Biology subjects

Irvine, A.

Publications and source records attributed to Irvine, A..

7 recordsLinked to original sources

bioRxiv2026

TEX15 safeguards neuronal diversity in the mouse olfactory system

Animals detect diverse chemicals using hundreds of chemoreceptor proteins. In many organisms, sensory chemoreceptors obey a one-receptor-type-per-cell rule, which organizes information gathered by sensory neurons. A key question remains how receptor expression gets diversified so that hundreds of chemoreceptors get expressed across the population of sensory neurons. Here we show that diverse odorant receptor (OR) expression in mice requires testis expressed gene 15 (Tex15). We find that Tex15 regulates OR expression in neuronal precursor cells. In Tex15 deficient (Tex15-/-) mice, OR transcript levels are increased in precursors, a handful of early-transcribed OR genes get expressed at abnormally high levels, and these ORs come to dominate the olfactory sensory neuron population. This results in a profound reduction in the diversity of OR gene choice as well as disrupted spatial patterning of the olfactory epithelium, without disrupting the one-receptor-type-per-cell rule. Tex15 encodes a transcriptional repressor, and we show that Tex15-/- mice have reduced heterochromatin-associated H3K9me3 on OR genes. Thus, we propose that Tex15 directs a heterochromatin-based transcriptional repression mechanism that prevents uneven transcriptional onset from skewing OR choice. This mechanism safeguards the cellular diversity that is essential for broadly tuned chemosensation.

genomics↗

bioRxiv2025

Dysregulated lymphocyte localization in idiopathic multicentric Castleman disease

Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening hematologic disease involving episodic flares of uncontrollable systemic inflammation by unknown causes. Hallmark features of iMCD include multiple enlarged lymph nodes with characteristic histopathological phenotypes and a potentially fatal, cytokine release syndrome. The key pathophysiologic drivers of disease are poorly understood and few effective treatment options exist. Here, we discovered an association between elevated chemokines, namely CXCL13, and lymph node size in iMCD, providing one possible explanation for the lymphadenopathy observed clinically. Instead of a concurrent increase in circulating CXCL13 and CXCR5-expressing cells that has been described in other contexts, during active disease, chemokine-responsive lymphocytes downregulated CXCR5 levels in iMCD. Despite heightened chemokine production by lymph node stromal cells, T and B cells failed to appropriately respond to their cues locally within the tissue and were particularly scarce within CXCL13-expressing germinal centers (GC). Inflammatory signals in iMCD lymph nodes appeared to restrict the production and movement of T follicular helper cells, which play an important role in facilitating appropriate GC responses. Together, these data provide a link between dysregulated chemokine production and germinal center lymphocyte trafficking, highlighting a potential mechanism and therapeutic target in iMCD lymphadenopathy. One Sentence SummaryLymphocyte chemotaxis to discrete areas of lymphoid tissue is disrupted in idiopathic multicentric Castleman disease.

immunology↗

bioRxiv2024

Musical training does not enhance neural sound encoding at early stages of the auditory system: A large-scale multisite investigation

Musical training has been associated with enhanced neural processing of sounds, as measured via the frequency following response (FFR), implying the potential for human subcortical neural plasticity. We conducted a large-scale multi-site preregistered study (n > 260) to replicate and extend the findings underpinning this important relationship. We failed to replicate any of the major findings published previously in smaller studies. Musical training was related neither to enhanced spectral encoding strength of a speech stimulus (/da/) in babble nor to a stronger neural-stimulus correlation. Similarly, the strength of neural tracking of a speech sound with a time-varying pitch was not related to either years of musical training or age of onset of musical training. Our findings provide no evidence for plasticity of early auditory responses based on musical training and exposure.

neuroscience↗

bioRxiv2023

Novel integrated computational AMP discovery approaches highlight diversity in the helminth AMP repertoire

Antimicrobial Peptides (AMPs) are immune effectors that are key components of the invertebrate innate immune system providing protection against pathogenic microbes. Parasitic helminths share complex interactions with their hosts and closely associated microbiota that are likely regulated by a diverse portfolio of antimicrobial immune effectors including AMPs. Knowledge of helminth AMPs has largely been derived from nematodes, whereas the flatworm AMP repertoire has not been described. This study highlights limitations in the homology-based approaches, used to identify putative nematode AMPs, for the characterisation of flatworm AMPs, and reveals that innovative algorithmic AMP prediction approaches provide an alternative strategy for novel helminth AMP discovery. The data presented here: (i) reveal that flatworms do not encode traditional lophotrochozoan AMP groups (Big Defensin, CS{beta} peptides and Myticalin); (ii) describe a unique integrated computational pipeline for the discovery of novel helminth AMPs; (iii) reveal >16,000 putative AMP-like peptides across 127 helminth species; (iv) highlight that cysteine-rich peptides dominate helminth AMP-like peptide profiles; (v) uncover eight novel helminth AMP-like peptides with diverse antibacterial activities, and (vi) demonstrate the detection of AMP-like peptides from helminth biofluids. These data represent a significant advance in our understanding of the putative helminth AMP repertoire and underscore a potential untapped source of antimicrobial diversity which may provide opportunities for the discovery of novel antimicrobials. Further, unravelling the role of endogenous worm-derived antimicrobials and their potential to influence host-worm-microbiome interactions may be exploited for the development of unique helminth control approaches. Author summaryInvertebrate antimicrobial peptides (AMPs) form the first line of defence against pathogenic microbes. Helminths are worms (flatworm, roundworm) that live in microbe-rich environments throughout their lifecycles however little is known about how they protect themselves against pathogens or how they interact with microbes. Understanding AMP profiles in helminths, their importance to helminth biology, and how they shape microbial communities could reveal novel approaches for anthelmintic and/or antimicrobial development. In this study we describe a novel integrated homology- and computational-based pipeline for the discovery of helminth AMPs. This approach revealed that, whilst flatworms do not possess traditional AMPs, they have a repertoire of unique AMP-like peptides that are predominantly cysteine-rich. Significantly eight novel helminth AMP-like peptides, discovered using this pipeline, have antibacterial activities against a range of bacteria highlighting their potential as novel antimicrobials. Further, peptidomics analyses demonstrate the presence of AMP-like peptides in helminth body fluids supporting the need to further characterise these peptides and their function(s) in helminths. These data present novel opportunities to better understand helminth biology, discover new antimicrobials and develop future control strategies for helminth parasites.

bioinformatics↗

bioRxiv2022

Elevated estradiol during a hormone simulated pseudopregnancy decreases sleep and increases hypothalamic activation in female Syrian hamsters

Sleep disruptions are a common occurrence during the peripartum period. While physical and environmental factors associated with pregnancy and newborn care account for some sleep disruptions, there is evidence that peripartum fluctuations in estrogens may independently impact sleep. We therefore used a hormone-simulated pseudopregnancy in female Syrian hamsters to test the hypothesis that pregnancy-like increases in estradiol decrease sleep in the absence of other factors. Adult female Syrian hamsters were ovariectomized and given daily hormone injections that simulate estradiol levels during early pregnancy, late pregnancy, and the postpartum period. Home cage video recordings were captured at seven timepoints and videos were analyzed for actigraphy. During "late pregnancy," total sleep time and sleep efficiency were decreased in hormone-treated animals during the white light period compared to vehicle controls. During both "early pregnancy" and "late pregnancy," locomotion was increased in the white light period for hormone-treated animals; this change continued into the "postpartum period" for animals who continued to receive estradiol treatment, but not for animals who were withdrawn from estradiol. At the conclusion of the experiment, animals were euthanized and cFos expression was quantified in the ventral lateral preoptic area (VLPO) and lateral hypothalamus (LH). Animals who continued to receive high levels of estradiol during the "postpartum" period had significantly more cFos in the VLPO and LH than animals who were withdrawn from hormones or vehicle controls. Together, these data suggest that increased levels of estradiol during pregnancy are associated with sleep suppression which may be mediated by increased activation of hypothalamic nuclei.

neuroscience↗

bioRxiv2022

The Nematode Antimicrobial Peptidome: a novel opportunity for parasite control?

Antimicrobial Peptides (AMPs) are key constituents of the invertebrate innate immune system where they provide critical protection against microbial threat. Knowledge of AMP complements within phylum Nematoda is limited however nematodes adopt diverse life strategies and frequently reside in microbe-rich environments such that they are likely possess broad AMP profiles with bioactivity against a range of microbiota. Indeed, parasitic nematode AMPs likely have roles in defence against invading pathogens and modulation of the host microbiome. In this study the distribution and abundance of AMP-encoding genes were examined in 134 nematode genomes providing the most comprehensive profile of AMPs within phylum Nematoda. We reveal that phylum Nematoda is AMP-rich and -diverse, where 5887 genes encode AMPs. Genome and transcriptome analyses broadly reveal: (i) AMP family profiles that are influenced by nematode lifestyle where free-living nematodes appear to have an expansion of AMPs relative to parasitic species; (ii) major differences in the AMP profiles between nematode clades where Clade 9/V and 10/IV species possess expanded AMP repertoires; (iii) AMP families with highly restricted profiles (e.g. Cecropins and Diapausins) and others [e.g. Nemapores and Glycine Rich Secreted Peptides (GRSPs)] which are more widely distributed; (iv) complexity in the distribution and abundance of Defensin subfamily members; and (v) expression of AMPs in key nematode life stages. These data indicate that phylum Nematoda has a diverse array of AMPs and underscores the need to interrogate AMP function to unravel their importance to nematode biology and host-worm-microbiome interactions. Enhanced understanding of the Nematode Antimicrobial Peptidome will inform drug discovery pipelines for pathogen control.

bioinformatics↗

bioRxiv2020

Extrasynaptic volume transmission: A novel route for neuropeptide signaling in nematodes

Neural circuit synaptic connectivities (the connectome) provide the anatomical foundation for our understanding of nematode nervous system function. However, other non-synaptic routes of communication are known in invertebrates including extrasynaptic volume transmission (EVT), which enables short- and/or long-range communication in the absence of synaptic connections. Although EVT has been highlighted as a facet of Caenorhabditis elegans neurosignaling, no experimental evidence identifies body cavity fluid (pseudocoelomic fluid; PCF) as a vehicle for either neuropeptide or biogenic amine transmission. In the parasitic nematode Ascaris suum FMRFamide-like peptides encoded on flp-18 potently stimulate female reproductive organs but are only expressed in cells that are anatomically distant from the reproductive organ, with no known synaptic connections to this tissue. Here we report a new non-synaptic mode of signaling in nematodes mediated by neuropeptides within the PCF. Our data show that: (i) A. suum PCF (As-PCF) contains a catalogue of neuropeptides including FMRFamide-like peptides and neuropeptide-like proteins; (ii) the A. suum FMRFamide-like peptide As-FLP-18A dominates the As-PCF peptidome; (iii) As-PCF potently modulates nematode reproductive muscle function ex vivo, mirroring the effects of synthetic FLP-18 peptides; (iv) As-PCF activates the C. elegans FLP-18 receptors NPR-4 and -5; (v) As-PCF alters C. elegans behavior and, (vi) FLP-18 and FLP-18 receptors display pan-phylum distribution in nematodes. Here we provide the first direct experimental evidence that supports an extrasynaptic volume route for neuropeptide transmission in nematodes. These data demonstrate non-synaptic signaling within the nematode functional connectome and are pertinent to receptor deorphanisation approaches underpinning drug discovery programs for nematode pathogens.

neuroscience↗