Biology subjects

Martin-McNulty, B.

Publications and source records attributed to Martin-McNulty, B..

5 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

Heterochronic myeloid cell replacement reveals the local brain environment as key driver of microglia aging

Aging, the key risk factor for cognitive decline, impacts the brain in a region-specific manner, with microglia among the most affected cell types. However, it remains unclear whether this is intrinsically mediated or driven by age-related changes in neighboring cells. Here, we describe a scalable, genetically modifiable system for in vivo heterochronic myeloid cell replacement. We find reconstituted myeloid cells adopt region-specific transcriptional, morphological and tiling profiles characteristic of resident microglia. Young donor cells in aged brains rapidly acquired aging phenotypes, particularly in the cerebellum, while old cells in young brains adopted youthful profiles. We identified STAT1-mediated signaling as one axis controlling microglia aging, as STAT1-loss prevented aging trajectories in reconstituted cells. Spatial transcriptomics combined with cell ablation models identified rare natural killer cells as necessary drivers of interferon signaling in aged microglia. These findings establish the local environment, rather than cell-autonomous programming, as a primary driver of microglia aging phenotypes.

neuroscience↗

bioRxiv2021

Intermittent fasting and caloric restriction interact with genetics to shape physiological health in mice

Dietary interventions can dramatically affect physiological health and organismal lifespan. The degree to which organismal health is improved depends upon genotype and the severity of dietary intervention, but neither the effects of these factors, nor their interaction, have been quantified in an outbred population. Moreover, it is not well understood what physiological changes occur shortly after dietary change and how these may affect the health of early adulthood population. In this article, we investigated the effect of six month exposure of either caloric restriction or intermittent fasting on a broad range of physiological traits in 960 one year old Diversity Outbred mice. We found caloric restriction and intermittent fasting affected distinct aspects of physiology and neither the magnitude nor the direction (beneficial or detrimental) of effects were concordant with the severity of the intervention. In addition to the effects of diet, genetic variation significantly affected 31 of 36 traits (heritabilties ranged from 0.04-0.65). We observed significant covariation between many traits that was due to both diet and genetics and quantified these effects with phenotypic and genetic correlations. We genetically mapped 16 diet-independent and 2 diet-dependent significant quantitative trait loci, both of which were associated with cardiac physiology. Collectively, these results demonstrate the degree to which diet and genetics interact to shape the physiological health of early adult-hood mice following six months of dietary intervention.

genetics↗

bioRxiv2020

Precise Estimation of In Vivo Protein Turnover Rates

Isotopic labeling with deuterium oxide (D2O) is a common technique for estimating in vivo protein turnover, but its use has been limited by two long-standing problems: (1) identifying non-monoisotopic peptides; and (2) estimating protein turnover rates in the presence of dynamic amino acid enrichment. In this paper, we present a novel experimental and analytical framework for solving these two problems. Peptides with high probabilities of labeling in many amino acids present fragmentation spectra that frequently do not match the theoretical spectra used in standard identification algorithms. We resolve this difficulty using a modified search algorithm we call Conditional Ion Distribution Search (CIDS). Increased identifications from CIDS along with direct measurement of amino acid enrichment and statistical modeling that accounts for heterogeneous information across peptides, dramatically improves the accuracy and precision of half-life estimates. We benchmark the approach in cells, where near-complete labeling is possible, and conduct an in vivo experiment revealing, for the first time, differences in protein turnover between mice and naked mole-rats commensurate with their disparate longevity.

bioinformatics↗

bioRxiv2019

Single-cell transcriptomics of the naked mole-rat reveals unexpected features of mammalian immunity

Using single-cell transcriptional profiling we mapped the immune system of the naked mole-rat (Heterocephalus glaber), a small but long-lived and cancer-resistant subterranean rodent. Both splenic and circulating immune cells were examined in healthy young animals and following an infection-mimicking lipopolysaccharide challenge. Our study revealed that the naked mole-rat immune system is characterized by a high myeloid to lymphoid cell ratio that includes a novel, lipopolysaccharide responsive, granulocyte cell subset not found in the mouse. Conversely, we find that naked mole-rats do not have a cell subset that corresponds to natural killer cells as defined in other well-characterized mammalian species. Supporting this finding, we show that the naked mole-rat genome has not expanded any of the gene families encoding diverse natural killer cell receptors, which are the genomic hallmarks of species in which natural killer cells have been described. These unusual features suggest an atypical mode of immunosurveillance and a greater reliance on myeloid-biased innate immunity.

immunology↗