Biology subjects

Alvarez, K.

Publications and source records attributed to Alvarez, K..

6 recordsLinked to original sources

bioRxiv2026

Hypoxia can set the elevational limits of dragonflies

Oxygen declines by ~10% for each 1000m gained above sea level. Although the impact of low oxygen on endotherms has received considerable attention, we know far less about whether or not hypoxia can set the elevational limits of terrestrial ectotherms. Here, we addressed this question using Nearctic dragonflies. First, we experimentally tested if dragonflies are vulnerable to the low oxygen found at high elevations. Our results show that even resting adults struggle with the PO2 that occurs at the highest elevations where dragonflies are found in Colorado, USA. Second, we used a comparative approach to test if the dragonfly species that can inhabit higher elevations are also more tolerant of low oxygen. Our analysis shows that a species upper elevational limit is precisely predicted by its vulnerability to low oxygen. Collectively, these results provide some of the first evidence that low oxygen can be an important constraint on the elevational maxima of terrestrial ectotherms.

ecology↗

bioRxiv2025

Mapping Structural Aging across Human Tissues reveals tissue-specific trajectories, coordinated deterioration and genetic determinants

1.Tissue structure, the organization of cells, vasculature and extracellular matrix, underpins organ function. Yet how it deteriorates with age remains largely uncharacterized. Current aging research focuses primarily on molecular changes, missing this structural dimension. Here we present PathStAR (Pathology-based Structural Aging Rate), a computational framework that quantifies tissue structural aging from histopathology images without training on chronological age. Applying PathStAR to 25,306 postmortem biopsies spanning 40 tissue types from 970 individuals aged 21-70, we show that structural aging unfolds through non-linear phases rather than gradual decline. We identify three distinct temporal programs: early-aging tissues (vascular system, peaking in the 30s), late-aging tissues (uterus and vagina, peaking around menopause) and biphasic-aging tissues (digestive and male reproductive organs, with two acceleration periods). During accelerated phases, tissues exhibit common molecular signature of increased inflammation, decreased energy production, regeneration and quality control alongside tissue-specific pathway disruptions related to its function: Artery-specific decline of peroxisomal function, responsible for fatty acid breakdown and testis-specific decline of spermatogenesis. Cross-organ analysis reveals coordinated deterioration within individuals, not only within expected organ systems but also unexpectedly between digestive and reproductive tissues, traced to shared sex hormone signaling. This reveals a role for sex hormones in maintaining structural integrity of non-reproductive organs during aging. Genome-wide association analysis identifies 123 germline variants associated with organ-specific accelerated structural aging, including variants in the longevity regulator SIRT6 linked specifically to vascular structural decline. As proof of concept, PathStAR captures the established non-linear functional decline of the ovary, fertility loss in the 30s and menopause in the 50s, that bulk transcriptomic and methylation profiles from matched samples fail to detect. PathStAR provides a systematic map of structural aging across the human body: when tissues structure decline, what molecular programs define each phase, and how organs deteriorate in coordination.

bioinformatics↗

bioRxiv2025

TLPath predicts telomere length in human tissues from histopathology images

Telomere dysfunction is a key hallmark of aging linked to numerous age-related diseases including cardiovascular disorders, pulmonary fibrosis, and metabolic syndromes. Despite decades of research yielding strong evidence linking telomere biology to aging processes, the field faces a critical bottleneck: current telomere measurement methods require specialized molecular techniques that prevent large-scale studies and clinical implementation. Here we present TLPath, a novel deep learning framework that extracts normal tissue architecture from routine histopathology (H&E) images to predict bulk-tissue telomere length. Trained on the Genotype-Tissue Expression cohort comprising >7.3 million patch images from >5,000 whole-slide images across 919 individuals, TLPath makes a remarkable discovery: the extracted morphological features spontaneously separate young, middle-aged, and elderly individuals within most tissue types-- demonstrating for the first time that aging causes substantial architectural changes in tissues detectable without explicit age supervision. These extracted features can predict bulk-telomere length with significant accuracy (>0.51 in well-represented tissues), outperforming chronological age as a predictor (correlation = 0.20) and identifying age-discordant cases - detecting both accelerated telomeres shortening in young individuals and preserved telomeres in older individuals. Mechanistic interpretation reveals that TLPath leverages established senescence morphological markers, including nuclear-to-cytoplasmic ratio and nuclear shape variation, for its predictions. We applied TLPath in [~]2,800 new GTEx biopsies where concordant with known association, the predicted telomere length is shorter across most tissues from individuals with Type 1/2 diabetes. Overall, we demonstrate that aging substantially alters tissue morphology, which TLPath captures and uses to predict telomere length, enabling large-scale telomere biology studies using existing tissue archives.

bioinformatics↗

bioRxiv2024

PFAS Compounds PFOA and Gen X are Teratogenic to Sea Urchin Embryos

Per-and polyfluorinated substances (PFAS) are synthetic chemicals that are used to make fluoropolymer coatings found in many products, such as non-stick pans, clothing, cosmetics, and food packaging. These highly persistent molecules are known as "forever chemicals" since they neither degrade environmentally nor break down enzymatically within biological systems. PFAS compounds readily contaminate water sources, and as a result, certain PFAS molecules have bioaccumulated in exposed species including humans. The purpose of this study was to define the effect of two PFAS molecules, the ostensibly more toxic perfluorooctanoic acid (PFOA) and the more recent, reportedly safer chemical hexafluoropropylene oxide dimer acid (Gen X), on the development of Lytechinus variegatus sea urchin embryos. We examined the effects of PFOA and Gen X on development and patterning using morphological analysis, immunostaining, HCR-FISH, and Particle Image Velocimetry (PIV). The results show that both PFAS compounds are teratogenic to sea urchin embryos. PFOA and Gen X each function at different intervals during development and provoke distinct phenotypic and gene expression outcomes. Despite beliefs that Gen X would be a safer alternative, our findings indicate that Gen X has earlier and more severe effects on endomesoderm and dorsal-ventral axis specification, neural development and function, and pattern formation compared to PFOA. These results illustrate the dangerous teratogenic potential of environmentally accumulating PFAS like Gen X, underscoring the negative ecological implications that accompany continuing commercial and industrial use of PFAS in the absence of remediation strategies. HIGHLIGHTSO_LIGen X is more teratogenic in sea urchins than PFOA C_LIO_LIGen X acts earlier than PFOA and perturbs axial and germ layer specification C_LIO_LIEach PFAS reduces neural numbers and perturbs ciliary behavior and swimming C_LI

developmental biology↗

bioRxiv2024

From Cardiac Myosin to the Beta Receptor: Autoantibodies Promote a Fibrotic Transcriptome and Reduced Ventricular Recovery in Human Myocarditis

BackgroundMyocarditis leads to dilated cardiomyopathy (DCM) with one-third failing to recover normal ejection fraction (EF50%), and there is a critical need for prognostic biomarkers to assess risk of nonrecovery. Cardiac myosin (CM) autoantibodies (AAbs) cross-reactive with the {beta}-adrenergic receptor ({beta}AR) are associated with myocarditis/DCM, but their potential for prognosis and functional relevance is not fully understood. MethodsCM AAbs and myocarditis-derived human monoclonal antibodies (mAbs) were investigated to define pathogenic mechanisms and CM epitopes of nonrecovery. Myocarditis patients who do not recover ejection fraction (EF<50%) by one year were studied in a longitudinal (n=41) cohort. Sera IgG and human mAbs were investigated for autoreactivity with CM and CM peptides by ELISA, protein kinase A (PKA) activation, and transcriptomic analysis in H9c2 heart cell line. ResultsCM AAbs were significantly elevated in nonrecovered compared to recovered patients and correlated with reduced EF (<50%). CM epitopes specific to nonrecovery were identified. Transcriptomic analysis revealed serum IgG and mAb 2C.4 induced fibrosis/apoptosis pathways in vitro similar to isoproterenol treated cells. Sera IgG and 2C.4 activated PKA in an IgG and {beta}AR-dependent manner. Endomyocardial biopsies from myocarditis/DCM revealed IgG+ trichrome+ tissues. ConclusionsCM AAbs were significantly elevated in nonrecovered patients, suggesting novel prognostic relevance. CM AAbs correlated with lower EF, and Ab-induced fibrosis/apoptosis pathways suggested a role for CM AAbs in patients who do not recover and develop irreversible heart failure. Homology between CM and {beta}ARs supports mechanisms related to cross-reactivity of CM AAbs with the {beta}AR, a potential AAb target in nonrecovery.

immunology↗

bioRxiv2021

A high-throughput fluorescence polarization assay to discover inhibitors of arenavirus and coronavirus exoribonucleases

Viral exoribonucleases are uncommon in the world of RNA viruses. To date, this activity has been identified only in the Arenaviridae and the Coronaviridae families. These exoribonucleases play important but different roles in both families: for mammarenaviruses the exoribonuclease is involved in the suppression of the host immune response whereas for coronaviruses, exoribonuclease is both involved in a proofreading mechanism ensuring the genetic stability of viral genomes and participating to evasion of the host innate immunity. Because of their key roles, they constitute attractive targets for drug development. Here we present a high-throughput assay using fluorescence polarization to assess the viral exoribonuclease activity and its inhibition. We validate the assay using three different viral enzymes from SARS-CoV-2, lymphocytic choriomeningitis and Machupo viruses. The method is sensitive, robust, amenable to miniaturization (384 well plates) and allowed us to validate the proof-of-concept of the assay by screening a small focused compounds library (23 metal chelators). We also determined the IC50 of one inhibitor common to the three viruses. HighlightsO_LIArenaviridae and Coronaviridae viral families share an exoribonuclease activity of common evolutionary origin C_LIO_LIArenaviridae and Coronaviridae exoribonuclease is an attractive target for drug development C_LIO_LIWe present a high-throughput assay in 384 well-plates for the screening of inhibitors using fluorescence polarization C_LIO_LIWe validated the assay by screening of a focused library of 23 metal chelators against SARS-CoV-2, Lymphocytic Choriomeningitis virus and Machupo virus exoribonucleases C_LIO_LIWe determined the IC50 by fluorescence polarization of one inhibitor common to the three viruses. C_LI

biochemistry↗