Biology subjects

Senchyna, F.

Publications and source records attributed to Senchyna, F..

7 recordsLinked to original sources

bioRxiv2026

Inferring organ aging, hallmark of aging and senescence scores from blood and facial photographs

Aging progresses asynchronously across organs, motivating the development of organ-resolved aging clocks. Direct assessment of organ aging in living humans, however, is largely impractical. Here, we construct tissue-specific transcriptomic aging clocks and infer organ biological age from paired whole-blood (blood-organ age) and tissue RNA sequencing data in the GTEx project. We observe high variability both in the strength of aging signatures across organs and in the ability to predict organ age and organ scores from blood. Pathway analysis shows that organ aging clocks are dominated by biological processes that differ across tissues. Age-associated multi-organ modules identified in an aging multi-organ network correlation analysis and organ age features causally mediated through organ-blood-organ transcriptomic interactions support a role for systemic signaling in coupling organ aging processes. Given the established role of cellular senescence as a driver of tissue dysfunction and its tissue-specific accumulation during aging, we extend this framework to estimate burden of organ-level senescence and hallmarks of aging. Using senescence- and hallmark-associated gene sets, we derive tissue-specific senescence and hallmark scores (organ scores) and demonstrate that these burdens across multiple organs can be inferred from blood transcriptomes (blood-organ scores). Finally, in pursuit of extending these models to other blood omics and alternative non-invasive assessments, we evaluate whether blood methylation (methylation-blood-organ age and scores) and facial photographs (facial-blood-organ age and scores) can serve as proxies for blood-organ age and blood-organ scores in independent cohorts (Edifice Health and Health and Retirement Study). The methylation- and facial-blood-organ age and scores were associated with mortality in additional testing cohorts (Framingham Heart Study and IMDB-WIKI dataset). These results establish a cross-modal framework for inferring organ-specific aging and senescence from minimally invasive data.

bioinformatics↗

bioRxiv2026

Cellular senescence dysregulates antiviral interferon responses in idiopathic pulmonary fibrosis

Patients with idiopathic pulmonary fibrosis (IPF) are highly vulnerable to respiratory virus infections, but the cellular mechanisms linking fibrotic remodeling to impaired local antiviral defense remain unclear. Here, we investigated how cellular senescence shapes the response of patient-derived healthy and IPF primary lung fibroblasts to influenza A virus (IAV) infection. Transcriptomic profiling identified infection as the driver of gene expression in both DNA damage-induced senescent healthy and IPF fibroblasts and revealed induction of canonical antiviral pathways in both cell states. However, senescent IPF fibroblasts adopted a distinct antiviral response state characterized by a broader set of uniquely induced genes and differential coordination of antiviral transcriptional networks. Functionally, senescence increased viral titers in healthy and IPF fibroblasts, while senescent IPF fibroblasts displayed an altered inflammatory response. Network analysis linked viral response- and cell cycle-associated modules specifically to the senescent healthy infected state, whereas these programs were weaker in senescent IPF fibroblasts. Transcription factor inference identified IRF3 and STAT1 as candidate regulators of this altered antiviral state in both senescent healthy and IPF fibroblasts. Consistent with the network and transcription factor analyses, siRNA-mediated depletion of IRF3 or STAT1 significantly reduced IFN-{beta} secretion in senescent healthy fibroblasts, whereas IPF fibroblasts showed only milder effects, indicating a disease-specific dependence on these pathways for antiviral control. Together, these findings show that the combination of cellular senescence and fibrotic fibroblast identity creates a dysfunctional antiviral state that may help explain the high susceptibility of IPF patients to virus-associated acute exacerbations and disease worsening.

cell biology↗

bioRxiv2026

DNA damage drives a unique, Alzheimer's disease-relevant senescent state in neurons

Alzheimers disease (AD) shares molecular hallmarks with the canonical drivers of cellular senescence. Senescent cells have also been shown to accumulate in the brain with age, yet the mechanisms linking AD pathology to the accumulation of senescent cells in the brain remain unclear. Here, we demonstrate that DNA damage in patient-derived directly induced neurons (iNs) drives a senescent-like cell state with relevance to AD. DNA damage-induced senescent iNs show significant transcriptional concordance with human AD neurons and a weighted gene co-expression network analysis (WGCNA) uncovers candidate regulators associated with the senescent-like state in neurons. Direct comparison of iNs to the original patient fibroblasts reveals striking cell-type specific senescence signatures following DNA damage. iNs adopt a p21-associated senescent-like state characterized by a senescence-associated secretory phenotype (SASP) and predicted activation of NF-{kappa}1. In contrast, fibroblasts develop a p16-associated senescent state lacking a SASP phenotype and show a predicted repression of NF-{kappa}1. Early responses to DNA damage further reveal divergent DNA damage response (DDR), with neurons exhibiting higher accumulation of damage lesions relative to fibroblasts. Together, these findings demonstrate that DNA damage drives a unique senescent-like neuronal state that models molecular features of AD, while also revealing fundamental cell-type specific differences in senescent-like phenotypes and DDR.

cell biology↗

bioRxiv2026

Proteogenomic Profiling Reveals a Distinct Endogenous p16INK4a-Associated Senescence Signature in the Human Ovary.

The tumor suppressor and cell cycle regulator, p16INK4a (p16), has been extensively linked to cellular senescence, and its accumulation can reflect endogenous senescence within ovarian tissue. However, gene and protein signatures associated with p16 have not been well defined in human tissue. We utilized immunohistochemical (IHC) staining for P16 to identify distinct positive (P16+) and negative (P16-) regions within the ovarian cortex and employed the GeoMx Digital Spatial Profiler for simultaneous proteomic and transcriptomic analyses on cortical tissue cores. Differential expression and translation between p16-positive and p16-negative cores identified genes and proteins that are cellular senescence related (e.g., CDKN1A, GADD45B, GADD45G, and MYC) or key regulators of the extracellular matrix (e.g., collagen I, ADAMTS4, and MMP11). Additionally, the transcriptomic signature identified here was significantly enriched for the spatially derived ovarian p16-associated signature, BuckSenOvary, but not for other senescence gene sets. Lastly, given the association between changes to the extracellular matrix in aged ovaries and ovarian cancer, we compared genes upregulated and downregulated in p16-positive regions relative to p16-negative regions against multiple ovarian cancer transcriptomic datasets. These findings provide new insight into the molecular landscape of naturally occurring ovarian senescence and its possible relationship to age-associated disease processes, including cancer development.

cell biology↗

bioRxiv2025

Uncovering senescent fibroblast heterogeneity connects DNA damage response to idiopathic pulmonary fibrosis

Cellular senescence is a largely heterogeneous state of cell stress that deleteriously accumulates with age. Many types of heterogeneity in senescence have been described; however, cellular senescence within the same cell type has only started to be documented. Here, we show primary, human lung fibroblasts from donors who are healthy or diagnosed with idiopathic pulmonary fibrosis (IPF) exhibit a subtle form of heterogeneity over time after DNA damage. Moreover, senescent IPF lung fibroblasts display a dysregulated transcriptional-protein DNA damage response (DDR). Weighted gene correlation network analysis (WGCNA) reveals unique and known targets linking senescent IPF lung fibroblast heterogeneity to genes associated with DNA damage and repair, cytokine and chemokine responses, and extracellular matrix (ECM) signaling. We combine our healthy and IPF senescent gene expression signatures to develop a novel gene set of senescence-associated genes that identify disease-relevant cells in human single-cell RNA-seq (scRNA-seq) data. Collectively, our results uncover human-relevant senescence signatures, highlight IPF-specific DDR, cytokine and chemokine, and ECM targets, and expand our understanding of how a dysregulated DDR contributes to senescent cell heterogeneity in IPF.

cell biology↗

bioRxiv2018

Precision Identification of Diverse Bloodstream Pathogens from the Gut Microbiome

Bloodstream infection is the most common infectious complication in hematopoietic cell transplantation recipients. To evaluate the genomic concordance of bloodstream pathogens and bacterial strains within the intestinal microbiome using whole genome sequencing, we developed StrainSifter, a bioinformatic pipeline to compare nucleotide variation between bacterial isolate strains and stool metagenomes. We applied StrainSifter to bloodstream isolates and stool metagenome samples from hematopoietic stem cell transplant recipients with bloodstream infections. StrainSifter is designed to identify single nucleotide variants between isolate and metagenomic short reads using stringent alignment, coverage, and variant frequency criteria for strain comparison. We identified enteric BSI isolates that were highly concordant with those in the gut microbiota, as well as highly concordant strains of typically non-enteric bacteria. These findings demonstrate the utility of StrainSifter in strain matching and provide a more precise investigation of the intestine as a reservoir of diverse pathogens capable of causing bloodstream infections.

genomics↗

bioRxiv2018

Diverse Mechanisms of Resistance in Carbapenem-Resistant Enterobacteriaceae at a Health Care System in Silicon Valley, California

Carbapenem-resistant Enterobacteriaceae (CRE) are emerging as a major health threat in North America. The mechanism of resistance to carbapenems has therapeutic and public health implications. We comprehensively characterized the underlying mechanisms of carbapenem resistance in CRE isolates recovered between 2013 and 2016 at a health system in Northern California. Genotypic methods were used to detect carbapenemases and plasmid-encoded cephalosporinases, and mass spectrometry was used to quantify relative porin levels for OmpC and OmpF and their analogs. MICs for imipenem-relebactam, meropenem-vaborbactam, ceftazidime-avibactam, and ceftolozane-tazobactam were measured. Whole genome sequencing was used for strain typing. A carbapenemase gene encoding blaOXA-48 like, blaNDM, blaKPC, blaSME, blaIMP, and blaVIM was detected in 38.7% (24/62) of CRE isolates. Porin levels was down at least 2-fold in 91.9% (57/62) of isolates. Including carbapenemase genes and porin loss, the mechanism of resistance was identified in 95.2% (59/62) of CRE isolates. Of the carbapenemase gene-positive isolates, blaKPC -positive isolates were 100% susceptible to ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam; blaOXA-48 like-positive isolates were 100% susceptible to ceftazidime-avibactam; and blaSME-positive isolates were 100% susceptible to meropenem-vaborbactam and ceftolozane-tazobactam. 100% (38/38), 92.1% (35/38), 89.5% (34/38), and 31.6% (12/38) of carbapenemase gene-negative CRE isolates were susceptible to ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, and ceftolozane-tazobactam, respectively. None of the CRE strains were genetically identical. In conclusion, at this health system in Silicon Valley, carbapenemase-producing CRE occurred sporadically and were mediated by diverse mechanisms. Nucleic acid testing for blaOXA-48 like, blaNDM, blaKPC, blaIMP, and blaVIM was sufficient to distinguish between carbapenemase-producing and non-producing CRE and accurately predicted susceptibility to ceftazidime-avibactam, meropenem-vaborbactam and imipenem-relebactam.

microbiology↗