Biology subjects

McDermott, C.

Publications and source records attributed to McDermott, C..

4 recordsLinked to original sources

bioRxiv2024

predicTTE: An accessible and optimal tool for time-to-event prediction in neurological diseases

Time-to-event prediction is a key task for biological discovery, experimental medicine, and clinical care. This is particularly true for neurological diseases where development of reliable biomarkers is often limited by difficulty visualising and sampling relevant cell and molecular pathobiology. To date, much work has relied on Cox regression because of ease-of-use, despite evidence that this model includes incorrect assumptions. We have implemented a set of deep learning and spline models for time-to-event modelling within a fully customizable app and accompanying online portal, both of which can be used for any time-to-event analysis in any disease by a non-expert user. Our online portal includes capacity for end-users including patients, Neurology clinicians, and researchers, to access and perform predictions using a trained model, and to contribute new data for model improvement, all within a data-secure environment. We demonstrate a pipeline for use of our app with three use-cases including imputation of missing data, hyperparameter tuning, model training and independent validation. We show that predictions are optimal for use in downstream applications such as genetic discovery, biomarker interpretation, and personalised choice of medication. We demonstrate the efficiency of an ensemble configuration, including focused training of a deep learning model. We have optimised a pipeline for imputation of missing data in combination with time-to-event prediction models. Overall, we provide a powerful and accessible tool to develop, access and share time-to-event prediction models; all software and tutorials are available at www.predictte.org.

neuroscience↗

bioRxiv2024

A novel regulatory pathway recognizes and degrades transcripts with long 3' untranslated regions

Quantitative control of gene expression is fundamental to cellular function, and post-transcriptional regulation is a consequential, additional layer of control over protein output. Within mammalian mRNAs, the 3' untranslated region (3'UTR) acts as a hub of regulatory control, typically mediated by regulatory sequence elements within the 3'UTR. We have found that expression from transcripts with long 3'UTRs is strongly repressed compared to those with short 3'UTRs, and this phenomenon appears to be independent of sequence elements within the 3'UTR. The repression increases with 3'UTR length and is substantial; reporters with 2,000 nucleotide long 3'UTRs are repressed >10-fold compared to 400 nucleotide 3'UTRs. Conversely, increasing the length of the coding region has no effect on expression, demonstrating that it is 3'UTR length, not transcript length, that elicits repression. Reporters with different length 3'UTRs show no difference in transcription rates nor translation efficiency but have clear differences in mRNA half-lives and nucleocytoplasmic distribution, indicating repression of long-3'UTR transcripts is mediated by accelerated RNA decay. However, this transcript degradation does not involve the nonsense-mediated decay (NMD) pathway nor other canonical RNA decay pathways. In order to identify trans factors involved in 3'UTR-length-mediated decay, we quantified the differences in proteins bound to reporters with long and short 3'UTRs, and identified over 100 differentially associated factors. Knockdowns of two differentially associating proteins, the mRNA nuclear export factors DDX39B and ZC3H11A, indicate they play a role in repression of mRNAs with long 3'UTRs. This study establishes a novel length-dependent regulatory feature of 3'UTRs, which potentially regulates many genes.

genetics↗

bioRxiv2020

Resting-state functional connectivity and psychopathology in Klinefelter syndrome (47, XXY)

Klinefelter syndrome (47, XXY; Henceforth: XXY syndrome) is a high impact but poorly understood genetic risk factor for neuropsychiatric impairment. Here, we provide the first neuroimaging study to map resting-state functional connectivity (rsFC) changes in XXY syndrome and ask how these might relate to brain anatomy and psychopathology. We collected resting state functional magnetic resonance imaging data from 75 individuals with XXY and 84 healthy XY males. We implemented a brain-wide screen to identify regions with altered global rsFC in XXY vs. XY males, and then used seed-based analysis to decompose these alterations. We further compared rsFC changes with regional changes in brain volume from voxel-based morphometry and tested for correlations between rsFC and symptom variation within XXY syndrome. We found that XXY syndrome was characterized by increased global rsFC in the left dorsolateral prefrontal cortex (DLPFC), associated with overconnectivity with diverse rsFC networks. Regional rsFC changes were partly coupled to regional volumetric changes in XXY syndrome. Within the precuneus, variation in DLPFC rsFC within XXY syndrome was correlated with the severity of psychopathology in XXY individuals. Our findings provide the first view of altered functional brain connectivity in XXY syndrome and delineate links between these alterations and those relating to both brain anatomy and psychopathology. Taken together, these insights advance biological understanding of XXY syndrome as a disorder in its own right, and as a model of genetic risk for psychopathology more broadly.

neuroscience↗

bioRxiv2018

Carriage of Supernumerary Sex Chromosomes Decreases the Volume and Alters the Shape of Limbic Structures.

Sex chromosome aneuploidy (SCA) enhances risk for several psychiatric disorders associated with the limbic system, including mood and autism spectrum disorders. These patients provide a powerful genetics-first model for understanding the biological basis of psychopathology. Additionally, these disorders are frequently sex-biased in prevalence, further suggesting an etiological role for sex chromosomes. To clarify how limbic anatomy varies across sex and sex chromosome complement, we characterized amygdala and hippocampus structure in a uniquely large sample of patients carrying supernumerary sex chromosomes (n = 132) and typically developing controls (n=166). After correction for sex-differences in brain size, karyotypically normal males (XY) and females (XX) did not differ in volume or shape of either structure. In contrast, all SCAs were associated with lowered amygdala volume relative to gonadally-matched controls. This effect was robust to three different methods for total brain volume correction, including an allometric analysis that derived normative scaling rules for these structures in a separate, typically developing population (n = 79). Hippocampal volume was insensitive to SCA after correction for total brain volume. However, surface-based analysis revealed that SCA, regardless of specific karyotype, was consistently associated with a spatially specific pattern of shape change in both amygdala and hippocampus. In particular, SCA was accompanied by contraction around the basomedial nucleus of the amygdala and an area within the hippocampal surface that cuts across hippocampal subfields. These results demonstrate the power of SCA as a model to understand how copy number variation can precipitate changes in brain systems relevant to psychiatric disease.

neuroscience↗