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An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Using their unique bioadhesives, barnacles can adhere to a great variety of surfaces. Here, Gohad et al.show that the barnacle larval bioadhesive contains lipids and phosphoproteins that are organized in a complex structure and work together to maximize adhesion.

An extinct prehistoric plague lineage of Yersinia pestis has been documented from Central Europe to Asia during the Late Neolithic and Bronze Age. Here, Swali et al. show that this lineage spread to Europe’s northwestern periphery by sequencing three ~4000 year-old Yersinia pestis genomes from Britain.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

Parity induces an accumulation of CD8⁺ T cells, including cells with a tissue-resident-memory-like phenotype within human normal breast tissue, offering long-term protection against triple-negative breast cancer.

Major histocompatibility complex (MHC) loss of heterozygosity, allele-specific mutation and measurement of expression and repression (MHC Hammer) detects disruption to human leukocyte antigens due to mutations, loss of heterogeneity, altered gene expression or alternative splicing. Applied to lung and breast cancer datasets, the tool shows that these aberrations are common across cancer and can have clinical implications.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

The ATPase activity of AAA+ proteins is regulated by their interaction with ligands, but depending on the particular protein it can be stimulated or inhibited, and the mechanism for such control remained unclear. An analysis of previous structural data on various AAA+ proteins now reveals that a conserved glutamate residue adopts two conformations and and thus regulates the ATPase activity.

Patients with metastatic cancers of unknown primary (CUP) are currently unable to gain access to drugs through standard of care or clinical trials. Here, the authors perform whole-genome and transcriptome sequencing (WGTS) on 72 patients with CUP and demonstrate the feasibility of using WGTS to determine the specific cancer types of CUP, thereby clinically benefiting patients with CUP.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Genome-wide analyses yield insights into the polygenic effects contributing to clinical heterogeneity in attention deficit hyperactivity disorder, advancing understanding of its genetic etiology and serving as a model for future studies in other complex disorders.

This Consensus Statement clarifies the existing subset-based nomenclature for T cells. Furthermore, it proposes an alternative modular nomenclature that is designed to be brief and flexible and to avoid ambiguity and unwanted implications. The authors also provide guidance on how T cell nomenclature should be described in research papers.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

A survey of astronomy and geophysics professionals has revealed prevalent bullying and harassment within the sector, with women and marginalized groups most likely to suffer. It is time for the community to face up to the issue and discuss ways of tackling it.

Immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS) infers B cell and T cell fractions from whole-genome sequencing data. Applied to the 100,000 Genomes Project datasets, circulating T cell fraction provides sex-dependent and prognostic insights in patients.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

Here, the authors use single-cell spatial transcriptomics to profile the airway wall landscape in health and during asthma. Discrete proinflammatory ecosystems containing alarmins, chemokines and a unique combination of stromal cells were identified in healthy individuals, and these were spatially dysregulated in asthma.

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

Swanton and colleagues present a clonal expression signature, ORACLE, which, in combination with clinicopathological and molecular risk factors, can predict survival of patients with lung adenocarcinoma, and they prospectively validate its prognostic value.

Lipopolysaccharide (LPS) from Gram-negative bacteria is a potent activator of the innate immune response. Clare Bryant and colleagues discuss recent exciting data that have revealed the structural basis of the recognition of LPS by the Toll-like receptor 4–MD2 complex.

A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

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.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

Mouse incisor growth depends upon mesenchymal stromal cells (MSCs) and transit amplifying cells (TACs). Here the authors describe a distinct population of MSCs that is maintained by TACs through Dlk1 ligand and that contribute to MTACs and mesenchymal lineages including dental pulp and odontoblasts.

Dense calcium imaging combined with co-registered high-resolution electron microscopy reconstruction of the brain of the same mouse provide a functional connectomics map of tens of thousands of neurons of a region of the primary cortex and higher visual areas.

The first report from the Cancer Programme of the 100,000 Genomes Project presents whole-genome sequencing profiles of 13,880 solid tumors spanning 33 cancer types, combined with real-world clinical data, providing insights for precision oncology.

Using viral sequence data, individuals with persistent SARS-CoV-2 infections were identified, and had higher odds of self-reporting long COVID, in a large community surveillance study.

Idiopathic pulmonary fibrosis has been associated with aberrant expansion of KRT5-expressing basal cells. Here the authors show how changes in the ECM glycoprotein SPARC restrict the movement of KRT5+ cells, affecting their retention within fibrotic tissue.

The Cdc45-MCM-GINS (CMG) helicase unwinds DNA during replication, a process that requires the ATPase-dependent activity of the MCM complex. Using cryo-EM reconstructions of the CMG complex in different conformations, the authors propose a model where the N-terminal and AAA+ domains of MCM work in concert to translocate along DNA.

Nuocytes are innate cells with critical roles during infection with parasitic worms. McKenzie and colleagues show that nuocytes differentiate from common lymphoid progenitors and require IL-7, IL-33, Notch and RORα for development.

A retrospective analysis of primary care records in the United Kingdom reveals individual symptoms associated with SARS-CoV-2 infections, which persisted for 12 weeks or more after infection, as well as risk factors associated with developing long COVID.

In studies in mammalian cells, polymerase theta (Polθ, also known as POLQ) is identified as the polymerase responsible for non-homologous end joining DNA repair; this DNA repair pathway acts in many tumours when homologous recombination is inactivated and the identification of the polymerase responsible may aid the development of new therapeutic approaches.

What are the most important questions that the HIV field needs to answer to make progress? Nature Medicine asked this question to a group of HIV researchers to identify some of the key roadblocks in HIV research.

Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.

A genetic atlas of the human plasma proteome, comprising 1,927 genetic associations with 1,478 proteins, identifies causes of disease and potential drug targets.

Kynurenine-3-monooxygenase (KMO) is an emerging clinical target for treatment of neurodegenerative diseases and acute pancreatitis. Here, the authors report potent inhibitors that bind KMO in an unexpected conformation, offering structural and mechanistic insights for future drug discovery ventures.