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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.

Traumatic brain injury (TBI) is a serious and poorly understood medical condition. Here, the authors show that TBI induces long-lasting deficits in brain lymphatic drainage. They report that defects in this drainage pathway provoke severe TBI pathogenesis that can be rescued with VEGF-C treatment.

Louveau et al. demonstrate that meningeal lymphatics drain CSF-derived macromolecules and immune cells and play a key role in regulating neuroinflammation. Meningeal lymphatics may represent a new therapeutic target for multiple sclerosis.

Unimolecular integration of NMDA receptor antagonism with GLP-1 receptor agonism effectively reverses obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease.

Meningeal lymphatic dysfunction promotes amyloid-β deposition in the meninges and worsens brain amyloid-β pathology, acting as an aggravating factor in Alzheimer’s disease and in age-associated cognitive decline; improving meningeal lymphatic function could help to prevent or delay age-associated neurological diseases.

Heart contraction, which is decreased in disease, is determined by Ca²⁺binding to troponin C. Here, the authors combine a protein engineering approach with gene therapy to modulate heart contractility in mice with the use of rationally designed Troponin C variants, suggesting a new therapy for diseased hearts.

The inability of the heart to efficiently relax as it beats, termed diastolic dysfunction, is a major underlying cause of heart disease. As a new strategy for treating diastolic dysfunction, Joseph Metzger and his colleagues engineered directed substitutions in the calcium-binding protein Parvalbumin to optimize its ability to promote cardiac myocyte relaxation. Gene transfer of this Parvalbumin variant promoted cardiac myocyte relaxation of rabbit and canine heart failure models in vitro and corrected heart function in two in vivo mouse models of diastolic dysfunction.

There is a need for an accurate measure of pulmonary oxygenation function that can be used as an intermediate endpoint in pragmatic clinical trials, to increase statistical power and efficiency. Here, the authors show that the S/F94, a modification of the S/F ratio, is a simple, meaningful and effective intermediate outcome measure.

The molecular mechanisms leading to heart failure in patients with Duchenne muscular dystrophy are unclear. Here the authors show that NF-κB is activated in the heart of dystrophin-deficient mice and that its ablation rescues cardiac function through chromatin remodeling and activation of gene expression.

Human WNT10A mutations are associated with dental defects and adult onset ectodermal dysplasia. Xuet al. show that WNT10A-activated ß-catenin plays dual roles in adult epithelial progenitor proliferation and differentiation by complexing with KLF4 in differentiating, but not proliferating, cells.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

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.

By combining experimental models with prospective clinical studies, the authors show that spinal cord injury causes a rapid reduction in cardiac function that precedes structural changes, and that the loss of descending sympathetic control is the major cause of reduced cardiac function following spinal cord injury.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

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.

Technologies that bias GPCR expression for formation of heterodimers show that, when heterodimerized, α_2C-AR and AT-1R exhibit atypical G_s-cAMP-PKA signaling upon ligand stimulation compared to either parent receptor expressed alone and mimic activation associated with arterial hypertension.

Military veterans with traumatic brain injuries who received treatment with the psychoactive compound ibogaine and magnesium experienced improvements in disability, psychiatric symptoms and cognition.

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

Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.

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.

The Dominantly Inherited Alzheimer Network neuroimaging repository is a free resource consisting of PET and MRI scans from 533 individuals across 206 families who are deeply phenotyped with genetic, clinical, cognitive and biofluid sampling.

Frozen shoulder is a fibroproliferative disorder of the shoulder characterized by pain and progressive loss of shoulder mobility. In this Primer, Millar et al. provide an overview of the epidemiology, pathophysiology, diagnosis and treatment of frozen shoulder, as well as how it affects patients’ quality of life.

Conditional deletion of the mitochondrial Na⁺/Ca²⁺ exchanger NCLX in adult mouse hearts causes sudden death due to mitochondrial calcium overload, whereas its overexpression limits cell death elicited by ischaemia reperfusion injury and heart failure.

Genome-wide association studies have identified regions which confer risk of high-grade serous epithelial ovarian cancer. Here the authors use expression quantitative train locus analysis to identify candidate genes and functionally characterise them, identifying a role for HOXD9 in ovarian cancer.

Polycomb Repressor Complex 2 (PRC2) is frequently up-regulated in cancers. Here, the authors show that the tyrosine kinase c-Src stimulates mitochondrial function to signal energy sufficiency to mTORC1, increasing translation of the PRC2 subunits EZH2 and SUZ12 to support ErbB2-dependent tumours.

Single-molecule fluorescence resonance energy transfer imaging of conformational states of HIV-1 envelope glycoprotein trimers on intact virus and of trimers used in previous structural studies reveal the latter as downstream—rather than pre-triggered—conformations.

Blocking the enzyme KMO with a small molecule reduces the levels of toxic tryptophan metabolites and reduces multiple extrapancreatic organ failure in a rat model of acute pancreatitis.