Biology subjects

Fares, W. A.

Publications and source records attributed to Fares, W. A..

3 recordsLinked to original sources

bioRxiv2026

Generalized inference of noise-corrected state variability in single cells

Single-cell omics methods operate at their detection limit and are less conducive to technical controls than mini-bulk approaches, which combine cells of the same type before profiling. To integrate mini-bulk samples with paired split-pool controls more holistically, we built stochprofIC, an algorithm that considers data, noise, and covariates in a distributional-regression framework. We vet stochprofIC with synthetic datasets and compare against an adjusted-variance alternative using mini-bulk data in mouse brains and human breast cancers. The noise-batch corrections provided by stochprofIC enable inference of the single-cell populations comprising the mini-bulk, which are validated repeatedly by RNA FISH in different contexts. We use stochprofIC outputs as input to a systems model of nucleocytoplasmic transport and distinguish heterogeneous trafficking states. Pharmacologic inhibition of a MAP3K11-high state inhibits apoptosis in primary breast-cancer organoids, supporting relevance to phenotypes. By deconvolving changes in location and scale, stochprofIC supports mini-bulking when high-sensitivity and reliability profiles are important.

systems biology↗

bioRxiv2026

TGFβ signaling systems are prone to inhibition and ligand competition by coreceptor

Transforming growth factor-{beta} (TGF{beta}) ligands and receptors interact with overlapping selectivity to form different signaling complexes. This many-to-many wiring provides versatility in how ligands are perceived and cell types become activated, but the systems-level impact of coreceptors, which bind TGF{beta} ligands yet do not signal, remains unresolved. We examined the role of canonical surface-bound coreceptors by numerically simulating TGF{beta} ligand-receptor systems of increasing complexity and pairing results with single-cell measurements in acutely stimulated cells. Using sampled combinations of biologically plausible rate parameters and initial conditions, we find that coreceptors inhibit downstream signaling six times more often than they promote it, and the models reconcile this inhibitory bias with the prevailing view that coreceptors either promote or inhibit signaling. In multi-ligand systems, coreceptor inhibition causes stimuli to be perceived differently by altering competition, and this threshold is confirmed in cells engineered to induce a single coreceptor heterogeneously. Coreceptors are among the most variably expressed components of TGF{beta} signaling, suggesting that cells exploit coreceptors as a way to switch active ligand-receptor landscapes with a single gene.

systems biology↗

bioRxiv2025

Multimodal analysis identifies pericyte-centered signaling programs altered by sex and brain region in Alzheimer's Disease

Pericytes are critical components of the neurovascular unit (NVU), regulating endothelial cell (EC) stability, blood-brain barrier (BBB) integrity, and neuroimmune signaling. However, their role in Alzheimers Disease (AD), particularly in the context of sex differences and brain region specificity, remains poorly defined. Here, we use single-nucleus RNA sequencing (snRNA-seq) to characterize transcriptional and intercellular signaling changes in pericytes across the middle temporal gyrus (MTG) and dorsolateral prefrontal cortex (DLPFC) of the same AD and non-AD donors, stratified by sex. Using LIANA and Tensor-cell2cell, we identify latent communication programs altered in female AD donors, including a pericyte-EC signaling pattern that activates TGF{beta} via extracellular matrix ligands and is upregulated in the MTG but not the DLPFC. A second communication pattern, downregulated in female AD donors, reveals impaired estrogen pathway signaling through ligand-receptor interactions between pericytes and astrocytes. Supporting this, we observe reduced expression of pericyte-derived neuroligins and increased pericyte-astrocyte separation in a spatial transcriptomic subset. Additionally, we identify a microglia-to-pericyte signaling program conserved across brain regions, enriched for inflammatory pathways including hypoxia and p53, and elevated in both male and female AD donors with regional specificity. This result contrasts with the more sex-and region-specific pericyte signaling programs and suggests parallel mechanisms of NVU disruption between brain regions in AD. Our findings reveal brain region-specific and sex-specific pericyte signaling changes in AD and implicate vascular-, immune-, and synapse-associated pathways in NVU dysfunction. Altogether, the data suggest pericyte-driven communication as a mechanistic contributor to female-biased vulnerability in AD and support the need for sex-aware and region-specific approaches in neurodegeneration research.

bioinformatics↗