Biology subjects

May, J.

Publications and source records attributed to May, J..

11 recordsLinked to original sources

bioRxiv2026

From Growth Faltering to Recovery: Gut Microbial and Body Composition Signatures of Early Childhood Malnutrition Phenotypes

BackgroundChronic malnutrition in early childhood is a multifactorial condition associated with long-term impairments, yet the physiological and gut microbial pathways underlying differential growth trajectories remain poorly understood. ObjectiveWe aimed to characterize phenotypic growth trajectories and identify the associated gut microbial and body composition signatures in infants during the first year of life. MethodsWe analyzed longitudinal data from birth to 12 months in a South African cohort (Soweto, n=45). Individual linear growth trajectories were modeled using the Jenss-Bayley equation, and children were clustered based on model parameters to identify phenotypic subgroups. Body composition (fat-free mass and fat mass) was measured via deuterium dilution at 6 and 12 months, and gut microbiome development was assessed using 16S rRNA gene amplicons at 4, 6, and 12 months. ResultsWe identified distinct phenotypic subgroups including healthy growth, catch-up growth, and growth faltering, that were obscured at the cohort level. These trajectories diverged most dynamically within the first 6 months of life. Integrated analysis revealed that in the growth faltering cluster, height-for-age and fat-free mass z-scores stabilized between 6 and 12 months, whereas fat mass z-scores (FMZ) declined. This trade-off is consistent with a catabolic state where energy reserves are prioritized for lean tissue and bone growth. Furthermore, at 6 months, the growth faltering cluster was enriched with opportunistic pathobionts (e.g., Paraclostridium). In contrast, the catch-up cluster exhibited a transient enrichment of facultative anaerobes (e.g., Enterobacter), supporting a hypothesis that these oxygen-tolerant taxa may help bridge a transitional microbial state in partially oxygenated or inflamed environments to enable physiological recovery. ConclusionsEarly childhood chronic malnutrition phenotypes in South African infants can be defined by distinct microbial and body composition signatures that diverge within six months of life. Integrated interventions should target both host anabolic state and microbiome transitions to support recovery.

microbiology↗

bioRxiv2026

Targeting AKAP13 RhoGEF activity ameliorates pro-fibrotic phenotypes driven by the IPF associated AKAP13 risk variant

RationaleIdiopathic pulmonary fibrosis (IPF) is a progressive, incurable scarring disease of the lung. A common genetic variant near AKAP13, a multifunctional scaffold protein that integrates intracellular signalling through its interactions with RhoA and protein kinase A (PKA), has been associated with IPF susceptibility and elevated AKAP13 mRNA expression in lung tissue from patients. However, its contribution to the pathogenesis of IPF remains unclear. ObjectiveThis study investigates how an AKAP13 variant alters epithelial signalling and evaluates the therapeutic potential of targeting AKAP13. Findingsrs62025270-bearing iHBECs exhibited selective upregulation of AKAP13 isoforms, accompanied by increased cell adhesion and reduced proliferation. Transcriptomic profiling revealed upregulated fibrosis-related genes in rs62025270-bearing iHBECs, including SAA1, FGF2, MMP1, CTSB, COL4A1, and CDKN1A. rs62025270-bearing iHBECs also displayed increased RhoA activation and SMAD2 phosphorylation following LPA stimulation. Furthermore, cells harbouring the AKAP13 variant showed reduced intracellular cAMP levels. Pharmacological inhibition of AKAP13 with A13 reversed the pro-adhesive phenotype and reduced RhoA activation in iHBECs. Moreover, in IPF-derived PCLS, A13 suppressed SERPINE1, CCN2, and MMP7 expression, reduced SMAD2 nuclear translocation, and decreased hydroxyproline levels. ConclusionsPresence of an AKAP13 variant disrupts epithelial homeostasis and promotes pro-fibrotic signalling. Inhibition of AKAP13s RhoGEF domain with A13 restores epithelial function and attenuates fibrotic activation, supporting AKAP13 as a therapeutic target in IPF.

genetics↗

bioRxiv2025

Discernibility in explanations: an approach to designing more acceptable and meaningful machine learning models for medicine

BackgroundAlthough the benefits of machine learning (ML) are undeniable in health-care, explainability plays a vital role in improving transparency and understanding the most decisive and persuasive variables for prediction. The challenge is to identify explanations that make sense to the biomedical expert. This work proposes discernibility as a new approach to faithfully reflect human cognition, with the users perception of a relationship between explanations and data for a given variable. MethodsA total of 50 participants (19 biomedical and 31 data scientists) evaluated their perception of the discernibility of explanations from both synthetic and human-based dataset (National Health and Nutrition Examination Survey). The inter-rater reliability was tested through the intraclass correlation coefficient (ICC). 13 statistical coefficients were considered to be able to capture for a given variable the relationship between its values and its explanations. A Passing-Bablok regression was performed for each user to highlight the consistency between user rating and each coefficient. FindingsThe low inter-rater reliability of discernibility (ICC{inverted exclamation}0.5) with no difference between areas of expertise or level of education underlines the need for an objective metric of discernibility. Among all evaluated metrics, dcor metric was found to be the most suitable to capture the intra-individual reliability of discernibility perceived by users (median slope closer to 1 and a narrower confidence interval width for the Passing-Bablok regression with the lowest differential bias between the most and least discernible values). Interpretationdcor was shown to be a reliable metric for assessing the discernibility of explanations, effectively capturing the clarity of the relationship between the data and their explanations, and providing clues to the underlying pathophysiological mechanisms that are not immediately apparent when examining individual predictors. Discernibility can also serve as an evaluation metric for model quality, used to prevent overfitting or aid in feature selection, providing medical practitioners with more accurate and persuasive results.

bioinformatics↗

bioRxiv2025

Genomic Insights into the Diversity, Antimicrobial Resistance, and Zoonotic Potential of Campylobacter fetus Across Diverse Hosts and Geographies

BackgroundCampylobacter fetus causes reproductive diseases in livestock and zoonotic infections in humans, especially in immunocompromised individuals. Despite its significance, its genomic characteristics are poorly understood. This study analyzed 114 publicly available C. fetus genomes to provide global insights into its genetic diversity, antimicrobial resistance (AMR) patterns, and zoonotic risk. ResultsA total of 32 distinct sequence types (STs), ranging from ST-1 to ST-74, were identified across 111 of the 114 C. fetus genomes, spanning six continents and diverse hosts (cattle, humans, sheep, and reptiles). ST-4 was the most prevalent (n = 45), followed by ST-3 (n = 8). A significant proportion (90.9%; n/N=40/44) of C. fetus subsp. venerealis (Cfv) and its biovar intermedius (Cfvi) were assigned to ST-4. Despite being isolated from five continents, Cfv and Cfvi genomes clustered closely, forming distinct branches at the biovar level; however, six Cfv genomes were located within Cfvi clades, suggesting a shared evolutionary lineage. In contrast, C. fetus subsp. testudinum (Cft) genomes, exhibiting 20 distinct STs, formed distinct clades from Cfv, Cfvi, and C. fetus subsp. fetus (Cff). While Cfv genomes from North America and Cfvi genomes from South America formed distinct geographic clusters, Cff genomes displayed no clear geographical patterns, with branches containing strains from multiple continents, indicating a globally dispersed distribution. Pangenomic analysis revealed pronounced clustering within Cft, characterized by unique gene presence/absence patterns. Five distinct AMR genes were detected, with tet(O) (n = 3) being the most common. Horizontal gene transfer analysis identified 140 genomic islands across 41 genomes, and virulence factor analysis revealed cheY as the sole conserved virulence gene across 35 genomes. ConclusionThese findings provide critical insights into the genomic diversity, zoonotic potential, and global distribution of C. fetus, emphasizing the need for integrated genomic and epidemiological strategies to assess its impact on human and animal health.

genomics↗

bioRxiv2024

RasGRP1 Signalling Programs Developing γδ-Thymocytes towards the γδT17 Lineage Through Control of c-Maf Expression

The {gamma}{delta} TCR instructively directs both lineage specification and effector programming of developing {gamma}{delta} T cells. However, the manner in which different TCR signal strengths and other auxiliary signals coordinate downstream of the {gamma}{delta} TCR to regulate {gamma}{delta} T cell development remains unclear. In this study we characterized the role of Ras guanyl-releasing protein 1 (RasGRP1) in the development and effector programming of {gamma}{delta} T cells. While RasGRP1 was not necessary for bulk {gamma}{delta} T cell generation, we found it required for efficient generation of V{gamma}4+ thymocytes, and lineage-committed CD73+ {gamma}{delta} T cells in the thymus and periphery. Despite a decrease in immature CD73+ {gamma}{delta} thymocytes, we report an expansion of the perinatal wave of CD8+IFN{gamma}+ {gamma}{delta} T cell population in the absence of RasGRP1. IL-17 producing {gamma}{delta} T cells were significantly reduced in RasGRP1 KO mice, with a specific loss of V{gamma}2+ {gamma}{delta} T cells that corresponds to a loss of c-Maf expression as early as the DN1d thymocyte stage. Critically, these adult-programmed {gamma}{delta}T17s could express c-Maf in response to CCR9 stimulation, with RasGRP1 being required for CCR9-induced c-Maf expression. Thus, RasGRP1 activation serves as an important signalling hub in the effector programming of {gamma}{delta} T cells, which integrates signals from both non-TCR and TCR inputs to direct differentiation.

immunology↗

bioRxiv2024

Multiscale single-cell assessment of the fibrotic niche in idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease characterised by excessive extracellular matrix deposition within the lung. Recent advances in single-cell RNA sequencing have identified distinct fibrotic populations, yet their origins and spatial relationships remain incompletely understood. MethodsUsing spatial transcriptomics and Hyperion imaging mass cytometry we compared the cellular composition in formalin fixed paraffin embedded fibrotic lesions (n=9 patients) with control lung (n=9), and cellular interactions were inferred using CellChat V2 ligand-receptor analysis. Monolayers of airway epithelial cells were used to identify changes in keratin (KRT) expression following cell detachment and cyclical mechanical stretch. ResultsSpatial multiomics profiling of human lung cells confirmed the in situ localisation of previously described IPF-enriched populations, and identified a previously unrecognized KRT5low/KRT17 epithelial population derived from airway basal cells that progressively acquiring molecular features of aberrant basaloid cells, forming a unique fibrotic niche enriched with the Secreted Phosphoprotein 1 (SPP1) positive macrophages. Functional studies demonstrated that epithelial detachment and cyclical mechanical stretch drive KRT5 reduction, providing a mechanism for the emergence of this transitional state. In addition, we also identified distinct immune-stromal niches enriched in lymphocytes and alveolar fibroblasts. ConclusionThese findings delineate distinct fibrotic epithelial niches in IPF and support a model in which epithelial loss induces aberrant basaloid differentiation and fibroblast activation, with subsequent airway traction and epithelial detachment generating a secondary niche enriched in basal-derived KRT5low/KRT17 cells and SPP1 macrophages.

molecular biology↗

bioRxiv2024

Internal regulation between constitutively expressed T cell coinhibitory receptors BTLA and CD5 and tolerance in recent thymic emigrants

Several coinhibitory receptors are upregulated upon activation, whereas a small number of coinhibitory receptors are expressed constitutively by naive T cells. The relationship between constitutively expressed coinhibitors is unknown. We found an inverse relationship between two constitutively expressed coinhibitors, CD5 and BTLA; BTLA expression was low in the thymus and high in the periphery, corresponding respectively with high and low CD5 expression. Germline or induced deletion of Btla in somatic cells demonstrated a causal relationship between BTLA expression and CD5 levels in T cells of central and peripheral lymphoid tissues. The effect of BTLA on CD5 expression on thymic and peripheral CD4 T cells was due to BTLA signaling, rather than signaling by its ligand, the herpes virus mediator (HVEM). Regulation was maintained in mice with a non-signaling HVEM mutant but was lost in Tnfrsf14-/- (Hvem-/-) mice. Increased CD5 levels have been positively associated with increased recognition of self-peptide MHC complexes. Thus, control of CD5 expression by BTLA signals early in T cell ontogeny suggested that BTLA might be important for establishing self-tolerance in newly generated T cells. Consistent with this concept, we found that BTLA, as well as the inducible coinhibitor PD-1, were needed post thymic selection in recent thymic emigrants (RTE) to establish self-tolerance. RTE lacking BTLA caused a multiorgan autoimmune disease whose development required CD4 T cells and MHC class II. Together, our findings identify a negative regulatory pathway allowing constitutively expressed coinhibitory receptors to calibrate their expression in thymic T cell differentiation. Expression of constitutive and induced coinhibitory receptors is needed to establish tolerance in the periphery for RTE.

immunology↗

bioRxiv2022

Moderate ART resistance mutations with low fitness cost in malaria parasites from Africa

Reduced susceptibility to ART, the first-line treatment against malaria, is common in South East Asia (SEA). It is caused by point mutations, mostly in kelch13 (k13) but also in other genes, like upb1. K13 and its compartment neighbors (KICs), including UBP1, are involved in endocytosis of host cell cytosol. We tested 135 mutations in KICs but none conferred ART resistance. Double mutations of k13C580Y with k13R539T or k13C580Y with ubp1R3138H, did also not increase resistance. In contrast, k13C580Y parasites subjected to consecutive RSAs did, but the k13 sequence was not altered. Using isogenic parasites with different k13 mutations, we found correlations between K13 protein amount, resistance and fitness cost. Titration of K13 and KIC7 indicated that the cellular levels of these proteins determined resistance through the rate of endocytosis. While fitness cost of k13 mutations correlated with ART resistance, ubp1R3138H caused a disproportionately higher fitness cost. SignificanceART resistance is only a partial resistance with a proportion of ring stages surviving physiological ART levels. The correlation of resistance with fitness cost in isogenic lines indicates that fitness cost likely prevents resistance levels permitting survival of all ring stages under physiological ART concentrations. We also found no indication that double mutations in k13, including the two most common resistance mutations in SEA, or with non-k13 genes, are a threat to lead to higher resistance. However, repeated ART exposure increased resistance by mechanisms not altering k13 gene sequence, indicating changes in the background of these parasites. The disproportionally high fitness cost of ubp1R3138H may explain why kic mutations affecting resistance are rare and highlights the unique property of K13 to influence endocytosis only in ring stages.

cell biology↗

bioRxiv2021

Prefrontal cortex neural compensation during an operant devaluation task

Deficits in goal-directed action are reported in multiple neuropsychiatric conditions, including schizophrenia. However, dysfunction is not always apparent in early stages of schizophrenia, possibly due to neural compensation. We designed a novel devaluation task in which goal-directed action could be guided by stimulus-outcome (S-O) [presumably orbitofrontal cortex (OFC)-mediated] or response-outcome (R-O) associations [presumably prelimbic cortex (PL)-mediated]. We previously found suggestive evidence that OFC and PL could compensate for each other in this task, and we more directly assessed this potential compensation here. In Experiment 1, rats received OFC, PL, combined OFC+PL, or sham lesions and then completed our devaluation task. The OFC+PL lesion group exhibited impaired devaluation. In Experiment 2, rats received cholera-toxin-b (CTb) into OFC and either neurotoxic or sham PL lesions. Rats were then sacrificed on the last training day to double-label for Arc and CTb. We found increased Arc+CTb in mediodorsal thalamus (MD) and increased Arc+ neurons in OFC when PL was lesioned, suggesting that PL lesions lead to a compensatory increased activation of the MD[->]OFC circuit. Our results suggest that our devaluation task can model neural compensation between OFC and PL and this compensation may be regulated by MD. Significance StatementTo detect compensatory responses, behavioral models that use different strategies must be developed to determine if the strategies shift when a brain area or circuit is incapacitated. Neural compensation is commonly observed in human research but only a few models of neural compensation exist, and few identify compensation within the prefrontal cortex. This research is among the first to show neural compensation between prefrontal cortex regions and implicate a thalamocortical circuit in modulating this compensation. Not only will this model provide a way to behaviorally identify subtle neurological shifts, it can also elucidate basic neurological mechanisms that mediate how circuits interact with each other and how dysfunction in one circuit can affect connectivity in other brain areas.

neuroscience↗

bioRxiv2020

The genomic epidemiology of multi-drug resistant nontyphoidal Salmonella causing invasive disease in sub-Saharan Africa

BackgroundInvasive nontyphoidal Salmonella (iNTS) is one of the leading causes of bacteraemia in sub-Saharan Africa. Multi-drug resistance (MDR) and further resistance to third generation cephalosporins and fluoroquinolones have emerged in multiple iNTS serotypes. Molecular epidemiological investigations of nontyphoidal Salmonella are needed to better understand the genetic characteristics and transmission dynamics associated with major MDR iNTS serotypes across the continent. MethodsA total of 166 nontyphoidal Salmonella isolates causing invasive disease were collected from a multi-centre study in eight African countries between 2010 and 2014, and whole-genome sequenced to investigate the geographical distribution, antimicrobial genetic determinants and population structure of iNTS serotypes-genotypes. Phylogeographical reconstruction was further conducted in context of the existing genomic framework of iNTS serotypes Typhimurium and Enteritidis. Population-based incidence of MDR-iNTS disease was also estimated. ResultsSalmonella enterica subsp. Enterica serotype Typhimurium (S. Typhimurium) sequence-type (ST) 313 and Salmonella enterica subsp. Enterica serotype Enteritidis (S. Enteritidis) ST11 were predominant, and both exhibited high frequencies of MDR. Salmonella enterica subsp. Enterica serotype Dublin (S. Dublin) ST10 emerged in West Africa. Mutations in the gyrA gene were identified in S. Enteritidis and S. Typhimurium in Ghana; and ST313 carrying blaCTX-M-15 was found in Kenya. Inter-country transmission of MDR ST313 lineage II and the West African Clade of MDR ST11 between Ghana and neighbouring countries including Mali, Burkina Faso, and Nigeria were evident. The incidence of MDR-iNTS disease exceeded 100/100,000-person years-of-observation (PYO) in children aged <5 years in several West African countries. ConclusionsMultiple MDR iNTS serotypes-sequence types, predominantly S. Typhimurium ST313 and S. Enteritidis ST11, are co-circulating in sub-Saharan Africa with evidence of transmission between West African countries. The development of safe and effective iNTS vaccines coupled with appropriate antimicrobial stewardship and adequate epidemiological monitoring are essential to limit the impact of these pathogens in Africa.

genomics↗

bioRxiv2020

Ebselen Exhibits Antimicrobial Activity Against Clostridioides difficile By Disrupting Redox Associated Metabolism

High recurrence rates and spread of antibiotic-resistant strains necessitate the need for alternative therapeutics for Clostridioides difficile infections (CDIs). Ebselen, a reactive organoselenium compound inhibits C. difficile virulence toxins TcdA and TcdB, by covalently binding to their cysteine protease domains. Ebselen is thought to lack antibacterial activity against C. difficile cells and its anti-toxin action is suggested to be solely responsible for its efficacy. However, C. difficile has several essential cysteine-containing enzymes that could be potential sites for covalent modification by ebselen; hence, we re-evaluated its anti-C. difficile properties. In BHI agar, ebselen inhibited almost all C. difficile strains (MICs of 2-8 {micro}g/ml), with ribotype 078 being intrinsically resistant (MIC>64 {micro}g/ml). Wilkins-Chalgren and Brucella agars are recommended media for anaerobic susceptibility testing. Ebselen was either slightly attenuated by pyruvate found in Wilkins-Chalgren agar or obliterated by blood in Brucella agars. Transcriptome analysis showed ebselen altered redox-associated processes, cysteine metabolism and significantly enhanced the expression of Stickland proline metabolism to likely regenerate NAD+ from NADH. Intracellularly cells increased the uptake of cysteines, depleted non-protein thiols and disrupted NAD+/NADH redox ratio. Growth inhibitory concentrations of ebselen also reduced toxin and spore production. Taken together, ebselen has bactericidal activity against C. difficile, with multiple mechanisms of action that negatively impacts toxin production and sporulation. To harness the polypharmacological properties of ebselen, chemical optimization is warranted, especially to obtain derivatives that could be effective in severe CDI, where intestinal bleeding could occur.

microbiology↗