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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).

The developmental mechanisms responsible for the structural defects observed in hypoplastic left heart syndrome remain controversial. Using rbfox-deficient zebrafish, the authors implicate impaired cardiac function as a primary driver of disease.

Candida albicans, the most common human fungal pathogen, causes local and life-threatening systemic infection. Here, the authors show that absence of tyrosine kinase 2 protects from invasive cutaneous candidiasis.

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.

Adult zebrafish possess the ability to regenerate injured hearts through a complex orchestration of molecular and cellular activities. Here, the authors present a single cell and spatially-resolved atlas of the regenerating zebrafish heart, which serves as a valuable resource for research on heart regeneration.

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.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

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

As solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Annexin A2 (ANXA2) is identified as the target of a pharmacological YAP activator and as a druggable component of the Hippo pathway.

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.

Epidermal homeostasis requires long term stem cell function. Here, the authors apply transcriptional circuitry analysis based on integrated epigenomic profiling of primary human keratinocytes with high and low stem cell function to identify IRF2 as a negative regulator of stemness.

The heart forms from combining the first with the second heart field, which in mammals creates left and right ventricle. Here transgenic zebrafish and physiology studies reveal that transcription factors controlling septation in mammals already in teleosts guide muscle coupling by controlling the relative contribution of the two fields to the heart.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Pregnant individuals infected with SARS-CoV-2 are at high risk of morbidity and mortality, in addition to adverse pregnancy outcomes, yet little is known regarding trimester-specific immunity and maternal protection from COVID-19 vaccine platforms. Authors utilise a systems serology approach to characterise the material antibody response and the transplacental antibody transfer, dependent on vaccine platform and trimester of vaccination.

Observations from the Lucy spacecraft of the small main-belt asteroid (152830) Dinkinesh reveals unexpected complexity, with a longitudinal trough and equatorial ridge, as well as the discovery of the first contact binary satellite.

Type 1 regulatory T cells control autoinflammatory diseases. In two linked papers, groups led by Kuchroo and Quintana demonstrate the role of the aryl hydrocarbon receptor in the differentiation of these cells.

Phil Beales and colleagues show that mutations in the lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome, a disorder that includes craniofacial defects, learning disability and other developmental phenotypes. They also present evidence that the COLEC11 gene product serves as a guidance cue for neural crest cell migration.

Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1Rsignificantly associated with these traits.

This Review explores the relationship between emerging infectious diseases and biodiversity loss, and how both are connected to global environmental changes in the Anthropocene.

During vertebrate embryogenesis, the pharyngeal arch arteries (PAA) connect segments of the primitive circulation. Burns and colleagues show that Nkx2.5⁺ heart precursors from the lateral plate mesoderm surprisingly give rise to the PAA angioblasts, and that Nkx2.5 is required for PAA development.

This protocol extension describes an improved method for global profiling of poly(A) RNA-binding proteins (RBPs) and quantitative analysis of RBP dynamics in response to biological and pharmacological cues that uses UV crosslinking, capture with LNA-modified oligo-dT probes, and proteomics.

Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.

Bartman et al. provide a detailed review of techniques for measuring metabolic fluxes in intact mammals, how to analyse and interpret the results and how these techniques can be applied to investigate metabolism in vivo.

Composition and function of immune populations at barrier surfaces is crucial for response to infection. Here, the authors identify a population of dendritic cells in human epidermis, abundant in anogenital epithelia and distinct from Langerhans cells by surface phenotype and by high capacity for HIV infection and transmission.

In top-down proteomics, intact proteins are analyzed by mass spectrometry. Toby et al. describe an approach for analyzing peripheral blood mononuclear cells by top-down Fourier-transform MS, with data analysis using ProSight Lite and TDPortal.

Here, the authors provide protocols for CRISPR–Cas9-based genetic manipulation of Candida albicans, using a gene-drive strategy that allows genetic interaction networks to be established for this important fungal pathogen.

IL-15-driven NK cells mediate anti-tumor immunity, but how IL-15 is negatively regulated remains unclear. Huntington and colleagues find that CIS, a member of the suppressor of cytokine signaling family, suppresses the response to IL-15 and, as a result, CIS-deficient mice are more resistant to cancer metastasis.

A complex interplay involving Notch- and Erbb2-mediated signalling between cardiomyocytes guides the morphogenesis of the ventricular wall.

Contrary to the view that urbanization is a major driver of the global rise in obesity, the global increase in body-mass index is shown to be mostly due to increases in the body-mass indexes of rural populations.