Biology subjects

Chavez, V.

Publications and source records attributed to Chavez, V..

6 recordsLinked to original sources

bioRxiv2026

Mucosal-associated invariant T cells support IL-15-dependent Treg response in skin injury and promote resolution of skin inflammation

Mucosal-associated invariant T (MAIT) cells are enriched at barrier sites, but their role in autoimmune skin inflammation remains unknown. Using cutaneous lupus as a model, we identify MAIT cells as protective regulators of skin inflammation and as critical upstream modulators of regulatory T cells (Treg). Topical MAIT cell activation with 5-OP-RU induced durable resolution of spontaneous skin lesions in MRL/lpr mice and suppressed TLR7-driven skin inflammation. MAIT cell activation selectively expanded and activated Treg populations in both healthy and lupus-like skin, while suppressing effector T cell cytokine production and cytotoxic programs. This MAIT-Treg axis was also activated in UV light-driven barrier injury in healthy murine and human skin, where MAIT cells were required for UV-elicited Treg expansion and function. In lupus-like skin, local MAIT cell activation restored the defective UVB-induced Treg response and limited CD8+ T cell expansion. Mechanistically, CCR2+ monocyte-derived antigen-presenting cells and IL-15 signaling were required for MAIT cell-driven Treg accumulation and therapeutic benefits of MAIT cells in inflamed skin. These studies identify a MAIT-IL-15-Treg axis that links barrier injury sensing to immune regulation, which is disrupted in cutaneous lupus, and nominate therapeutic MAIT cell activation as an unappreciated strategy for restoring immune homeostasis in inflamed skin.

immunology↗

bioRxiv2026

LizardMorph: A generalizable machine learning framework for automated anatomical landmark detection in digital images

Morphological measurements underpin a wide range of ecological and evolutionary research, yet the manual landmarking workflows on which most morphometric studies depend remain a persistent bottleneck that limits both the pace and scale of biological research. Machine learning offers compelling solutions, but most automated landmarking tools require substantial computational expertise, creating a gap between technical capability and practical adoption by biologists. Here, we present LizardMorph, an integrated machine learning pipeline and web-based interface for semi-automated anatomical landmark detection on biological images. LizardMorph couples a fine-tuned ML-Morph shape predictor with an accessible, browser-based interface that enables researchers to upload images, review automated landmark predictions, interactively correct outliers through point-and-click editing, and export results in standard morphometric formats--all without programming expertise or local software installation. Using dorsal X-ray radiographs of Anolis lizards with 34 anatomical landmarks as a proof-of-concept, we show that the ML-Morph model achieves high predictive accuracy, with landmarks on well-defined skeletal structures predicted with 100% accuracy within a 1 mm tolerance threshold. A controlled user study comparing LizardMorph against traditional manual landmarking (TpsDig2) demonstrated significant efficiency gains: experienced annotators completed LizardMorph landmark verification 37.5% faster than manual annotation. Extrapolated to batch processing 1,000 lizards, LizardMorph saves experienced researchers approximately 6.5 hours of manual processing time. Critically, LizardMorph implements a human-in-the-loop design in which automated predictions serve as editable starting points, preserving researcher oversight and enabling correction of the occasional large-error outliers that would be unacceptable in fully automated workflows. LizardMorph is freely available as an open-source tool and provides a replicable framework for developing ML-assisted annotation tools that can democratize access to high-quality morphometric analysis across diverse biological research communities.

evolutionary biology↗

bioRxiv2026

VesSynth: Tubes Are All You Need for Robust Cross-Scale Cross-Modal 3D Vessel Segmentation

The cerebral vasculature is central to brain function, with alterations linked to numerous cerebrovascular and neurological disorders. Yet, no single imaging modality can capture the entire cerebral vascular network in humans. Instead, an array of techniques are sensitized to different spatial scales, while trading off resolution for coverage. Magnetic Resonance Imaging (MRI) typically resolves only large pial vessels, while high-resolution microscopy allows micrometer-scale vessels to be mapped over limited spatial extents. These techniques must therefore be combined to obtain a complete mapping of the cerebral angioarchitecture, which underscores the need for automatic, cross-modal vessel segmentation. Here, we introduce VesSynth, a flexible vessel segmentation framework that achieves state-of-the-art accuracy across multiple modalities and spatial resolutions (MR, optical and X-ray imaging), despite being trained entirely on synthetic data. By enabling consistent vascular mapping across scales, this framework paves the way to comprehensive investigation of cerebrovascular organization and its role in health and disease.

bioengineering↗

bioRxiv2026

Mutant p53 Directs PARP to Regulate Replication Stress and Drive Breast Cancer Metastasis

TP53 mutations occur in 80-90% of triple-negative breast cancers (TNBCs) and drive genomic instability and metastatic progression. Poly (ADP-ribose) polymerase (PARP) is critical for DNA repair and replication fork stability. How oncogenic signaling influences PARP function to sustain proliferation during replication stress remains unclear. Mutant p53 (mtp53) R273H associates tightly with chromatin, forms complexes with PARP, and enhances PARP recruitment to replication forks [1-3]. The C-terminal region of mtp53 mediates mtp53-PARP and mtp53-Poly (ADP-ribose) (PAR) interactions that facilitate S phase progression [4, 5]. The PARP inhibitor talazoparib (TAL) combined with the alkylating agent temozolomide (TMZ) produces synergistic cytotoxicity selectively in mtp53, but not wild-type p53 (wtp53), breast cancer cells and organoids. Herein we evaluated the mechanism of mtp53-associated cell death and tested if this could translate to a preclinical xenograft model. We found that TMZ+TAL treatment induced elevated cleaved PARP and {gamma}H2AX and reduced the metastasis-promoting oncoprotein MDMX. In orthotopic xenografts expressing mtp53 R273H, but not wtp53, combination therapy significantly decreased circulating tumor cells (CTCs) and lung metastases. Transcriptomic profiling of tumors from combination treated animals demonstrated downregulation of MDMX, VEGF, and NF-{kappa}B, consistent with the observed suppression of CTCs and lung metastasis, and increased {gamma}H2AX, indicative of replication stress in mtp53 xenografts. Inhibition of metastasis was also observed in mtp53 R273H WHIM25 and p53-undetectable WHIM6 TNBC patient-derived xenografts (PDX). The mtp53 C-terminal domain (347-393) demonstrated a critical tumor promoting function, as CRISPR-mediated deletion impaired replication fork progression, tumor growth, and metastatic dissemination. DNA fiber combing showed that expression of full-length mtp53 R273H, but not C-terminal deleted {Delta}347-393, supported sustained single-stranded DNA gaps (ssGAPs) following Poly (ADP-ribose) glycohydrolase (PARG) inhibition. These findings support that mtp53 uses C-terminal amino acids to exploit PARP to enable replication stress adaptation and that mtp53 is a predictive biomarker for combined PARP inhibitor and DNA damaging therapies targeting TNBC. Significance statementTP53 mutations are the most common genetic alterations in TNBC and a major driver of replication stress and metastasis. This study shows that missense mutant p53 uses C-terminal amino acids to reprogram PARP activity to maintain tumor cell survival under replication stress. We demonstrate that p53 status governs the response to combined PARP inhibitor (PARPi) and DNA-damaging chemotherapy, establishing an additional molecular basis beyond BRCA1 mutations for treating TNBC with PARPi therapy. These findings reveal a previously unrecognized mechanism by which the mutant p53-PARP axis enables replication stress tolerance and drives cancer metastasis. We show mutation of p53 in TNBC provides an additional biomarker-guided framework to improve PARPi therapeutic outcomes.

cancer biology↗

bioRxiv2022

AI-Assisted Chemical Probe Discovery for the Understudied Calcium-Calmodulin Dependent Kinase, PNCK

PNCK, or CAMK1b, is an understudied kinase of the calcium-calmodulin dependent kinase family which recently has been identified as a marker of cancer progression and survival in several large-scale multi-omics studies. The biology of PNCK and its relation to oncogenesis has also begun to be elucidated, with data suggesting various roles in DNA damage response, cell cycle control, apoptosis and HIF-1-alpha related pathways. To further explore PNCK as a clinical target, potent small-molecule molecular probes must be developed. Currently, there are no targeted small molecule inhibitors in pre-clinical or clinical studies for the CAMK family. Additionally, there exists no experimentally derived crystal structure for PNCK. We herein report a three-pronged chemical probe discovery campaign which utilized homology modeling, machine learning, virtual screening and molecular dynamics to identify small molecules with low-micromolar potency against PNCK activity from commercially available compound libraries. We report the first described inhibitor hit series for PNCK that will serve as the starting point for future medicinal chemistry efforts for hit-to-lead optimization of potent chemical probes.

pharmacology and toxicology↗

bioRxiv2021

Innate immune signaling drives late cardiac toxicity following DNA damaging cancer therapies

Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. Here we report DNA damaging agents such as radiation and anthracycline chemotherapies induce delayed cardiac inflammation following therapy due to activation of cGAS and STING-dependent type I interferon signaling. Genetic ablation of cGAS-STING-signaling in mice inhibits DNA damage induced cardiac inflammation, rescues late cardiac functional decline, and prevents death from cardiac events. Treatment with a STING antagonist suppresses cardiac interferon signaling following DNA damaging therapies and effectively mitigates cardiotoxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.

immunology↗