Biology subjects

McGovern, A.

Publications and source records attributed to McGovern, A..

11 recordsLinked to original sources

bioRxiv2026

Chronic unpredictable stress induces negative cognitive bias in rats with sex-specific changes in neurogenesis and functional connectivity

Background: Females are more likely to be diagnosed with major depressive disorder (MDD) than males. Cognitive symptoms of MDD include negative cognitive bias, the perception of ambiguous situations as negative, which predicts MDD episode onset and severity. MDD is associated with changes to functional connectivity between regions involved in cognition, emotion, attention, and memory. Methods: Here we examined the impact of chronic unpredictable stress (CUS) on negative cognitive bias in male (n=18) and female (n=22) Sprague-Dawley rats. We assessed hippocampal neurogenesis and c-Fos expression in response to an ambiguous context across 15 regions of the frontal cortex, amygdala, nucleus accumbens, and hippocampus, including in newborn dentate gyrus (DG) neurons, to examine functional connectivity during cognitive bias testing. We conducted a graph-based network analysis and constructed linear models to predict freezing in the ambiguous context based on regional activation. Results: CUS-exposed rats froze more to the ambiguous context than non-CUS-exposed rats, regardless of sex. CUS decreased neurogenesis in the ventral DG of both sexes, and increased activation of new neurons in the dorsal DG of males only. In response to the ambiguous context, CUS males had an increase in c-Fos expression in the amygdala. CUS produced extensive, sex-specific network reorganization, decreasing global network efficiency in males but not in females. Freezing in the ambiguous context was predicted by activation of new neurons in combination with the ventral CA1 in opposing directions across sex. Conclusions: These findings suggest that sex-specific pathways drive the expression of CUS-induced negative cognitive bias, underscoring the necessity of sex-stratified preclinical and clinical research on negative cognitive bias in depression.

neuroscience↗

bioRxiv2026

Sex and APOE Genotype Differentially Shape Microglial Transcriptomic Profiles Across the Hippocampus and Cortex

Female sex and the APOEe4 allele are top risk factors for Alzheimers disease (AD). Microglia play a role in the pathogenesis of AD, yet how sex and APOE genotype affect microglia remain poorly understood. Here, we characterized the transcriptomic and morphological profiles in the hippocampus and cortex of microglia from humanized APOEe3 and APOEe4 mice of males and females. The hAPOEe4 genotype was associated with sex-dependent effects on microglia co-expression modules in both brain regions, involving cellular stress and immunometabolism processes. In females, a hippocampal cell cycle module was supported by reduced microglial proliferation. Cortical modules were enriched for lipid metabolism and immune-related processes whose expression decreased in females but increased in male hAPOEe4. Male, but not female, hAPOEe4 microglia shifted toward an ameboid state in both regions. Together, these findings reveal sex-dependent microglial responses to APOEe4 across brain regions and highlight the need to incorporate sex-specific approaches into AD research.

neuroscience↗

bioRxiv2025

Decoding the Spatial and Epigenetic Logic of Early Skin Development

The embryonic epidermis originates from a simple single-layered ectoderm that undergoes precise transcriptional and morphological transitions to generate a self-replenishing, multi-layered epidermis. A key early milestone is the emergence of the periderm; a transient, protective layer whose disruption underlies a series of devastating human congenital disorders. Despite its importance, the gene regulatory networks that drive periderm formation remain poorly defined. Here, we integrate single-cell multiome profiling with high-resolution spatial transcriptomics analysis in wild-type and transcription factor p63 mutant (Trp63-/-) embryos to dissect the transcriptional and epigenetic programs driving epidermal lineage diversification. We resolve the cellular repertoire of early embryonic skin, define epithelial subpopulations and reconstruct the transcriptional dynamics underlying the periderm emergence. We show that p63 sits at the core of a multilayered enhancer-gene regulatory network, demonstrate how this network is perturbed in vivo, and functionally validate key targets using comparative cellular models. Together, these findings delineate the gene regulatory architecture of early skin development and establish a framework for understanding epithelial-associated congenital disorders.

developmental biology↗

bioRxiv2025

Conjugated GLP-1 and Estradiol Treatment as a Novel Treatment for Age-related Cognitive Decline in Males and Females

Middle age represents a critical window for metabolic and cognitive health, particularly in the context of rising obesity and diabetes rates. Glucagon-like peptide-1 (GLP-1)-based therapies, which regulate blood glucose and body weight, show sex-specific effects, with estradiol potentiating their metabolic benefits. However, research on GLP-1s cognitive and neuroprotective roles has largely been conducted in males. Here, we investigated the effects of GLP-1 conjugated to estradiol (GE2) on metabolism, cognition, cytokine levels and neurogenesis in the dentate gyrus of middle-aged male and female rats fed a standard (SD) or Western (WD) diet. In both sexes, WD increased body weight and plasma leptin levels, regardless of sex. GE2 treatment led to weight loss, enhanced cued and contextual fear memory, reduced cytokine levels in the hippocampus in SD rats, and increased neurogenesis in the dorsal dentate gyrus (DG), regardless of sex. Sex-specific differences were observed in fat distribution, glucose regulation, central cytokine levels, and neuroplasticity after WD and GE2 treatment. In females only, GE2 reduced visceral (gonadal) fat, reduced cytokines in the dorsal hippocampus, and improved basal blood glucose in response to a WD. In males only, GE2 restored neurogenesis in the DG after WD exposure, and reduced cytokine levels in the amygdala. These findings suggest that although WD increased body weight and GE2 improved associative learning in both sexes, both WD and GE2 had differential affects on metabolic hormones, insulin regulation, cytokine levels and neuroplasticity. Our findings underscore the importance of sex-specific approaches in metabolic and neuroprotective therapeutics in middle age.

neuroscience↗

bioRxiv2025

Short-term alterations in dietary amino acids override host genetic susceptibility and reveal mechanisms of Salmonella Typhimurium small intestine colonization

In addition to individual genetics, environmental factors (e.g., dietary changes) may influence host susceptibility to gastrointestinal infection through unknown mechanisms. Herein, we developed a model in which CBA/J mice, a genetically resistant strain that tolerates intestinal colonization by the enteric pathogen Salmonella Typhimurium (S. Tm), rapidly succumb to infection after exposure to a diet rich in L-amino acids (AA). In mice, S. Tm-gastroenteritis is restricted to the large intestine (cecum), limiting their use to understand S. Tm small intestine (ileum) colonization, a feature of human Salmonellosis. Surprisingly, CBA mice fed AA diet developed ileitis with enhanced S. Tm ileal colonization. Using germ-free mice and ileal-fecal slurry transplant, we found diet-mediated S. Tm ileal expansion to be microbiota-dependent. Mechanistically, S. Tm relied on Fructosyl-asparagine utilization to expand in the ileum during infection. We demonstrate how AA diet overrides host genetics by altering the gut microbiotas ability to prevent S. Tm ileal colonization.

microbiology↗

bioRxiv2025

Parity and APOEε4 genotype contribute distinct changes to functional connectivity across the middle-aged brain

Cognition and its underlying neurobiology change throughout the trajectory of aging, with prominent sex differences and influences of sex-specific factors. Research has shown that parity (pregnancy and parenthood) uniquely altered various biomarkers of brain health in middle age depending on presence of Alzheimers disease (AD) risk. The present study builds on prior work by providing a comprehensive view of functional connectivity changes and elucidating how network-level dynamics contribute to cognitive outcomes depending on primiparity and APOE{varepsilon}4 genotype, the top genetic risk factor for late-onset sporadic AD risk. We assessed neural activation in middle-aged wildtype and hAPOE{varepsilon}4 rats that were either nulliparous (0 litters) or primiparous (1 litter). Activation of the immediate early gene zif268 was quantified across 19 brain regions implicated in memory and AD. Primiparous hAPOE{varepsilon}4 rats exhibited widespread reductions in neural activation, particularly in the dorsal striatum, nucleus accumbens, frontal cortex, and retrosplenial cortex. Network analyses further revealed that primiparous wildtype rats had the most cohesive and efficient functional connectivity networks. Notably, the hierarchy of influence of brain regions within the neural network shifted based on parity and hAPOE{varepsilon}4 genotype. Activation of hippocampal new-born neurons in conjunction with subregions of the dorsal striatum, frontal cortex, and retrosplenial cortex dynamically predicted cognitive performance in a parity- and genotype-dependent manner. These findings underscore the lasting impact of reproductive history on brain health and cognitive aging, highlighting the need to consider sex-specific experiences in aging and AD research.

neuroscience↗

bioRxiv2024

Capacity building needed to reap the benefits of access to biodiversity collections

SummaryO_LIThis research examines biodiversity specimens from two areas of the Caribbean to understand patterns of collection and the roles of the people involved. Using open data from the Global Biodiversity Information Facility (GBIF) and Wikidata, we aimed to uncover geographic and historical trends in specimen use. This study aims to provide concrete evidence to guide collaboration between collection-holding institutions and the communities that need their resources most. C_LIO_LIWe analysed biodiversity specimens from Montserrat and the Cayman Islands in three steps. First, we extracted specimen data from GBIF, disambiguated collector names, and linked them to unique biographical entries. Next, we connected collectors to their publications and specimens. Finally, we analysed the modern use of these specimens through citation data, mapping author affiliations and research themes. C_LIO_LISpecimens are predominantly housed in the Global North and were initially used by their collectors, whose focus was largely on taxonomy and biogeography. With digitisation, use of these collections remains concentrated in the Global North and covers a broader range of subjects, although Brazil and China stand out as significant users of digital collection data compared to other similar countries. C_LIO_LIThe availability of open digital data from collections in the Global North has led to a substantial increase in the reuse of these data across biodiversity science. Nonetheless, most research using these data is still conducted in the Global North. For the non-monetary benefits of digitisation to extend to the countries of origin, capacity building in the Global South is crucial, Open Data alone are insufficient. C_LI Societal Impact StatementDigital biodiversity data from herbaria and museums hold significant potential for nature conservation in the Global South, yet many regions, like Montserrat and the Cayman Islands in the Caribbean, are, for multiple reasons, unable to fully leverage this information. This lack of skills and resources limits local conservation efforts, showing the need for more investment in training, facilities, and expertise. Although past funding has helped improve coordination and build skills, our findings show that more work is needed to make sure conservation in these biodiverse areas can continue in the long term.

scientific communication and education↗

bioRxiv2023

Evidence for vagal sensory neural involvement in influenza pathogenesis and disease

Influenza A virus (IAV) is a common respiratory pathogen and a global cause of significant and often severe morbidity. Although inflammatory immune responses to IAV infections are well described, little is known about how neuroimmune processes contribute to IAV pathogenesis. In the present study, we employed surgical, genetic, and pharmacological approaches to manipulate pulmonary vagal sensory neuron innervation and activity in the lungs to explore potential crosstalk between pulmonary sensory neurons and immune processes. Intranasal inoculation of mice with H1N1 strains of IAV resulted in stereotypical antiviral lung inflammation and tissue pathology, changes in breathing, loss of body weight and other clinical signs of severe IAV disease. Unilateral cervical vagotomy and genetic ablation of pulmonary vagal sensory neurons had a moderate effect on the pulmonary inflammation induced by IAV infection, but significantly worsened clinical disease presentation. Inhibition of pulmonary vagal sensory neuron activity via inhalation of the charged sodium channel blocker, QX-314, resulted in a moderate decrease in lung pathology, but again this was accompanied by a paradoxical worsening of clinical signs. Notably, vagal sensory ganglia neuroinflammation was induced by IAV infection and this was significantly potentiated by QX-314 administration. This vagal ganglia hyperinflammation was characterized by alterations in IAV-induced host defense gene expression, increased neuropeptide gene and protein expression, and an increase in the number of inflammatory cells present within the ganglia. These data suggest that pulmonary vagal sensory neurons play a role in the regulation of the inflammatory process during IAV infection and suggest that vagal neuroinflammation may be an important contributor to IAV pathogenesis and clinical presentation. Targeting these pathways could offer therapeutic opportunities to treat IAV-induced morbidity and mortality. Author summaryInfluenza viruses are a common respiratory pathogen that represent a constant and pervasive threat to human health. Although the inflammatory and immune responses to influenza viral infections are well described, little is known about the role the nervous system plays in the formation and progression of disease. The lungs receive a rich supply of sensory nerve fibers from the vagus nerve. These nerves are critical for protecting the lungs against harmful stimuli and play an important defence role against pathogens, including viruses. Here we use several complex animal models to demonstrate the impact lung sensory neurons have on influenza viral infection and disease outcome. We demonstrate that ablation of lung sensory neurons and inhibition of their neural activity significantly worsens the clinical outcome in mice infected with influenza virus, however with only a moderate impact on lung pathology. Interestingly, when the activity of these neurons is inhibited during influenza viral infection, this drives a hyper neuroinflammatory response within the vagal sensory ganglia, where their cell bodies are located. Our work provides new insights into how these lung sensory neurons are involved in influenza viral infections and may offer therapeutic opportunities to treat influenza-induced morbidity and mortality.

neuroscience↗

bioRxiv2023

Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively

While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities. Here, we describe a proof-of-concept study using novel heterobifunctional small molecules called Regulated Induced Proximity Targeting Chimeras or RIPTACs, which elicit a stable ternary complex between a target protein selectively expressed in cancer tissue and a pan-expressed protein essential for cell survival. The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to cell death selectively in cells expressing the target protein. This approach not only opens new target space by leveraging differentially expressed intracellular proteins but also has the advantage of not requiring the target to be a driver of disease. Thus, RIPTACs can address non-target mechanisms of resistance given that cell killing is driven by inactivation of the essential protein. Using the HaloTag7-FKBP model system as a target protein, we describe RIPTACs that incorporate a covalent or non-covalent target ligand connected via a linker to effector ligands such as JQ1 (BRD4), BI2536 (PLK1), or multi-CDK inhibitors such as TMX3013 or dinaciclib. We show that these RIPTACs exhibit positive co-operativity, accumulate selectively in cells expressing HaloTag7-FKBP, form stable target:RIPTAC:effector trimers in cells, and induce an anti-proliferative response in target-expressing cells. We propose that RIPTACs are a novel heterobifunctional therapeutic modality to treat cancers that are known to selectively express a specific intracellular protein.

cancer biology↗

bioRxiv2019

Simultaneous analysis of open chromatin, promoter interactions and gene expression in stimulated T cells implicates causal genes for rheumatoid arthritis

Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T-cells over 24 hours, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T-cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9.

genomics↗

bioRxiv2019

Chromatin-based techniques map DNA interaction landscapes in psoriasis susceptibility loci and highlight KLF4 as a target gene in 9q31

Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. Here, we use a disease-focused Capture Hi-C experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. In the 9q31 risk locus we combine further epigenomic evidence to demonstrate how the psoriasis association forms a functional interaction with the distant (>500 kb) KLF4 gene. We use CRISPR activation coupled with RNA-seq to demonstrate how activation of psoriasis-associated enhancers upregulates KLF4 in HaCaT cells. Our study design provides a robust pipeline for following up on GWAS disease-associated variants, paving the way for functional translation of genetic findings into clinical benefit.

genomics↗