Biology subjects

Wang, J. H.

Publications and source records attributed to Wang, J. H..

6 recordsLinked to original sources

bioRxiv2026

sigNATURE maps cohort-specific T-cell states to reproducible programs of ICI response

Immune checkpoint inhibitors (ICIs) can induce durable responses across cancers, yet T-cell biomarkers of response remain difficult to reproduce across single-cell RNA-seq studies. A major reason is that T-cell states are typically defined de novo within each cohort, making reported marker genes sensitive to cohort composition and analytic choices rather than stable cellular programs. Here we present sigNATURE (signature Normalization and Atlas-based T-cell Understanding for Reproducibility and Evaluation), a reference-guided framework that maps query cells onto large CD4+ and CD8+ T-cell atlases, evaluates published ICI-response markers in an atlas-aligned coordinate system, and quantifies the atlas support of mapped cells through a cell-level identifiability score. We applied sigNATURE to two independent ICI scRNA-seq cohorts comprising 36 non-small cell lung cancer patients and 15 skin cancer patients (11 basal cell carcinoma and 4 squamous cell carcinoma). Across cohorts, sigNATURE-derived features more robustly resolved response-associated T-cell structure than cohort-derived state definitions, yielding clearer unsupervised separation of responders and non-responders, enabling integrated analysis of independent studies in a shared atlas-aligned space, and improving mean response-prediction AUC from 0.469 to 0.746. Using identifiability score, we further identify terminally differentiated effector CD8+ T cells and regulatory CD4+ T cells as prominent response-associated states across studies, prioritizing published markers in terms of robust, atlas-resolvable cell states. Using this framework. Together, these results establish sigNATURE as a framework for improving the reproducibility, cross-cohort comparability, and mechanistic interpretability of single-cell ICI biomarkers.

immunology↗

bioRxiv2026

PRDX6 Modulates Immune Checkpoint Inhibitor Response by Antagonizing Ferroptosis Induced By HDAC Inhibitors

Therapeutic resistance limits the efficacy of histone deacetylase (HDAC) inhibitors and immune checkpoint therapies in cancer. While HDAC inhibitors can induce ferroptosis, tumor cells often evade this cell death via antioxidant defenses. Here we identify peroxiredoxin 6 (PRDX6) as a critical modulator of resistance to HDAC inhibitor largazole by suppressing ferroptosis through its phospholipase A2 activity and maintaining GPX4 expression. Using genome-wide CRISPR activation screening, biochemical assays, and syngeneic tumor models, we show that PRDX6 depletion enhances largazole-induced lipid peroxidation, ferroptotic stress, and reshapes the tumor microenvironment to promote T-cell infiltration and inflammatory cytokine release. Importantly, combining PRDX6 knockdown with HDAC inhibition potentiates anti-PD-L1 immunotherapy efficacy and prolongs survival in vivo. These findings reveal PRDX6 as a redox gatekeeper linking ferroptosis resistance to immune evasion and suggest that co-targeting PRDX6 and HDAC pathways may improve responses to cancer immunotherapy.

cancer biology↗

bioRxiv2025

Multi-modal, multi-species, and multi-task latent-space model for decoding level of consciousness

Assessing the degree and characteristics of consciousness is central to caring for patients with Disorders of Consciousness (DoC), yet current standard of care is a bedside questionnaire. Using a laminar neural probe we introduce a self-supervised, multi-modal representation learning approach that constructs an interpretable 2-D latent space of brain state from continuous neural recordings. We jointly encode local field potentials (LFPs), single-unit firing rates, and a movement proxy into a time-aware autoregressive VAE (TN-VAE). In rats, pigs and humans undergoing controlled depth anesthesia experiments, the learned latent trajectories nonlinearly, but smoothly, separate four expert-defined states (awake, light, moderate, deep) at 2s resolution, exceeding the temporal granularity of behavioral scoring (15m). The latent space supports linear readout of both coarse state and individual behavioral components, and its axes align with known physiology: delta/alpha power differentiates unconscious sub-states, while gamma and unit firing distinguish wakefulness. To enable cross-species use and incomplete modality sets, we add lightweight, species-specific stitching layers. This model pretrained on tri-modal rat data and fine-tuned with unimodal (LFP) pig data and unimodal human intraoperative data, successfully separates awake versus anesthetized states in new unseen human subjects, demonstrating zero-shot multi-subject transfer without per-patient calibration. The model further generalizes in a multi-task manner to predict the results of additional stimuli. These results highlight a path toward a foundation model for DoC that generalizes across sessions, subjects, species, and stimuli to enable scalable, continuous brain-state monitoring and clinical decision support.

neuroscience↗

bioRxiv2024

Hyaluronic Acid and Emergent Tissue Mechanics Orchestrate Digit Tip Regeneration

Tissue regeneration is a dynamic process requiring coordinated cell fate decisions to restore structure and function. For instance, the tips of human and rodent digits fully regrow after amputation, although more proximal injuries fail to regenerate. While biochemical cues have been widely studied in wound healing, the role of the physical microenvironment remains less understood. Here, we discovered that tissue mechanics and extracellular matrix (ECM) composition differ markedly between non-regenerating and regenerating wounds. These differences are due to specific fibroblast sub-types which predominate in the non-regenerating wound and form fibrotic collagen networks. Conversely, bone-forming progenitors in regenerating digits synthesize abundant hyaluronic acid, which mediates collagen fibrillogenesis. By modeling the tissue mechanics of non-regenerative and regenerative wounds using hydrogels, we showed that substrate stiffness regulates the synthesis of fibrotic and regenerative ECM. We further revealed that mimicking the regenerative wound mechanics upregulated bone morphogenic protein signaling and osteogenic differentiation. We ultimately demonstrated that the link protein HAPLN1 promotes hyaluronic acid deposition in vivo, reduces scar formation, and induces bone repair after non-regenerative amputations. These findings emphasize the interplay among the ECM, tissue mechanics, and cell behavior in digit regeneration and point towards ECM modulation as a strategy to improve wound healing. HighlightsO_LINon-regenerating and regenerating digit tips diverge in their cellular and ECM composition C_LIO_LIRegeneration requires hyaluronic acid matrix, which mediates collagen assembly and tissue mechanics C_LIO_LISoft substrates enhance BMP signaling and propagate the synthesis of regenerative ECM C_LIO_LIHAPLN1 overexpression initiates rescue of non-regenerative digit tip amputations C_LI

developmental biology↗

bioRxiv2023

Immunogenicity of COVID-19 vaccines and their effect on the HIV reservoir in older people with HIV

Older individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity of these vaccines and their effects on HIV reservoirs are not available. We followed 68 PWH aged 55 and older and 23 age-matched HIV-negative individuals for 48 weeks from the first vaccine dose, after the total of three doses. All PWH were on antiretroviral therapy (cART) and had different immune status, including immune responders (IR), immune non-responders (INR), and PWH with low-level viremia (LLV). We measured total and neutralizing Ab responses to SARS-CoV-2 spike and RBD in sera, total anti-spike Abs in saliva, frequency of anti-RBD/NTD B cells, changes in frequency of anti-spike, HIV gag/nef-specific T cells, and HIV reservoirs in peripheral CD4+ T cells. The resulting datasets were used to create a mathematical model for within-host immunization. Various regimens of BNT162b2, mRNA-1273, and ChAdOx1 vaccines elicited equally strong anti-spike IgG responses in PWH and HIV- participants in serum and saliva at all timepoints. These responses had similar kinetics in both cohorts and peaked at 4 weeks post-booster (third dose), while half-lives of plasma IgG also dramatically increased post-booster in both groups. Salivary spike IgA responses were low, especially in INRs. PWH had diminished live virus neutralizing titers after two vaccine doses which were rescued after a booster. Anti-spike T cell immunity was enhanced in IRs even in comparison to HIV- participants, suggesting Th1 imprinting from HIV, while in INRs it was the lowest. Increased frequency of viral blips in PWH were seen post-vaccination, but vaccines did not affect the size of the intact HIV reservoir in CD4+ T cells in most PWH, except in LLVs. Thus, older PWH require three doses of COVID-19 vaccine to maximize neutralizing responses against SARS-CoV-2, although vaccines may increase HIV reservoirs in PWH with persistent viremia.

immunology↗

bioRxiv2021

Fluorescence Activation Mechanism and Imaging of Drug Permeation with New Sensors for Smoking-Cessation Ligands

Nicotinic partial agonists provide an accepted aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug sensing fluorescent reporters ("iDrugSnFRs") for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives - 10-fluorocytisine and 9-bromo-10-ethylcytisine. We report the first atomic-scale structures of liganded periplasmic binding protein-based biosensors, accelerating development of iDrugSnFRs and also explaining the activation mechanism. The nicotinic iDrugSnFRs detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by > 30 fold. The new nicotinic iDrugSnFRs provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience.

pharmacology and toxicology↗