Biology subjects

Cotton, S.

Publications and source records attributed to Cotton, S..

3 recordsLinked to original sources

bioRxiv2024

Multiscale heterogeneity of white matter morphometry in psychiatric disorders

BackgroundInter-individual variability in neurobiological and clinical characteristics in mental illness is often overlooked by classical group-mean case-control studies. Studies using normative modelling to infer person-specific deviations of grey matter volume have indicated that group means are not representative of most individuals. The extent to which this variability is present in white matter morphometry, which is integral to brain function, remains unclear. MethodsWe applied Warped Bayesian Linear Regression normative models to T1- weighted magnetic resonance imaging data and mapped inter-individual variability in person-specific white matter volume deviations in 1,294 cases (58% male) diagnosed with one of six disorders (attention-deficit/hyperactivity, autism, bipolar, major depressive, obsessive-compulsive and schizophrenia) and 1,465 matched controls (54% male) recruited across 25 scan sites. We developed a framework to characterize deviation heterogeneity at multiple spatial scales, from individual voxels, through inter- regional connections, specific brain regions, and spatially extended brain networks. ResultsThe specific locations of white matter volume deviations were highly heterogeneous across participants, affecting the same voxel in fewer than 8% of individuals with the same diagnosis. For autism and schizophrenia, negative deviations (i.e., areas where volume is lower than normative expectations) aggregated into common tracts, regions and large-scale networks in up to 35% of individuals. ConclusionsThe prevalence of white matter volume deviations was lower than previously observed in grey matter, and the specific location of these deviations was highly heterogeneous when considering voxel-wise spatial resolution. Evidence of aggregation within common pathways and networks was apparent in schizophrenia and autism but not other disorders.

neuroscience↗

bioRxiv2024

Early life intestinal inflammation alters gut microbiome, impairing gut-brain communication and reproductive behavior in mice

Despite recent advances in understanding the connection between the gut microbiota and the adult brain, there remains a wide knowledge gap in how gut inflammation impacts brain development. We hypothesized that intestinal inflammation in early life would negatively affect neurodevelopment through dysregulation of microbiota communication to the brain. We therefore developed a novel pediatric chemical model of inflammatory bowel disease (IBD), an incurable condition affecting millions of people worldwide. IBD is characterized by chronic intestinal inflammation, and has comorbid symptoms of anxiety, depression and cognitive impairment. Significantly, 25% of patients with IBD are diagnosed during childhood, and the effect of chronic inflammation during this critical period of development is largely unknown. This study investigated the effects of early-life gut inflammation induced by DSS (dextran sulfate sodium) on a range of microbiota, endocrine, and behavioral outcomes, focusing on sex-specific impacts. DSS-treated mice exhibited increased intestinal inflammation, altered microbiota membership, and changes in microbiota-mediated circulating metabolites. The majority of behavioral measures were unaffected, with the exception of impaired mate-seeking behaviors in DSS-treated males. DSS-treated males also showed significantly smaller seminal vesicles, lower circulating androgens, and decreased intestinal hormone-activating enzyme activity. In the brain, microglia morphology was chronically altered with DSS treatment in a sex-specific manner. The results suggest that early-life gut inflammation causes changes in gut microbiota composition, affecting short-chain fatty acid (SCFA) producers and glucuronidase (GUS) activity, correlating with altered SCFA and androgen levels. The findings emphasize the developmental sensitivity to inflammation-induced changes in endocrine signalling and underscore long-lasting physiological and microbiome changes associated with juvenile IBD. HighlightsEarly-life gut inflammation produces sex-specific effects on i) microbiome, ii) sex hormones and iii) behaviour. Both sexes show disrupted gut bacterial members that regulate sex hormone levels. Male mice demonstrate deficits in mate seeking, which may be mediated by reduced androgen levels. Both male and female mice demonstrate shifts in hippocampal microglial morphology.

neuroscience↗

bioRxiv2023

Multilevel Plasticity and Altered Glycosylation Drive Aggressiveness in Hypoxic and Glucose-Deprived Bladder Cancer Cells

Bladder tumours with aggressive characteristics often present with microenvironmental niches marked by low oxygen levels (hypoxia) and limited glucose supply due to inadequate vascularization. The molecular mechanisms facilitating cellular adaptation to these stimuli remain largely elusive. Employing a multi-omics approach, we discovered that hypoxic and glucose- deprived cancer cells enter a quiescent state supported by mitophagy, fatty acid {beta}-oxidation, and amino acid catabolism, concurrently enhancing their invasive capabilities. Reoxygenation and glucose restoration efficiently reversed cell quiescence without affecting cellular viability, highlighting significant molecular plasticity in adapting to microenvironmental challenges. Furthermore, cancer cells exhibited substantial perturbation of protein O-glycosylation, leading to simplified glycophenotypes with shorter glycosidic chains. Exploiting glycoengineered cell models, we established that immature glycosylation contributes to reduced cell proliferation and increased invasion. Our findings collectively indicate that hypoxia and glucose deprivation trigger cancer aggressiveness, reflecting an adaptive escape mechanism underpinned by altered metabolism and protein glycosylation, providing grounds for clinical intervention.

biochemistry↗