Biology subjects

Madan, R.

Publications and source records attributed to Madan, R..

6 recordsLinked to original sources

bioRxiv2026

Cellular stemness identifies high-risk ductal carcinoma in situ and offers a therapeutic interception opportunity

Ductal carcinoma in situ (DCIS) exhibits substantial heterogeneity in its risk of progression to invasive breast cancer, yet the cellular and molecular determinants of high-risk lesions remain incompletely defined. Using spatially resolved single-cell transcriptomic and epigenomic profiling of 43 patient-derived DCIS and DCIS/invasive ductal carcinoma (IDC) samples, we delineate cellular programs, spatial organization, and epigenetic regulatory mechanisms associated with invasive potential. We identify an epithelial population with stemness features within luminal hormone-responsive (LumHR) cells that progressively expands from benign tissue to DCIS and IDC, and is strongly associated with invasive progression and recurrence-linked transcriptional programs. Spatial mapping reveals discrete DCIS niches enriched for stem-like LumHR cells, characterized by elevated CEACAM6 expression and enhanced ligand-receptor interactions, including CEACAM6-EGFR signaling between epithelial and stromal compartments, including cancer-associated fibroblasts, macrophages (APOC1-positive) and perivascular cells. These niches define a microenvironmental context that supports stemness and invasive potential. Epigenomic analyses implicate FOXA1 as a key regulator of these stem-like transcriptional states. Pharmacologic disruption of FOXA1-regulatory network using LSD1 inhibition suppresses stemness-associated transcriptional programs in vitro and significantly restrains tumor growth in vivo. Collectively, these findings define high-risk DCIS as a stemness-driven disease embedded within specialized microenvironments, and identify associated regulatory networks as candidate biomarkers and therapeutic vulnerabilities.

cancer biology↗

bioRxiv2026

QNPtoVox: A methods pipeline for mapping 2D quantitative neuropathology to 3D MNI voxel space.

1.Quantitative neuropathology has advanced through whole-slide imaging and digital histology platforms. Yet, these measurements rarely align with neuroimaging coordinate frameworks that may be useful for spatial modeling and other applications. QNPtoVox, short for quantitative neuropathology to voxels, is a reproducible, modular pipeline that transforms quantitative metrics generated by digital pathology software (HALO) into voxel-based maps registered to a standard common coordinate (MNI) template. The workflow integrates digital histopathology, gross tissue photography, ex-vivo MRI, and nonlinear registration to generate spatially standardized 3D pathology representations. This Methods article provides a complete procedural description, including required materials, step-wise instructions, operator-dependent checkpoints, expected outputs, reproducibility evaluation, and troubleshooting. QNPtoVox enables voxel-level integration of neuropathology with neuroimaging tools, unlocking existing histopathology datasets for computational modeling and cross-cohort harmonization.

neuroscience↗

bioRxiv2023

Olfactomedin-4+ neutrophils exacerbate intestinal epithelial damage and worsen host survival after Clostridioides difficile infection.

Neutrophils are key first responders to Clostridioides difficile infection (CDI). Excessive tissue and blood neutrophils are associated with worse histopathology and adverse outcomes, however their functional role during CDI remains poorly defined. Utilizing intestinal epithelial cell (IEC)-neutrophil co-cultures and a pre-clinical animal model of CDI, we show that neutrophils exacerbate C. difficile-induced IEC injury. We utilized cutting-edge single-cell transcriptomics to illuminate neutrophil subtypes and biological pathways that could exacerbate CDI-associated IEC damage. As such, we have established the first transcriptomics atlas of bone marrow (BM), blood, and colonic neutrophils after CDI. We found that CDI altered the developmental trajectory of BM and blood neutrophils towards populations that exhibit gene signatures associated with pro-inflammatory responses and neutrophil-mediated tissue damage. Similarly, the transcriptomic signature of colonic neutrophils was consistent with hyper-inflammatory and highly differentiated cells that had amplified expression of cytokine-mediated signaling and degranulation priming genes. One of the top 10 variable features in colonic neutrophils was the gene for neutrophil glycoprotein, Olfactomedin 4 (OLFM4). CDI enhanced OLFM4 mRNA and protein expression in neutrophils, and OLFM4+ cells aggregated to areas of severe IEC damage. Compared to uninfected controls, both humans and mice with CDI had higher concentrations of circulating OLFM4; and in mice, OLFM4 deficiency resulted in faster recovery and better survival after infection. Collectively, these studies provide novel insights into neutrophil-mediated pathology after CDI and highlight the pathogenic role of OLFM4+ neutrophils in regulating CDI-induced IEC damage. One Sentence SummaryUtilizing single-cell transcriptomics, IEC-epithelial co-cultures, and pre-clinical models of CDI, we have identified a subset of neutrophils that are marked by OLFM4 expression as pathogenic determinants of IEC barrier damage after CDI.

immunology↗

bioRxiv2023

All about urine: Longitudinal examination of urine pH, specific gravity, proteins, culture, and resistance profiles in healthy dogs

BackgroundUrine is routinely evaluated in dogs to assess health. Reference ranges for many urine properties are well established, but the scope of variation in these properties over time within heathy dogs is not well characterized. ObjectivesLongitudinally characterize urine properties in healthy dogs over 3 months. AnimalsFourteen healthy client-owned dogs. MethodsDogs were evaluated for health; then, mid-stream free catch urine was collected from each dog at 12 timepoints: Mornings / afternoons of Days 1, 2, 3; end of Weeks 4, 5, 6, 7 and Months 2 and 3. Urine pH, urine specific gravity (USG), protein, cultures, and antimicrobial resistance profiles were evaluated at each timepoint. ResultsUrine pH varied significantly within and between dogs over time (Friedmans test: within p = 0.031; between p < 0.005). However, USG, protein, and bacterial richness of urine were consistent within dogs over time, and only varied significantly between dogs (Kruskal-Wallis: between all p < 0.005). Antimicrobial resistant isolates were identified in 13 out of 14 dogs with 71% (34 of 48) of the isolates demonstrating resistance to amoxicillin. Conclusions and clinical importance1) Urine pH should be assessed at multiple timepoints via pH meter prior to making clinical decisions. 2) Mid-stream free catch urine from multiple healthy dogs yielded high concentrations of bacteria in culture (>105 CFU/mL) and should not be considered the only indicator of urinary tract infection. 3) Bacterial isolates demonstrated widespread resistance to amoxicillin / oxacillin underscoring the need for antimicrobial stewardship.

zoology↗

bioRxiv2022

Competition between action plans tracks with evidence accumulation during flexible decision-making

Changing your mind requires shifting the way streams of information lead to a decision. Using in silico experiments we show how the cortico-basal ganglia-thalamic (CBGT) circuits can feasibly implement shifts in the evidence accumulation process. When action contingencies change, dopaminergic plasticity redirects the balance of power, both within and between action representations, to divert the flow of evidence from one option to another. This finding predicts that when competition between action representations is highest, the rate of evidence accumulation is lowest. We then validate this prediction in a sample of homo sapiens as they perform an adaptive decision-making task while whole-brain hemodynamic responses are recorded. These results paint a holistic picture of how CBGT circuits manage and adapt the evidence accumulation process in mammals. One-sentence SummaryInteractions between cortical and subcortical circuits in the mammalian brain flexibly control the flow of information streams that drive decisions by shifting the balance of power both within and between action representations.

neuroscience↗

bioRxiv2021

Gut microbiota and age shape susceptibility to clostridial enteritis in lorikeets under human care

BackgroundEnteritis is a common cause of morbidity and mortality in lorikeets that can be challenging to diagnose and treat. In this study, we examine gut microbiota in two lorikeet flocks with enteritis (Columbus Zoo and Aquarium - CZA; Denver Zoo - DZ). Since 2012, the CZA flock has experienced repeated outbreaks of enteritis despite extensive diet, husbandry, and clinical modifications. In 2018, both CZA and DZ observed a spike in enteritis. Recent research has revealed that the gut microbiota can influence susceptibility to enteropathogens. We hypothesized that a dysbiosis, or alteration in the gut microbial community, was making some lorikeets more susceptible to enteritis, and our goal was to characterize this dysbiosis and determine the features that predicted susceptibility. ResultsWe employed 16S rRNA sequencing to characterize the cloacal microbiota in lorikeets (CZA n = 67, DZ n = 24) over time. We compared the microbiota of healthy lorikeets, to lorikeets with enteritis, and lorikeets susceptible to enteritis, with "susceptible" being defined as healthy birds that subsequently developed enteritis. Based on sequencing data, culture, and toxin gene detection in intestinal contents, we identified Clostridium perfringens type A (CZA and DZ) and C. colinum (CZA only) at increased relative abundances in birds with enteritis. Histopathology and immunohistochemistry further identified the presence of gram-positive bacilli and C. perfringens, respectively, in the necrotizing intestinal lesions. Finally, using Random Forests and LASSO models, we identified several features (young age and the presence of Rhodococcus fascians and Pseudomonas umsongensis) associated with susceptibility to clostridial enteritis. ConclusionsWe identified C. perfringens type A and C. colinum associated with lorikeet necrohemorrhagic enteritis at CZA and DZ. Susceptibility testing of isolates lead to an updated clinical treatment plan which ultimately resolved the outbreaks at both institutions. This work provides a foundation for understanding gut microbiota features that are permissive to clostridial colonization and host factors (e.g. age, prior infection) that shape responses to infection.

microbiology↗