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Preventing endosomal damage sensing or using lipids that create reparable endosomal holes reduces inflammation caused by RNA–lipid nanoparticles while enabling high RNA expression.

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).

Pressure overload in the heart, such as from aortic stenosis, triggers early molecular changes before visible damage occurs. Here, the authors show that combining proteomics, transcriptomics, and genetic data reveals key drivers of heart failure, highlighting potential targets for treatment.

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.

A study of dependencies associated with cancer-causing mutations has identified a small molecule that binds to SHOC2 and inhibits RAS signalling in cells carrying NRAS Q61 mutations, a common oncogenic driver in melanoma.

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.

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.

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

A structure of the MRAS–SHOC2–PP1C complex supports a RAS-driven and multi-molecular model for RAF activation in which individual RAS–GTP molecules recruit RAF–14-3-3 and SHOC2–PP1C to activate the downstream pathway.

Dissecting the adaptive exercise response of the neurogenic stem-cell niche in the dentate gyrus by single-nucleus RNA sequencing reveals the molecular mediators that underlie exercise’s protective effects in Alzheimer’s disease.

Genome-wide association analyses identify new risk loci for heart failure and its subtypes, extending understanding of the underlying biological pathways and disease mechanisms.

Epidemiological analyses coupled with immunological phenotyping suggest that humoral immunity induced by COVID-19 vaccines wanes more rapidly in individuals with severe obesity compared to individuals with a BMI within the normal range.

Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.

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.

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.

An exome-wide association study of six smoking phenotypes in up to 749,459 individuals identifies associations of rare coding variants in CHRNB2 that may reduce the likelihood of smoking.

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.

CB₂ receptor agonists are developed as potential analgesics or immune-modulatory compounds. Here, the authors characterize the pharmacological properties of widely used CB₂ receptor agonists and antagonists, recommending three that appear most suitable for in vitro and in vivostudies.

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.

Alvarez and colleagues develop a bispecific anti-PD-1–GITR-L agonist that activates T cells via a mechanism distinct from those found with individual PD-1 and GITR-L agonists and demonstrate its antitumor activity in mice and nonhuman primates.

A design pipeline is presented whereby binding proteins can be designed de novo without the need for prior information on binding hotspots or fragments from structures of complexes with binding partners.

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.

Serological analysis and infection outcomes of participants in the multi-center, prospectively enrolled OCTAVE cohort, comprising 2,686 participants with immune-suppressive diseases who recieved two COVID-19 vaccines, reveals specific clinical phenotypes that might benefit from specific COVID-19 therapeutic strategies.

Here, the authors computationally designed and produced small protein antagonists to target IL-6 and IL-1β signaling to develop modulators of CRS.

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.

Genomic studies often lack representation from diverse populations, limiting equitable insights. Here, the authors show that the BIG Initiative captures extensive genetic diversity and reveals ancestry-linked health disparities in a community-based Mid-South cohort.

A dataset of coding variation, derived from exome sequencing of nearly one million individuals from a range of ancestries, provides insight into rare variants and could accelerate the discovery of disease-associated genes and advance precision medicine efforts.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

An apparent redundant role with EZH2 has rendered EZH1 as a secondary player in PRC2-mediated homeostasis regulation. Here, the authors report that gain- and loss-of-function variants in EZH1 cause neurodevelopmental disorders, highlighting its functional relevance.

T cell responses can be generated to either pathogen infection or from priming with a vaccine. Here the authors compare T cell generation, phenotype and single cell transcriptome of participants vaccinated with a mpox vaccine or infected with the virus showing that the virus induced T cells showed more effective function and phenotype.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

Genome-scale genetic screens identify the small RNA-binding protein La as a strong mediator of prime editing.

Urine can be used to easily analyse the health of patients. Here, the authors identify proteins in urinary extracellular vesicles that distinguish prostate cancer from benign lesions.

The genome of the grey short-tailed opossum Monodelphis domestica has been sequenced and analyzed, giving a first peek at a marsupial's genetic code. Of particular interest are the genetics of the immune system, which has been studied as a model for humans, and of the X chromosome for historical reasons.

UDP-glucuronic acid is a component of the extracellular matrix. Here, the authors report biallelic variants in the gene encoding UDP-Glucose 6-Dehydrogenase (UGDH) in individuals affected by developmental epileptic encephalopathies that impair UGDH stability, oligomerization, or enzymatic activity in vitro.

A computational approach is used to design modular proteins that bind to synthetic peptides and disordered regions of human proteins with high affinity and specificity.

A combination of multiphoton laser scanning microscopy and second harmonic generation (SHG) imaging is used to track tumor associated fibroblasts and extracellular matrix remodeling in living mice. The SHG signal is used for image registration over several days.

Stroke is a multifactorial disease influenced by genetic and environmental factors. Here, the authors apply exome-wide association analysis to find rare coding variants associated with stroke in a Pakistani cohort, finding a significant association of a variant in NOTCH3 that is highly enriched in South Asians.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

A nanoparticle influenza vaccine candidate is shown to induce broad cross-reactive antibody responses in animal models.

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

Circulating liver enzymes, like alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are highly heritable and predictive of disease. Here, the authors perform a genome-wide association study on ALT and AST, revealing a rare variant in SLC30A10 associated with elevated ALT and AST.

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

Attenuated viruses can be highly effective vaccines. In this issue, Ralph Baric and colleagues report that inactivating mutations in the exonuclease ExoN of a mouse-adapted SARS coronavirus impair replication fidelity and cause a mutator phenotype. The resulting attenuated virus protected mice against a lethal coronavirus challenge.

COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.

Identification and characterization, using a comprehensive embryonic phenotyping pipeline, of 410 lethal alleles during the generation of the first 1,751 of 5,000 unique gene knockouts produced by the International Mouse Phenotyping Consortium.

SARS-CoV-2 neutralizing antibodies are readily detected with a biosensor.