Biology subjects

West, K. A.

Publications and source records attributed to West, K. A..

5 recordsLinked to original sources

bioRxiv2026

Multi-Omic Dissection of Autism Reveals Dominant Effects of Family, Sex, and Host-Microbe Metabolic Interactions

Autism spectrum disorder (ASD) has been associated with gut microbiome and metabolic alterations, but reported biomarkers are inconsistent and often inadequately account for family and shared environment. We analysed 620 children, including 334 with ASD and 286 neurotypical siblings, with a median age of 6.0 years (IQR 4.0-8.0). Faecal and urine samples were collected monthly up to eight times. After quality control, 869 microbiome, 754 faecal metabolome and 787 urine metabolome samples were analysed using 16S rRNA sequencing, NMR and LC-MS metabolomics. Mixed models accounted for family, repeated sampling and biological sex. Family membership explained 46.1% of variation across microbiome and metabolome profiles, compared with 8.0% attributable to ASD. After family adjustment, ASD explained only 0.1% to 0.3% of microbiome beta diversity. No stable taxonomic biomarkers were identified, and microbial classification was poor (AUROC <0.75). Urinary metabolomics identified elevated 5-hydroxy-L-tryptophan and altered phenylalanine metabolism. Structural equation modelling found no direct associations between selected taxa and metabolites. These findings argue against a universal ASD microbiome and indicate that family context contributes more strongly than diagnosis to microbial and metabolic variation.

microbiology↗

bioRxiv2026

TIMS-Bench: Towards community standards for benchmarking untargeted trapped ion mobility metabolomics tools and datasets

Untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics is an important technology for unbiased discovery of small molecules in biomedical (e.g., drug discovery to diagnostics), animal, plant, environmental, and microbial research. Over the past decade, ion mobility has added an additional dimension to the triplet of MS1, MS2, and retention time, helping resolve co-eluting or isomeric features in an LC-MS/MS that aid in compound identification. Here, we focused on evaluating the current trapped ion mobility spectrometry (TIMS)-amenable feature-finding tools (MZmine 4.9, MS-DIAL 5.5, and MetaboScape 2025 14.0.3) for pre-processing of metabolomics data generated using a popular ion mobility mass spectrometry (IM-MS) technique, TIMS. We leveraged ten public and three benchmark TIMS datasets to evaluate these tools for their strengths and weaknesses. Our results show that MZmine consistently identified the highest number of features and confidently annotated features; however, this performance was accompanied by an increased number of false positives, due to peak splitting, as well as reduced accuracy in collision cross section (CCS) measurements. In contrast, MetaboScape achieved the highest fraction of high-quality MS2 spectra, reflecting a more conservative feature detection strategy. MS-DIAL demonstrated balanced performance, identifying features that other tools missed. Finally, we publicly release the ground-truth datasets and code to support future developments in improving IMS data analysis.

bioinformatics↗

bioRxiv2024

Malat1 regulates female Th2 cell cytokine expression through controlling early differentiation and response to IL2

Identifying cell intrinsic regulators of immune sexual dimorphism is critical for treatment of several immunopathologies. We show that Malat1 is required for appropriate cytokine expression in female but not male Th2 cells. Malat1 deficiency impairs in vitro Th2 differentiation of naive CD4+ T cells from female mice, characterised by transcriptome-wide effects and suppression of cytokine expression, particularly IL10. Upon IL10R blockade a pronounced effect is also seen on IL4 and IL13. Mechanistically, naive CD4+ T cells from Malat1-/- female mice demonstrate altered early activation kinetics and impaired early differentiation gene expression, including up-regulation of an interferon stimulated gene (ISG) module. This is followed by suppression of IL2R and IL2R{gamma} expression and IL2-mediated differentiation. Mimicking the effect of Malat1 loss by maintaining early ISG expression in WT cells with IFN{beta} treatment partially phenocopies the effects of Malat1 deficiency. A subset of the effects of Malat1 loss in female cells is also observed in male cells. However, this does not affect endpoint Th2 differentiation. Male CD4+ T cells demonstrate stronger early activation, higher ISG expression during early differentiation, maintenance of IL2R expression independently of Malat1, and lower sensitivity to exogenous IL2 during late differentiation compared to female cells. In vivo, female, but not male, Malat1-/- mice demonstrate altered Th2 cytokine expression characterised by a reduction in IL10+ Th2 cells in both lung and spleen following priming and challenge with Schistosoma mansoni eggs, a model of lung type 2 inflammation. Overall, these findings reveal Malat1 as a novel determinant of immune sexual dimorphism.

immunology↗

bioRxiv2024

Hypoxia-Inducible Factor-1 activated by PIM1 assembles a non-canonical transcription complex and resultant regulon that drives progression of JAK2V617F myeloproliferative neoplasms

Hypoxia-inducible factors (HIFs) are master transcriptional regulators, central to cellular survival under limited oxygen (hypoxia) and frequently activated within malignancy. Malignant context affects the role of HIFs within oncogenesis; however, the mechanisms regulating HIF context-specificities are not well characterised. Applying the JAK2V617F (JVF) model of myeloproliferative neoplasms (MPNs), in which HIF-1 is active in normoxia (20% O2), we sought to determine whether the modality of HIF-1 activation directs its function. We identify that HIF-1 is stabilised in JVF cells downstream of STAT1/5 signalling and upregulation of PIM1: PIM1 mediates phosphorylation of HIF-1 (Thr498/Ser500) in JVF cells that inhibits proteasomal degradation. PIM1 inhibition eradicates HIF-1 from JVF cells. Applying a single-input dual-omics output chromatin interactome methodology (DOCIA), we define JVF-specific transcription cofactors and genomic redistribution of HIF-1, and a JVF-HIF-1 regulon in primary haematopoietic stem/progenitor cells. In a cohort of 172 JVF-MPN patients, we observe significant association of the JVF-HIF-1 regulon (but strikingly, not canonical HIF-1 genes) with disease severity, progression, and patient survival. Finally, we identify a core set of JVF-HIF-1 targets significantly associated with spontaneous transformation of MPNs to AML. Our findings identify that HIF-1 activation by the JVF-PIM1 axis substantially alters its function, and that this reprogramming drives MPN disease progression, restoring the potential for targeted therapies that delineate HIF-1 activity co-opted by malignancy from essential roles within physiological oxygen homeostasis. Key PointsO_LIHIF-1 activation via PIM1 in JAK2V617F-MPNs drives non-canonical transcription complex formation/function. C_LIO_LIThe JAK2V617F-HIF-1 regulon drives MPN disease progression, transformation to AML and worse patient outcomes. C_LI

cancer biology↗

bioRxiv2021

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

To date severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease 2019 (COVID-19) including two novel mRNA-based vaccines1,2. These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies is not known3-6. Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines. Consistent with prior reports, 8 weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti-SARS-CoV-2 spike protein (S) and receptor binding domain (RBD) binding titers3,5,6. Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection7,8. However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes in common with mAbs isolated from infected donors. Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD antibodies. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy.

immunology↗