Biology subjects

Dunn, L.

Publications and source records attributed to Dunn, L..

4 recordsLinked to original sources

bioRxiv2026

A Trisomy 21 Model Atlas reveals conserved dosage effects and context-specific transcriptional responses across mouse and human models of Down syndrome

Trisomy 21, the genetic basis of Down syndrome, causes widespread transcriptional dysregulation with tissue-specific phenotypic consequences, but how this propagates across tissues, developmental stages, and model systems remains incompletely understood. We present the initial release of the Trisomy 21 Model Atlas, comprising bulk transcriptomic profiling and histopathology across seven tissues and three developmental timepoints in the Dp(16)1Yey mouse model along with transcriptional profiles from human iPSC-derived cell types. Triplicated genes show consistent, largely dosage-proportional increases in expression across tissues, developmental stages, sexes, and species. Nontriplicated genes, which account for the substantial majority of differential expression, are instead highly context-specific. Inflammatory and interferon-related gene sets are broadly enriched yet composed of distinct genes in each context, and integration with histopathology links expression signatures to tissue-specific pathological features. The Atlas is openly accessible and designed for expansion, providing a framework for interpreting conserved and context-specific consequences of chromosome 21 gene dosage.

genomics↗

bioRxiv2025

Oligomeric assemblies of plant biotin carboxylase revealed by cryo-EM and cross-linking

Due to the interest in fatty acid synthesis by oilseed crops, we conducted structural studies of the biotin carboxylase (BC) subunit of the plastid acetyl-CoA carboxylase. Acetyl-CoA carboxylase catalyzes the first committed step in the fatty acid synthesis pathway and is highly regulated. Cryo-electron microscopy revealed that pennycress apo-BC forms a symmetric dimer and contains a subpopulation of a dimer-of-dimers. The domain of BC that closes over the catalytic cleft (the B-domain) appears to be dynamic, judging from the b-factors, normal mode analysis of BC structures, and its high susceptibility to acetylation. An increase in the BC concentration decreased the reactivity of the B-domain, however, suggesting structural hindrance. The partial protection of the B-domain was consistent with cross-links that formed between dimers of BC using a cross-linker cleavable in the mass spectrometer. Cross-links guided HADDOCK docking calculations suggesting a dimer of dimers of pennycress BC that is asymmetric, staggered, and tilted between dimers, with conservation in the interface. In contrast, a minimal population of a symmetric dimer of dimers with a small, non-conserved interface was observed by cryo-EM. Taken together, our structural models are the first for Brassicaceae family BC homologs and are the first from plants. These models suggest dimer interactions that might contribute to larger oligomers of BC and influence associations with other subunits of the heteromeric acetyl-CoA carboxylase.

biochemistry↗

bioRxiv2022

MECP2 expression coincides with age-dependent tactile sensory deficits in a female mouse model for Rett syndrome

Rett syndrome is characterized by an early period of typical development and then, regression of learned motor and speech skills in girls. Loss of MECP2 protein is thought to cause Rett syndrome phenotypes. The specific underlying mechanisms from typical developmental trajectory to regression features throughout life are unclear. Lack of established timelines to study the molecular, cellular, and behavioral features of regression in female mouse models is a major contributing factor. Due to random X-chromosome inactivation, female patients with Rett syndrome and female mouse models for Rett syndrome (Mecp2Heterozygous, Het) express a functional copy of wild-type MECP2 protein in approximately half of all cells. As MECP2 expression is regulated during early postnatal development and experience, we characterized the expression of wild-type MECP2 in the primary somatosensory cortex of female Het mice. Here, we report increased MECP2 levels in non-parvalbumin-positive neurons of 6-week-old adolescent Het relative to age-matched wild-type controls, while also displaying similar levels of perineuronal net expression, mild tactile sensory perception deficits, and efficient pup retrieval behavior. In contrast, 12-week-old adult Het express MECP2 at levels similar to age-matched wild-type mice, show increased perineuronal net expression in the cortex, and display significant tactile sensory perception deficits. Thus, we have identified a set of behavioral metrics and the cellular substrates to study regression during a specific time in the female Het mouse model, which coincide with changes in wild-type MECP2 expression. We speculate that the precocious increase in MECP2 expression within specific cell types of adolescent Het may provide compensatory benefits at the behavioral level, while the inability to further increase MECP2 levels leads to regressive behavioral phenotypes over time.

neuroscience↗

bioRxiv2017

Trends in Escherichia coli bloodstream infection, urinary tract infections and antibiotic susceptibilities in Oxfordshire, 1998-2016: an observational study

BackgroundThe incidence of Escherichia coli bloodstream infections (EC-BSIs), particularly those caused by antibiotic-resistant strains, is increasing in the UK and internationally. This is a major public health concern but the evidence base to guide interventions is limited.\n\nMethodsIncidence of EC-BSIs and E. coli urinary tract infections (EC-UTIs) in one UK region (Oxfordshire) were estimated from anonymised linked microbiological and hospital electronic health records, and modelled using negative binomial regression based on microbiological, clinical and healthcare exposure risk factors. Infection severity, 30-day allcause mortality, and community and hospital co-amoxiclav use were also investigated.\n\nFindingsFrom 1998-2016, 5706 EC-BSIs occurred in 5215 patients, and 228376 EC-UTIs in 137075 patients. 1365(24%) EC-BSIs were nosocomial (onset >48h post-admission), 1863(33%) were community (>365 days post-discharge), 1346(24%) were quasi-community (31-365 days post-discharge), and 1132(20%) were quasi-nosocomial ([≤]30 days postdischarge). 1413(20%) EC-BSIs and 36270(13%) EC-UTIs were co-amoxiclav-resistant (41% and 30%, respectively, in 2016). Increases in EC-BSIs were driven by increases in community (10%/year (95% CI:7%-13%)) and quasi-community (8%/year (95% CI:7%-10%)) cases. Changes in EC-BSI-associated 30-day mortality were at most modest (p>0{middle dot}03), and mortality was substantial (14-25% across groups). By contrast, co-amoxiclav-resistant EC-BSIs increased in all groups (by 11%-19%/year, significantly faster than susceptible EC-BSIs, pheterogeneity<0{middle dot}001), as did co-amoxiclav-resistant EC-UTIs (by 13%-29%/year, pheterogeneity*0{middle dot}001). Co-amoxiclav use in primary-care facilities was associated with subsequent co-amoxiclav-resistant EC-UTIs (p=0{middle dot}03) and all EC-UTIs (p=0{middle dot}002).\n\nInterpretationCurrent increases in EC-BSIs in Oxfordshire are primarily community-associated, with high rates of co-amoxiclav resistance, nevertheless not impacting mortality. Interventions should target primary-care facilities with high co-amoxiclav usage.\n\nFundingNational Institute for Health Research.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for publications from inception up until October 26, 2017, with the terms \"Escherichia coli\", \"E. coli\", \"bacteraemia\", \"bloodstream infection\", restricting the search to English language articles, and also reviewed references from retrieved articles. Escherichia coli (E. coli) is the most common cause of bloodstream infection, and the incidence of E. coli bloodstream infection, and particularly antibiotic-resistant infections, is increasing in the UK and internationally. Although the UK government aims to reduce healthcare-associated E. coli bloodstream infection, there is only limited evidence to inform appropriate interventions.\n\nAdded value of this studyWe investigated potential drivers for these increases in incidence by exploiting available linked electronic health records over 19 years for ~5200 patients with E. coli bloodstream infection and ~140000 with E. coli urinary tract infection, together with community antimicrobial prescribing data for the most recent six years. Our study identified several findings with significant implications for health policy and patient care: O_LIIncreases in the incidence of E. coli bloodstream infections were driven mainly by non-hospital-associated cases; however, neither patients with previous urinary tract infections nor having previously had urine specimens sent from catheters appeared to be driving the increases\nC_LIO_LICo-amoxiclav-resistant bloodstream infections rose significantly faster than co-amoxiclav-susceptible bloodstream infections, with the greatest number of co-amoxiclav-resistant bloodstream infections in 2016 being in patients discharged more than a month previously (i.e. community-associated)\nC_LIO_LIHigher co-amoxiclav use in primary care was associated with higher rates of both co-amoxiclav-resistant E. coli urinary tract infections and E. coli urinary tract infections overall, supporting drives to reduce broad-spectrum and inappropriate antibiotic use in primary care\nC_LIO_LIDespite substantial increases in co-amoxiclav-resistant bloodstream infections there was no evidence that mortality was increasing in these cases; this does not support moving to broader empiric antibiotic prescribing in hospitals (i.e. carbapenems, piperacillin-tazobactam)\nC_LI\n\nImplications of all available adviceThis suggests that government strategies to effectively reduce E. coli bloodstream infections should target community settings, as well as healthcare-associated settings. The absence of an increased mortality signal suggests that co-amoxiclav resistant E. coli infections are either being successfully treated by dual empiric therapy in severe cases (e.g. with concomitant gentamicin), can be \"rescued\" once isolate susceptibilities become available, or currently deployed phenotypic susceptibility testing breakpoints do not adequately correlate with clinical outcome.

epidemiology↗