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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).

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.

Sequencing of marine sediments finds 136 newly identified Heimdallarchaeia and several novel lineages, and indicates that Heimdallarchaeia evolved distinct metabolic capabilities from other Asgardarchaeota, in conditions that may have given rise to early eukaryotes.

The lowest-frequency gravitational wave background may be shaped by supermassive black hole binaries that scatter nearby stars or dark matter. In this case, the NANOGrav 15-year dataset favours dense galactic centres with 10⁶ solar masses per cubic parsec.

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.

Obesity is marked by a state of low-grade inflammation, including the accumulation of macrophages in the adipose tissue, which results in insulin resistance. Kathryn Moore and her colleagues now show that the neuronal guidance molecule, netrin-1, is upregulated in fat cells during obesity and leads to the retention of macrophages in this tissue. They also show that its genetic deletion in mice prevents the development of insulin resistance by a high-fat diet.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

Here, the authors examine the mechanisms behind cheatgrass’s successful invasion of North American ecosystems. Their genetic analyses and common garden experiments demonstrate that multiple introductions and migrations facilitated cheatgrass local adaptation.

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.

In this Review, Moore and co-workers provide an overview of the mechanisms and functions of microRNAs and long non-coding RNAs in vascular biology and the regulation of lipid metabolism, as well as the effects of non-coding RNAs on atherosclerotic plaque formation and progression.

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.

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.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Glioblastoma (GBM) is an aggressive tumor characterized by an immunosuppressive microenvironment. Here, the authors present a therapeutic approach based on the implantation of a biodegradable scaffold for the sustained, local release of a TLR7/8 agonist at the time of tumor resection, to achieve anti-tumor immunity and protection from future tumor challenge.

Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages.

Moore and colleagues show that Mycobacterium tuberculosis induces miR-33 and miR-33* in macrophages to inhibit integrated pathways involved in autophagy, lysosomal function and fatty acid oxidation, and to support bacterial replication.

Post-international travel quarantine has been widely implemented to mitigate SARS-CoV-2 transmission, but the impacts of such policies are unclear. Here, the authors used linked genomic and contact tracing data to assess the impacts of a 14-day quarantine on return to England in summer 2020.

This prospective cohort study of patients with cancer incorporated antemortem follow-up visits and rapid autopsy analyses, and reports that spikes—rapidly increasing levels—of circulating tumor cell clusters, observed immediately before and at the time of death, along with tumor masses infiltrating large vessels, were cancer-related events associated with patient mortality.

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

Barcia Durán, Dayasagar, et al. map the expression of immune checkpoints in human atherosclerosis and examine the influence of lipid-lowering treatments and type 2 diabetes to understand how immune checkpoint inhibitors worsen cardiovascular risk in survivors of cancer.

Bacteria possess many types of antiviral immune systems, some of which are present also in eukaryotes. Here, Leão et al. explore the diversity and distribution of antiviral defense systems in archaea and their evolutionary relationships with bacterial and eukaryotic immune systems, supporting that Asgard archaea played important roles in the origin of eukaryotic innate immunity.

The molecular mechanisms behind recognition of altered self remain unclear. Moore and co-workers show that oxidized low-density lipoprotein (LDL) and β-amyloid trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6.

Inventory data from more than 1 million trees across African, Amazonian and Southeast Asian tropical forests suggests that, despite their high diversity, just 1,053 species, representing a consistent ~2.2% of tropical tree species in each region, constitute half of Earth’s 800 billion tropical trees.

Phenotype variation is higher in mutants than wild types. Examining a range of mutant severities, this study unexpectedly found that variation decreases in severe conditions. A quadratic trend best fits the relationship between severity and variation.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Unlike Amazonian forests, African forests have maintained their carbon sink until recently but by 2030 the African carbon sink will have shrunk by 14 per cent and the Amazonian sink will reach almost zero.

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

Lipid-engorged macrophages accumulate in atherosclerotic plaques where chronic inflammation ensues. Moore and colleagues show that macrophage migration to chemokines and egress is arrested by netrin-1, which is secreted in the plaque lesions.

Transancestral GWAS meta-analysis in 160,420 individuals identifies 139 loci associated with refractive error, including myopia. Newly identified genes implicate pathways involved in eye growth and light signaling cascades.

Data from a variety of sources—including satellite, climate and soil data, as well as field-collected information on plant traits—are pooled and analysed to map the functional diversity of tropical forest canopies globally.

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.

The protein corona formed on nanoparticles can impact bioactivity. Here the authors show that the protein corona on lipid nanoparticles alters their function and reduces transfection efficiency, showing the importance of considering the protein corona in designing lipid nanoparticle-based therapeutics.

Particulate crystals can activate the NLRP3 inflammasome. Moore and colleagues show that the scavenger protein CD36 contributes to sterile inflammation via uptake of soluble cholesterol and amyloid peptides that nucleate into intracellular crystals.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

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.

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.

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.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

A perturbative method is proposed for the systematic design of mechanical metamaterials, where each element of the discrete model is associated with individual geometric features of the metamaterial, through the weak interaction between the unit cells.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

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.