Biology subjects

Ruby, J. G.

Publications and source records attributed to Ruby, J. G..

7 recordsLinked to original sources

bioRxiv2026

AP-1 specifies developmental versus fibrotic extracellular matrix transcriptional programs in the lung

Lung function requires an elastic extracellular matrix (ECM). However, the adult lung does not regenerate the elastic architecture established during development, and deposition of fibrous ECM characterizes many lung diseases. We generated a multimodal, single-nuclei atlas across development, homeostasis, aging, and fibrosis to identify lung fibroblast populations, transcriptional programs, and regulatory logic governing these divergent matrix outcomes. We discovered differential AP-1 transcription factor activity orchestrates distinct ECM programs via preferential binding to TPA-responsive elements (TRE) in fibrosis and cAMP-responsive elements (CRE) in development. Antagonizing AP-1 TRE-signaling in lung fibroblasts repressed the fibrotic program and re-engaged a developmental, elastogenic state, and MEK inhibition produced similar transcriptional phenotypes. Pathological fibroblasts in interstitial lung diseases upregulated TRE motif activity, and expression of downstream fibrosis signatures positively correlated with disease severity. These results uncover AP-1 as a critical signaling hub governing lung fibroblast ECM deposition that can potentially be exploited to improve disease outcomes.

cell biology↗

bioRxiv2025

Geographic distribution of genetic diversity of Heterocephalus glaber analyzed using whole genome sequencing and a chromosome-scale genome assembly

Naked mole-rats (Heterocephalus glaber) are a species of rodent endemic to the Horn of Africa, notable among mammals for their long lifespans, resistances to a variety of stresses, and eusocial mating behavior. Though their natural range extends across large portions of Kenya, Ethiopia, Somalia, and Djibouti, the large majority of genetic and genomic analyses focus on Kenyan specimens. Here, we constructed a chromosome-scale reference genome assembly for H.glaber, along with new reference assemblies of both the Damaraland mole-rat (Fukomys damarensis) and guinea pig (Cavia porcellus) genomes to aid annotation. We leveraged our H.glaber assembly, along with modern whole-genome sequencing, to characterize the genetic diversity of specimens deriving from Kenya, southern Ethiopia, and eastern Ethiopia. We found the Kenyan and southern Ethiopian specimens to be closely related to each other and highly diverged from eastern Ethiopian specimens. We also found specimens collected from nearby locations in southern Ethiopia to be more closely related to Kenyan specimens than to each other. This unexpected distribution of shared genetic diversity highlights the importance of local migration barriers to gene flow in wild H.glaber populations.

ecology↗

bioRxiv2025

Genetic correlation-guided mega-analysis of DO mice provides mechanistic insight and candidate genes for age-related pathologies

Diversity Outbred (DO) mice are a powerful model system for mapping complex traits due to their high genetic diversity and mapping resolution. However, while there are extensive tools available for standard genetic analysis in DO mice, fewer techniques have been implemented to facilitate integrated, cross-study analysis. Here, we implement Haseman-Elston regression to estimate genetic correlations among 7,233 phenotypes measured across eleven independent DO mouse studies. We used this network of genetic correlations to cluster phenotypes according to shared genetics, which enhanced the power to detect quantitative trait loci (QTL). This approach empowered the detection of 884 QTL for 383 meta-phenotypes, explaining an average of 40.36% of the total genetic variance per mega-analysis. We leveraged this network for insights into specific areas of biology, including lifespan, frailty, immune composition, histological and functional lung phenotypes, and histological phenotypes of the aorta. We found the genetics of lifespan to share limited correlation with the genetics of frailty but stronger correlation with the genetics of immune cell composition. Additionally, mega-analyses driven by genetic correlations identified candidate genes (e.g. Cdkn2b) associated with degraded extracellular matrix in the aorta. Finally, an ensemble of genetic analyses implicated pulmonary neuroendocrine cell signaling and/or differentiation as a key driver of multiple lung pathophenotypes.

genetics↗

bioRxiv2024

Analysis of lifespan across Diversity Outbred mouse studies identifies multiple longevity-associated loci

Lifespan is an integrative phenotype whose genetic architecture is likely to highlight multiple processes with high impact on health and aging. Here, we conduct a genetic meta-analysis of longevity in Diversity Outbred (DO) mice that includes 2,444 animals from three independently conducted lifespan studies. We identify six loci that contribute significantly to lifespan independently of diet and drug treatment, one of which also influences lifespan in a sex-dependent manner, as well as an additional locus with a diet-specific effect on lifespan. Collectively, these loci explain over half of the estimated heritable variation in lifespan across these studies and provide insight into the genetic architecture of lifespan in DO mice.

genetics↗

bioRxiv2024

Substrate stiffness dictates unique paths towards proliferative arrest in WI-38 cells

Finite replicative potential is a defining feature of non-transformed somatic cells, first established by Leonard Hayflick in vitro using WI-38 human lung fibroblasts. Once proliferative capacity is exhausted due to telomere shortening, cells enter into a state called replicative senescence, which can be avoided through ectopic expression of telomerase reverse transcriptase (hTERT). As WI-38 cells approach replicative arrest, molecular pathways linked to mechanotransduction are induced, including YAP signaling, but the potential interplay between replicative lifespan and the mechanical environment of the cell remains unexplored. Here, we investigate the influence of mechanosensation on the trajectory towards replicative arrest taken by WI-38 cells by growing cells on substrates of varying stiffnesses. Matrix softening slowed proliferation, altered cellular phenotypes, and shortened proliferative lifespan while hTERT expression abrogated or reduced these responses. Our analyses of bulk and single-cell RNA-sequencing and ATAC-sequencing revealed the emergence of a unique G1 transcriptional state on soft substrates, characterized by an AP-1 transcription factor program, which failed to manifest with hTERT expression. Together, these findings reveal how the mechanical environment alters WI-38 cell proliferative lifespan and dictates unique paths towards growth arrest.

cell biology↗

bioRxiv2023

Five years later, with double the demographic data, naked mole-rat mortality rates continue to defy Gompertzian laws by not increasing with age

The naked mole-rat (Heterocephalus glaber) is a mouse-sized rodent species, notable for its eusociality and long lifespan. Previously, we reported that demographic aging, i.e., the exponential increase of mortality hazard that accompanies advancing age in mammals and other organisms, does not occur in naked mole-rats (Ruby et al, 2018). The demographic data supporting that conclusion had taken over three decades to accumulate, starting with the original rearing of H.glaber in captivity. In the five years following that study, we [~]doubled our quantity of demographic data. Here, we re-evaluated our prior conclusions in light of these new data and found them to be supported and indeed strengthened. We additionally provided insight into the social dynamics of captive H.glaber with data and analyses of body weight and colony size versus mortality. Finally, we provide a phylogenetically-proximal comparator in the form of lifespan data from our Damaraland mole-rat (Fukomys damarensis) colony and demographic meta-analysis of those data along with published data from Ansells mole-rat (Fukomys anselli). We found Fukomys mortality hazard to increase gradually with age, an observation with implications on the evolution of exceptional lifespan among mole-rats and the ecological factors that may have accompanied that evolution.

ecology↗

bioRxiv2022

A home-cage, video monitoring-based mouse frailty index detects age-associated morbidity in the absence of handler-induced stress.

Frailty indexes provide quantitative measurements of non-specific health decline and are particularly useful as longitudinal monitors of pre-mortal morbidity in aging studies. For mouse studies, frailty assessments can be taken non-invasively, but they require handling and direct observation that is labor-intensive to the scientist and stress-inducing to the animal. Here, we implement, evaluate, and provide a digital frailty index composed entirely of computational analyses of home-cage video and compare it to manually obtained frailty scores in genetically diverse mice. We show that the frailty scores assigned by our digital index correlate with both manually obtained frailty scores and chronological age. Thus, we provide a tool for frailty assessment that reduces stress to the animal and can be collected consistently, at scale, without substantial labor cost.

animal behavior and cognition↗