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Vaccines inducing mucosal immunity may provide better protection from respiratory viruses. Here, Ykema et al. demonstrate the utility of a bivalent, mucosally delivered nanostructured lipid carrier-replicon vaccine for induction of mucosal and systemic immunity and protection against morbidity and mortality from H5N1 and H7N9 influenza.

Rathmell and colleagues show that metabolic reprograming of regulatory T cells is associated with severity of critical illness in patients with and without sepsis.

Vibrio cholerae O1 outbreak strains are classified as Ogawa or Inaba serotypes, but the impact of serotype on pathogenicity is understudied. Here, the authors show that O1 antigen methylation in Ogawa strains promotes colonization and infectivity.

Elevated levels of IL-33 induce the production of autoantibodies through an unknown mechanism. Here, the authors show that IL-33 disrupts splenic architecture and germinal center organization, causing an expansion of antibody-secreting plasmablasts and plasma cells. In multiple mouse models of inflammation, administration of IL-33 exacerbates the pathology, increasing the production of autoantibodies, whereas IL-33 blockade reverses autoantibody production in a model of lung inflammation.

Muscularis macrophages, housekeepers of enteric nervous system integrity and intestinal homeostasis, modulate α-synuclein pathology and neurodegeneration in models of Parkinson’s disease, and understanding the accompanying mechanisms could pave the way for early-stage biomarkers.

Neural circuits in adult mouse visual cortex are stabilized by astrocytes, which secrete CCN1, resulting in reduced plasticity and increased maturation of multiple cell types.

H5N1 avian influenza viruses caused an outbreak in dairy cattle. We show that the potential for avian viruses to replicate in cow cells varies across H5N1 evolution, suggesting that the risk of spillover into mammals differs between variants.

Allogeneic T cell therapies could be used in therapeutic applications because of their potential for ‘off-the-shelf’ access and standardised production. Here the authors have developed a multidimensional workflow profiling platform for EBV-specific T cell therapy and show that correlative biomarkers of T cell potency and effector function are associated with therapeutic effectiveness in xenogeneic mouse EBV-LCL models.

CD44 expressed by fibroblastic reticular cells in secondary lymphoid organs regulates trafficking of dendritic cells, and thus has an essential role in the priming of T cells and the adaptive immune response.

Roles of of viruses in ocean subsurface oxygen maxima are unclear. Here, the authors analyse Bermuda Atlantic Time Series data to show that viruses may drive SOM in stratified oceans by boosting nutrient recycling and phytoplankton productivity linking virus activity to oxygen buildup and a stronger microbial loop.

The potential roles of viruses in microbial-induced permafrost thaw, which is accelerated by climate change, are unclear. Here, Trubl et al. sample a permafrost thaw gradient and identify thousands of new viruses carrying genes with metabolic-related functions, which might influence the fate of stored carbon.

Clear cell renal cell carcinoma (ccRCC) bears the hallmark loss of VHL but remains incurable. Here, the authors identify the SLC1A1 dicarboxylic amino acid transporter as an actionable, oncogenic, HIF-independent, metabolic dependency in VHL-deficient ccRCCs.

How the complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth is explored.

Mosquitoes are major vectors for the transmission of many serious pathogens. This study uses genome-wide CRISPR screens in the mosquito, Anopheles gambiae, to reveal new insights into mosquito fitness and the function of clodronate-liposome mediated immune cell ablation.

Adherent-invasive strains of E. coli are commonly isolated from patients with Crohn’s disease. Here, the authors show that an AIEC harbours a hybrid Type IV secretion system (T4SS) that mediates pilin polymerization and biofilm formation in vivo.

Determinants of Vibrio cholerae transmission are incompletely understood. Here, the authors use an infant mouse model to show that events in the intestine govern inter-animal transmission and that bacterial motility along with cholera toxin-driven diarrhea are critical for pathogen spread.

Adjuvants are an important component of modern vaccines. Here, the authors employ a phenotypic screen of ~200k compounds and identify PVP-057, a TLR3 agonist with a simple scalable 3-step synthesis, as an adjuvant that induces durable humoral and cellular immunity to varicella-zoster virus (VZV) gE in mice.

Human RIF1 protein protects cells from DNA replication stress, through mechanisms that remain uncertain. Here the authors demonstrate that the RIF1-Long isoform interacts with BRCA1 upon extended replication stress, enabling RAD51-dependent repair of broken replication forks.

Lu et al. perform systematic functional analyses using data from the TRACERx cohort of patients with non-small-cell lung cancer and delineate how FAT1 regulates homologous recombination repair, chromosomal instability and whole-genome doubling with distinct mechanisms.

Eosinophils exist as a functionally heterogeneous population. Whether the heterogeneity is driven by cell-intrinsic or extrinsic factors is underexplored. Here, by leveraging single-cell transcriptomic data and epigenomic analysis, the authors propose that local environmental cues define the gene expression program of murine esophageal eosinophils and identify AP-1 family members, including ATF3, as key regulators of gene expression.

The inner ear is highly organized, with distinct domains being located across the Line of Polarity Reversal (LPR). Here they show that Emx2 establishes the LPR and bidirectional selectivity of otolith organs, and that loss of the LPR in mice affects swimming and balance.

Structural, genetic, functional and biochemical analyses of the complex flagellar motor of Campylobacter jejuni reveal structural adaptations with an ancient origin also found more widely across bacterial species, including elements exapted from the type IV pilus machinery.

Galsky and colleagues report the results of a phase 1 clinical trial of anti-programmed cell death protein 1 ligand 1 atezolizumab in combination with PGV001, a personalized neoantigen vaccine, in participants with urothelial cancer.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

In this study, the authors generated iPSC lines from more than 100 sporadic ALS cases, which recapitulated key disease phenotypes and enabled large-scale drug screening, identifying a promising combination therapy of baricitinib, memantine and riluzole.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Here, using longitudinal pre- and post-infection samples from the RV217 Early Capture HIV Cohort Study, the authors show that mucosa-associated invariant T (MAIT) cells become activated and expand during the early acute phase of HIV infection, with subsequent reprogramming towards innate-like functionality.

Gene duplications and deletions are important drivers of evolution and disease. Here, the authors show that excess DNA generated at a replication fork barrier can be integrated at a new genomic site causing both a gene duplication and a deletion.

Single-cell profiling of human prostate cancer and studies in mouse models show that macrophages expressing SPP1 mediate immunotherapeutic resistance through adenosine pathway activation and represent a potential target for future studies.

A newly developed monoclonal antibody, MARV16, broadly neutralizes all Marburg virus isolates and provides effective protection in guinea pigs with Marburg virus disease.

Lim and colleagues present the UK PROSECO study where they assess humoral and cellular immune responses to one, two and three doses of vaccination against SARS-CoV-2 in patients with B-cell malignancies in a prospective observational study.

Pathogenic variants of DDX3X are associated with neurodevelopmental disorders (NDD) and cancer. Here, the authors perform saturation genome editing of DDX3X to test the functional impact of 12,776 variants, develop a machine learning classifier to identify variants relevant for NDD, and show that DDX3X predominantly acts as a tumour suppressor in cancer.

Here, Andrade et al. assess the memory B cell (MBC) and antibody response to Zika virus (ZIKV) in individuals with and without prior dengue virus (DENV) infection and find that ZIKV infection elicits a robust and specific MBC response that is only modestly affected by the number of prior DENV infections.

Using visible-light-induced crosslinking, a local stiffening approach is developed for ex vivo mouse and human lung tissue as an early lung injury model, directing epithelial cell mechanosensing, differentiation and nascent protein deposition.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

At the mucosal interface of the gut and microbiome immune cells play pivotal roles to regulate between commensalism, colonisation and pathogenic invasion. Here, Lo et al. show CTLA-4 expression in innate lymphoid cells is linked to mucosal homeostasis in a microbiome dependent manner.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

The extent of antibody protection against SARS-CoV-2 remains unclear. Here, using a cohort of 120 seroconverted individuals, the authors longitudinally characterize neutralization, Fc-function, and SARS-CoV-2 specific T cell responses, which they show to be prominent only in those subjects that elicited receptor-binding domain (RBD)-specific antibody titers above a certain threshold, suggesting that development of T cell responses to be related to anti-RBD Ab production.

Less is known about SARS-CoV-2 infection in unstudied geographical areas such as sub-Saharan Africa. Here the authors use multi-omics to characterize the immune response to SARS-CoV-2 in Uganda and consider how people living with HIV immunologically differentially respond to the virus.

The effects of antibiotics on the gut microbiota can lead to enhanced colonization of Clostridioides difficile (C. difficile) and toxin-mediated pathogenesis. Here, using defined toxin-mutant strains and a murine model, the authors provide insights into how toxin-induced inflammation alters C. difficile metabolism, host tissue gene expression and gut microbiota, together influencing a beneficial niche for infection.

Vaccines for SARS-COV-2 are needed in the ongoing pandemic. Here the authors characterize a vaccine candidate that presents the receptor-binding domain (RBD) of SARS-CoV-2 spike protein on a synthetic VLP platform using SpyTag/SpyCatcher technology and show immunogenicity of a prime-boost regimen in mice and pigs.

Autoantibody production is a hallmark of systemic lupus erythematosus (SLE). Here, the authors demonstrate that antibody-secreting cells from patients with SLE display features of premature maturation and increased survival, which are mediated by intrinsic and extrinsic programmes including autocrine APRIL.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Available wheat genomes are annotated by projecting Chinese Spring gene models across the new assemblies. Here, the authors generate de novo gene annotations for the 9 wheat genomes, identify core and dispensable transcriptome, and reveal conservation and divergence of gene expression balance across homoeologous subgenomes.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

In this work, authors develop obex inhibitors that target a distinct binding pocket in the ATPase domain of Topoisomerase II. They demonstrate how Topobexin, a Topoisomerase IIβ - selective catalytic inhibitor, blocks conformational changes and protects against anthracycline cardiotoxicity.

The authors describe the mechanism of exo-endocytosis coupling at synapses. They find that actin forms a ring around the region of exocytosis. This ring conserves membrane area, allowing induction of inward membrane buckling following exocytosis.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.