Sanford Burnham Prebys 医学发现研究所

The colonic mucosal barrier protects against infection, inflammation, and tissue ulceration. Composed primarily of Mucin-2, proteolytic erosion of this barrier is an invariant feature of colitis; however, the molecular mechanisms are not well understood. We have applied a recurrent food poisoning model of acquired inflammatory bowel disease using Salmonella enterica Typhimurium to investigate mucosal barrier erosion. Our findings reveal an innate Toll-like receptor 4-dependent mechanism activated by previous infection that induces Neu3 neuraminidase among colonic epithelial cells concurrent with increased Cathepsin-G protease secretion by Paneth cells. These anatomically separated host responses merge with the desialylation of nascent colonic Mucin-2 by Neu3 rendering the mucosal barrier susceptible to increased proteolytic breakdown by Cathepsin-G. Depletion of Cathepsin-G or Neu3 function using pharmacological inhibitors or genetic-null alleles protected against Mucin-2 proteolysis and barrier erosion and reduced the frequency and severity of colitis, revealing approaches to preserve and potentially restore the mucosal barrier.

Characterizing cellular aging is essential for understanding age-related diseases. While tissue-level studies reveal broad age-associated changes, they often reflect compositional shifts rather than cell-level reprogramming. The cellular damage hypothesis posits that aging involves the accumulation of DNA, chromatin, and other damage across molecular layers, increasing transcriptional entropy. Existing supervised methods for detecting cellular senescence yield cell type-specific senescence scores but rely on labeled data and lack generalizability. Here, we introduce a first-principles framework for quantifying transcriptional entropy in single cells as each cell's deviation from a transcriptomic manifold, capturing breakdown of transcriptional coordination. This unsupervised approach identifies aging-affected cell types and distinguishes two cellular aging mechanisms: loss of expression precision and activation of stress-response pathways in high entropy cells. Applied to Tabula Muris Senis and SenNet Multiome datasets, transcriptional entropy correlates with chromatin-based mitotic age and highlights regenerative tissue compartments as most affected by aging.

Dimensionality reduction is routinely applied to single-cell transcriptomic data to improve interpretability, remove noise and redundancy, and enable visualization. Most existing methods aim at preserving the most prominent data properties, which can lead to omission of rare but important signals. Here we propose a novel framework, SAKURA, that uses knowledge-derived genes of interest to guide dimensionality reduction, which can help cluster rare cells and separate highly similar cell subpopulations. We demonstrate the utility of our framework in identifying endocrine cell subtypes in the pancreatic islet, highly similar hematopoietic subpopulations, and rare senescent cells.

The luminal surface of blood vessels is covered by a hydrated mesh of sugars and proteins termed the endothelial glycocalyx. The glycocalyx forms a permeability barrier and helps regulate leucocyte migration. Directly detecting glycocalyx damage could provide a major advance in vascular health monitoring. Here we show that red blood cell glycocalyx mirrors the endothelial glycocalyx in health and disease. Using peripherally sampled blood, we confirm that red blood cell glycocalyx measurements predict cardiac and renal endothelial glycocalyx alterations and direct measures of endothelial barrier function in male rats. To investigate the underlying mechanism, we use Azide-Alkyne cycloaddition ('Click' chemistry) to confirm that contact between endothelial and red blood cells results in continual reciprocal transfer of glycocalyx components. These discoveries facilitate real-time monitoring of endothelial damage in patients whilst simultaneously providing a potential explanation as to how red blood cells maintain their glycocalyx during circulation.

Cognitive impairment in schizophrenia remains insufficiently addressed by existing treatments. Current FDA-approved therapies primarily modulate neurotransmitter systems, resulting in incomplete symptom control and substantial adverse effects. There is therefore a critical need for therapeutic strategies that more directly address the intracellular signaling mechanisms underlying synaptic dysfunction and cognitive deficits in schizophrenia. Protein phosphatases represent an essential but historically underexplored class of signaling enzymes that regulate phosphorylation-dependent control of synaptic receptor trafficking, plasticity, and neuronal circuit function. Although multiple phosphatases have been implicated in schizophrenia through genetic, post-mortem, and functional studies, their therapeutic targeting has been limited by challenges related to selectivity, cellular permeability, and pleiotropy. Here, we review the etiology of schizophrenia and limitations of current pharmacological approaches, synthesize evidence linking specific protein phosphatases to schizophrenia pathophysiology, and discuss emerging strategies, including allosteric modulation and targeted protein degradation, that may enable selective intervention in phosphatase-driven signaling pathways. We highlight the striatal-enriched tyrosine phosphatase STEP (PTPN5) as a case study illustrating how selective phosphatase modulation can restore synaptic signaling in schizophrenia-relevant models.