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rhinotypeR enables reproducible rhinovirus genotype assignment from VP4/2 sequences
Get PDFRhinoviruses (RVs) are among the most prevalent human respiratory pathogens, yet their molecular characterization remains fragmented across analytical tools and inconsistent between studies. Current genotype assignment typically relies on sequence alignment, pairwise distance calculation, and prototype comparison. This fragmentation hinders reproducibility and scalability. Here, we present rhinotypeR, an open-source R package that provides a scriptable and transparent workflow for RV genotyping based on the VP4/2 genomic region. The package integrates multiple analytical steps; alignment, distance calculation, genotype assignment, and visualization within the Bioconductor ecosystem and applies standardized species-specific thresholds (10.5% for HRV-A/C and 9.5% for HRV-B). Using a validation dataset encompassing over 90% of known RV types, rhinotypeR reproduced pairwise genetic distances obtained with ape and MEGA X with Mantel correlation (r = 1.000, p = 0.001) and negligible numerical deviation (< 10⁻10). Approximately 80% of sequences showed complete agreement with previous genotype assignments by multiple analysts, and most remaining discrepancies occurred near the classification thresholds. Ct value distributions were broadly similar across matched, mismatched, and unassigned sequences, indicating that discrepancies were unlikely to be driven by viral load. By consolidating fragmented analytical steps into a reproducible and automated framework, rhinotypeR improves consistency in rhinovirus genotyping and supports scalable, transparent molecular surveillance. The package is freely available through Bioconductor for research and routine public health applications
Polymerase mutations underlie early adaptation of H5N1 influenza virus to dairy cattle and other mammals
Get PDFIn 2024, an unprecedented outbreak of H5N1 high pathogenicity avian influenza was detected in dairy cattle in the USA resulting in spillbacks into poultry, wild birds and other mammals including humans. Here, we present molecular and virological evidence that the cattle B3.13 genotype H5N1 viruses rapidly accumulated adaptations in polymerase genes that enabled better replication in bovine cells and tissues, as well as cells of other mammals including humans. We find evidence of several mammalian adaptations in cattle including PB2 M631L, which is found in all cattle sequences, and PA K497R, which is found in the majority. Structurally, PB2 M631L maps to the polymerase-ANP32 interface, an essential host factor for viral genome replication. We show that this mutation adapts the polymerase to better interact with bovine ANP32 proteins, particularly ANP32A, and thereby enhances virus replication in bovine mammary systems and primary human airway cultures. We show that ongoing evolution in the PB2 gene, including E627K and a convergently arising D740N substitution, further increase polymerase activity and virus replication in a range of mammalian cells. Thus, circulation of H5N1 in dairy cattle allows virus adaption improving replicative ability in cattle and poses a continued risk of zoonotic spillover
Neurosynth Compose: A web-based platform for flexible and reproducible neuroimaging meta-analysis
Get PDFThe rapid growth of the functional neuroimaging literature presents significant challenges for synthesizing findings across studies. Although automated meta-analysis platforms such as Neurosynth.org facilitate large-scale literature exploration, their capacity for addressing nuanced research questions is limited. As a result, manual meta-analyses remain prevalent despite being highly time intensive, often suffering from limited reproducibility, and frequently resulting in the loss of valuable expert-curated data due to idiosyncratic workflows. To address these limitations, we introduce Neurosynth Compose, a web-based platform designed to streamline the creation of transparent, reproducible, and high-quality neuroimaging meta-analyses. Neurosynth Compose features a user-friendly interface for study curation and annotation, adhering to PRISMA guidelines, and is integrated with NeuroStore, a centralized database containing over 30,000 studies with pre-extracted activation coordinates. Meta-analytic models are specified using the Neuroimaging Meta-Analysis Data Standard (NiMADS) and executed via the comprehensive NiMARE Python library, which supports diverse coordinate- and image-based algorithms. Analyses can be executed locally or in the cloud using portable execution bundles, and results are uploaded back to the online platform, facilitating interactive review and rapid sharing to colleagues and the community. By combining automated data collection with expert-guided study selection and powerful analysis tools in an open and flexible system, Neurosynth Compose streamlines the process of creating high-quality neuroimaging meta-analyses. At the same time, this open and collaborative framework encourages users to share their valuable annotations and meta-analyses, fostering a valuable crowdsourced knowledge base, and enabling users to update existing meta-analyses, paving the way for "living" syntheses that can be updated as new research emerges
Reliability of LLMs as medical assistants for the general public: a randomized preregistered study
Get PDFGlobal healthcare providers are exploring the use of large language models (LLMs) to provide medical advice to the public. LLMs now achieve nearly perfect scores on medical licensing exams, but this does not necessarily translate to accurate performance in real-world settings. We tested whether LLMs can assist members of the public in identifying underlying conditions and choosing a course of action (disposition) in ten medical scenarios in a controlled study with 1,298 participants. Participants were randomly assigned to receive assistance from an LLM (GPT-4o, Llama 3, Command R+) or a source of their choice (control). Tested alone, LLMs complete the scenarios accurately, correctly identifying conditions in 94.9% of cases and disposition in 56.3% on average. However, participants using the same LLMs identified relevant conditions in fewer than 34.5% of cases and disposition in fewer than 44.2%, both no better than the control group. We identify user interactions as a challenge to the deployment of LLMs for medical advice. Standard benchmarks for medical knowledge and simulated patient interactions do not predict the failures we find with human participants. Moving forward, we recommend systematic human user testing to evaluate interactive capabilities before public deployments in healthcare
Ectopic NMDAR expression in cancer unmasks germline-encoded autoimmunity
No full textAutoimmunity and anG-cancer immunity lie on the same biological conGnuum1,2 , but their link remains obscure. The paraneoplasGc neurological syndrome anG-NMDA receptor (NMDAR) encephaliGs (ANRE) is a paradigm for their connecGvity3 given that intratumoral NMDAR expression correlates with the generaGon of anG-NMDAR anGbodies . Here, we verify ectopic expression of GluN1 and GluN2B NMDAR sub-units in triple-negaGve breast cancer (TNBC) and model this using orthotopic TNBC tumors with inducible expression of GluN1-GluN2B NMDARs. We show that NMDAR expression is sufficient to induce B cell recruitment and their affinity maturaGon, consistent with an integrated adapGve immune response. ReconstrucGon of extended intratumoral B cell phylogenies and cryo-EM structural analyses demonstrated that affinity-matured hypermutated and class-switched anGbodies emerged from pre-exisGng germline-configuraGon lower-affinity anG-NMDAR anGbodies. DisGnct matured anGbodies targeted specific epitopes and induced conformaGonal rearrangements within the NMDAR amino-terminal domain, predicGve of their funcGonal effects, ranging from inhibiGon to potenGaGon. Passive transfer of an NMDAR-potenGaGng anGbody caused autonomic dysregulaGon and lowered the seizure threshold in healthy female mice, recapitulaGng key diagnosGc criteria of ANRE. We further idenGfy a correlaGon between intratumoral NMDAR expression and anG-NMDAR anGbody Gters in TNBC paGents. Taken together, our data establish a direct connecGon between intratumoral NMDAR expression, anGbody maturaGon, and the onset of autoimmunity. These findings suggest that germline-encoded anG-NMDAR anGbodies contribute to immune surveillance but can also trigger autoimmune disease upon maturaGon, revealing a mechanisGc tradeoff between cancer immunity and neurotoxicity
Investigating the role of social relationships in children's emotional and behavioural difficulties
Get PDFRelationships with family and friends are foundational to children’s emotional and behavioural development. Developmental and family systems frameworks highlight that children’s emotional and behavioural difficulties arise, in part, through children’s interactions across multiple interconnected systems in their lives, including their family and school. Importantly, children’s interactions within one subsystem (e.g., the parent-child relationship), can influence their emotions and behaviours in ways which affect their interactions in other subsystems (e.g., their sibling or peer relationships). This can initiate cascading cycles that either support healthy development or escalate emotional and behavioural difficulties.However, important gaps persist in our understanding of the influence of social relationships in children’s emotional and behavioural difficulties, which this thesis aimed to address. First, while friendships are associated with children’s better-than-expected functioning (i.e., resilience) following adversities such as maltreatment, the dynamic unfolding of these processes across development is not well understood. Furthermore, despite behavioural parenting programmes being the recommended strategy to reduce child behavioural difficulties, their effects on children’s behaviour beyond the parent-child subsystem, including on the behaviour of other children in the family, and on children’s sibling and peer relationships, are largely unexplored.Therefore, grounded in a systems framework, this thesis aimed to: 1) determine individual differences in co-occurring patterns of children’s emotional resilience, behavioural resilience, and friendship support, given their level of exposure to maltreatment; 2) examine the spillover effects of parenting programmes on sibling behaviour; and 3) consider the impact of parent training on children’s interpersonal conflict. To address these gaps and allow for the study of both developmental processes, and the causal effects of intervening in the parent-child relationship, this thesis leveraged the complementary strengths of longitudinal birth cohort data and individual-level pooled data from 15 randomised controlled trials of a behavioural parenting programme. Advanced quantitative methods, including group-based multi-trajectory modelling and latent transition analysis, were used to identify individual differences in patterns of outcomes over time.Results from examining co-occurring resilience and friendship support trajectories showed that while there was variation in children’s emotional and behavioural resilience, perceptions of friendship support were generally high, even among groups of children with more vulnerable resilience trajectories. Findings on the broader effects of behavioural parenting programmes highlight their potential to reduce sibling conflict where this is a concern. However, for most families, the programme did not reduce behaviour problems in more than one child per family and showed no effects on children’s conflict with peers, highlighting potential boundaries of such programmes in their current format.Across all studies, findings underscore the necessity of looking beyond single systems of functioning (e.g., the parent-child subsystem or friendships) for a complete understanding of the role of social relationships in children’s emotional and behavioural difficulties. Findings also highlight the utility of person-centred analytic approaches in revealing individual differences in outcomes. This has important implications for future observational and intervention work wishing to take a systems approach to advance the study of children’s relationships and behaviour
Neighbourhood social gifting and multiple long-term conditions: a nationally representative analysis of the Scottish population aged 40–75 years
Get PDFLittle is known regarding the relationship between the local social environment and multiple long-term conditions (MLTC, also referred to as multimorbidity). We investigated the association between social gifting, the neighbourhood-level latent willingness to gift time for community reciprocity, and four measures of MLTC presence (‘2+ long-term conditions (LTCs)’, mental-physical MLTC, ‘3+ LTCs’ and complex MLTC). We further explored variations in these relationships across types of urban–rural settlement. We linked participants of the Scottish Longitudinal Study who participated in Census 2011, aged 40–75, with no MLTC before 2010 (n = 98 296), to their hospitalisation records (2010–19) and an established neighbourhood-level index reflecting social gifting. Two-level logistic regression was used to model the onset of MLTC (2010–19), accounting for the clustered data structure of individuals nested within neighbourhoods. Lower social gifting was associated with increased odds of MLTC in all measures, except for ‘2+ LTCs’, with the strongest association observed for mental-physical MLTC. There was a statistically significant interaction between social gifting and types of urban–rural settlement for mental-physical MLTC but not for other measures of MLTC, suggesting that social gifting was more strongly associated with mental-physical MLTC in urban than other areas. The findings highlight the important role of the local social environment in the development of MLTC. Policies targeted at supporting neighbourhood-level social cohesion and social participation may benefit population health, particularly for mental-physical MLTC in urban areas where observed associations were strongest
Cardiac resident macrophages: the emerging role in arrhythmogenesis
Get PDFArrhythmia is a prevalent complication associated with various cardiovascular diseases. The onset of cardiac disease or injury can impair the normal function of cardiomyocytes, thereby precipitating arrhythmic events. Moreover, non-cardiomyocytes, including immune cells, may also play a contributory role in arrhythmogenesis. For instance, processes such as the infiltration of inflammatory cells that secrete pro-inflammatory mediators, fibroblast-to-myofibroblast transformation, and endothelial-to-mesenchymal transition have all been implicated in this process. Recent investigations have identified a distinct subset of resident macrophages within cardiac tissue that exhibit functional properties differing from those of bone marrow-derived macrophages. Cardiac tissue-resident macrophages (CRMs) are distinguished from bone marrow-derived macrophages by their developmental origin, transcriptomic profile, and functional traits. Beyond their canonical immune functions shared with bone marrow-derived macrophages, CRMs uniquely contribute to cardiac homeostasis by exerting direct electrophysiological modulation via ion channels and gap junctions. This constitutes a distinct mechanism underlying their role in arrhythmogenesis. Advanced methodologies, such as patch-clamp electrophysiology, high-throughput sequencing, and proteomic analyses in mammalian models, have revealed the complex electrophysiological interactions between CRMs and cardiomyocytes. While both CRMs and bone marrow-derived macrophages play roles in arrhythmia initiation and progression, existing reviews have primarily focused on bone marrow-derived macrophages. This review seeks to clarify the electrophysiological properties of CRMs and to delineate the specific mechanisms through which these cells contribute to arrhythmogenesis, thereby providing novel perspectives for the development of anti-arrhythmic therapeutic strategies
Remote digital cognitive assessment for aging and dementia using the Oxford Cognitive Testing Portal OCTAL
Get PDFThe global rise in dementia necessitates scalable cognitive assessments that can evolve to serve both clinical and research applications. We present the Oxford Cognitive Testing Portal (OCTAL), a remote, browser-based platform providing performance metrics for memory, attention, visuospatial and executive function domains. Four validation studies (N = 1664) confirmed cross-cultural applicability, lifespan sensitivity and clinical utility. Task performance was equivalent in English- and Chinese-speaking younger adults and mapped domain-specific ageing trajectories in mid- to late-adulthood. In a memory-clinic cohort (N = 194), 5-minute OCTAL screen distinguished patients with Alzheimer’s disease dementia from subjective cognitive decline (AUC = 0.92), matching a standard paper-based test, while a 20-minute subset surpassed this (AUC = 0.97; p = 0.04). Test-retest reliability was very good (ICC ≥ 0.79; N = 118). OCTAL enables remote assessment for large-scale research and screening, with an open, modular architecture that makes it a uniquely sustainable and evolvable tool for the research community
Mu rhythm motor–auditory delay in imagined speech mirrors overt speech timing
Get PDFSpeaking—whether overtly or covertly—requires a mapping between motor commands and their sensory consequences, a process of sensorimotor coordination. The timing of sensorimotor coordination during overt speech is relatively well established. Here we asked whether during imagined speech sensorimotor coordination can preserve this timing and remain grounded in the same biophysical constraints underlying vocal articulation. We instructed participants to imagine producing visually presented syllables (/pa/, /ta/, /ka/). Using magnetoencephalography (MEG), we investigated the spatiotemporal dynamics of mu rhythm (8–30 Hz) power suppression. Cluster-based permutation analysis reveals a segregation of alpha (8–12 Hz) and beta (15–30 Hz) frequencies to auditory and motor areas, respectively. Latency analyses show that beta suppression in motor areas precedes alpha suppression in auditory areas by ~ 120 ms. This delay closely matches sensorimotor coordination time windows previously reported for overt speech. While prior work provided only indirect evidence for the temporal equivalence between imagined and overt speech—by probing the system with altered auditory feedback—our findings offer direct evidence by measuring strictly internal neural processes. Together, the results demonstrate the suitability of alpha–beta power suppression as a neural marker that separately indexes motor and auditory processes associated with imagined speech production