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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.

Treatments to prevent thrombosis are suboptimal. Here, the authors identify a lead an antithrombotic drug targeting polyphosphate based on switchable protonation states for the anion-binding groups, demonstrating antithrombotic activity in multiple mouse models, not causing bleeding, and well tolerated.

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.

Corticosteroid binding globulin modulates circulating glucocorticoids, but its metabolic implications remain unclear. Here, the authors show that CBG regulators neutrophil elastase and alpha-1-antitrypsin control glucocorticoid bioavailability in adipose tissue, linking obesity and inflammation to metabolic outcomes in a sex-specific manner in mice and revealing parallels with human carriers of deleterious SERPINA1 mutations.

PNMA-family genes are gag-like elements of ancient retrotransposon origin whose roles in mammalian genomes is incompletely understood. Wood et al. found that two retrotransposon-derived proteins, PNMA1 and PNMA4, support mammalian fertility in both sexes and become increasingly important during aging. These proteins assemble into capsid-like structures that contain RNA and exit human cells.

WHaloCaMP is a chemigenetic calcium indicator that can be combined with different rhodamine dyes for multiplexed or FLIM imaging in vivo, as demonstrated for calcium imaging in neuronal cultures, brain slices, Drosophila, zebrafish larvae and the mouse brain.

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.

O’Sullivan and colleagues show that liver-resident type 1 ILCs have enhanced protective effector responses to secondary challenge with mouse cytomegalovirus, dependent on the viral glycoprotein m12.

4Pi single-molecule switching microscopy combined with ‘salvaged fluorescence’ enables improved ratiometric imaging that bypasses chromatic aberrations and allows for multicolor whole-cell imaging with sub-10-nm localization precision.

Chris Garcia, David Baker and colleagues use a computational approach to develop designed repeat protein binders (DRPBs), which function as human Frizzled (Fz) subtype-selective antagonists and enable identification of Fz subtypes active in different organs.

Androgen receptor (AR) signaling is regulated by multiple post-translational modifications. Here, the authors identify the writer and reader enzymes for AR ADP-ribosylation and show how they modulate AR signaling output in prostate cancer cells.

The use of oncolytic viruses as a therapy for cancer is limited by mechanisms inhibiting viral replication in the tumor. Here, the authors show that a chemical derivative of itaconate, 4-octyl itaconate, increases oncolytic virus VSVΔ51 efficacy in various cancer models, through decreasing antiviral immunity.

Infectious disease associated with excessive inflammation can result in coagulopathy. Here the authors show use of the clinically approved therapy dimethyl fumarate, as well as the pre-clinical tool compound 4- octyl itaconate, modulate tissue factor related coagulopathy via inhibition of the myeloid type I interferon pathway-tissue factor axis.

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.

Analysis of data collected from mice learning a trace conditioning paradigm shows that phasic dopamine activity in the brain can regulate direct learning of behavioural policies, and dopamine sets an adaptive learning rate rather than an error-like teaching signal.

In the ongoing phase 1/2 BNT211-01 trial, CLDN6-specific chimeric antigen receptor (CAR)-T cells given with or without CARVac, a CAR-T cell-amplifying RNA vaccine, were well-tolerated and exhibited encouraging clinical activity in patients with relapsed or refractory CLDN6-positive solid tumors, with the highest response rate in patients with germ cell tumors.

Despite an emerging role for cerebrovascular endothelial cells in a range of neurological pathologies, AAV vector development to date has focused on tools designed to target neurons or astrocytes. Here, Krolak et al. describe a specific variant of AAV (AAV-BI30), with high specificity and efficacy for transduction of endothelial cells across the central nervous system.

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.

Lymphocytes are considered one of the most radiosensitive cell types in the body. Here the authors show that unlike circulating lymphocytes, tumor-infiltrating T cells survive therapeutic doses of irradiation, remaining functional and contributing to radiotherapy induced anti-tumor immunity.

Adjuvanting the lipid and the encapsulated messenger RNA-encoded antigen in lipid-nanoparticle mRNA vaccines can enhance the efficiency of mRNA delivery and the activation of the immune responses, as shown for a COVID-19 vaccine in mice.

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

The epithelial protein Coxsackievirus Adenovirus Receptor (CAR) is a virus receptor but may have other functions. Here the authors show that deletion of CAR in mice leads to reduced house dust mite-induced lung inflammation, reduced neutrophil accumulation and alterations in airway remodelling.

In a mouse model of progeria, an adenine base editor delivered with adeno-associated virus corrects the pathogenic mutation in LMNA, rescues vascular pathology and markedly extends the lifespan of the mice.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

The team of authors led by Seon-Kyeong Jang use whole-genome sequencing data and show that rare genetic variants explain much of the ‘missing heritability’ in smoking behaviours. These results help address a long-standing mystery in behavioural genetics.

Transcription can pose a threat to genomic instability through the formation of R-loops, which are RNA–DNA hybrids with a displaced non-template DNA strand. Here the authors mapped the R-loop proximal proteome in human cells and identified a role of the tumor suppressor DDX41 in opposing R-loop and double strand DNA break accumulation in gene promoters.

This Consensus Statement presents the standards for technical reporting in environmental and host-associated microbiome studies (STREAMS) guidelines.

The authors assess the durability and long-term cross-reactivity of neutralizing antibodies raised in response to infections with SARS-CoV-2 or variants of concern in humans.

The immunosuppressive tumor environment and the lack of functional anti-tumor immunity are major limiting factors in immunotherapy. Here the authors show that human and mouse tumors are infiltrated by virus-specific memory T cells, which can be harnessed by viral peptides to induce local and systemic anti-tumor immunity and synergize with checkpoint blockade.

As naive mice learn a stimulus–reward association, DA neuron activity first reflects the timing of reward-seeking actions relative to predictable stimuli & rewards. As actions are refined by learning, DA neuron activity can reflect prediction errors.

Proliferation of cardiomyocytes typically ceases shortly after birth. Here the authors show that decreasing fatty-acid oxidation extends the perinatal cardiomyocyte proliferative window and can reintroduce cell-cycle activity in adult cardiomyocytes.

Winter and colleagues demonstrate that metabolic adaptation to nutrient stress in the tumor microenvironment of pancreatic cancer leads to a dependency on IDH1, which is therapeutically actionable regardless of IDH1 mutation status.

Two conditional transgenic mouse lines based on CRISPRa and CRISPRi enable epigenome editing in vivo.

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.

The potential of all-virtual clinical trials in cardiology is shown by the CHIEF-HF trial, conducted in the midst of the COVID-19 pandemic, which found that an SGLT2 inhibitor can alleviate heart failure symptoms in patients irrespective of ejection fraction or diabetes status.

Multiple sclerosis is associated with a deficiency in generation of mature oligodendroctyes; an image-based screen for oligodendrocyte differentiation inducers identified the compound benztropine, which enhances remyelination acting through muscarinic receptors and decreases clinical severity in a multiple sclerosis model system.

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 this Resource, Buckley and colleagues profile patients with Crohn’s disease and ulcerative colitis before and after adalimumab therapy. Specific pretreatment differences in the epithelial and myeloid compartments were associated with remission outcomes in both diseases. The authors also describe the cellular circuitry in nonremission patients following treatment.

Although Capicua (Cic), a transcriptional repressor, is linked to cancer, little is known about its function in the non-diseased brain. Here, authors show that Cic is strongly expressed in astrocytic and neuronal lineage cells during development and regulates proliferation and lineage selection via de-repression of Ets transcription factors.

Some enhancers can limit their activities to specific spatial–temporal domains by enhancer suboptimization. Ou et al. find that classical dendritic cell (cDC) development depends on Irf8 suboptimization, which prevents unwanted IRF8 autoactivation in developing cDC2s while maximizing IRF8 expression in developed cDC1s.

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.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

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

Host metabolic reprogramming plays a role in functional responses against pathogens. Here, the authors characterise malonylated proteins in macrophages and show that malonylation of the glycolytic enzyme GAPDH impacts cytokine production by modulating both its enzymatic activity and RNA-binding capacity.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Imbalanced proteostasis is associated with diverse diseases, including ischemia/reperfusion injury in the heart. Here the authors show that the ATF6 arm of the unfolded protein response can be pharmacologically activated with a small molecule in vivo, providing protection from ischemia/reperfusion injury in the heart, the brain, and the kidney.

ApoE is a direct checkpoint inhibitor of unresolvable inflammation in neurodegenerative and cardiovascular diseases

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.