Biology subjects

Hodgson, D.

Publications and source records attributed to Hodgson, D..

8 recordsLinked to original sources

bioRxiv2026

TOMM40 '523' genotype induces sex- and tissue- specific differences in cholesterol and triglyceride levels in an APOE-TOMM40 humanized mouse model

IntroductionGenetic variants within the APOE-TOMM40 locus are associated with Alzheimers disease (AD). A specific role for TOMM40 is indicated by the finding that 523 poly-T variants are associated with AD risk, but the mechanism for this effect has not been established. Our studies have shown that suppression of Tomm40 in mice increased brain cholesterol content, an AD risk factor, and thus the present study sought to assess whether major 523 poly-T variants (Short [S] and Very Long [VL]) are associated with altered lipid content of brain and other tissues. MethodsWe utilized a mouse model containing the entire human APOE3-TOMM40 locus to quantify cholesterol and triglyceride levels in brain, liver, and white adipose tissue (WAT), as well as brain content of the AD biomarkers A{beta} 42 and tau, in mice carrying two homozygous TOMM40 523 poly-T genotypes (S/S and VL/VL). ResultsMale mice carrying the 523-S/S genotype, but not females, showed higher brain cholesterol and triglyceride levels than VL/VL carriers, together with greater brain A{beta} 42 content. WAT showed similar lipid differences as in the brain, while hepatic lipid content was broadly similar between 523-S/S and -VL/VL genotypes, though there was a trend for higher triglycerides in VL/VL mice in a sex- and age-dependent manner. DiscussionThese results demonstrate that TOMM40 523 poly-T variants drive tissue-specific, sex-, and age-dependent lipid differences in humanized APOE3-TOMM40 mice, with the S/S genotype linked to elevated brain cholesterol and A{beta} 42 levels, effects that link this locus to AD pathogenesis.

genetics↗

bioRxiv2025

SNCA-targeted epigenome therapy for Parkinsons disease alleviates pathological and behavioral perturbations in a mouse model

Alpha-synuclein (SNCA) overexpression is implicated in Parkinsons disease (PD) pathogenesis, making SNCA downregulation a promising therapeutic strategy. We developed a SNCA-targeted epigenome therapy using an all-in-one lentiviral vector (LV) carrying deactivated CRISPR/(d)Cas9, gRNA targeted at SNCA-intron1, and either the catalytic domain of DNA-methyltransferase3A (DNMT3A), or a synthetic repressor molecule of Kruppel-associated box (KRAB)/ methyl CpG binding protein 2 transcription repression domain (MeCp2-TRD). Therapeutic efficacy was evaluated in a new PD mouse model, generated with an adeno-associated viral vector carrying an engineered minigene comprised of the human (h)A53T-SNCA expressed via the human native regulatory region. Both therapeutic vectors reduced expression of -synuclein in the substantia nigra (SN), with LV/dSaCas9-KRAB-MeCP2(TRD) demonstrating greater repression. LV/dSaCas9-KRAB-MeCP2(TRD) also significantly reduced pathological -synuclein aggregation and phosphorylation (Ser129), and preserved tyrosine hydroxylase expression in the SN and the striatum. Behavioral analysis following LV/dSaCas9-KRAB-MeCP2(TRD) injection, showed significant improvement in motor deficits characteristic of our PD-mouse model. Safety assessments found normal blood counts, serum chemistry, and weights. Collectively, we provide in vivo proof-of-concept for our SNCA-targeted epigenome therapy in a PD-mouse model. Our results support the systems therapeutic potential for PD and related synucleinopathies and establish the foundation for further preclinical studies toward investigational new drug enablement.

neuroscience↗

bioRxiv2024

Comprehensive characterization of the T cell receptor repertoire in bladder cancer

T cells are one of the primary effector cells in the endogenous defense against cancer, yet the clinical impact of their quantity, diversity, and dynamics remains underexplored. Here we investigated the clinical relevance of the T cell receptor (TCR) repertoire in patients with bladder cancer. In advanced-stage bladder cancer, low pre-treatment peripheral TCR diversity was associated with worse overall survival (p=0.024), particularly when it coincided with a low fraction of circulating T cells (p=0.00049). The low-diversity TCR repertoires were dominated by expanded clones that persisted throughout treatment and disproportionately targeted latent viral infections. Longitudinal analysis revealed a reduction in TCR diversity after treatment indicating an adverse effect on the immune system. In early-stage bladder cancer, we showed that immunotherapy had a stimulatory effect on TCR diversity in patients with good outcomes. Single-cell sequencing identified most expanded clones as cytotoxic T cells, while non-expanded clones were predominantly naive T cells. Overall, our findings suggest that TCR diversity is a promising new biomarker that may offer new avenues for tailored oncological treatment to enhance clinical outcomes for bladder cancer patients.

cancer biology↗

bioRxiv2023

A standard protocol to report discrete stage-structured demographic information

O_LIStage-based demographic methods, such as matrix population models (MPMs), are powerful tools used to address a broad range of fundamental questions in ecology, evolutionary biology, and conservation science. Accordingly, MPMs now exist for over 3,000 species worldwide. These data are being digitised as an ongoing process and periodically released into two large open-access online repositories: the COMPADRE Plant Matrix Database and the COMADRE Animal Matrix Database. During the last decade, data archiving and curation of COMPADRE and COMADRE, and subsequent comparative research, have revealed pronounced variation in how MPMs are parameterized and reported. C_LIO_LIHere, we summarise current issues related to the parameterisation and reporting of MPMs that arise most frequently and outline how they affect MPM construction, analysis, and interpretation. To quantify variation in how MPMs are reported, we present results from a survey identifying key aspects of MPMs that are frequently unreported in manuscripts. We then screen COMPADRE and COMADRE to quantify how often key pieces of information are omitted from manuscripts using MPMs. C_LIO_LIOver 80% of surveyed researchers (n=60) state a clear benefit to adopting more standardised methodologies for reporting MPMs. Furthermore, over 85% of the 300 MPMs assessed from COMPADRE and COMADRE omitted one or more elements that are key to their accurate interpretation. Based on these insights, we identify fundamental issues that can arise from MPM construction and communication and provide suggestions to improve clarity, reproducibility, and future research utilising MPMs and their required metadata. To fortify reproducibility and empower researchers to take full advantage of their demographic data, we introduce a standardized protocol to present MPMs in publications. This standard is linked to www.compadre-db.org, so that authors wishing to archive their MPMs can do so prior to submission of publications, following examples from other open-access repositories such as DRYAD, Figshare, and Zenodo. C_LIO_LICombining and standardising MPMs parameterized from populations around the globe and across the tree of life opens up powerful research opportunities in evolutionary biology, ecology, and conservation research. However, this potential can only be fully realised by adopting standardised methods to ensure reproducibility. C_LI

ecology↗

bioRxiv2019

Interspecific social interactions shape public goods production in natural microbial communities

Evolution can occur over ecological timescales, suggesting a potentially important role for rapid evolution in shaping community trait distributions. However, evidence of concordant eco-evolutionary dynamics often comes from in vitro studies of highly simplified communities, and measures of ecological and evolutionary dynamics are rarely directly comparable. Here, we quantified how ecological species sorting and rapid evolution simultaneously shape community trait distributions by tracking within and between-species changes in a key trait in a complex bacterial community. We focused on the production of siderophores; bacteria use these costly secreted metabolites to scavenge poorly soluble iron and to detoxify environments polluted with toxic non-ferrous metals. We found that responses to copper-imposed selection within and between species were ultimately the same - intermediate siderophore levels were favored - and occurred over similar timescales. Despite being a social trait, this level of siderophore production was selected regardless of whether species evolved in isolation or in a community context. Our study suggests that evolutionary selection can play a pivotal role in shaping community trait distributions within natural, highly complex, bacterial communities. Furthermore, trait evolution may not always be qualitatively affected by interactions with other community members. SignificanceBacterial communities possess remarkable taxonomic and metabolic diversity and play a key role in nearly every biogeochemical process on Earth. Rapid evolution (occurring over ecological time scales) can in principle shape these processes, yet we have little understanding of its importance in natural communities. Here, we quantified how the production of metal-detoxifying siderophores is driven by species compositional changes and evolution in a compost community in response to copper stress. We found that siderophore production converged at intermediate levels, with evolutionary and ecological changes occurring at similar rates. Understanding how ecological and evolutionary processes contribute to shaping trait distributions will improve our ability to predict ecosystem responses to global change, and aid in the engineering of microbial consortia.

evolutionary biology↗

bioRxiv2018

Glucosinolates promote initial population establishment of feral oilseed rape

BackgroundCrops are often selected for traits that confer a selective disadvantage in the wild. A key trait that has been greatly altered by domestication is investment in herbivore defence. It remains unclear, however, whether variation in chemical defence affects a crops ability to colonize semi-natural habitats where it typically has to compete with a resident community. Here, we investigate how breeding efforts aimed at reducing glucosinolate levels in seeds - canonical herbivore deterrents - influence initial establishment of Brassica populations spanning a wild-feral-domesticated gradient.\n\nMethodsWe followed the dynamics of twenty-nine Brassica accessions in two experimental fields by recording life table parameters and vegetation cover biannually over a two-year period. Accessions were selected to vary in their glucosinolate content, and included lines of wild turnip (B. rapa), feral B. napus as well as modern canola and historical oilseed rape cultivars. Populations were established by sowing seeds on bare soil after which the natural vegetation was allowed to regenerate, providing a temporal gradient in the degree of interspecific competition.\n\nResultsPopulations flourished in the first year, but many perished during a second year of growth, in particular those of oilseed rape. Declines coincided with an increase in vegetation cover, but were slower in populations harbouring more glucosinolates. These compounds had opposing effects on different life cycle stages: seedling establishment was greater in high-glucosinolate lines, which traded off with reduced post-recruitment survival. Crucially, the effect of glucosinolates on persistence was lost when focussing on oilseed rape only, but the underlying demographic trade-off remained.\n\nDiscussionOur study illustrates that initial establishment of feral oilseed rape is governed by glucosinolate-mediated trade-offs between seedling recruitment and subsequent survival, with low-glucosinolate lines (modern canola) being most successful when post-recruitment conditions are relatively benign. Such demographic trade-offs likely extend to other species, and must be considered when managing escaped crops and invasive plants.

ecology↗

bioRxiv2018

Estimates for quality of life loss due to RSV

A number of vaccines against Respiratory Syncytial Virus (RSV) infection are approaching licensure. Deciding which RSV vaccine strategy, if any, to introduce, will partly depend on cost-effectiveness analyses, which compares the relative costs and health benefits of a potential vaccination programme. Health benefits are usually measured in Quality Adjusted Life Year (QALY) loss, however, there are no QALY loss estimates for RSV that have been determined using standardised instruments. Moreover, in children under the age of five years in whom severe RSV episodes predominantly occur, there are no appropriate standardised instruments to estimate QALY loss. We estimated the QALY loss due to RSV across all ages by developing a novel regression model which predicts the QALY loss without the use of standardised instruments. To do this, we conducted a surveillance study which targeted confirmed episodes in children under the age of five years (confirmed cases) and their household members who experienced symptoms of RSV during the same time (suspected cases.) All participants were asked to complete questions regarding their health during the infection, with the suspected cases aged 5-14 and 15+ years old additionally providing Health-Related Quality of Life (HR-QoL) loss estimates through completing EQ-5D-3L-Y and EQ-5D-3L instruments respectively. The questionnaire responses from the suspected cases were used to calibrate the regression model. The calibrated regression model then used other questionnaire responses to predict the HR-QoL loss without the use of EQ-5D instruments. The age-specific QALY loss was then calculated by multiplying the HR-QoL loss on the worst day predicted from the regression model, with estimates for the duration of infection from the questionnaires and a scaling factoring for disease severity. Our regression model for predicting HR-QoL loss estimates that for the worst day of infection, suspected RSV cases in persons five years and older who do and do not seek healthcare have an HR-QoL loss of 0{middle dot}616 (95% CI 0{middle dot}155-1{middle dot}371) and 0{middle dot}405 (95% CI 0{middle dot}111-1{middle dot}137) respectively. This leads to a QALY loss per RSV episode of 1{middle dot}950 x 10-3 (95% CI 0{middle dot}185 x 10-3 -9{middle dot}578 x 10-3) and 1{middle dot}543 x 10-3 (95% CI 0{middle dot}136 x 10-3 -6{middle dot}406 x 10-3) respectively. For confirmed cases in a child under the age of five years who sought healthcare, our model predicted a HR-QoL loss on the worst day of infection of 0{middle dot}820 (95% CI 0{middle dot}222-1{middle dot}450) resulting in a QALY loss per RSV episode of 3{middle dot}823 x 10-3 (95% CI 0{middle dot}492 x 10-3 -12{middle dot}766 x 10-3). Combing these results with previous estimates of RSV burden in the UK, we estimate the annual QALY loss of healthcare seeking RSV episodes as 1,199 for individuals aged five years and over and 1,441 for individuals under five years old. The QALY loss due to an RSV episode is less than the QALY loss due to an Influenza episode. These results have important implications for potential RSV vaccination programmes, which has so far focused on preventing infections in infants--where the highest reported disease burden lies. Future potential RSV vaccination programmes should also evaluate their impact on older children and adults, where there is a substantial but unsurveilled QALY loss.

epidemiology↗

bioRxiv2017

Ecological selection of siderophore-producing microbial taxa in response to heavy metal contamination

Some microbial public goods can provide both individual and community-wide benefits, and are open to exploitation by non-producing species. One such example is the production of metal-detoxifying siderophores. Here, we investigate whether heavy metals select for increased siderophore production in natural microbial communities, or whether exploitation of this detoxifying effect reduces siderophore production. We show that the proportion of siderophore-producing taxa increases along a natural heavy metal gradient. A causal link between metal contamination and siderophore production was subsequently demonstrated in a microcosm experiment in compost, in which we observed changes in community composition towards taxa that produce relatively more siderophores following copper contamination. We confirmed the selective benefit of siderophores by showing that taxa producing large amount of siderophores suffered less growth inhibition in toxic copper. Our results suggest that ecological selection will favour siderophore-mediated decontamination, with important consequences for potential remediation strategies.\n\nAuthorshipEH, SOB, AL, DJH, EvV, AB conceived and designed the experiment. DJH provided new perspectives. EH, SOB, FB, AL collected the data. EH, FB, NT, DJH carried out the data analyses. EH & AB wrote the first draft of the manuscript, and all authors contributed substantially to revisions.\n\nData accessibilityUpon acceptance, data presented in the manuscript will be made available on Dryad.

ecology↗