combination strategy to improve KRAS inhibitor efficacy, response duration, and to mitigate emergence of resistance.

cancer biology↗

bioRxiv2026

Endocardial TIE1 synergizes with TIE2 to regulate the atrial internal muscular network assembly

Atrial cardiomyopathy is characterized by altered atrial structures, yet its underlying genetic basis remains inadequately explored. TIE1 mutations are reported in lymphedema patients, but whether they exhibit cardiac defects alongside lymphatic abnormalities remains unknown. Here, single-cell RNA sequencing showed high Tie1 and Tek expression in atrial endocardial cells. TIE1 deficiency severely disrupted atrial morphogenesis, with only minor ventricular defects. Bulk RNA-seq showed reduced transcripts for endothelial development and cardiac trabeculation in Tie1 mutants. Separate RNA-seq analysis of the atria and ventricles further confirmed these findings, revealing a more pronounced downregulation of trabecular genes, including Tek, in the atria upon Tie1 loss. Endothelial deletion of Tek impaired trabeculation, particularly in atria. Consistently, Tie1 loss combined with a single null Tek allele disrupted both atrial and ventricular trabeculation. Strikingly, atrial morphogenesis defects appeared within 48 hours of induced endothelial Tie1 loss coupled with Tek heterozygous deletion, implying a critical endocardial role in organizing the atrial muscular network. The synergy of TIE1 and TIE2 in remodeling atrial trabeculae was confirmed postnatally, whereas TIE1 insufficiency alone had no effect. Together, TIE1 is differentially required for atrial versus ventricular development, acting synergistically with TIE2 to regulate endocardial cell-coordinated assembly of atrial internal muscular network.

developmental biology↗

bioRxiv2026

Discovery of inhibitors of the Pseudomonas aeruginosa NADH:ubiquinone oxidoreductase (NQR) that hinder virulence factors

The growing threat of antimicrobial resistance has created an urgent need to identify novel therapeutic targets in bacteria. The NADH:ubiquinone oxidoreductase (NQR) is a potential target in a number of bacteria that transfers electrons from NADH to ubiquinone while pumping ions from the cytoplasm to the periplasm. In most species, this complex pumps sodium ions, whereas in Pseudomonas aeruginosa it pumps protons, thereby functioning as a member of the electron transport chain. Using a strain of PAO1 with the NQR knocked out, we demonstrate that the NQR complex plays a crucial role in the motility and biofilm development virulence factors in P. aeruginosa. We develop and execute a high-throughput inhibitor screen to identify and confirm compounds that inhibit NADH oxidation by this complex. Using single-particle cryogenic electron microscopy (cryoEM), we determine high-resolution structures of the NQR complex, both inhibitor-free and bound to one of the confirmed hits from our screen, demonstrating that it binds to the ubiquinone binding site. These structures provide insight into conformational dynamics controlled by binding at the ubiquinone site, with potential implications for the coupling between electron transfer and proton pumping in this complex. Biofilm development and motility assays with selected compounds from the screen show that they affect these virulence factors similarly to the NQR knockout.

biochemistry↗

bioRxiv2026

Modeling Microbiome Modulation of Tumor Metabolic Networks to Predict Synergistic Therapies

Differences in microbiome composition profoundly influence drug response, yet methods to model the metabolic interplay between tumors, microbes, and therapeutics remain limited. We present a generalizable framework combining machine-learning and genome-scale metabolic modeling to prioritize combination therapies for colorectal cancer (CRC) in the presence of Fusobacterium nucleatum (Fn) and other pathogenic, probiotic, and commensal microbes. Trained on 6,514 drug combinations in microbe-free CRC cell lines, the model predicted synergistic combinations in both microbe-free and microbe-associated contexts and generalized to immunotherapy-associated conditions. Predictions were validated using an asymmetric co-culture system that mimics the colons normoxic-anaerobic gradient, confirming synergistic combinations in HCT116 cells with Fn, including drugs not typically used in CRC therapy. Mechanistic analysis and targeted pharmacological perturbations revealed phospho-inositol metabolism and cysteine transport as key determinants of Fn-dependent drug synergy. Together, this work introduces a scalable, microbiome-aware framework to enable discovery of context-specific combination therapies.

bioinformatics↗

bioRxiv2026

Sphingolipid regulation by yeast Mdm1 supports adaptive remodeling of the methionine transporter Mup1

Membrane lipid composition influences endocytic remodeling of nutrient transporters, yet how lipid metabolism is spatially coordinated to support sustained adaptation to nutrient limitations remains unclear. Here, we investigated whether the ER-vacuole tether Mdm1 links sphingolipid homeostasis to regulation of the high-affinity methionine permease Mup1 in budding yeast. To test this, we examined Mup1 trafficking, amino acid homeostasis, and sphingolipid composition in mdm1{Delta} cells during starvation. We found that loss of Mdm1 causes persistent retention of Mup1 at the plasma membrane, accompanied by reduced intracellular methionine and broad amino acid depletion. Lipidomic analyses revealed decreased sphingoid bases and altered ceramide composition in mdm1{Delta} cells. Importantly, supplementation with the sphingolipid precursor phytosphingosine restored sphingolipid pools, rescued Mup1 endocytosis, and improved amino acid homeostasis. Consistent with a chronic amino acid restriction-like state, mdm1{Delta} cells exhibited extended chronological lifespan. Together, these findings identify Mdm1 as a spatial organizer of sphingolipid metabolism required for adaptive endocytic remodeling of Mup1, thereby linking ER-vacuole contact site function to plasma membrane proteostasis and metabolic adaptation.

cell biology↗

bioRxiv2026

Integrative Multi-Scale Sequence-Structure Modeling for Antimicrobial Peptide Prediction and Design

Antimicrobial resistance (AMR) is accelerating worldwide, undermining frontline antibiotics and making the need for novel agents more urgent than ever. Antimicrobial peptides (AMPs) are promising therapeutics against multidrug-resistant pathogens, as they are less prone to inducing resistance. However, current AMP prediction approaches often treat sequence and structure in isolation and at a single scale, leading to mediocre performance. Here, we propose MultiAMP, a framework that integrates multi-level information for predicting AMPs. The model captures evolutionary and contextual information from sequences alongside global and fine-grained information from structures, synergistically combining these features to enhance predictive power. MultiAMP achieves state-of-the-art performance, outperforming existing methods by over 10% in MCC when identifying distant AMPs sharing less than 40% sequence identity with known AMPs. To discover novel AMPs, we applied MultiAMP to marine organism data, discovering 484 high-confidence peptides with sequences that are highly divergent from known AMPs. Notably, MultiAMP accurately recognizes various structural types of peptides. In addition, our approach reveals functional patterns of AMPs, providing interpretable insights into their mechanisms. Building on these findings, we employed a gradient-based strategy and achieved the design of AMPs with specific motifs. We believe MultiAMP empowers both the rational discovery and mechanistic understanding of AMPs, facilitating future experimental validation and therapeutic design. The codebase is available at https://github.com/jiayili11/multi-amp.

bioinformatics↗

bioRxiv2026

An ancient gene duplication is implicated in virulence in the human pathogen, Histoplasma

Histoplasma spp. is a dimorphic fungal primary pathogen that infects people worldwide and frequently affects immunosuppressed patients. Previous studies have identified the AMY1 gene product, the -amylase Amy1p, as essential for -glucan production and virulence in Histoplasma capsulatum. We identified two new genes (AMY2 and AMY3) in the Histoplasma genome that encode putative -amylases and made mutants using CRISPR/Cas9 technology, followed by evaluation of their role in -glucan biosynthesis and virulence. We also searched for AMY gene copies in 19 fungal genomes with the goals of identifying orthologs for AMY2 and AMY3, and establishing how many AMY copies existed across different fungi. We found that the number and type of -amylases vary depending on the fungal species; that all -amylases related to Histoplasma Amy1p belong to the GH13_5 subfamily, and all orthologs related to Histoplasmas Amy2p and Amy3p belong to the GH13_1 subfamily. We performed phylogenetic analyses of the three paralogs and revealed that the Histoplasma AMY duplications are ancient. We further established Amy2 is an ortholog of Aspergillus niger AgtA, and Aspergillus nidulans AmyD, and that it is partially involved in Histoplasma -glucan biosynthesis and virulence, while Amy3p is an ortholog of Aspergillus flavus Amy1, and it is dispensable for -glucan biosynthesis and virulence.

microbiology↗

bioRxiv2026

Field-isolate recombinant tick-borne encephalitis viruses define reporter-stability guidelines for antiviral screening in flaviviruses

As arthropod-borne viruses continue to threaten populations globally, there is a pressing need for experimental systems that enable rapid antiviral discovery. Reverse-genetics platforms producing recombinant reporter orthoflaviviruses have been developed to address this gap. Here, we present two new recombinant tick-borne encephalitis viruses (TBEVrec) generated on a European-subtype Haselmuehl Tiho1 isolate backbone. A reporter gene, either eGFP or Nluc, was inserted in the capsid-coding region of the genome downstream of the capsid RNA regulatory signal and separated from the complete viral polyprotein by a 2A self-cleaving peptide. TBEVrec was better rescued using the circular polymerase extension reaction (CPER) than with the infectious subgenomic amplicon (ISA) method. TBEVrec replicated efficiently in relevant human cell lines, with comparable replication to wild-type TBEV in a neuronal cell line and moderately reduced titers and RNA levels in immune-derived cell lines. Using either eGFP or Nluc, we illustrate how TBEVrec enabled high-content RNAi screening, highlighting Nucleolin and PRKD1 as potential TBEV host factors, and drug testing on a benchtop plate reader. Nanopore sequencing of the eGFP insert revealed that the reporter is excised without affecting flanking regions. Comparative analysis of eGFP and Nluc further shows that this instability is time- and cell type-dependent, and that Nluc is comparatively more stable. From these observations, we outline safeguards and design principles that are broadly applicable both to the rescue of existing constructs and to the design of future recombinant reporter virus platforms.

microbiology↗

bioRxiv2026

NRF2 pathway activation and SPP1⁺TREM2⁺ macrophages drive chemoradiotherapy resistance in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is among the most aggressive cancers, with low rates of durable response to chemoradiotherapy and limited therapeutic options for relapsed disease. To uncover mechanisms of treatment resistance and relapse, we performed comprehensive multi-omics profiling of >100 pre-treatment and post-relapse ESCC tumors from a prospective clinical trial (NCT04694391), integrating whole-exome/genome sequencing, bulk RNA-sequencing, single-cell RNA sequencing, and spatial transcriptomics. We identify somatic alterations in NFE2L2/KEAP1 in nearly 40% of relapsed patients, which are associated with upregulation of NRF2 signaling targets in resistant tumors and cell line models. At single-cell and spatial resolution, relapsed tumors are enriched for NRF2-activated epithelial cells that physically co-localize with immunosuppressive SPP1TREM2 macrophages. This co-localization suggests a synergistic interaction between NRF2-driven tumor programs and macrophage-mediated immune suppression that promotes relapse after chemoradiotherapy. Our findings nominate NFE2L2/KEAP1 mutations as predictive biomarkers for patient stratification and highlight therapeutic targeting of NRF2 signaling and SPP1TREM2 macrophages as rational strategies to overcome resistance in ESCC.

cancer biology↗

bioRxiv2026

Super-resolution single-cell spatial atlas of plant de novo regeneration

Plant de novo regeneration, a capacity absent in animals, relies on stem-cell-niche formation rather than pre-existing reservoirs. Growth hormones such as auxin and cytokinin, together with numerous genetic regulators, participate in regeneration, but the architectural principles coordinating extensive cellular reprogramming at the individual-cell scale remain elusive. Using super-resolution multimodal spatial transcriptomics to 1.16 million cells, we tracked tomato regeneration across temporal intervals from wounding to organogenesis. Datasets are available at http://www.single-cell-spatial.com.

cell biology↗