Biology subjects

McNerney, M. W.

Publications and source records attributed to McNerney, M. W..

6 recordsLinked to original sources

bioRxiv2026

Convergent Mitochondrial and Oxidative Stress Signatures in Spaceflight and Tauopathy: A Comparative Multi-Omics Reanalysis in Drosophila melanogaster

Mitochondrial dysfunction is a shared biological thread between terrestrial Alzheimer's disease (AD) and in the unique stress environment of spaceflight, making mitochondrial pathophysiology a compelling target for comparative investigation. In AD, mitochondrial impairment is closely linked to defective oxidative phosphorylation, reactive oxygen species accumulation, calcium dysregulation, and neuronal injury, while spaceflight stressors such as microgravity and radiation disrupt mitochondrial homeostasis and increase oxidative stress. Understanding how the extreme stressors of spacelight affect mitochondrial function may provide insights into conserved mitochondrial stress responses and their implications for neurodegenerative diseases, including AD. Our study compares datasets from ground control Drosophila melanogaster RNA-seq with isolated radiation and microgravity exposure to discern conserved mitochondrial pathways and molecular signatures that may provide insights into AD mechanisms.

cell biology↗

bioRxiv2026

The Social Cognition Paradox in Long-Duration Spaceflight: A VEN Fatigue Hypothesis for Duration-Dependent Emotion Recognition Decline

Long-duration spaceflight may alter social cognition, yet the underlying biological mechanisms remain unclear. Emotion Recognition Task (ERT) performance remains stable during typical 6-month International Space Station (ISS) missions but declines markedly during the 340-day NASA Twins Study, suggesting duration-dependent vulnerability. Here, we propose the Von Economo Neuron (VEN) Fatigue Hypothesis, which posits that microgravity increases demand on VEN-associated social cognitive networks, eliciting adaptive myelination during shorter missions before compensatory mechanisms fail with prolonged exposure. To evaluate this hypothesis, we integrated evidence from rodent, human cortical organoid, astronaut plasma proteomic, and neuroimaging datasets. ISS-flown rodent frontal cortex demonstrated increased expression of myelination-related genes, while spaceflown cortical organoids exhibited changes consistent with oligodendrocyte remodeling. Astronaut plasma transcriptomics identified reproducible alterations in VEN-associated and myelination-related proteins across independent missions, and resting-state fMRI revealed transient changes in frontal insula connectivity following long-duration spaceflight. Together, these findings provide convergent evidence supporting the VEN Fatigue Hypothesis and identify adaptive myelination and VEN-associated network remodeling as candidate mechanisms underlying duration-dependent changes in social cognition during long-duration spaceflight.

neuroscience↗

bioRxiv2025

Next-Generation Multiplexed Targeted Proteomics Quantifies Post-Translational Modifications, Compound-Protein Interactions, and Disease Biomarkers with High Throughput

The GoDig platform enables sensitive, multiplexed targeted pathway proteomics without manual scheduling or synthetic standards. Here we present GoDig 2.0, which increases sample multiplexing to 35-fold, improves time efficiency and reduces scan delays for higher success rates, and allows flexible spectral and elution library generation from different mass spectrometry data types. GoDig 2.0 measures 2.4x more targets than GoDig 1.0, quantifying >99% of 800 peptides in a single run. We compiled a library of 23,989 human phosphorylation sites from a phosphoproteomic dataset and used it to profile kinase signaling differences across cell lines. In human brain tissue, we established a hyperphosphorylated tau assay including pTau127, revealing potential biomarkers for Alzheimers disease. We also quantified diglycyl-lysine peptides to assess polyubiquitin branching. Finally, we built a library of 20,946 reactive cysteines and profiled covalent compound-protein interactions spanning diverse pathways. GoDig 2.0 enables high-throughput analyses of site-specific protein modifications across many biological contexts.

biochemistry↗

bioRxiv2021

Visualizing the Costs and Benefits of Correcting P-Values for Multiple Hypothesis Testing in Omics Data

The multiple hypothesis testing problem is inherent in high-throughput quantitative genomic, transcriptomic, proteomic, and other "omic" screens. The correction of p-values for multiple testing is a critical element of quantitative omic data analysis, yet many researchers are unfamiliar with the sensitivity costs and false discovery rate (FDR) benefits of p-value correction. We developed models of quantitative omic experiments, modeled the costs and benefits of p-value correction, and visualized the results with color-coded volcano plots. We developed an R Shiny web application for further exploration of these models which we call the Simulator of P-value Multiple Hypothesis Correction (SIMPLYCORRECT). We modeled experiments in which no analytes were truly differential between the control and test group (all null hypotheses true), all analytes were differential, or a mixture of differential and non-differential analytes were present. We corrected p-values using the Benjamini-Hochberg (BH), Bonferroni, and permutation FDR methods and compared the costs and benefits of each. By manipulating variables in the models, we demonstrated that increasing sample size or decreasing variability can reduce or eliminate the sensitivity cost of p-value correction and that permutation FDR correction can yield more hits than BH-adjusted and even unadjusted p-values in strongly differential data. SIMPLYCORRECT can serve as a tool in education and research to show how p-value adjustment and various parameters affect the results of quantitative omics experiments.

bioinformatics↗

bioRxiv2021

A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk

The human brain vasculature is of vast medical importance: its dysfunction causes disability and death, and the specialized structure it forms--the blood-brain barrier--impedes treatment of nearly all brain disorders. Yet, no molecular atlas of the human brain vasculature exists. Here, we develop Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) to profile the major human brain vascular and perivascular cell types through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 17 control and Alzheimers disease (AD) patients. We identify brain region-enriched pathways and genes divergent between humans and mice, including those involved in disease. We describe the principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum; but discover that many zonation and cell-type markers differ between species. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In AD, we observe a selective vulnerability of ECM-maintaining pericytes and gene expression patterns implicating dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 AD GWAS genes are expressed in the human brain vasculature, confirmed in situ. Vascular GWAS genes map to endothelial protein transport, adaptive immune, and ECM pathways. Many are microglia-specific in mice, suggesting an evolutionary transfer of AD risk to human vascular cells. Our work unravels the molecular basis of the human brain vasculature, informing our understanding of overall brain health, disease, and therapy.

neuroscience↗

bioRxiv2020

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Though SARS-CoV-2 primarily targets the respiratory system, it is increasingly appreciated that patients may suffer neurological symptoms of varied severity1-3. However, an unbiased understanding of the molecular processes across brain cell types that could contribute to these symptoms in COVID-19 patients is still missing. Here, we profile 47,678 droplet-based single-nucleus transcriptomes from the frontal cortex and choroid plexus across 10 non-viral, 4 COVID-19, and 1 influenza patient. We complement transcriptomic data with immunohistochemical staining for the presence of SARS-CoV-2. We find that all major cortex parenchymal and choroid plexus cell types are affected transcriptionally with COVID-19. This arises, in part, from SARS-CoV-2 infection of the cortical brain vasculature, meninges, and choroid plexus, stimulating increased inflammatory signaling into the brain. In parallel, peripheral immune cells infiltrate the brain, microglia activate programs mediating the phagocytosis of live neurons, and astrocytes dysregulate genes involved in neurotransmitter homeostasis. Among neurons, layer 2/3 excitatory neurons--evolutionarily expanded in humans4--show a specific downregulation of genes encoding major SNARE and synaptic vesicle components, predicting compromised synaptic transmission. These perturbations are not observed in terminal influenza. Many COVID-19 gene expression changes are shared with those in chronic brain disorders and reside in genetic variants associated with cognitive function, schizophrenia, and depression. Our findings and public dataset provide a molecular framework and new opportunities to understand COVID-19 related neurological disease.

neuroscience↗