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Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

Photovoltaic devices attached to immune cells travel through the blood to inflamed brain regions.

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology.

The canonical BRG1/BRM-associated factor (cBAF) complex is recruited by HNF1A/B to angiotensin-converting enzyme 2 (ACE2) enhancers, promoting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inhibition of the catalytic activity of SMARCA4 precludes ACE2 expression and reduces susceptibility to SARS-CoV-1 and major SARS-CoV-2 variants.

A longitudinal analysis of humoral immune responses in patients with COVID-19 with varying disease severities reveals that mortality does not correlate with antiviral antibody levels but, instead, with slower seroconversion.

Ibogaine is a natural substance that interrupts opioid addiction but has cardiac risks. This article introduces novel ibogaine analogs that show reduced cardiac risk and enhanced neuroplasticity and therapeutic-like effects in models of opioid use disorder.

The UK Government aims to reduce premature deaths from non-communicable diseases by one-third by 2030 (SDG 3). Using life table methodology and data from the UK Biobank, this study indicates that sustained dietary changes—from median or unhealthy to a longevity-associated dietary pattern or to the Eatwell Guide recommendations—could lead to substantial life expectancy gains.

It is elusive why some heavy drinkers progress to severe alcohol-related liver disease (ALD) while others do not. Here we show that people who have a poor diet, as indicated with a data-driven score, might be more susceptible to severe ALD due to alcohol consumption.

A new technology for proteome-scale assessment of human exoproteome–microbiome interactions exposes an extensive network of transkingdom connectivity.

Thierer and colleagues identify PLA2G12B as a key gene driving triglyceride incorporation into lipoproteins and show that disruption of this activity provides protection from atherosclerosis.

Large sequences are integrated site specifically into the human genome without double-strand DNA cleavage.

Wiskott-Aldrich syndrome is caused by mutations in WASP, but the underlying mechanisms remain to be explored. Here the authors reveal that WASP deficiency results in aberrant RNA splicing, and that WASP regulates the transcription of splicing factor genes and co-transcriptional RNA splicing via a phase-separation process that involves splicing factors and nascent RNA.

A pooled genetic, transcriptomic and immunopathologic analysis of over 500 tumors from patients with advanced renal cell cancer suggests that response to PD-1 blockade depends on both CD8⁺ T cell infiltration and enrichment of tumor-intrinsic somatic alterations.

The authors identify genetic variation associated with properties of the internal biological structures of blood cells in hundreds of genes and show how such discoveries can be used to improve understanding of cellular mechanisms causing disease.

The molecular mechanism underlying the severe neurogenic inflammation induced by Clostridioides difficile is presented, providing a therapeutic target for treating this infection.

Variability in the individual response to dietary interventions has been reported. Here a Dietary Metabotype Score is developed to embody those interindividual responses by coupling data from highly controlled dietary studies with urinary metabolic phenotypes. This score may offer a method to target and to enhance dietary response at the individual level, thereby reducing the burden of diet-related disease at the population level.

Rapid extracellular antigen profiling of a cohort of 194 individuals infected with SARS-CoV-2 uncovers diverse autoantibody responses that affect COVID-19 disease severity, progression and clinical and immunological characteristics.

A comparative analysis of Cryptosporidium genome sequences elucidates the evolutionary history of these parasites and highlights changes associated with its human adaptation.

Smith et al. report that age-associated mutations in mitochondrial DNA cause defects in oxidative phosphorylation. This results in metabolic rewiring, which subsequently contributes to accelerated development of colorectal cancer.

Missense variants in RNA-binding proteins underlie many diseases. Here the authors report an oculopharyngeal muscular dystrophy caused by heterozygous frameshift mutations in HNRNPA2B1 that alter its nucleocytoplasmic transport dynamics and result in cytoplasmic accumulation of hnRNPA2 protein.

Targeted gene delivery to the brain is a critical tool for neuroscience research and has significant potential to treat human disease. Here the authors engineer the protein shell of a common gene therapy vector for enhanced efficiency and specificity of brain delivery in ultrasound-targeted brain regions.

The CRISPR/Cas9 system can be used for genome editing. Here, Liao et al. show that the system can be adapted to inhibit HIV expression and replication, excise the integrated HIV genome and provide long-term protection against new infections in human cells, including pluripotent stem cells.

A cryo-electron microscopy structure of the neurotensin receptor 1 in complex with β-arrestin 1 is reported.

Here, the authors identify and validate the emergence of a SARS-CoV-2 resistance mutation to Remdesivir, associated with virological recrudesce in an immunocompromised patient with persistent COVID-19.

Although rare, antibodies against the receptor-binding domain of SARS-CoV-2 that showed potent antiviral activity were obtained from all tested convalescent individuals, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

Male patients with COVID-19 have higher plasma levels of innate immune cytokines and chemokines such as IL-8, IL-18 and CCL5 and more non-classical monocytes than female patients, whereas female patients mount robust T cell activation maintained even in older age.

A longitudinal analysis of immune responses in patients with moderate or severe COVID-19 identifies a maladapted immune response profile linked to severe disease.

The cellular organelles peroxisomes contribute to the sensitivity of cells to ferroptosis by synthesizing polyunsaturated ether phospholipids, and changes in the abundances of these lipids are associated with altered sensitivity to ferroptosis during cell-state transitions.

Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

Derek Mann and his colleagues have found that experimental induction of liver fibrosis in male rats results in an epigenetic modification of the chromatin in their sperm such that their offspring have a more mild wound-healing response to hepatic fibrogenic insults. The mechanism responsible for this phenomenon is not clear, but it seems to involve a yet unidentified soluble factor released by myofibroblasts that act on either the germ cells or mature sperm.

Synthetic chimeric orthogonal IL-2 receptors that incorporate the intracellular domain of receptors for other γ-chain cytokines such as IL-9 can reroute orthogonal signalling and alter the phenotype of T cells to improve anti-tumour responses.

In the USA, scientific merit is the main criterion determining funding for biomedical research, but not for the institutional space or support needed to perform it. Realigning the incentives of academic institutions with those of funding sources could produce better science.

X-ray crystallography and molecular dynamics simulations of the μ-opioid receptor reveal the conformational changes in the extracellular and intracellular domains of this G-protein-coupled receptor that are associated with its activation.