Xiaoyang Wu

Chemical vesicants cause severe skin injury characterized by inflammation, tissue destruction, and separation of the epidermis from the underlying dermis. However, the molecular mechanisms linking vesicant exposure to the disruption of epidermal adhesion remain poorly understood. Phenylarsine oxide (PAO), a commonly used lewisite analog, is a potent inducer of cutaneous blistering and a strong inhibitor of protein tyrosine phosphatases. Here, we show that PAO rapidly induces focal adhesion kinase (FAK) phosphorylation and downstream signaling in epidermal keratinocytes, accompanied by accelerated focal adhesion disassembly and molecular turnover. Genetic ablation of FAK stabilizes focal adhesions and markedly suppresses PAO-induced adhesion remodeling. Importantly, epidermal-specific deletion of FAK protects mouse skin from PAO-induced microvesication, inflammatory responses, and cell death. Pharmacological inhibition of FAK similarly preserves focal adhesion stability in vitro and attenuates PAO-induced skin injury in vivo , phenocopying the protective effects of genetic FAK deficiency. Together, our findings identify aberrant FAK activation as a critical signaling event linking arsenical vesicant exposure to focal adhesion failure and skin vesication, and suggest that targeting FAK may provide a therapeutic strategy to mitigate chemical vesicant-induced skin injury. Highlights: First demonstration that focal adhesion kinase (FAK) is a critical molecular target of chemical vesicants whose dysregulation disrupts epidermal–dermal junctional integrity and initiates micro-vesicant injury. Establishes FAK-mediated junctional disruption as an early pathogenic event that triggers and amplifies subsequent inflammatory and programmed cell-death responses following vesicant exposure. Integrating in vivo genetic and pharmacological approaches, identifies FAK as a mechanistically validated and therapeutically actionable target for development of a mechanism-based medical countermeasure (MCM) against chemical vesicant injury.

The impairment of neural crest cells (NCCs) plays a pivotal role in the pathogenesis of fetal alcohol spectrum disorders (FASD). Epigenetic regulators mediate ethanol-induced disruptions in NCC development and represent promising targets for nutritional interventions. Here, we developed a biologically informed machine learning framework to predict nutritional supplements that modulate five key epigenetic regulators (miR-34a, DNMT3a, HDAC, miR-125b, and miR-135a) and mitigate ethanol’s adverse effects on NCCs. The optimized models demonstrated robust predictive performance and identified a number of nutritional supplements that could attenuate ethanol-induced NCC impairment, including resveratrol, vitamin B12, emodin, quercetin, and broccoli sprout-derived compounds. Our optimized models also revealed structural features that are critical for mitigating ethanol-induced NCC impairment through specific epigenetic mechanisms. These findings support predictive modeling as a tool to prioritize nutritional supplements for further investigation and the development of dietary strategies to prevent or reduce the risk of FASD.

Angiotensin-I converting enzyme (ACE) regulates the levels of disparate bioactive peptides, notably converting angiotensin-I to angiotensin-II and degrading amyloid beta. ACE is a heavily glycosylated dimer, containing four analogous catalytic sites, and exists in membrane-bound and soluble (sACE) forms. ACE inhibition is a frontline, FDA-approved, therapy for cardiovascular diseases yet is associated with significant side effects, including higher rates of lung cancer. To date, structural studies have been confined to individual domains or partially denatured cryo-EM structures. Here, we report the cryo-EM structure of the glycosylated full human sACE dimer. We resolved four structural states at 2.99 – 3.65 Å resolution which are primarily differentiated by varying degrees of solvent accessibility to the active sites and reveal the full dimerization interface. We also employed all-atom molecular dynamics (MD) simulations and heterogeneity analysis in cryoSPARC, cryoDRGN, and RECOVAR to elucidate the conformational dynamics of sACE and identify key regions mediating conformational change. We identify differences in the mechanisms governing the conformational dynamics of individual domains that have implications for the design of domain-specific sACE modulators.

Angiotensin-I converting enzyme (ACE) regulates the levels of disparate bioactive peptides, notably converting angiotensin-I to angiotensin-II and degrading amyloid beta. ACE is a heavily glycosylated dimer, containing 4 analogous catalytic sites, and exists in membrane bound and soluble (sACE) forms. ACE inhibition is a frontline, FDA-approved, therapy for cardiovascular diseases yet is associated with significant side effects, including higher rates of lung cancer. To date, structural studies have been confined to individual domains or partially denatured cryo-EM structures. Here we report the cryo-EM structure of the glycosylated full sACE dimer. We resolved four structural states at 2.99 to 3.65 Å resolution which are primarily differentiated by varying degrees of solvent accessibility to the active sites and reveal the full dimerization interface. We also employed all-atom molecular dynamics (MD) simulations and heterogeneity analysis in cryoSPARC, cryoDRGN, and RECOVAR to elucidate the conformational dynamics of sACE and identify key regions mediating conformational change. We identify differences in the mechanisms governing the conformational dynamics of individual domains that have implications for the design of domain-specific sACE modulators.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. UC treatments are limited by significant adverse effects associated with non‐specific drug delivery, such as systematic inhibition of the host immune system. Endoscopic delivery of a synthetic hydrogel material with biocompatible gelation that can efficiently cover irregular tissue surfaces provides an effective approach for targeted drug delivery at the gastrointestinal (GI) tract. An ideal integration of synthetic material with intestinal epithelium entails an integrated and preferable chemically bonded interface between the hydrogel and mucosal surface. In this study, a photo‐triggered coupling reaction is leveraged as the crosslinking platform to develop a mucosal‐adhesive hydrogel, which is compatible with endoscope‐directed drug delivery for UC treatment. The results demonstrated superior spatiotemporal specificity and drug pharmacokinetics with this delivery system in vivo. Delivery of different drugs with the hydrogel leads to greatly enhanced therapeutic efficacy and significantly reduced systemic drug exposure with rat colitis models. The study presents a strategy for targeted and persistent drug delivery for UC treatment.

Angiotensin-I converting enzyme (ACE) regulates the levels of disparate bioactive peptides, notably converting angiotensin-I to angiotensin-II and degrading amyloid beta. ACE is a heavily glycosylated dimer, containing 4 analogous catalytic sites, and exists in membrane bound and soluble (sACE) forms. ACE inhibition is a frontline, FDA-approved, therapy for cardiovascular diseases yet is associated with significant side effects, including higher rates of lung cancer. To date, structural studies have been confined to individual domains or partially denatured cryo-EM structures. Here we report the cryo-EM structure of the glycosylated full sACE dimer. We resolved four structural states at 2.99 to 3.65 Å resolution which are primarily differentiated by varying degrees of solvent accessibility to the active sites and reveal the full dimerization interface. We also employed all-atom molecular dynamics (MD) simulations and heterogeneity analysis in cryoSPARC, cryoDRGN, and RECOVAR to elucidate the conformational dynamics of sACE and identify key regions mediating conformational change. We identify differences in the mechanisms governing the conformational dynamics of individual domains that have implications for the design of domain-specific sACE modulators.

Continuous monitoring of glucose allows diabetic patients to better maintain blood glucose level by altering insulin dosage or diet according to prevailing glucose values and thus to prevent potential hyperglycemia and hypoglycemia. However, current continuous glucose monitoring (CGM) relies mostly on enzyme electrodes or micro‐dialysis probes, which suffer from insufficient stability, susceptibility to corrosion of electrodes, weak or inconsistent correlation, and inevitable interference. A fluorescence‐based glucose sensor in the skin will likely be more stable, have improved sensitivity, and can resolve the issues of electrochemical interference from the tissue. This study develops a fluorescent nanodiamond boronic hydrogel system in porous microneedles for CGM. Fluorescent nanodiamond is one of the most photostable fluorophores with superior biocompatibility. When surface functionalized, the fluorescent nanodiamond can integrate with boronic polymer and form a hydrogel, which can produce fluorescent signals in response to environmental glucose concentration. In this proof‐of‐concept study, the strategy for building a miniatured device with fluorescent nanodiamond hydrogel is developed. The device demonstrates remarkable long‐term photo and signal stability in vivo with both small and large animal models. This study presents a new strategy of fluorescence based CGM toward treatment and control of diabetes.