Biology subjects

McMahon, A.

Publications and source records attributed to McMahon, A..

16 recordsLinked to original sources

bioRxiv2026

First detected incursions of avian influenza H5N1 clade 2.3.4.4b into mainland Australia from the Southern Ocean

High pathogenicity avian influenza H5N1 clade 2.3.4.4b has caused a panzootic of devastating impact to poultry and wildlife globally. The Australian continent and broader Oceania until recently remained the last major region without confirmed detections. Here we report the first H5N1 clade 2.3.4.4b detections from two live seabirds - a brown skua and a southern giant petrel - found on the south coast of Western Australia in June 2026. Virus genome sequencing showed that both viruses were most closely related to H5N1 viruses detected recently on sub-Antarctic islands in the Southern Indian Ocean. In time-calibrated phylogeographic analyses, both viruses sampled in Western Australia clustered with viruses from Heard Island, a sub-Antarctic external territory of Australia. Ancestral location reconstruction also identified Heard Island as the most probable source location, although unsampled intermediate locations cannot be excluded. The two Western Australian detections were estimated to be independent incursions from Heard Island, rather than local transmission on mainland Australia. There was no evidence of reassortment with endemic avian influenza viruses in Australia, and both virus sequences retained key avian-like genetic markers and lacked known substitutions for reduced antiviral susceptibility. These detections revealed a Southern Ocean pathway of recurrent H5N1 incursions into Australia, highlighting the risk of potential establishment on the mainland and the need for heightened surveillance and rapid, nationally-coordinated, virus genomic characterisation.

microbiology↗

bioRxiv2026

Predicted Effector Gene Aggregation, Standards and Unified Schema (PEGASUS): A Community Framework for Effector Gene Reporting

Genome-wide association studies (GWAS) increasingly report predicted effector genes (PEGs) - genes hypothesised to mediate the biological effects of associated variants. These function as key outputs for advancing variant-to-function research, mechanistic understanding, and therapeutic discovery. However, the rapid growth of PEG lists has not been matched by standards for organising, annotating, and reporting these predictions. As shown by recent landscape analyses, PEG lists vary widely in methodology, evidence definition, nomenclature, provenance tracking, and data structure, limiting interoperability, benchmarking, reuse, and adherence to FAIR principles. To address this gap, we convened an international multi-stakeholder community comprising method developers, data generators, resource maintainers, curators, funders, journal editors, and downstream users. Through a 2024 workshop and a 2025 working group series, we developed the Predicted Effector Gene Aggregation, Standards and Unified Schema (PEGASUS) framework. PEGASUS specifies (i) a metadata standard to capture provenance, trait and GWAS descriptors, evidence sources, and integration methods; (ii) a structured evidence matrix reporting all genes and all evidence underpinning prioritisation at each locus; and (iii) a concise PEG list that summarises author-prioritised genes linked transparently to underlying evidence. The framework balances transparency, machine readability, burden on submitters, and alignment with existing community standards. PEGASUS provides the first community-developed schema for reporting predicted effector genes and their supporting evidence. Adoption of this framework by authors will improve the comparability, reproducibility, and reusability of PEG outputs across studies, facilitating more robust biological inference, enabling cross-resource comparison of gene-prioritisation methods to support community benchmarking, and integration into downstream resources and analytical pipelines. PEGASUS-compliant data can be shared via the PEG Data Registry platform (https://kpndataregistry.org/peg), promoting re-use and establishing the basis for future integration with publicly shared GWAS data.

genomics↗

bioRxiv2026

Dissecting the coordinated progression of cell states in spatial transcriptomics with CoPro

Spatial transcriptomics enables the study of how cells coordinate their molecular states within tissue, providing insight into both normal function and disease processes. A key challenge is to identify gene expression programs that vary continuously across space and are coordinated between cell types. We present CoPro, a computational framework for detecting the spatially coordinated progression of cellular states. CoPro can operate in both supervised and unsupervised modes to identify gene programs that co-vary within or between cell types, and to disentangle multiple overlapping spatial patterns. CoPro can be applied to single-cell-level spatial transcriptomics datasets, including MERFISH, SeqFISH+, Xenium, and histology-imputed transcriptomic data. We demonstrate the utility of CoPro with data collected from colon, brain, liver, and kidney tissues. In the colon, CoPro separates epithelial differentiation along the crypt axis from spatially localized inflammatory signals. In the aging liver, it identifies multiple aging-associated cellular programs superimposed on anatomical zonation. In the brain, the flexible kernel design enables the decoupling of the gene expression gradient along the dorsal-ventral and medial-lateral axes. In the kidney, CoPro identifies tubule-vasculature coordination that is essential in nephron function. These results demonstrate CoPros utility for analyzing spatial coordination of gene expression in complex tissues and disentangling overlapping biological processes, such as anatomical organization and disease-associated variation.

bioinformatics↗

bioRxiv2026

Dyrk1a inhibition with the Novel Compound DYR533: A Cross-Disease Therapeutic Strategy Targeting Amyloidosis, Tau Pathogenesis, and Neuroinflammation

Alzheimers disease (AD) and related dementias are rapidly increasing in prevalence, yet disease-modifying therapies remain largely focused on amyloid-{beta} (A{beta}) with limited efficacy against tau pathology and neuroinflammation--key drivers of neurodegeneration and clinical decline. Dual-specificity tyrosine-phosphorylation-regulated kinase 1a (Dyrk1a) phosphorylates tau and amyloid precursor protein and regulates inflammatory signaling, positioning it as a convergence point across pathogenic pathways. We show that brain Dyrk1a protein levels are consistently elevated across ADRDs, replicating findings in AD, confirming prior observations in Picks disease, and demonstrating dysregulation in corticobasal degeneration and progressive supranuclear palsy. We developed DYR533, a selective, orally bioavailable, brain-penetrant Type 1 Dyrk1a kinase inhibitor that also inhibits autophosphorylation and reduces kinase abundance. Across three mouse models (3xTg-AD, PS19, Ts65Dn), DYR533 reduced pathological tau hyperphosphorylation, attenuated neuroinflammation, ameliorated amyloidosis, and improved anxiety-like behavior and spatial memory, collectively supporting Dyrk1a inhibition and DYR533 as a therapeutic strategy for ADRD.

neuroscience↗

bioRxiv2026

Isothermal Detection of Influenza D using RT-LAMP

The Orthomyxoviridae family includes influenza D virus (IDV), an emerging pathogen primarily affecting cattle and swine, with evidence of cross-species transmission and potential zoonotic risk. Although active human infections have yet to been confirmed, high seroprevalence in cattle-exposed populations highlights the need for continued surveillance. Here, a rapid, field-deployable RT-LAMP assay for IDV detection was developed and validated, with 99.2% specificity and sensitivity ranging from 95.6% (Cq < 30) to 81.8% (Cq < 40). This method offers a cost-effective, accessible alternative to RT-qPCR, enabling improved monitoring of IDV, and reinforcing preparedness for emerging influenza threats.

microbiology↗

bioRxiv2025

NeuroDISK: An AI Approach to Automate Continuous Inquiry-Driven Discoveries in Neuroimaging Genetics

Collaborative and multi-site neuroimaging studies have greatly accelerated the rate at which new and existing data can be aggregated to answer a neuroscientific question. New research initiatives are continuously collecting more data, allowing opportunities to refine previous published findings through continuous and dynamic updates. Yet, we lack a practical framework for researchers to systematically, automatically, and continuously update published findings. We developed NeuroDISK, an automated artificial intelligence based framework that: 1) performs automated and inquiry-driven analyses, and 2) continuously updates these analyses as new data becomes available. NeuroDISK was evaluated using published results from the ENIGMA consortiums work on the genetic architecture of the cerebral cortex. We incorporate both meta-analysis and meta-regression options to showcase our framework on the effect of specific genotypes and moderators on select brain regions. Initial NeuroDISK meta-analysis results replicate the original publication, and we show result updates after adding new data. The NeuroDISK framework can be generalized for users to define question(s), run corresponding workflow(s) and access results interactively and continuously.

bioinformatics↗

bioRxiv2024

Improving GWAS performance in underrepresented groups by appropriate modeling of genetics, environment, and sociocultural factors

Genome-wide association studies (GWAS) and polygenic score (PGS) development are typically constrained by the data available in biobank repositories in which European cohorts are vastly overrepresented. Here, we increase the utility of non-European participant data within the UK Biobank (UKB) by characterizing the genetic affinities of UKB participants who self-identify as Bangladeshi, Indian, Pakistani, "White and Asian" (WA), and "Any Other Asian" (AOA), towards creating a more robust South Asian sample size for future genetic analyses. We assess the relationships between genetic structure and self-selected ethnic identities and use consistent patterns of clustering in the dataset to train a support vector machine (SVM). The SVM was utilized to reassign n = 1,853 AOA and WA participants at the subcontinental level, and increase the sample size of the UKB South Asian group by 1,381 additional participants. We further leverage these samples to assess GWAS performance and PGS development. We include environmental covariates in the height GWAS by implementing a rigorous covariate selection procedure, and compare the outputs of two GWAS models: GWASnull and GWASenv. We show that PGS performance derived from both GWAS models yield comparable prediction to PGS models developed with an order of magnitude larger training, and environmentally-adjusted PGS models reduce the sex-bias in predictive performance. In summary, we demonstrate how GWAS performance can be improved by leveraging ambiguous ethnicity codes, ancestry matched imputation panels, and including environmental covariates.

genetics↗

bioRxiv2024

The NHGRI-EBI GWAS Catalog: standards for reusability, sustainability and diversity

The NHGRI-EBI GWAS Catalog serves as a vital resource for the genetic research community, providing access to the most comprehensive database of human GWAS results. Currently, it contains close to 7,000 publications for more than 15,000 traits, from which more than 625,000 lead associations have been curated. Additionally, 85,000 full genome-wide summary statistics datasets - containing association data for all variants in the analysis - are available for downstream analyses such as meta-analysis, fine-mapping, Mendelian randomisation or development of polygenic risk scores. As a centralised repository for GWAS results, the GWAS Catalog sets and implements standards for data submission and harmonisation, and encourages the use of consistent descriptors for traits, samples and methodologies. We share processes and vocabulary with the PGS Catalog, improving interoperability for a growing user group. Here, we describe the latest changes in data content, improvements in our user interface, and the implementation of the GWAS-SSF standard format for summary statistics. We address the challenges of handling the rapid increase in large-scale molecular quantitative trait GWAS and the need for sensitivity in the use of population and cohort descriptors while maintaining data interoperability and reusability.

genetics↗

bioRxiv2024

Mechanistic insights into the activity of SARS-CoV-2 RNA polymerase inhibitors using single-molecule FRET

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has resulted in significant global mortality and disruption. Despite extensive research, the precise molecular mechanisms underlying SARS-CoV-2 replication remain unclear. To address this, we developed a single-molecule Forster resonance energy transfer (smFRET) assay to directly visualize and analyse in vitro RNA synthesis by the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We purified the minimal replication complex, comprising nsp12, nsp7, and nsp8, and combined it with fluorescently labelled RNA substrates, enabling real-time monitoring of RNA primer elongation at the single-molecule level. This platform allowed us to investigate the mechanisms of action of key inhibitors of SARS-CoV-2 replication. In particular, our data provides evidence for remdesivirs mechanism of action, which involves polymerase stalling and subsequent chain termination dependent on the concentration of competing nucleotide triphosphates. Our study demonstrates the power of smFRET to provide dynamic insights into SARS-CoV-2 replication, offering a valuable tool for antiviral screening and mechanistic studies of viral RdRp activity.

microbiology↗

bioRxiv2023

Cadherin Adhesion Complexes Direct Cell Aggregation in the Epithelial Transition of Wnt-Induced Nephron Progenitor Cells

In the developing mammalian kidney, nephron formation is initiated by a subset of nephron progenitor cells (NPCs). Wnt input activates a {beta}-catenin (Ctnnb1)-driven, transcriptional nephrogenic program. In conjunction, induced mesenchymal NPCs transition through a pre-tubular aggregate to an epithelial renal vesicle, the precursor for each nephron. How this critical mesenchymal-to-epithelial transition (MET) is regulated is unclear. In an in vitro mouse NPC culture model, activation of the Wnt pathway results in the aggregation of induced NPCs into closely-packed, cell clusters. Genetic removal of {beta}-catenin resulted in a failure of both Wnt pathway-directed transcriptional activation and the formation of aggregated cell clusters. Modulating extracellular Ca2+ levels showed cell-cell contacts were Ca2+-dependent, suggesting a role for cadherin (Cdh)-directed cell adhesion. Molecular analysis identified Cdh2, Cdh4 and Cdh11 in uninduced NPCs and the up-regulation of Cdh3 and Cdh4 accompanying the Wnt pathway-induced MET. Genetic removal of all four cadherins, and independent removal of -catenin, which couples Cdh-{beta}-catenin membrane complexes to the actin cytoskeleton, abolished cell aggregation in response to Wnt pathway activation. However, the {beta}-catenin driven inductive transcriptional program was unaltered. Together with the accompanying paper (Bugacov et al., submitted), these data demonstrate that distinct cellular activities of {beta}-catenin - transcriptional regulation and cell adhesion - combine in the mammalian kidney programs generating differentiated epithelial nephron precursors from mesenchymal nephron progenitors. Summary statementOur study highlights the role of Wnt-{beta}-catenin pathway regulation of cadherin-mediated cell adhesion in the mesenchymal to epithelial transition of induced nephron progenitor cells.

developmental biology↗

bioRxiv2023

Canonical Wnt transcriptional complexes are essential for induction of nephrogenesis but not maintenance or proliferation of nephron progenitors

Wnt regulated transcriptional programs are associated with both the maintenance of mammalian nephron progenitor cells (NPC) and their induction, initiating the process of nephrogenesis. How opposing transcriptional roles are regulated remain unclear. Using an in vitro model replicating in vivo events, we examined the requirement for canonical Wnt transcriptional complexes in NPC regulation. In canonical transcription, Lef/Tcf DNA binding proteins associate the transcriptional co-activator {beta}-catenin. Wnt signaling is readily substituted by CHIR99021, a small molecule antagonist of glycogen synthase kinase-3{beta} (GSK3{beta}). GSK3{beta} inhibition blocks Gsk{beta}-dependent turnover of {beta}-catenin, enabling formation of Lef/Tcf/{beta}-catenin transcriptional complexes, and enhancer-mediated transcriptional activation. Removal of {beta}-catenin activity from NPCs under cell expansion conditions (low CHIR) demonstrated a non-transcriptional role for {beta}-catenin in the CHIR-dependent proliferation of NPCs. In contrast, CHIR-mediated induction of nephrogenesis, on switching from low to high CHIR, was dependent on Lef/Tcf and {beta}-catenin transcriptional activity. These studies point to a non-transcriptional mechanism for {beta}-catenin in regulation of NPCs, and potentially other stem progenitor cell types. Further, analysis of the {beta}-catenin-directed transcriptional response provides new insight into induction of nephrogenesis. Summary StatementThe study provides a mechanistic understanding of Wnt/ {beta}-catenin activity in self-renewal and differentiation of mammalian nephron progenitors.

developmental biology↗

bioRxiv2023

Direct androgen receptor regulation of sexually dimorphic gene expression in the mammalian kidney

Mammalian organs exhibit distinct physiology, disease susceptibility and injury responses between the sexes. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments. Bulk RNA-seq data demonstrated sex differences were established from 4 and 8 weeks after birth under gonadal control. Hormone injection studies and genetic removal of androgen and estrogen receptors demonstrated androgen receptor (AR) mediated regulation of gene activity in PT cells as the regulatory mechanism. Interestingly, caloric restriction feminizes the male kidney. Single-nuclear multiomic analysis identified putative cis-regulatory regions and cooperating factors mediating PT responses to AR activity in the mouse kidney. In the human kidney, a limited set of genes showed conserved sex-linked regulation while analysis of the mouse liver underscored organ-specific differences in the regulation of sexually dimorphic gene expression. These findings raise interesting questions on the evolution, physiological significance, and disease and metabolic linkage, of sexually dimorphic gene activity.

developmental biology↗

bioRxiv2022

APE1 assembles biomolecular condensates to promotethe ATR-Chk1 DNA damage response in nucleolus

Multifunctional protein APE1/APEX1/HAP1/Ref-1 (designated as APE1) plays important roles in nuclease-mediated DNA repair and redox regulation in transcription. However, it is unclear how APE1 regulates the DNA damage response (DDR) pathways and influences genome integrity directly or indirectly. Here we show that siRNA-mediated APE1-knockdown or APE1 inhibitor treatment attenuates the ATR-Chk1 DDR under stress conditions in multiple immortalized cell lines. Congruently, APE1 overexpression (APE1-OE) activates the ATR DDR under unperturbed conditions, which is independent of APE1 nuclease and redox functions. Structural and functional analysis reveals a direct requirement of the extreme N-terminal 33 amino acids (NT33) within APE1 in the assembly of distinct biomolecular condensates in vitro and DNA/RNA-independent activation of the ATR DDR. Overexpressed APE1 co-localizes with nucleolar NPM1 and assembles biomolecular condensates in nucleoli in cancer but not non-malignant cells, which recruits ATR and its direct activator molecules TopBP1 and ETAA1. APE1 W119R mutant is deficient in nucleolar condensation and liquid-liquid phase separation and is incapable of activating nucleolar ATR DDR. Lastly, APE1-OE-induced nucleolar ATR DDR activation leads to compromised ribosomal RNA transcription and reduced cell viability. Taken together, we propose distinct mechanisms by which APE1 regulates ATR DDR pathways and functions in genome integrity maintenance.

molecular biology↗

bioRxiv2022

APE1 recruits ATRIP to ssDNA in an RPA-independent manner to promote the ATR DNA damage response

Cells have evolved the DNA damage response (DDR) pathways in response to DNA replication stress or DNA damage. In the ATR-Chk1 DDR pathway, it has been proposed that ATR is recruited to RPA-coated single-strand DNA (ssDNA) by direct ATRIP-RPA interaction. However, it remains elusive whether and how ATRIP is recruited to ssDNA in an RPA-independent manner. Here, we provide evidence that APE1 directly associates ssDNA to recruit ATRIP onto ssDNA in an RPA-independent fashion. The N-terminal motif within APE1 is required and sufficient for the APE1-ATRIP interaction in vitro and the distinct APE1-ATRIP interaction is required for ATRIP recruitment to ssDNA and the ATR-Chk1 DDR pathway activation in Xenopus egg extracts. In addition, APE1 directly associates with RPA70 and RPA32 via two distinct motifs. Taken together, our evidence identifies APE1 as a direct recruiter of ATRIP onto ssDNA independent of RPA in the activation of ATR DDR pathway. SummaryO_LIAPE1 associates with ssDNA and ATRIP directly via distinct motifs and thereby recruits ATRIP onto ssDNA independent of RPA to promote the ATR DDR. C_LIO_LIAPE1 interacts with RPA via distinct two motifs in vitro but such RPA-APE1 interaction is dispensable for ATRIP recruitment onto ssDNA. C_LI

molecular biology↗

bioRxiv2022

A community driven GWAS summary statistics standard

Summary statistics from genome-wide association studies (GWAS) represent a huge potential for research. A challenge for researchers in this field is the access and sharing of summary statistics data due to a lack of standards for the data content and file format. For this reason, the GWAS Catalog hosted a series of meetings in 2021 with summary statistics stakeholders to guide the development of a standard format. The key requirements from the stakeholders were for a standard that contained key data elements to be able to support a wide range of data analyses, required low bioinformatics skills for file access and generation, to have easily accessible metadata, and unambiguous and interoperable data. Here, we define the specifications for the first version of the GWAS-SSF format, which was developed to meet the requirements discussed with the community. GWAS-SSF consists of a tab-separated data file with well-defined fields and an accompanying metadata file.

bioinformatics↗

bioRxiv2021

High-throughput super-resolution analysis of influenza virus pleomorphism reveals insights into viral spatial organization

Many viruses form highly pleomorphic particles; in influenza, these particles range from spheres of ~ 100 nm in diameter to filaments of several microns in length. Virion structure is of interest, not only in the context of virus assembly, but also because pleomorphic variations may correlate with infectivity and pathogenicity. We have used fluorescence super-resolution microscopy combined with a rapid automated analysis pipeline to image many thousands of individual influenza virions, gaining information on their size, morphology and the distribution of membrane-embedded and internal proteins. We observed broad phenotypic variability in filament size, and Fourier transform analysis of super resolution images demonstrated no generalized common spatial frequency patterning of HA or NA on the virion surface, suggesting a model of virus particle assembly where the release of progeny filaments from cells occurs in a stochastic way. Finally, we showed that in long filaments, viral RNP complexes are located preferentially within Archetti bodies, suggesting that these structures may play a role in virus transmission. Our approach therefore offers exciting new insights into influenza virus morphology and represents a powerful technique that is easily extendable to the study of pleomorphism in other pathogenic viruses.

microbiology↗