Biology subjects

Alexander, T.

Publications and source records attributed to Alexander, T..

6 recordsLinked to original sources

bioRxiv2026

Melanopsin regulates axonal translation underlying retinohypothalamic circuit assembly

Intrinsically photosensitive retinal ganglion cells (ipRGCs) influence visual system development via melanopsin before photoreceptor-mediated vision, but how melanopsin signaling contributes to ipRGC circuit assembly remains unknown. Here we show that melanopsin coordinates retinohypothalamic tract development by regulating local translation in developing ipRGC axons. Loss of melanopsin selectively disrupted local translation in axons without affecting somatic translation. The affected transcripts encoded cytoskeletal regulators, adhesion molecules, and trafficking proteins, and activity-dependent changes in translation were restricted to the period before eye-opening. Consistent with impaired axonal growth and synaptogenesis, Opn4 knockout mice showed reduced ipsilateral suprachiasmatic nucleus innervation and fewer retinohypothalamic synapses, while nanoscale synaptic molecular organization and microglial engulfment were unaffected. Reduced visual drive in Opn4 knockouts further altered developmental gene expression programs across the retina, suprachiasmatic nucleus, and lateral geniculate nucleus, with region-specific differences in expression timing. These findings identify melanopsin as a regulator of local axonal translation during early circuit development, linking sensory phototransduction to translational control mechanisms that guide retinohypothalamic tract assembly and postsynaptic target maturation.

neuroscience↗

bioRxiv2023

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness

Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial dysfunction is an important contributor to GWI, based on the similarity of some GWI symptoms to those occurring in some mitochondrial diseases; the plausibility that certain pollutants to which GW veterans were exposed affect mitochondria; mitochondrial effects observed in studies in laboratory models of GWI; and previous evidence of mitochondrial outcomes in studies in GW veterans. A primary role of mitochondria is generation of energy via oxidative phosphorylation. However, direct assessment of mitochondrial respiration, reflecting oxidative phosphorylation, has not been carried out in veterans with GWI. In this case-control observational study, we tested multiple measures of mitochondrial function and integrity in a cohort of 114 GW veterans, 80 with and 34 without GWI as assessed by the Kansas definition. In circulating white blood cells, we analyzed multiple measures of mitochondrial respiration and extracellular acidification, a proxy for non-aerobic energy generation; mitochondrial DNA (mtDNA) copy number; mtDNA damage; and nuclear DNA damage. We also collected detailed survey data on demographics; deployment; self-reported exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents; and current biometrics, health and activity levels. We observed a 9% increase in mtDNA content in blood in veterans with GWI, but did not detect differences in DNA damage. Basal and ATP-linked oxygen consumption were respectively 42% and 47% higher in veterans without GWI, after adjustment for mtDNA amount. We did not find evidence for a compensatory increase in anaerobic energy generation: extracellular acidification was also lower in GWI (12% lower at baseline). A subset of 27 and 26 veterans returned for second and third visits, allowing us to measure stability of mitochondrial parameters over time. mtDNA CN, mtDNA damage, ATP-linked OCR, and spare respiratory capacity were moderately replicable over time, with intraclass correlation coefficients of 0.43, 0.44, 0.50, and 0.57, respectively. Other measures showed higher visit- to-visit variability. Many measurements showed lower replicability over time among veterans with GWI compared to veterans without GWI. Finally, we found a strong association between recalled exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents and GWI (p < 0.01, p < 0.01, and p < 0.0001, respectively). Our results demonstrate decreased mitochondrial respiratory function as well as decreased glycolytic activity, both of which are consistent with decreased energy availability, in peripheral blood mononuclear cells in veterans with GWI.

pharmacology and toxicology↗

bioRxiv2022

A Single Intranasal Dose of Bacterial Therapeutics to Calves Confers Longitudinal Modulation of the Nasopharyngeal Microbiota

To address the emergence of antimicrobial-resistant pathogens in livestock, microbiome-based strategies are increasingly being sought to reduce antimicrobial use. Here, we describe the intranasal application of bacterial therapeutics (BTs) for mitigating bovine respiratory disease (BRD) and used structural equation modeling to investigate the causal networks after BT application. Beef cattle received i) an intranasal cocktail of previously characterized BT strains, ii) an injection of metaphylactic antimicrobial (tulathromycin), or iii) intranasal saline. Despite being transient colonizers, inoculated BT strains induced longitudinal modulation of the nasopharyngeal bacterial microbiota while showing no adverse effect on animal health. The BT-mediated changes in bacteria included reduced diversity and richness and strengthened cooperative and competitive interactions. In contrast, tulathromycin increased bacterial diversity and antibiotic resistance, and disrupted bacterial interactions. Overall, a single intranasal dose of BTs can modulate the bovine respiratory microbiota, highlighting that microbiome-based strategies have the potential in being utilized to mitigate BRD in feedlot cattle.

microbiology↗

bioRxiv2020

The MRC IEU OpenGWAS data infrastructure

Data generated by genome-wide association studies (GWAS) are growing fast with the linkage of biobank samples to health records, and expanding capture of high-dimensional molecular phenotypes. However the utility of these efforts can only be fully realised if their complete results are collected from their heterogeneous sources and formats, harmonised and made programmatically accessible. Here we present the OpenGWAS database, an open source, open access, scalable and high-performance cloud-based data infrastructure that imports and publishes complete GWAS summary datasets and metadata for the scientific community. Our import pipeline harmonises these datasets against dbSNP and the human genome reference sequence, generates summary reports and standardises the format of results and metadata. Users can access the data via a website, an application programming interface, R and Python packages, and also as downloadable files that can be rapidly queried in high performance computing environments. OpenGWAS currently contains 126 billion genetic associations from 14,582 complete GWAS datasets representing a range of different human phenotypes and disease outcomes across different populations. We developed R and Python packages to serve as conduits between these GWAS data sources and a range of available analytical tools, enabling Mendelian randomization, genetic colocalisation analysis, fine mapping, genetic correlation and locus visualisation. OpenGWAS is freely accessible at https://gwas.mrcieu.ac.uk, and has been designed to facilitate integration with third party analytical tools.

genetics↗

bioRxiv2020

Mobilization of tissue-resident memory CD4+ T lymphocytes and their contribution to a systemic secondary immune reaction

While it is generally accepted that tissue-resident memory T lymphocytes protect host tissues from secondary immune challenges, it is unclear whether, and if so, how they contribute to systemic secondary immune responses. Here we show that in human individuals with an established immune memory to measles, mumps and rubella viruses, when challenged with the measles-mumps-rubella (MMR) vaccine again, tissue-resident memory CD4+ T cells are mobilized into the blood within 16 to 48 hours after vaccination. These cells then leave the blood again, and apparently contribute to the systemic secondary immune reaction, as is evident from the representation of mobilized T cell receptor V{beta} clonotypes among newly generated circulating memory T lymphocytes, from day 7 onwards. Mobilization of the tissue-resident memory T cells is cognate, in that memory T lymphocytes recognizing other antigens, e.g. tetanus toxin, are not mobilized, unless they cross-react with the vaccine. These data originally demonstrate the essential contribution of tissue-resident memory T cells to secondary systemic immune responses, confirming that immunological memories to systemic pathogens are maintained (also) by tissue-resident memory T cells. In practical terms, the present work defines day 1 to 2 after antigenic challenge as a time window to assess the entire immunological T cell memory for a certain pathogen, including mobilized tissue-resident memory T cells, and its correlates of effectivity. Capsule summaryThe study demonstrates the rapid and cognate mobilization of tissue-resident memory CD4+ T cells into the blood upon antigenic rechallenge, and their contribution to secondary systemic immune responses.

immunology↗

bioRxiv2019

Low-Density Granulocytes are a novel immunopathological feature in both Multiple Sclerosis and Neuromyelitis optica spectrum disorder.

ObjectiveTo investigate whether low-density granulocytes (LDGs) are a immunophenotypic feature of patients with multiple sclerosis (MS) and/or neuromyelitis optica spectrum disorder (NMOSD).\n\nMethodsBlood samples were collected from 26 patients with NMOSD and 20 patients with MS, as well as from 18 patients with Systemic Lupus Erythematosus (SLE) and 23 Healthy Donors (HD). We isolated peripheral blood mononuclear cells (PBMCs) with density gradient separation and stained the cells with antibodies against CD14, CD15, CD16, and CD45, and analysed the cells by flow cytometry or imaging flow cytometry. We defined LDGs as CD14-CD15high and calculated their share in total PBMC leukocytes (CD45+) as well as the share of CD16hi LDGs. Clinical data on disease course, medication, and antibody status were obtained.\n\nResultsLDGs were significantly more common in MS and NMOSD than in HDs, comparable to SLE samples (median values HD 0.2%, MS 0.9%, NMOSD 2.1%, SLE 4.3%). 0/23 of the HDs, but 17/20 NMOSD and 11/17 MS samples as well as 13/15 SLE samples had at least 0.7 % LDGs. NMOSD patients without continuous immunosuppressive treatment had significantly more LDGs compared to their treated counterparts. LDG nuclear morphology ranged from segmented to rounded, suggesting a heterogeneity within the group.\n\nConclusionLDGs are a feature of the immunophenotype in some patients with MS and NMOSD.

immunology↗