Biology subjects

Nolan, A.

Publications and source records attributed to Nolan, A..

3 recordsLinked to original sources

bioRxiv2026

Single nucleus RNA sequencing and spatial transcriptomics reveal unique functionalities of gray matter versus white matter oligodendrocytes in aging and Alzheimer's Disease

Oligodendrocyte (OL) dysfunction and white-matter (WM) vulnerability are increasingly recognized as important aspects of aging and Alzheimer's Disease (AD), yet human WM-focused, cellular-resolution transcriptomic data remain limited. Here, we profiled prefrontal WM from 48 brain donors spanning young adulthood and late-life with low versus high AD Neuropathologic Change (ADNC) using single-nucleus RNA sequencing followed by spatial transcriptomics (CosMx) in a subset of matched donors. We integrated aged WM OLs with a reference dorsolateral prefrontal cortex grey-matter (GM) OL dataset (SEA-AD) to define region- and pathology-associated OL programs. Across modalities, GM OLs exhibited a robust synapse/neurotransmitter-associated transcriptional signature relative to WM OLs, whereas this program was reduced with aging and attenuated in high ADNC GM. In contrast, WM OLs showed stronger immune-associated programs with aging and further enhancement in high ADNC, including cytokine/chemokine signaling and antigen presentation-related pathways. High ADNC WM OLs also displayed amplified proteostasis and stress-adaptation signatures, including selective upregulation of chaperone/heat shock genes and ferritin subunits, consistent with increased protein-folding demand and altered iron handling. To resolve OL state organization beyond static differential expression, we annotated OL sub-states using marker panels and inferred pseudotime-guided directional state-to-state flows within each tissue/condition stratum. This analysis identified a conserved newly formed differentiating (NFOL)/differentiating [->] lipid remodeling (APOE/ABCA1/LPL+) [->] Stress/ISR-reactive architecture, with a pronounced expansion of the Stress/ISR-reactive compartment and altered transition-associated pathway enrichment in high ADNC WM. Together, these data define WM-specific OL programs linked to aging and ADNC and nominate a stress/immune-enriched OL state landscape consistent with a putative senescence-like phenotype in diseased WM.

neuroscience↗

bioRxiv2018

Gut microbiota density influences host physiology and is shaped by host and microbial factors

To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohns disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.

microbiology↗

bioRxiv2016

Retargeting: an unrecognized consideration in endonuclease-based gene drive biology

There is intense interest surrounding the use of gene editing nucleases in gene drive systems to control agricultural insect pests and insect vectors of infectious diseases such as malaria, dengue and Zika virus. While gene drive systems offer immense promise for the beneficial modification of deleterious insect populations, their unique mechanism of action also raises novel safety concerns and regulatory issues. A recent US National Academies of Science report provides a list of potential regulatory issues associated with implementation of homologous recombination (HR)-mediated gene drive systems, based on the premise that all such systems would exhibit similar biological behaviors. Here we examine how HR-mediated gene drive systems based on different gene editing nuclease platforms could be affected by mutations that occur during host cell transcription, genome replication, and, in conjunction with gene editing nuclease activity, during HR-mediated gene drive. Our analysis suggests that the same feature that makes RNA-guided nucleases such attractive research tools--their ease of reprogramming by alterations to their guide RNA components--might also contribute to increased rates of retargeting that could influence the long term behavior of RNA-guided gene drive systems. Predictability of behavior over time is an issue that should be addressed by in-depth risk assessment before field testing of organisms incorporating nuclease-mediated gene drives.

synthetic biology↗