Biology subjects

Hughes, J.

Publications and source records attributed to Hughes, J..

At least 19 recordsLinked to original sources

bioRxiv2026

ULK1 and ULK2 Restrain Skeletal Myofiber Growth by Balancing Protein Synthesis and Degradation

Background Skeletal muscle is vital for mobility and metabolic regulation, impacting independence and overall health. Increases in skeletal muscle mass and contractile function during development, and their maintenance during adulthood and aging, rely on an intricate coordination between protein synthesis and degradation processes that remains incompletely understood. Here, we investigated a potential role for the autophagy-initiating kinases ULK1 and ULK2 in broadly modulating protein metabolism in skeletal muscle. Methods Studies were conducted in young (4-6 wk-old) and adult (7-10 mo.-old) mice with skeletal muscle-specific knockout of Ulk1 and Ulk2 (i.e., Ulk1/2skmDKO) and wild-type littermates (WT). Short-term deficiency of these proteins was achieved via electroporation of plasmids (encoding specific microRNAs targeting Ulk1 and Ulk2) into muscles of 4 mo.-old wild-type mice. Protein metabolism was assessed via deuterium oxide (D2O) labeling, whereas anabolic signaling was investigated under insulin and leucine administration. Results Lifelong Ulk1/2 deficiency markedly impaired autophagy flux (i.e., LC3-II accumulated with colchicine treatment only in wild-type mice, P<0.001), compromised muscle quality, as evidenced by an increase in centrally nucleated fibers (from 0.1% to 4.5% in females, and from 0.8% to 22.7% in males (P<0.001), primarily involving MyHC type 2b fibers) and impaired force of dorsiflexors and plantar flexors in males (20%, P<0.01), and plantar flexors in females (24%, P<0.01). Despite these deficits, Ulk1/2 deficiency promoted robust muscle hypertrophy, evidenced by increased diameters of all major MyHC fiber types in the tibialis anterior and soleus muscles (i.e., by 10-15% in males, and 14-20% in females, P<0.05). Short-term deficiency (up to 4 weeks) of Ulk1/2 in adult skeletal muscle, however, led to myofiber hypertrophy (13%, P<0.05) without impairments in force or changes in central nucleation of fibers, pointing to an initial period of muscle quality preservation. Mechanistically, Ulk1/2 deficiency led to elevated myofibrillar protein synthesis (23% higher Ksyn, P<0.05) and decreased mitochondrial and sarcoplasmic protein degradation (16% and 14% lower Kdeg, P=0.09 and P<0.05, respectively). Further mechanistic studies revealed that hypertrophy was accompanied by enhanced mTORC1 activity independent of AKT in Ulk1/2-deficient muscle. Conclusions These results indicate that ULK1 and ULK2 jointly sustain autophagy and limit mTORC1-driven protein synthesis to govern skeletal muscle protein metabolism, with lifelong deficiency increasing muscle size at the expense of quality and function, while short-term deficiency permits hypertrophy without impairment. These findings identify ULK1/2 as a novel node coordinating protein turnover in skeletal muscle, warranting investigation as a therapeutic strategy for atrophy and weakness.

cell biology↗

bioRxiv2026

Protein language models learn underlying mutation biases alongside fitness landscapes

Protein language models (PLMs) score the effects of amino acid replacements as pseudo-probabilities, which are widely utilised to map protein fitness landscapes. However, because their training data relies on natural amino acid sequences, these models conflate protein structural constraints with nucleotide mutation biases and codon accessibility. Using the rapid emergence of the divergent influenza A H3N2 K lineage as a stress test, we investigate how base PLMs (ESM-2 and ESM-C) versus fine-tuned versions of these models capture mutational processes. We systematically implement a parameter sweep to explicitly couple (or decouple) empirical nucleotide mutational supply from PLM-assessed amino acid substitution pseudo-probabilities across evolutionary forecasting tasks. We find that base PLMs implicitly learn generic nucleotide-level mutational constraints, an effect strongly amplified by virus-specific fine-tuning. Incorporating explicit mutational accessibility significantly improves the binary prediction of observed amino acid changes. Conversely, when predicting the final circulating frequency of variants that have already emerged, adding mutational supply degrades performance, confirming that selection dominates post-emergence dynamics. Additionally, we perform amino-acid-level epistatic scanning to investigate protein structural constraints in the context of genetic background. This indicates the improbable antigenic substitution I160K is dependent on co-occurring S144N and N158D mutations in the H3N2 K lineage. Ultimately, current PLM pseudo-probabilities are a composite metric that conflates protein structural fitness with historical biases in mutational supply. Explicitly decoupling these independent evolutionary processes optimises predictive accuracy for real-world pathogen forecasting and isolates pure protein fitness for synthetic design pipelines.

evolutionary biology↗

bioRxiv2026

Regulation of Human Erythroferrone Expression

Erythroferrone (ERFE) is an erythroblast-secreted hormone that suppresses hepatic hepcidin expression to increase iron availability for erythropoiesis, ensuring recovery from anaemia. ERFE excess drives iron overload in disorders of ineffective erythropoiesis. Despite its pivotal role in systemic iron homeostasis and diseases of erythropoiesis, ERFEs molecular regulation has remained undefined. Here, we applied a genomic approach to characterise the molecular mechanisms governing ERFE expression. Using the HUDEP-2 human erythroid progenitor model, integrative ATAC-seq, CUT&RUN and micro capture-C analysis we identified a stage-specific accessible chromatin region within the ERFE 3 UTR that interacts with the promotor. We also identified enhancer-associated chromatin marks including H3K4me1 and H3K27ac in this region, and demonstrate that this cis-regulatory element is bound by key erythroid transcription factors KLF1, GATA1, TAL1 and STAT5. Functional dissection using CRISPR-Cas9-mediated deletion of the central 3 UTR enhancer element led to marked reduction in ERFE mRNA expression, and we show a corresponding reduction in nascent mRNA, confirming a key role for this region in transcriptional regulation. We define the transcriptional regulatory mechanism by which maturing human erythroblasts activate ERFE, the endocrine signal that coordinates erythropoietic demand with systemic iron mobilisation.

molecular biology↗

bioRxiv2026

CD8scape: an accessible, command-line tool for predicting viral escape from the CD8+ T cell response

The CD8+ T cell response is a critical component of antiviral immunity, particularly in hosts who are immunocompromised or undergoing B cell-depleting therapy, such as rituximab. As viral evolution can lead to escape from CD8+ T cell recognition, tools that predict such escape are increasingly relevant. Here, we present CD8scape, an accessible command-line tool designed to predict viral escape from the CD8+ T cell response based on within-host sequence variation and HLA class I genotype. CD8scape is primarily a Julia wrapper for NetMHCpan v4.2, a neural network-based predictor trained on mass spectrometry-derived peptide presentation data. CD8scape integrates variant data and viral reading frames to identify all overlapping 8-11mer peptides at variant sites in both ancestral and derived states. These peptides are evaluated using NetMHCpan, which outputs eluted ligand (EL) scores as allele-specific percentile ranks to account for differences in MHC binding fastidiousness, and these are passed back to CD8scape itself. For each variant, the best-ranking peptide across all alleles is identified, and a harmonic mean is used to summarize presentation likelihood across the hosts HLA genotype. A fold-change between ancestral and derived harmonic means quantifies the likelihood of immune escape, with values >1 indicating reduced predicted presentation, and therefore a potential escape from the CD8+ T cell response. This is converted to a log2 value of this fold-change so that the metric is symmetric around 0, with positive values representing predicted escape. CD8scape can operate with known HLA genotypes or a representative HLA supertype panel for generalizable predictions. We demonstrate our method by application to within-host SARS-CoV-2 evolution in a rituximab-treated patient and discuss its implications for population-level CD8+ T cell escape.

bioinformatics↗

bioRxiv2025

MOPRs in mouse islets of Langerhans modulate cell signaling and secretion

Article highlightsO_LIMu opioid receptors are expressed on multiple islets of Langerhans cell types C_LIO_LIMu opioid receptors on islets engage canonical Gi signaling cascades in islets C_LIO_LIMu opioid receptors on islets modulate calcium influx and oscillations C_LIO_LIMu opioid receptors on islets modulate insulin and glucagon secretion. C_LI Most clinically and recreationally used opioids drugs act on the endogenous mu opioid receptor (MOPR). While MOPR is typically studied in the context of addiction and analgesia, decades of evidence indicates that they have a strong modulatory role on metabolism and glycemia. However, whether these effects are directly driven by MOPR actions on pancreatic islets remains poorly understood. Here we sought to comprehensively profile MOPRs on islets to assess how their activity shapes cellular physiology and secretion. First, we used RNA-seq, fluorescent in situ hybridization, and immunoblotting approaches to map islet expression. We observed robust expression of MOPR across multiple cell types in islets. Next, using a FRET-based approach, we show that MOPRs recruit canonical inhibitory pathways, reducing cAMP accumulation. Correspondingly, islets from constitutive MOPR knockout mice showed increased calcium influx and oscillations. However, MOPR knockout had no effect on insulin secretion, instead increase glucagon secretion. Surprisingly, while MOPR antagonism increased overall calcium, it reduced calcium oscillations and suppressed insulin secretion. By contrast MOPR agonism suppressed calcium, increased oscillations, and had no effect on overall hormone secretion. Collectively, these results suggest that MOPR can profoundly shape islet activity, with these effects likely driven by their actions on distinct cell types.

pharmacology and toxicology↗

bioRxiv2025

Zone Equalisation Normalisation For Improved Alignment of Epigenetic Signal

High-throughput genomic technologies have transformed our understanding of biological systems, but analysing these complex datasets remains challenging. Existing normalisation methods often struggle to accurately correct for technical variations across different experimental conditions, potentially leading to misleading biological interpretations. We introduce Zone Equalisation Normalisation (ZEN), a novel approach designed to improve signal normalisation across genomic datasets. By developing a flexible method that reduces technical noise whilst preserving biological signals, ZEN addresses critical limitations in current normalisation techniques. By applying ZEN to diverse genomic techniques, we reveal its robust performance in managing technical variations across different experimental platforms. ZEN provides researchers with a robust tool for more accurate and reliable genomic data analysis, potentially revealing biological insights that were previously obscured by technical variations.

bioinformatics↗

bioRxiv2025

Fast segmentation with the NextBrain histological atlas

Structural brain analysis at the subregion level offers critical insights into healthy aging and neurodegenerative diseases. The NextBrain histological atlas was recently introduced to support such fine-grained investigations, but its existing Bayesian segmentation framework remains computationally prohibitive, particularly for large-scale studies. We present a new, open-source tool that dramatically accelerates segmentation using a hybrid approach combining: machine learning, contrast-adaptive segmentation; target-specific image synthesis; and fast diffeomorphic registration (all three with GPU support). Our method enables highly granular segmentation of brain MRI scans of any resolution and contrast (in vivo or ex vivo) at a fraction of the computational cost of the original method (<5 minutes on a GPU). We validate our tool on four different modalities (in vivo MRI, ex vivo MRI, HiP-CT, and photography) across a total of approximately 4,000 brain scans. Our results demonstrate that the accelerated approach achieves comparable accuracy to the original method in terms of Dice scores, while reducing runtime by over an order of magnitude. This work enables high-resolution anatomical analysis at unprecedented scale and flexibility, providing a practical solution for large neuroimaging studies. Our tool is publicly available in FreeSurfer (https://surfer.nmr.mgh.harvard.edu/fswiki/HistoAtlasSegmentation).

neuroscience↗

bioRxiv2025

ChatMDV: Democratising Bioinformatics Analysis Using Large Language Models

BackgroundThe rapid advancement in single-cell, spatial omics, imaging, and genomic technologies requires robust analytical and visualisation platforms capable of managing complex biological data. Tools such as Multi-Dimensional Viewer (MDV) offer comprehensive interfaces for data exploration, but still require manual configuration and computational expertise to generate visualisation outputs, limiting accessibility for many users. ResultsWe present ChatMDV, a natural language interface integrated with MDV that allows users to generate high-quality interactive visualisations through natural language commands. ChatMDV employs a retrieval-augmented generation (RAG) pipeline combined with large language models (LLMs) to translate user queries into reproducible Python code and interactive output. This approach enables exploratory and targeted analysis in diverse biological domains. We demonstrate ChatMDVs capabilities using three datasets of increasing complexity: the Peripheral Blood Mononuclear Cells 3K (PBMC3K) dataset, the lung cancer atlas dataset hosted at the Human Cell Atlas and the longitudinal TAURUS study single-cell RNA-sequencing (scRNA-seq) dataset. ConclusionsBy bridging the gap between natural language processing and bioinformatics visualisation, ChatMDV reduces technical barriers, enhances reproducibility, and supports more inclusive scientific inquiry. Its modular design and adherence to FAIR (Findability, Accessibility, Interoperability, and Reuse) principles make it a scalable and adaptable framework for accelerating biological data analysis. Key PointsO_LIChatMDV enables users to create interactive visualisations from biological datasets using natural language. C_LIO_LIThe system combines large language models with MDVs graphical platform to simplify data exploration. C_LIO_LIIt supports reproducibility, adaptability, and FAIR data practices, making it suitable for a wide range of users and use cases. C_LI

bioinformatics↗

bioRxiv2025

The SHR/Akr Y chromosome reveals repeated turnover of the rat pseudoautosomal region

Crossing-over between Chr X and Chr Y was first observed 90 years ago, in the brown rat, Rattus norvegicus. However, the sequence of the rat pseudoautosomal region (PAR) has remained a mystery. We produced a near-complete sequence of Chr Y from the SHR strain, along with nearly a megabase of sequence from both telomeres of Chr X. Both telomeric ends of Chr Y display extensive homology to Chr X, but no homology to the ancestral PAR of placental mammals. Using rat Y BACs probes for FISH on meiotic cells, we show that pairing almost always occurs between the tips of Yq and Xp, which are virtually identical in nucleotide sequence, but contain no protein-coding genes. Homology at the other ends of Chr X and Chr Y is likely the result of a recent transposition of five genes from Xq to Yp. These sequences are only 99.5% identical and pair infrequently, but show signs that it may have been pseudoautosomal in the ancestor of the rat genus. The rat Chr Y sequence presents opportunities for experimental studies of meiotic phenomena in a tractable model organism. The short PAR, with a correspondingly high recombination rate, represents a unique substrate for molecular studies of crossing-over. Likewise, the absence of extensively co-amplified testis gene families on the rat X and Y suggests they might serve as control for the intense competition between selfish elements that completely remodeled the mouse sex chromosomes.

genomics↗

bioRxiv2024

Viro3D: a comprehensive database of virus protein structure predictions

Viruses are intracellular parasites of organisms from all domains of life. They infect and cause disease in humans, animals and plants but also play crucial roles in the ecology of microbial communities. Tolerance to genetic change, high-mutation rates, adaptations to hosts and immune escape has driven high divergence of viral genes, hampering their functional annotation and phylogenetic inference. The protein structure is more conserved than sequence and can be used for searches of distant homologs and evolutionary analysis of divergent proteins. Structures of viral proteins are traditionally underrepresented in public databases, but recent advances in protein structure prediction allows us to address this issue. Combining two state-of-the-art approaches, AlphaFold2-ColabFold and ESMFold, we predicted models for 85,000 proteins from 4,400 human and animal viruses, expanding the structural coverage for viral proteins by 30 times compared to experimental structures. We also performed structural and network analyses of the models to demonstrate their utility for functional annotation and inference of distant phylogenetic relationships. Taking this approach, we examined the deep evolutionary history of viral class-I fusion glycoproteins, gaining insights on the origins of coronavirus spike protein. To enable further discoveries, we have created Viro3D (https://viro3d.cvr.gla.ac.uk/), a virus species-centred protein structure database. It allows users to search, browse and download protein models from a virus of interest and explore similar structures present in other virus species. This resource will facilitate fundamental molecular virology, investigation of virus evolution, and may enable structure-informed design of therapies and vaccines.

microbiology↗

bioRxiv2024

XRN1 supplies free nucleotides to feed alphavirus replication

Several RNA viruses induce widespread degradation of cellular mRNAs upon infection; however, the biological significance and mechanistic details of this phenomenon remain unknown. Here, we make use of a model alphavirus, Sindbis virus (SINV), to fill this knowledge gap. We found that SINV triggers cellular RNA decay through the exonuclease XRN1 and the 5-to-3 degradation machinery (5-3DM). These proteins accumulate at viral replication organelles (VROs) and interact with the non-structural protein 1 (nsP1), bringing mRNA degradation into proximity with vRNA synthesis. Our data suggest that monophosphate nucleotides released by cellular RNA decay are recycled through the salvage pathway to feed viral replications. Our work thus reveals a fundamental connection between cellular mRNA degradation and viral replication via nucleotides repurposing. Research highlightsO_LI5-3 RNA decay is essential for the replication of a wide range of viruses. C_LIO_LIXRN1 directly interacts with transcripts which are degraded during infection. C_LIO_LIRNA decay factors and salvage pathway members localise to viral factories. C_LIO_LISupplying nucleosides to several 5-3DM deficient cells facilitates SINV infection. C_LI

biochemistry↗

bioRxiv2024

POLYGENIC DETERMINANTS OF H5N1 ADAPTATION TO BOVINE CELLS

Avian influenza H5N1 clade 2.3.4.4b viruses caused a global panzootic and, unexpectedly, widespread outbreaks in dairy cattle, therefore representing a pandemic threat. To inform effective control strategies, it is critical to determine whether the potential to adapt to bovine cells is a generalised feature of H5N1 viruses, or is specific to clade 2.3.4.4b, or even more restricted to specific genotypes within this clade (e.g., B3.13 and D1.1). Using a large panel of H5N1 viruses representing >60 years of their natural history and other IAV for comparative purposes, we demonstrate that virus adaptation to bovine cells is: (i) highly variable across 2.3.4.4b genotypes, (ii) limited in viruses predating the global expansion of this clade, (iii) determined by the viral internal gene cassette, and (iv) not restricted to udder epithelial cells. Mutations in the PB2 polymerase subunit, particularly M631L, emerge as key determinants of adaptation, although their phenotypic effects are context dependent and have limited enhanced viral polymerase activity in human cells. Bovine B3.13 and some avian genotypes also exhibit enhanced modulation of bovine interferon-induced antiviral responses, determined by at least the viral PB2, nucleoprotein, and the non-structural protein NS1. Our results highlight the polygenic nature of IAV host range and reveal that the potential to cross the species barrier varies during the evolutionary trajectory of H5N1, with some avian viruses more predisposed to spillover than others.

microbiology↗

bioRxiv2024

From a single sequence to evolutionary trajectories: protein language models capture the evolutionary potential of SARS-CoV-2 protein sequences

Protein language models (PLMs) capture features of protein three-dimensional structure from amino acid sequences alone, without requiring multiple sequence alignments (MSA). The concepts of grammar and semantics from natural language have the potential to capture functional properties of proteins. Here, we investigate how these representations enable assessment of variation due to mutation. Applied to SARS-CoV-2s spike protein using in silico deep mutational scanning (DMS) we demonstrate the PLM, ESM-2, has learned the sequence context within which variation occurs, capturing evolutionary constraint. This recapitulates what conventionally requires MSA data to predict. Unlike other state-of-the-art methods which require protein structures or multiple sequences for training, we show what can be accomplished using an unmodified pretrained PLM. We demonstrate that the grammaticality and semantic scores represent novel metrics. Applied to SARS-CoV-2 variants across the pandemic we show that ESM-2 representations encode the evolutionary history between variants, as well as the distinct nature of variants of concern upon their emergence, associated with shifts in receptor binding and antigenicity. PLM likelihoods can also identify epistatic interactions among sites in the protein. Our results here affirm that PLMs are broadly useful for variant-effect prediction, including unobserved changes, and can be applied to understand novel viral pathogens with the potential to be applied to any protein sequence, pathogen or otherwise.

bioinformatics↗

bioRxiv2024

Diversity and evolution of the human anellome

Anelloviruses are a group of small, circular, single-stranded DNA viruses that are found ubiquitously across mammalian hosts. Here, we explored a large number of publicly available human microbiome datasets and retrieved a total of 829 anellovirus genomes, substantially expanding the known diversity of these viruses. The majority of new genomes fall within the three major human anellovirus genera: Alphatorquevirus, Betatorquevirus and Gammatorquevirus, while we also present one new genome of the under-sampled Hetorquevirus genus. The phylogeny reconstructed from the conserved ORF1 gene reveals three additional, previously undescribed, human anellovirus clades. We performed recombination analysis and show evidence of extensive recombination across all human anelloviruses. Interestingly, more than 95% of the detected events are between members of the same clade and only 15 inter-clade recombination events were detected. The breakpoints of recombination cluster in hotspots at the ends and outside of the ORF1 gene, while a recombination coldspot was detected within the gene. Our analysis suggests that anellovirus evolution is governed by homologous recombination, however events between distant viruses or ones producing chimaeric ORF1s likely lead to non-viable recombinants. The large number of genomes further allowed us to examine how essential genomic features vary across anelloviruses. These include functional domains in the ORF1 protein and the nucleotide motif of the replication loop region, required for the viruses rolling-circle replication. A subset of the genomes assembled in both this and previous studies are completely lacking these essential elements, opening up the possibility that anellovirus intracellular populations contain defective virus genomes (DVGs). Overall, our study highlights key features of anellovirus genomics and evolution, a largely understudied group of viruses whose potential in virus-based therapeutics is recently being explored.

evolutionary biology↗

bioRxiv2024

Id1, Spp1 and Pak3 are biomarkers of Smad4 and TGF-β1 dependency in conditional intestinal adenoma, organoids and colorectal cancer.

TGF-{beta} ligand activation suppresses cell growth yet can paradoxically and potently promote cancer invasion and metastasis depending on downstream pathway mutational context. Here, we evaluated the basis of this observation in conditional murine intestinal adenoma models with and without loss of Mothers against decapentaplegic homolog 4 (Smad4), with the aim of identifying TGF-{beta}-BMP-SMAD4 pathway dependent gene expression biomarkers for translational application. Conditional Lgr5-CreERT2 activation in Apcfl/flSmad4fl/flresulted in adenoma formation with recombined homozygote floxed alleles (Apc{Delta}/{Delta}Smad4{Delta}/{Delta}). The adenoma phenotype was discordant, with a reduced small intestinal adenoma burden yet development of large non-metastatic caecal adenoma with nuclear localisation of phospho-Smad2/3. Derived Apc{Delta}/{Delta}Smad4{Delta}/{Delta} adenoma organoids resisted TGF-{beta}1 dose dependent growth arrest and cell death (IC50 534pM) compared to Apc{Delta}/{Delta}Smad4+/+ (IC 24pM). TGF-{beta}1 (390pM) modified adenoma mRNA expression (bulk RNA-Seq) most significantly for Id1low and Spp1high in Apc{Delta}/{Delta}Smad4{Delta}/{Delta}. Single cell RNAseq of caecal adenoma identified expansion of Lgr5low, Pak3high and Id1low progenitor populations in Apc{Delta}/{Delta}Smad4{Delta}/{Delta}. Of the 76 Smad4 and TGF-{beta}1 dependent genes identified in adenoma organoids, 7 human equivalent genes were also significantly differentially expressed in colorectal cancer, including ID1low, SPP1high and PAK3high that also correlated with poorer survival (TCGA cohorts). Murine conditional models identified Smad4 loss of function mRNA expression biomarkers that require further evaluation as functional classifiers of colorectal cancer subtypes.

cancer biology↗

bioRxiv2024

A next-generation, histological atlas of the human brain and its application to automated brain MRI segmentation

Magnetic resonance imaging (MRI) is the standard tool to image the human brain in vivo. In this domain, digital brain atlases are essential for subject-specific segmentation of anatomical regions of interest (ROIs) and spatial comparison of neuroanatomy from different subjects in a common coordinate frame. High-resolution, digital atlases derived from histology (e.g., Allen atlas [7], BigBrain [13], Julich [15]), are currently the state of the art and provide exquisite 3D cytoarchitectural maps, but lack probabilistic labels throughout the whole brain. Here we present NextBrain, a next - generation probabilistic atlas of human brain anatomy built from serial 3D histology and corresponding highly granular delineations of five whole brain hemispheres. We developed AI techniques to align and reconstruct [~]10,000 histological sections into coherent 3D volumes with joint geometric constraints (no overlap or gaps between sections), as well as to semi-automatically trace the boundaries of 333 distinct anatomical ROIs on all these sections. Comprehensive delineation on multiple cases enabled us to build the first probabilistic histological atlas of the whole human brain. Further, we created a companion Bayesian tool for automated segmentation of the 333 ROIs in any in vivo or ex vivo brain MRI scan using the NextBrain atlas. We showcase two applications of the atlas: automated segmentation of ultra-high-resolution ex vivo MRI and volumetric analysis of Alzheimers disease and healthy brain ageing based on [~]4,000 publicly available in vivo MRI scans. We publicly release: the raw and aligned data (including an online visualisation tool); the probabilistic atlas; the segmentation tool; and ground truth delineations for a 100 m isotropic ex vivo hemisphere (that we use for quantitative evaluation of our segmentation method in this paper). By enabling researchers worldwide to analyse brain MRI scans at a superior level of granularity without manual effort or highly specific neuroanatomical knowledge, NextBrain holds promise to increase the specificity of MRI findings and ultimately accelerate our quest to understand the human brain in health and disease.

neuroscience↗

bioRxiv2023

Ancient genomic linkage couples metabolism with erythroid development

Generation of mature cells from progenitors requires tight coupling of differentiation and metabolism. During erythropoiesis, erythroblasts are required to massively upregulate globin synthesis then clear extraneous material and enucleate to produce erythrocytes1-3. Nprl3 has remained in synteny with the -globin genes for >500 million years4, and harbours the majority of the -globin enhancers5. Nprl3 is a highly conserved inhibitor of mTORC1, which controls cellular metabolism. However, whether Nprl3 itself serves an erythroid role is unknown. Here, we show that Nprl3 is a key regulator of erythroid metabolism. Using Nprl3-deficient fetal liver and adult competitive bone marrow - fetal liver chimeras, we show that NprI3 is required for sufficient erythropoiesis. Loss of Nprl3 elevates mTORC1 signalling, suppresses autophagy and disrupts erythroblast glycolysis and redox control. Human CD34+ progenitors lacking NPRL3 produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Finally, we show that the -globin enhancers upregulate NprI3 expression, and that this activity is necessary for optimal erythropoiesis. Therefore, the anciently conserved linkage of NprI3, -globin and their associated enhancers has enabled coupling of metabolic and developmental control in erythroid cells. This may enable erythropoiesis to adapt to fluctuating nutritional and environmental conditions.

cell biology↗

bioRxiv2023

The recency and geographical origins of the bat viruses ancestral to SARS-CoV and SARS-CoV-2

The emergence of SARS-CoV in 2002 and SARS-CoV-2 in 2019 has led to increased sampling of related sarbecoviruses circulating primarily in horseshoe bats. These viruses undergo frequent recombination and exhibit spatial structuring across Asia. Employing recombination-aware phylogenetic inference on bat sarbecoviruses, we find that the closest-inferred bat virus ancestors of SARS-CoV and SARS-CoV-2 existed just [~]1-3 years prior to their emergence in humans. Phylogeographic analyses examining the movement of related sarbecoviruses demonstrate that they traveled at similar rates to their horseshoe bat hosts and have been circulating for thousands of years in Asia. The closest-inferred bat virus ancestor of SARS-CoV likely circulated in western China, and that of SARS-CoV-2 likely circulated in a region comprising southwest China and northern Laos, both a substantial distance from where they emerged. This distance and recency indicate that the direct ancestors of SARS-CoV and SARS-CoV-2 could not have reached their respective sites of emergence via the bat reservoir alone. Our recombination-aware dating and phylogeographic analyses reveal a more accurate inference of evolutionary history than performing only whole-genome or single gene analyses. These results can guide future sampling efforts and demonstrate that viral genomic fragments extremely closely related to SARS-CoV and SARS-CoV-2 were circulating in horseshoe bats, confirming their importance as the reservoir species for SARS viruses.

evolutionary biology↗