Biology subjects

Dean, R.

Publications and source records attributed to Dean, R..

10 recordsLinked to original sources

bioRxiv2026

Corpus Callosum Dysgenesis impairs metacognition: evidence from multi-modality and multi-cohort replications

The corpus callosum is the largest commissure in the mammalian brain and plays a major role in supporting cognitive processes required for adapting to complex environments. Individuals born with Corpus Callosum Dysgenesis (CCD), characterized by malformations of the corpus callosum, commonly exhibit deficits in social navigation, abstract problem-solving, decision-making, and self-awareness. Metacognition is a key cognitive process that supports these functions; however, it has yet to be tested comprehensively in individuals with CCD. Over three experiments, and three CCD cohorts, we tested the impact of this neurodevelopmental disorder on perceptual accuracy, confidence judgements, and metacognitive efficiency using two variants of a Random Dot Kinematogram task within lab, online, and VR conditions. We found that individuals with CCD typically displayed normal perceptual accuracy but failed to adjust their confidence judgements in line with task difficulty. Computational modelling revealed that this difference was explained by lower metacognitive efficiency driven by consistently lower metacognitive sensitivity. Together, these results provide evidence that the corpus callosum plays a crucial role in supporting metacognition.

neuroscience↗

bioRxiv2025

Sperm storage reduces sperm and embryo quality in animals

In many animals, sperm are stored for extended periods either in the reproductive tracts of males before ejaculation, or of females after copulation. Sperm storage reduces the risk of sperm limitation in both sexes and avoids the costs of female re-mating. However, sperm storage can lead to post-meiotic sperm senescence, i.e. within-sperm-age-dependent deterioration, potentially impacting conceived offspring and lowering male and female fitness. Yet, the extent and magnitude of such deterioration and the variables modulating it during sperm storage are not well understood. Using a meta-analysis across humans (115 studies) and non-human animals (56 studies from 30 species), we investigate how in-vivo sperm storage affects sperm quality, fertilisation success, and offspring quality. In humans, sperm storage leads to greater sperm oxidative stress and DNA damage, and reduces sperm viability and motility. In other animals, sperm performance and embryo quality decline. We identify the duration of sperm storage, the design used for sampling individuals, and the sex of the individual storing sperm as potentially important moderators of the effects of sperm storage. These findings have key biomedical implications, including optimising the timing of ejaculation and fertilisation in fertility clinics or captive breeding programs. Overall, our results reveal the mechanisms that cause post-meiotic sperm senescence, the fitness consequences of sperm storage, and provide evolutionary insights into sex-specific adaptations that potentially mitigate the detrimental effects of sperm storage.

evolutionary biology↗

bioRxiv2024

Trace DNA from kill sites identifies predating tigers

Predation ecology and evidence-based conflict management strategies require reliable and accurate identification of individual predators. Identifying predators is, however, complex, as they are secretive and individual identification is difficult. Trace DNA that predators leave behind at kill sites might provide an effective strategy to identify them but remains poorly evaluated at scale. We use non-invasive genetic samples from kill sites to assess their utility for predator identification. We systematically investigated 198 livestock kills in two critical source tiger populations in central India: Kanha and Bandhavgarh Tiger Reserves. We collected 342 salivary swabs from carcasses, 33 scat and 395 shed hair samples as potential sources of predator DNA, and individual tigers were identified using up to 123 SNP markers. All three sample sources identified predator species with high success (>95%). We identified individuals (with at least one sample per kill site, based on >40 SNPs) at 86% of all kill sites where tigers were detected. Shed hair samples were most effective for individual identification, followed by saliva and scat. Sample source and sampling season were the primary determinants of the number of SNPs typed per sample and the success of individual identification. Based on the site and type of sample collection, we classify species and individuals into three categories: true predator (high confidence as predator), circumstantial predator (medium confidence) and predator uncertain (low confidence). Individuals were classified as a true predator at 72 sites, circumstantial predator at 34 sites and predator uncertain at 49 sites. Our protocol allowed us to differentiate between predators and scavengers, even when multiple tigers were detected at the same kill site. Surprisingly, [~]40% of Bandhavgarhs tigers were identified at at least one kill site. We suggest that when paired with systematic kill site investigation and sample collection, these methods can be effectively used to understand predation ecology better and facilitate evidence-based conflict management.

genetics↗

bioRxiv2024

Sticking together: Independent evolution of biofilm formation in different species of staphylococci has occurred multiple times via different pathways

Various species of staphylococci cause a wide range of infections, including implant-associated infections which are often difficult to treat due to the presence of biofilms. Whilst some proteins involved in biofilm formation are known, the differences in biofilm production between staphylococcal species remains understudied. Currently biofilm formation by Staphylococcus aureus is better understood than for other members of the genus as more research effort has focused on this species. We assembled a panel of 385 non-aureus Staphylococcus isolates of 19 species from prosthetic joint infection as well as other clinical sources and reference strains. We assessed the biofilm forming ability of all strains using a high-throughput crystal violet assay. This identified distinct biofilm formation categories and we then compared the prevalence of Pfam domains and identified those which distinguished the categories as well as using machine learning to identify amino acid 20-mers linked to biofilm formation. This identified some domains within proteins already positively linked to biofilm formation but we also identified important domains not previously linked to biofilm formation. RT-qPCR confirmed the expression of selected genes predicted to encode important domains within biofilms in Staphylococcus epidermidis. The prevalence and distribution of biofilm associated domains showed a link to phylogeny, suggesting different Staphylococcus species have independently evolved different mechanisms of biofilm production. This work has identified different routes to biofilm formation in diverse species of Staphylococcus as well as suggesting independent evolution of biofilm has occurred multiple times across the genus. Understanding the mechanisms of biofilm formation in any given species is likely to require detailed study of relevant strains and the ability to generalise across the genus may be limited.

microbiology↗

bioRxiv2023

Variant Mapping Application: Customize And Annotate Figures Of Voltage-Gated Sodium Channel

Voltage-gated sodium ion channels allow for the initiation and transmission of action potentials. There is a high interest in research and drug development to selectively target these ion channels to treat epilepsy and other disorders such as pain. Scientific literature and presentations often incorporate maps of these integral membrane proteins with markers indicating gene mutations to highlight genotype/phenotype correlations. There is a need for automated tools to create high quality figures with mutation (variant) locations displayed on these channel maps. This manuscript introduces a simple application to create visualization for mutations on alpha voltage-gated sodium channels, created using the D3.js library. The application allows for mapping of variant sequences, as well as important properties like the type of variant and the phenotypes linked to the variant. It also allows for customizability and the production of high-quality images for publication. This application and code base can further be extrapolated to other ion channels as well.

neuroscience↗

bioRxiv2022

Characterisation of neonatal Staphylococcus capitis NRCS-A isolates compared with non NRCS-A Staphylococcus capitis from neonates and adults.

Staphylococcus capitis is a frequent cause of Late-Onset Sepsis (LOS) in neonates admitted to Neonatal Intensive Care Units (NICU). The NRCS-A clone of S. capitis has been isolated from NICUs globally although the reasons for the global success of this clone are not understood. We analysed a collection of S. capitis colonising babies admitted to two NICUs, one in the UK and one in Germany as well as corresponding pathological clinical isolates. Genome analysis identified 3 groups; non-NRCS-A isolates, NRCS-A isolates, and a group of proto NRCS-A - isolates closely related to NRCS-A but not associated with neonatal infection. All bloodstream isolates belonged to the NRCS-A group and were indistinguishable from strains carried on the skin or in the gut. NRCS-A isolates showed increased tolerance to chlorhexidine and antibiotics relative to the other S. capitis as well as enhanced ability to grow at higher pH values. Analysis of 138 pangenomes of the clades identified characteristic nsr and tarJ genes in the NRCS-A and proto groups with a CRISPR-cas system only seen in NRCS-A isolates which also showed enrichment of genes for metal acquisition and transport. We found evidence for transmission of S. capitis NRCS-A within NICU, with related isolates shared between babies and multiple acquisitions by some babies. Our data show NRCS-A strains commonly colonise uninfected babies in NICU representing a potential reservoir for potential infection. This work provides more evidence that adaptation to survive in the gut and on skin facilitates spread of NRCS-A, and that metal acquisition and tolerance may be important to the biology of NRCS-A. Understanding how NRCS-A survives in NICUs can help develop infection control procedures against this clone.

genomics↗

bioRxiv2021

NBI-921352, a First-in-Class, Na V 1.6 Selective, Sodium Channel Inhibitor That Prevents Seizures in Scn8a Gain-of- Function Mice, and Wild-Type Mice and Rats

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Moller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC50 0.051 {micro}M), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756X for NaV1.1, 134X for NaV1.2, 276X for NaV1.7, and >583X for NaV1.3, NaV1.4, and NaV1.5). NBI-921352 is a state-dependent inhibitor, preferentially inhibiting activated (inactivated or open) channels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse, as well as in wild-type mouse and rat seizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor antiseizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 was well tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.

pharmacology and toxicology↗

bioRxiv2020

DRAXIN regulates interhemispheric fissure remodelling to influence the extent of corpus callosum formation

Corpus callosum dysgenesis (CCD) is a congenital disorder that incorporates either partial or complete absence of the largest cerebral commissure. Remodelling of the interhemispheric fissure (IHF) provides a substrate for callosal axons to cross between hemispheres, and its failure is the main cause of complete CCD. However, it is unclear whether defects in this process could give rise to the heterogeneity of expressivity and phenotypes seen in human cases of CCD. We identify incomplete IHF remodelling as the key structural correlate for the range of callosal abnormalities in inbred and outcrossed BTBR mouse strains, as well as in humans with partial CCD. We identify an eight base pair deletion in Draxin and misregulated astroglial and leptomeningeal proliferation as genetic and cellular factors for variable IHF remodelling and CCD in BTBR acallosal strains. These findings support a model where genetic events determine corpus callosum structure by influencing leptomeningeal-astroglial interactions at the IHF.

neuroscience↗

bioRxiv2019

An exposition of ejaculate senescence and its inhibition in Drosophila

Declining ejaculate performance with male age is taxonomically widespread and has broad ramifications for fertility and fitness. However, we have a poor understanding of age-related changes to specific ejaculate components, how they cause reduced performance, and whether the decline is ameliorable. Here, we show that, in Drosophila, sperm production chronologically declines with age, invariant to mating activity, while repeated mating causes infertility via reduced sperm stores and viability. However, changes to sperm do not fully explain ejaculate deterioration: impacts on seminal fluid contribute to aspects of reduced ejaculate performance, associated with shifts in proteome abundance and quality. We show that ablation of insulin-like peptide-producing cells in males ameliorates aspects of ejaculate performance loss, suggesting that anti-ageing interventions can be coopted to benefit male reproductive health.\n\nOne Sentence SummaryEjaculate performance declines with male age via mating-dependent sperm and seminal protein deterioration, but it can be ameliorated.

evolutionary biology↗

bioRxiv2018

Quantitative proteomics identification of seminal fluid proteins in male Drosophila melanogaster

Seminal fluid contains some of the fastest evolving proteins currently known. These seminal fluid proteins (Sfps) play crucial roles in reproduction, such as supporting sperm function, and - particularly in insects - modifying female physiology and behaviour. Identification of Sfps in small animals is challenging, and often relies on samples taken from the female reproductive tract after mating. A key pitfall of this method is that it might miss Sfps that are of low abundance due to dilution in the female-derived sample or rapid processing in females. Here we present a new and complimentary method, which provides added sensitivity to Sfp identification. We applied label-free quantitative proteomics to Drosophila melanogaster male reproductive tissue - where Sfps are unprocessed, and highly abundant - and quantified Sfps before and immediately after mating, to infer those transferred during copulation. We also analysed female reproductive tracts immediately before and after copulation to confirm the presence and abundance of known and candidate Sfps, where possible. Results were cross-referenced with transcriptomic and sequence databases to improve confidence in Sfp detection. Our data was consistent with 124 previously reported Sfps. We found 8 high-confidence novel candidate Sfps, which were both depleted in mated versus unmated males and identified within the reproductive tract of mated but not virgin females. We also identified 31 more candidates that are likely Sfps based on their abundance, known expression and predicted characteristics, and revealed that four proteins previously identified as Sfps are at best minor contributors to the ejaculate. The estimated copy numbers for our candidate Sfps were lower than for previously identified Sfps, supporting the idea that our technique provides a deeper analysis of the Sfp proteome than previous studies. Our results demonstrate a novel, high-sensitivity approach to the analysis of seminal fluid proteomes, whose application will further our understanding of reproductive biology.

genomics↗