Biology subjects

Jiang, H.

Publications and source records attributed to Jiang, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Endolysosomal damage promotes intraluminal protein condensate formation that limits cytosolic leakage

Endolysosomal membrane damage is a detrimental process in mammalian cells that results in leakage of the luminal contents into the cytosol. However, the nature and extent of the leakage during membrane damage is unknown. Here, we show that endomembrane damage induces the rapid formation of intraluminal condensates in endolysosomes. A subset of resident luminal proteins undergo spatially coordinated condensation upon endomembrane damage. Electron microscopy reveals distinct luminal morphology, and cryo-electron tomography confirms the condensed ultrastructure in their native state. Condensate formation occurs across mechanistically distinct modes of membrane injury and is reversibly dissociated upon lysosomal recovery. Remarkably, these condensates impose a previously unrecognised barrier to endolysosomal escape of therapeutic oligonucleotides. Despite endomembrane damage, luminal oligonucleotide therapeutics are sequestered in damaged endolysosomes through condensate-mediated biophysical immobilisation. Targeting condensate sequestration could represent a novel strategy to improve oligonucleotide-based therapeutics.

cell biology↗

bioRxiv2026

C. albicans ergosterol modulates the antifungal response of human neutrophils by masking β-glucan

IntroductionErgosterol-targeting azoles are widely used in the treatment of Candida albicans infection. In addition to direct antifungal activity, azoles are known to enhance neutrophil-mediated killing of C. albicans, but the underlying mechanisms remain unclear, particularly whether ergosterol depletion directly modulates host immune responses. Gap StatementIt remains unknown whether reduced ergosterol levels alone, independent of broader disruption to sterol biosynthesis and fungal morphogenesis, influence neutrophil antifungal activity. AimThis study aimed to determine how genetic disruption of late-stage ergosterol biosynthesis affects neutrophil-mediated responses to C. albicans. MethodologyDoxycycline-repressible GRACE mutants targeting late-stage ergosterol biosynthesis genes (ERG4, ERG5, ERG3 and ERG28) were co-incubated with primary human neutrophils. Fungal survival, oxidative burst, phagocytosis, neutrophil extracellular trap (NET) formation and cell wall composition were assessed. ResultsAll ergosterol-deficient strains induced elevated neutrophil reactive oxygen species (ROS) production; however, only ERG4 depletion was associated with enhanced fungal clearance. This phenotype correlated with increased phagocytosis and reduced NET formation. Cell wall analysis revealed no changes in total chitin or mannan content but demonstrated significantly increased surface exposure of {beta}-1,3-glucan in ERG4-depleted cells. ConclusionThese findings indicate that disruption of late-stage ergosterol biosynthesis, particularly via ERG4, enhances neutrophil antifungal responses and is associated with increased {beta}-glucan exposure. This study highlights a potential role for ergosterol in immune evasion and suggests that targeting terminal steps of the pathway may improve host-mediated clearance of C. albicans.

microbiology↗

bioRxiv2026

IL-36γ Drives Th9 cell Differentiation via IκBζ to Sustain Antitumor Immunity

Th9/Tc9 cells polarized with TGF-{beta} and IL-4 exhibit superior antitumor efficacy, prompting extensive efforts to optimize their differentiation protocols and augment therapeutic potency. In the current study, we identified IL-36{gamma} as a potent cytokine that synergizes with TGF-{beta} to robustly drive Th9 differentiation both in the presence and absence of IL-4. IL-36{gamma}-programmed Th9 cell subsets exhibited phenotypic and transcriptional profiles identical to classic Th9 cells. Mechanistically, IL-36{gamma} drove Th9 cell differentiation through amplifying key signaling pathways such as STAT6, STAT5, and NF-{kappa}B that are essential for classic Th9 programming. Notably, we uncovered a novel regulatory axis wherein IL-36{gamma} upregulates the transactivation factor I{kappa}B{zeta}, which directly governs Th9 lineage specification. In in adoptive cell therapy (ACT) models, IL-36{gamma}-polarized Th9 cell subsets demonstrated enhanced antitumor efficacy, attributable to their sustained persistence, reduced exhaustion markers and stem-like/memory properties. Collectively, this study elucidates a previously unrecognized I{kappa}B{zeta}-dependent mechanism underpinning Th9 differentiation and highlights the translational potential of IL-36{gamma}-engineered Th9 cells as a valuable ACT strategy for refractory tumors.

immunology↗

bioRxiv2026

Automated Multimodal Correlative Registration for Organelle-Specific Molecular Imaging

Mapping subcellular drug distribution is essential for understanding trafficking and off-target effects. NanoSIMS enables chemical imaging of labeled therapeutics, but signal interpretation requires ultrastructural correlation with electron microscopy, a manual and laborious process. We present an automated AI-driven pipeline for correlating chemical and ultrastructural images, enabling multiscale, organelle-precise imaging of molecules in cells and tissues. The method integrates bidirectional optical flow, confidence-guided affine transformation, and automated template matching for cross-scale EM alignment. Morphology-rich ion channels (e.g., 32S) estimate transformations that propagate to sparse therapeutic signals (e.g., 79Br, 15N), overcoming low signal-to-noise challenges. We validate this framework across diverse cell and tissue types, tracking oligonucleotide and antibody therapeutics in vitro and in vivo to reveal cell-type- and organelle-specific distribution patterns. This work establishes a generalizable platform for automated multimodal registration and organelle-resolved subcellular pharmacology.

bioinformatics↗

bioRxiv2026

The tongue-brain axis mediates a hidden amino acid appetite

Selecting a diet containing all essential amino acids (EAAs) is critical for health. Following EAA deprivation, animals can select a nutritiously complete food source; however, the underlying mechanisms in vertebrates remain unclear. In mice, we show that leucine deficiency activates hypothalamic agouti-related protein (AgRP) neurons, which project to the paraventricular thalamus (PVT) via {gamma}-aminobutyric acid and are required for EAA deficiency-induced leucine appetite in mice. Furthermore, the peripheral tongue amino acid sensor general control nonderepressive-2 (GCN2) mediates acute EAA appetite via AgRP neurons. Together, these findings identify a tongue-AgRP-PVT circuit underlying EAA appetite, which is important for the rapid and accurate selection of essential nutrients.

neuroscience↗

bioRxiv2026

Metabolic Drivers of Disease Activity and Complications in Crohns Disease: A Retrospective Cross-Sectional Study

BackgroundThis study aims to examine the independent relationships between individual components of metabolic syndrome (MetS) and two key clinical outcomes in patients with Crohns disease (CD): disease activity, as quantified by the Crohns Disease Activity Index (CDAI), and the occurrence of complications. MethodsThis retrospective cross-sectional study included 376 adults with newly diagnosed Crohns disease. Multiple linear regression was used to examine associations between metabolic parameters and CDAI scores, while multivariate logistic regression assessed links to complications. Analyses were also based on clinical CDAI cut-offs. Predictive nomograms were developed and internally validated via bootstrap resampling. ResultsMultiple linear regression indicated that higher CDAI scores were independently associated with lower BMI (B = -5.866, P < 0.001), lower HDL-C levels (B = -81.770, P < 0.001), higher triglycerides (B = 15.618, P = 0.001), and lower ESR (B = -0.375, P = 0.03). Multivariate logistic regression established low HDL-C (OR = 0.042, P < 0.001), low BMI (OR = 0.915, P = 0.034), and high triglycerides (OR = 1.792, P = 0.007) as significant independent risk factors for complications. The developed nomograms demonstrated strong predictive performance, with an adjusted R2 of 0.207 for the CDAI model and an AUC of 0.765 for the complication model. For both predictive tasks, the model incorporating separate TG and HDL-C measurements significantly outperformed the TG/HDL-C ratio model. ConclusionMetabolic disturbances demonstrate a significant association with increased disease severity and a higher risk of complication development in Crohns disease. Core tipO_LIDual-outcome study reveals HDL-C and TG differentially link to CD inflammation and complications, pointing to distinct mechanisms. C_LIO_LILow HDL-C is the strongest independent predictor for CD complications, underscoring its protective role beyond cholesterol transport. C_LIO_LIIndividual TG and HDL-C metrics outperform their ratio in prediction, challenging its use and suggesting independent pathways in CD. C_LIO_LILow BMI independently associates with both adverse outcomes, refining the "obesity paradox" and highlighting malnutritions key role. C_LIO_LIA practical, validated nomogram (AUC=0.765) integrates HDL-C, TG, and BMI to stratify complication risk, aiding clinical decision-making. C_LI

immunology↗

bioRxiv2026

FoTO1 is an epoxide isomerase in paclitaxel biosynthesis

Paclitaxel biosynthesis is limited by the instability of taxadiene-4(5)-epoxide, which readily diverts to the non-productive byproduct 5(12)-oxa-3(11)-cyclotaxane (OCT) instead of rearranging to taxadiene-5-ol. Although FoTO1 suppresses OCT accumulation, its molecular function has been unclear. Here we identify FoTO1 as a dedicated epoxide isomerase that directs productive rearrangement. Biochemical characterization, site-directed mutagenesis, and QM/MM calculations reveal a pre-organized D68-D149 dyad that electrostatically activates epoxide ring opening and stereospecific rearrangement. Modular dissection of the C-terminal extension further reveals a functional partition between catalytic integrity and productive coupling with T5OH, mediated by specific hydrophobic contacts that enforce precise geometric complementarity at the binary complex interface. These results demonstrate how electrostatic activation and enzyme association cooperate to control the fate of a highly reactive intermediate in paclitaxel biosynthesis.

biochemistry↗

bioRxiv2026

A cerebellar cognitive rheostat bidirectionally controls attention

Attention requires filtering distractors and amplifying signals, processes classically attributed to cortico-thalamic networks. Here, we reveal that the cerebellum operates as a bidirectional "cognitive rheostat" to optimize attentional states. In mice, the anterior and posterior cerebellar vermis exert opposing control over attention. Granule cells in the anterior vermis are functionally suppressed to gate sensorimotor noise via reticular nucleus-driven feedforward inhibition. Conversely, posterior granule cells are recruited by pontine inputs to amplify cognitive signals, a process relying on Grin1-mediated NMDA receptor plasticity. Circuit-specific manipulations targeting this push-pull mechanism, or localized pharmacological modulation, successfully rescued attentional deficits in an ADHD mouse model. These findings fundamentally expand the cerebellums role beyond motor coordination, identifying a topographic circuit algorithm essential for cognitive control.

animal behavior and cognition↗

bioRxiv2026

The enhanced multi-tissue atlas of regulatory effects in cattle

Cattle are integral to global food security, yet the molecular architecture of their complex traits remains poorly understood. Here, we present the Cattle Genotype-Tissue Expression (CattleGTEx) Phase 1 resource (https://cattlegtex.farmgtex.org/), a substantial expansion of the pilot study. By leveraging 12,422 RNA-seq profiles across 43 tissues and 82 breeds, we characterized 433,972 primary and 161,428 non-primary regulatory effects spanning seven molecular phenotypes. This high-resolution atlas resolves 75% of GWAS signals for 44 complex traits, significantly addressing the "missing regulation" in livestock. We propose a genetic regulatory model demonstrating how variants across multiple biological layers interact with specific biological contexts to shape phenotypic variation. Furthermore, CattleGTEx elucidates mechanisms underlying adaptive evolution between Bos taurus and Bos indicus, as well as artificial selection in dairy and beef breeds. Finally, by mapping evolutionary constraints on these regulatory effects, we demonstrate the translational value of this resource for prioritizing causal variants in human complex diseases. Together, Phase 1 of CattleGTEx provides a transformative framework for functional genomics, precision breeding, and comparative genetics.

genetics↗

bioRxiv2026

CD8+ T cells are primed by cDC1 and exacerbate tau-mediated neurodegeneration

There are changes in adaptive immunity in Alzheimers disease (AD) and increases in activated CD8+ T cells in brain correlate with tau pathology1-3. However, which cells mediate T cell priming in tau-mediated neurodegeneration remains unclear. In different conditions such as cancer, viral infections, and autoimmune diseases outside the CNS, conventional type-1 dendritic cells (cDC1) perform antigen cross-presentation to prime CD8+ T cells4,5. We demonstrate that tauopathy mice deficient in cDC1 are markedly protected against tau-mediated neurodegeneration and display a selective decrease in brain CD8+ T cell infiltration and glial reactivity. The remaining CD8+ T cells showed an antigen inexperienced status with less clonal expansion, indicating suboptimal T cell priming. We confirm that brain derived antigens are presented in secondary lymphoid tissues to prime CD8+ T cells. Our study identifies cDC1 cells as critical for CD8+ T cell priming outside the CNS. This priming is required for a large increase of activated CD8+ T cells in the brain which promotes tau-mediated neurodegeneration.

neuroscience↗

bioRxiv2026

Development of functional topography of the default mode subnetworks revealed by precision mapping

The default mode network (DMN) is a functionally and anatomically heterogeneous network comprising distinct subsystems that support internally directed processes such as memory and self-related thought. Specialization and segregation of functional brain networks are critical for cognitive maturation, yet how DMN subnetworks develop remains unclear. Group-average approaches obscure individual variability and blur spatial details, limiting precise characterization of network topography. Using precision mapping in 547 participants aged 5-21 years, we delineated individualized DMN subnetworks and examined their development across multiple aspects, including functional segregation and spatial topography. We found that DMN subnetworks become increasingly functionally segregated from each other and from non-DMN networks with age, and exhibit greater topographic distinctiveness through boundary sharpening and reduced spatial overlap. Furthermore, we observed a selective spatial contraction of the memory-related subnetwork, which correlated with better episodic memory. Our findings underscore the importance of characterizing multidimensional functional and topographical features at the individual level to better understand typical neurodevelopment and neurodevelopmental and psychiatric conditions.

neuroscience↗

bioRxiv2026

Unleashed condensation by recurrent mutations of an epigenetic regulator promotes cancer

The pathological mechanisms and significance for the prevalent hotspot mutations in disordered protein regions are poorly understood. ASXL1 is an obligate co-factor for BAP1 in H2AK119 deubiquitination. ASXL1 mutations are very frequent in myeloid malignancies, and are mostly C-terminal truncating mutations concentrated in a specific disordered region of ASXL1. ASXL1 truncations are gain-of-function mutations that promote myeloid malignancies, but the underlying mechanisms remain poorly understood. Here we show that the frequently truncated mutants of ASXL1 possess an intrinsic property of forming phase-separated biomolecular condensates, and this property is normally suppressed by the frequently deleted regions. A disease-mutant of the endogenous ASXL1 in leukemia cells forms dynamic nuclear co-condensates with other endogenous factors important for gene activation. The ASXL1 disease-mutants can greatly enhance H2A deubiquitination activity of BAP1 in cells and in vitro reconstituted system, enhance myeloid leukemia cell growth, and promote leukemogenesis in a mouse transplant model by turning on myeloid leukemogenic transcriptional programs. However, substitution of residues important for condensation disrupted or impaired all these abilities, suggesting that the condensation property is crucially important for the ASXL1 mutants in promoting cancer. Moreover, we discover that the conserved negative charges in the highly disordered and frequently deleted region on ASXL1 suppress the condensation of the wild type ASXL1. Charge-neutralizing mutations in this region restores condensation of the full-length ASXL1, and are sufficient to turn ASXL1 into a leukemogenic protein. Biochemical, biophysical, and simulation analyses suggest the intramolecular interactions normally mask the N-terminal region in engaging intermolecular interactions required for phase separation, and disease truncations escape from the regulatory interactions and unleash the phase separation property to form nuclear hubs to promote expression of tumorigenic gene programs. Finally, by showing a striking correlation of the mutation frequencies with the condensation properties and leukemogenesis activity for a series of human patient mutations, we suggest that dysregulation of condensation is a central mechanism for ASXL1 mutations in promoting myeloid malignancies. This suggests that dysregulation of condensation may be a key mechanism for some of the prevalent hotspot disease mutations in the disordered proteomes.

biochemistry↗

bioRxiv2026

Preserved Embedding of Neural Population Activity for Brain Computer Interfaces

Inferring neural population dynamics from motor cortex recordings is essential for brain-computer interface (BCI) control. However, neural activity patterns during similar behaviors exhibit systematic variability across recording sessions, subjects, and task contexts due to neural plasticity, anatomical differences, and varying movement distances. This variability degrades BCI decoder performanc when applied to different sessions, subjects, and task contexts. Here, we introduce Multi-Aligned Neural Data Transformer (MANDT) that extracts consistent embeddings of the motor cortical dynamics. By learning these consistent embeddings, MANDT enables generalization of BCI decoding: a decoder trained on data from one session maintains robust performance when applied to new sessions without recalibration. We validated our approach on neural recordings from rhesus monkeys performing the delayed-reach task. Lastly, we show that CEBRA can be used for the robotic control, enabling direct neural control of a humanoid robot, allowing monkeys to guide complex robotic manipulation tasks through brain signal.

neuroscience↗

bioRxiv2026

Selective Immune Silencing by Targeted TGF-β Agonists

Depletion of pathogenic T and B cells is a pillar of therapies for autoimmune, inflammatory, and transplantation-related immunological diseases. However, adverse events, safety concerns in immunocompromised patients, and disease relapse limit clinical utility. Here, we exploit the immunosuppressive properties of a transforming growth factor beta (TGF-{beta}) mimic repurposed from helminths for cell type-specific therapeutic silencing, as a new approach to complement existing therapies. Mouse CD4 and CD8 T cell-targeted TGF-{beta} agonists selectively and potently silence antigen-specific T cell responses in OVA-immunized mice by suppressing pro-inflammatory effector, cytotoxic, and T follicular helper programs, while skewing cells toward a quiescent state biased toward regulatory and type 17 T cell phenotypes. Similarly, human CD4 and CD8 T cell-targeted TGF-{beta} agonists precisely and effectively suppress live-attenuated influenza vaccine (LAIV)-induced T cell activation and expansion in human spleen organoids. Correspondingly, CD4 T cell-targeted TGF-{beta} agonist effectively ameliorated disease activity and promoted disease remission in CD4 T cell-driven models of autoimmune neuroinflammation and allergic airway inflammation, demonstrating efficacy in both prophylactic and established inflammatory settings. Moreover, both CD4 and CD8 T cell-targeted TGF-{beta} agonists ameliorated disease activity in graft-versus-host disease. Additionally, a human CD19 B cell-targeted TGF-{beta} agonist robustly inhibits germinal center B cell-to-plasmablast maturation and antibody responses in LAIV-stimulated human spleen organoids. These early-stage results suggest that cell-selective TGF-{beta} agonism merits further investigation as a versatile therapeutic approach for the precise silencing of pathogenic adaptive immune responses.

immunology↗

bioRxiv2026

Chromatin assembly at replication forks enables differentiation of human iPSCs

DNA replication is both productive and disruptive, synthesising new DNA while dismantling chromatin to allow fork progression. Because of its disruptive nature, DNA replication has been suggested to enable chromatin changes facilitating cell fate transitions. However, the role of DNA replication in cell fate transitions remains incompletely understood. Here we show that upon differentiation of human induced Pluripotent Stem Cells (iPSCs) into presomitic mesoderm, DNA replication allows hundreds of proteins, including transcription factors, histone chaperones, and histone methyltransferases, to access chromatin. Moreover, H3K9 methylation is enhanced upon differentiation through a DNA replication-coupled process. Most of the proteins recruited to (or evicted from) nascent chromatin during differentiation are already present in iPSCs, suggesting they may play a role in the early response to differentiation. Among these, we identified ERH and SETDB1 as essential for mesoderm differentiation. Our work reveals a new paradigm to explore: how differentiation signals exploit the replisome interactome to enable rapid chromatin changes.

cell biology↗

bioRxiv2025

Post-weaning social isolation impairs the orbitofrontal cortical circuit subserving contagious pain and prosocial behaviors

Empathic behaviors are sensitive to environmental factors like post-weaning social isolation (SI), yet the mechanisms by which SI affects empathy remain unclear. Here, we show that mice subjected to SI exhibit marked impairments in contagious pain and prosocial behaviors, including allo-grooming and allo-licking toward cagemates experiencing inflammatory pain. Mechanistically, we identify the glutamatergic projection from the ventromedial thalamic nucleus (VM) to the orbitofrontal cortex (OFC) as critical for these empathy-like responses. SI induces hypoexcitability of OFC glutamatergic neurons and attenuates excitatory synaptic transmission within the VM[->]OFC pathway. Remarkably, chemogenetic activation of OFC neurons or the VM[->]OFC projection restores empathic behaviors in SI mice. Furthermore, we uncover a molecular basis for SI-induced OFC hypoexcitability: the downregulation of Grik3, encoding a kainate-type glutamate receptor subunit. These findings reveal a previously uncharacterized thalamocortical mechanism through which early-life social deprivation disrupts empathic behaviors, offering insights into the underpinnings of social-affective dysfunction.

neuroscience↗

bioRxiv2025

Confinement prevents postmenopausal osteoporosis and obesity via nuclear mechanical remodeling

Postmenopausal osteoporosis (PMOP), affecting about half of postmenopausal women, is a major global health burden characterized by fragile bones and frequent comorbidity with obesity. Bone marrow mesenchymal stem cells (BMSCs) differentiation imbalance underpins PMOP pathogenesis and represents an attractive therapeutic target. Here, we demonstrate mechanically confining BMSCs to soft substrates mimicking physiological bone marrow stiffness completely suppresses adipogenic differentiation while inducing osteogenic differentiation. Mechanistically, confinement-induced elevation of nuclear envelope tension upregulates Lamin A/C expression, which in turn modulates Runx2 nuclear localization by activating histone acetylation via KAT2B, thereby directing BMSCs osteogenesis. Remarkably, FDA-approved deacetylation inhibitor Chidamide significantly enhances bone regeneration while concurrently suppressing obesity in a PMOP animal model, highlighting the significant therapeutic potential of nuclear mechanotransduction as a target for PMOP and obesity treatment. This work not only provides new insights into the mechanical regulation of bone homeostasis but also opens new avenues for the treatment of osteoporosis-related disorders.

biophysics↗

bioRxiv2025

Mining of natural diversity enables efficient and expressible peptide asparaginyl ligases

Peptide asparaginyl ligases (PALs) are powerful tools for protein engineering but are limited by natural rarity and poor expression. We mined 23 cyclotide-rich Viola species, uncovering 29 new PALs that expanded the known repertoire to 47. A dual-objective screen identified VdiPAL1 as the best-performed natural PAL, with twice efficiency of wt-VyPAL2 and 12 mg L-1 soluble expression in E. coli. A broad P2 specificity including Trp/Ile/Leu/Phe/Tyr/Met was discovered across diverse PALs, which enables sequential click-compatible liposome dual-functionalization. 1.8L[A] crystal structure of VdiPAL1 reveals a pre-organized near-attack conformation (NAC), supported by constant-pH MD simulations linking pH-dependent reactivity to NAC geometry. Our homology- and structure-based design yielded VyOpt1, a quintuple mutant of VyPAL2 with over 24-fold improved expression via enhanced cap-domain foldability in a single design-test cycle. This work expands the PAL family and demonstrates a transferable cap-domain-based engineering strategy, highlighting natural diversity as a powerful driver of enzyme discovery and optimization. TOC summaryMining of cyclotide-rich Viola genus expanded the total number of natural peptide asparaginyl ligases (PALs) to 47, including the discovery of highly expressible VdiPAL1. Its high-resolution structure provided new insights for mechanism, and its sequence guided us to a generalized PAL engineering strategy, leading to 24-fold increment in VyPAL2 expression.

biochemistry↗