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Nomenclature for tracking of genetic variation of seasonal influenza viruses.
No full textBACKGROUND: Genomic surveillance of human seasonal influenza viruses is an essential component of the Global Influenza Surveillance and Response system (GISRS) and informs the recommendations for the seasonal influenza vaccine composition. Phylogenetic analysis of viral genome sequences is used to identify groups of viruses sharing potential antigenic change, and computational models are used to predict which viral variants are likely to circulate at high levels in upcoming seasons. To facilitate discussion and reporting of genetic diversity, as well as to communicate antigen recommendations, up-to-date and sufficiently granular definitions of genetic clades are important. METHODS: We implemented a nomenclature system for Segments 4 (haemagglutinin) and 6 (neuraminidase) of human Influenza A(H3N2), A(H1N1)pdm09, and Influenza B that dynamically adapts to the diversity of circulating viruses. New subclades were proposed by a clade suggestion algorithm based on criteria including (i) the number of sequences in the group, (ii) the distance from the direct parent clade, and (iii) the weighted number of amino acid substitutions on the branch leading to the common ancestor of the subclade. RESULTS: Algorithmic clade proposals were reviewed and assigned a systematic hierarchical label consisting of a leading letter, followed by numbers (e.g., G.1.3). Names are kept short by aliasing that is collapsing prefixes into unique letters. Subclade definitions are shared openly to promote adoption and tool development. Nextclade is supporting this new nomenclature, and it is being used routinely by the GISRS network. CONCLUSIONS: With increasing genomic surveillance, the need for up-to-date classification schemes is growing and we hope that the current dynamic proposal will adapt to growing data volumes and aid in simplifying the interpretation of these data
Cellular quiescence uncouples the proteome from the transcriptome in neural stem cells.
No full textQuiescence is a cellular state defined by reversible cell-cycle arrest and diminished biosynthesis, particularly of nucleic acids and proteins. These features protect stem cells from proliferation-induced mutations, self-renewal exhaustion, and environmental insults. Despite relevance to development, tissue homeostasis and cancer, we lack understanding about many aspects of quiescence regulation and unique molecular markers for this state. Here, we employ Drosophila and mammalian neural stem cells to reveal that a mechanism for inhibiting translation in quiescence is selective nuclear enrichment of transcripts from more than 2000 genes, resulting in uncoupling between transcriptome and proteome. Three-quarters of these transcripts become increasingly nuclear as quiescence deepens, and nuclear bias predicts protein downregulation for the large majority of targets. We find that a large fraction of nuclear-biased transcripts present GA-rich multivalency and relocalise to nuclear speckles with increased SR-protein enrichment, which we propose promotes their nuclear retention. Finally, our evidence for differing degrees of transcript processing in steady-state quiescence suggests regulated sequential deployment of factors towards cell-cycle reentry. In brief, we present a previously unappreciated layer of post-transcriptional control of quiescence
Management of Charles Bonnet syndrome in routine eye care services.
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Micro-elimination of Hepatitis C virus (HCV) infection in the General Population Cohort in rural Uganda: Long-term follow-up to assess feasibility and outcomes of a screening and treatment intervention.
No full textBACKGROUND: The availability of highly effective curative direct acting antiviral (DAA) therapy for hepatitis C virus (HCV) is a cornerstone of elimination strategies. We report on long-term follow-up as part of a programme that delivered HCV screening and treatment in a population cohort in Uganda. METHODS: Screening for HCV, HIV and HBV was offered to > 7000 participants in the Kyamulibwa General Population Cohort (GPC) in Kalungu District in rural South-West Uganda in 2011. In 2017, DAA treatment was offered to those individuals who had previously tested HCV RNA positive who could still be traced, with fixed dose combination ledipasvir + sofosbuvir (LED/SOF) for 12 weeks, and post-treatment follow-up at 24 weeks. Clinical review and elastography was repeated in 2023, and verbal autopsy data reviewed. RESULTS: 13 individuals tested HCV RNA positive, of whom five had been born in Uganda and eight originated from Rwanda. The median age at HCV diagnosis was 61 (range 48-90) and 10/13 (77 %) were male. Six years later, five had died, one had left the area, and seven individuals were traced, all of whom accepted treatment, with confirmed cure (sustained virologic response (SVR)). After a further six year interval, four of those treated were followed up. Among those who had died, a high prevalence of liver disease was suggested by verbal autopsies. CONCLUSION: Among individuals offered DAA treatment, acceptance and cure rate were high. In this setting, HCV infection likely contributed to mortality, and affected older adults and migrants, suggesting these groups might be priorities for future micro-elimination programmes
Control of microglial dynamics by the Arp2/3 complex and the autism- and schizophrenia-associated protein CYFIP1.
No full textMicroglia use a highly complex and dynamic network of branched processes to sense and respond to their surroundings. Despite emerging evidence that microglial motility plays important roles in brain development, neurodegeneration, and neuropsychiatric disease, little is known about the intracellular machinery orchestrating microglial process dynamics. Here, we identify roles for regulators of the actin cytoskeleton in controlling microglial behavior. We show that the actin branching Arp2/3 complex is critical for maintaining microglial morphology and is required for surveillance but not chemotactic motility. Neuropsychiatric disease-associated CYFIP1, a core component of the WAVE regulatory complex linking upstream signaling pathways to activation of the Arp2/3 complex, is highly expressed in microglia but has an unknown function. We report that conditional deletion of Cyfip1 in mouse microglia reduces their morphological complexity and surveillance of the brain parenchyma, with no effect on chemotaxis. Deletion of Cyfip1 also increased microglial CD68 positive lysosome volume and engulfment of presynapses. Thus, actin remodeling by CYFIP1 and the Arp2/3 complex controls microglial dynamics and shifts microglia away from a homeostatic state with potential implications for neuropsychiatric disease
HIF-1α-mediated feedback prevents TOR signalling from depleting oxygen supply and triggering stress during normal development.
No full textGrowth deceleration before growth termination is a universal feature of growth during development. Transcriptomics analysis reveals that during their two-day period of growth deceleration, wing imaginal discs of Drosophila undergo a progressive metabolic shift from oxidative phosphorylation towards glycolysis. Ultra-sensitive reporters of HIF-1α stability and activity show that imaginal discs become increasingly hypoxic during development in normoxic conditions, suggesting that limiting oxygen supply could underlie growth deceleration. We confirm the expectation that rising levels of HIF-1α dampen TOR signalling activity through transcriptional activation of REDD1. Conversely, excess TOR leads, in a tissue-size-dependent manner, to hypoxia, which boosts HIF-1α levels and activity. Thus, HIF-1α mediates a negative feedback loop whereby TOR signalling triggers hypoxia, which in turn reduces TOR signalling. Abrogation of this feedback by Sima/HIF-1α knockdown leads to cellular stress, which is alleviated by reduced TOR signalling or a modest increase in environmental oxygen. We conclude that Sima/HIF-1α prevents TOR-mediated growth from depleting local oxygen supplies during normal development
Covalent fragment screening to inhibit the E3 ligase activity of bacterial NEL enzymes SspH1 and SspH2.
No full textAs the global fight against antimicrobial resistance in bacteria becomes increasingly pressing, new tool compounds are needed to study and evaluate novel therapeutic targets. Here, cysteine-directed fragment-based drug discovery is coupled with high throughput chemistry direct-to-biology screening to target the catalytic cysteine of a family of bacterial effector proteins, the novel E3 ligases (NELs) from Salmonella and Shigella. These effector E3 ligases are attractive as potential drug targets because they are delivered into host cells during infection, have no human homologues and disrupt host immune response to infection. We successfully identify hit compounds against the SspH subfamily of NELs from Salmonella and show that these proteins are inhibited by compound treatment, representing an exciting starting point for development into specific and potent tool compounds
Spatial data analysis for characterisation of human lung
No full textThe use of spatial multiplexed imaging of tissue allows for the exploration between cellular, structural and microenvironmental relationships within a sample. Imaging systems like the Xenium Analyzer (10X Genomics) and CosMX Spatial Molecular Imager (Nanostring) are used for multiplex antibody imaging, corresponding to different proteins in multiple compartments within the tissue rather than being limited to just 3-4 wavelengths via traditional confocal imaging. Using a 19-plex panel with the Phenocycler (Akoya Biosciences), we studied spatial relationships between cells in healthy lung and fibrotic disease, using human tissue samples from control and interstitial lung disease (ILD)/idiopathic pulmonary fibrosis (IPF). The architecture of the distal lung is unique, composed of many cell types- from fine, one cell thick to cuboidal- like epithelial structures, intertwined with the corresponding endothelial layer and held open under tension to permit gaseous exchange. Using the commercial platform Visiopharm, integrated analysis protocol packages (APPs) were customised to correctly segment and identify the lung parenchyma through scripts before phenotypic exploration of healthy vs. disease.Poster presented as part of the Crick BioImage Analysis Symposium 2025.Permission has been given by authors to upload to Crick Figshare. Copyright remains with the original authors.</p
Vinorelbine enhances the efficacy of oncolytic vaccinia virus in a preclinical model of ovarian high-grade serous carcinoma
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A circadian checkpoint relocates neutrophils to minimize injury.
No full textInflammation-driven injury, a significant source of morbidity and mortality worldwide, is largely mediated by the cytotoxic activities of neutrophils, which extend the initial lesion and jeopardize organ function. Intriguingly, inflammatory injury naturally declines at specific times of day, suggesting that circadian mechanisms exist that mitigate the destructive activity of neutrophils and protect the host. Here, we show that the periods of diurnal protection coincide with peaks in plasma CXCL12, a chemokine that inhibits the neutrophil-intrinsic circadian clock by signaling through CXCR4. Genetic deletion of this clock, or a hyperactive form of CXCR4, prevented the diurnal spikes of injury, and treatment with a synthetic CXCR4 agonist conferred protection from myocardial and vascular injury. In tissues, this protection was mediated by repositioning neutrophils in the wound core, which spared neighboring host cells from apoptotic death. Thus, a circadian neutrophil checkpoint protects from exuberant inflammation and can be activated to protect the host