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Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

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.

Questions have arisen as to whether patients with severe COVID-19 disease can generate a T cell response against SARS-CoV-2. Tao Dong and colleagues report that convalescent patients with COVID-19 harbor functional memory CD4⁺ and CD8⁺ T cells that recognize multiple epitopes that span the viral proteome. CD4⁺ T cells predominated the memory response in patients with severe disease, whereas higher proportions of CD8⁺ T cells were found in patients with mild disease.

The alignment of the bandgap of adjacent materials in a heterostructure largely determines the electronic properties of a device. Here, the authors measure the conduction and valance band offsets at the interface between two two-dimensional materials: molybdenum disulphide and tungsten diselenide.

In most materials, the hall conductivity has a scaling to the longitudinal resistance that varies between linear and quadratic. Here, Zhang et al demonstrate a hall conductivity proportional to the fifth power of the longitudinal conductivity in Mn₃Si₂Te₆, which they attribute to enhanced force on charge carriers due to chiral orbital currents.

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.

Computationally designed genetically encoded proteins can be used to target surface proteins, thereby triggering endocytosis and subsequent intracellular degradation, activating signalling or increasing cellular uptake in specific tissues.

The authors characterize immune response in Omicron-infected vaccinated individuals and observe an immune enhancement. While increases in neutralizing antibodies and spike T cells are stronger in previously naïve individuals, mucosal antibodies and non-spike responses increase regardless of infection history.

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.

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.

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.

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.

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.

Macrophages are revealed to adopt a polymerase II pause/release process to effectively deal with ingested apoptotic corpses and for continuous efferocytosis.

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.

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.

In multiple myeloma, disease progresses via seeding to different anatomic sites and clonal expansion. Here, utilising autopsy material, the authors show that systemic seeding accelerates at relapse following treatment.

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.

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.

The authors demonstrate efficient and direct correction of the DNA mutation causing Haemoglobin E β-thalassaemia with CRISPR Cas9 base editors. The work includes profiling of off-target effects using deep neural networks.

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

Whole-exome sequencing of 250 parent–offspring trios identifies an enrichment of rare damaging de novo mutations in individuals with cerebral palsy and implicates genetically mediated dysregulation of early neuronal connectivity in the etiology of this disorder.

It is increasingly recognised that the spatial localisation of RNA is important for proper cellular function. Here, the authors investigate RNA localisation in skeletal muscle and develop methods to show that global active transport of RNA is required to maintain dispersion of gene products in the large muscle syncytium.

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.

Malignant pleural effusion (MPE) is the terminal stage of cancer and the current standard of care for MPE is largely palliative. Here the authors design a liposomal nanoparticle loaded with cyclic dinucleotide for targeted activation of STING signalling in macrophages and dendritic cells and show that, on intrapleural administration, the nanoparticle effectively mitigates the immune cold MPE and significantly augments the checkpoint blockade immunotherapy in a mouse MPE model and clinical patients’ samples.

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

ABBV-744, a selective inhibitor of the BD2 domains of BET family proteins, is effective against prostate cancer in mouse xenograft models, with lower toxicities than the dual-bromodomain BET inhibitor ABBV-075.

In pancreatic cancer the Kras and Trp53 transgene driven KPC mouse model is used to experimentally study disease processes. Here, the authors analyse tumour evolution within the KPC model, finding both linear and branched evolution and highlighting the utility of this model in mechanistic research of tumour evolution.

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 and poor outcomes. Here the authors compare the transcriptomes of single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in these patients.

Detailed mechanistic insight into fetal globin gene induction during hypoxia-associated stress erythropoiesis provides new therapeutic approaches to treat β-haemoglobinopathies, such as sickle cell disease and β-thalassaemia.

Current-control of chiral orbital current-enabled colossal magnetoresistance offers a new paradigm for quantum technologies.

A massively parallel computational and experimental approach for de novo designing and screening small hyperstable proteins targeting influenza haemagglutinin and botulinum neurotoxin B identifies new therapeutic candidates more robust than traditional antibody therapies.

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.

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.

ILC3s expressing MHC class II control the fate of inflammatory versus tolerogenic T cells that respond to the microbiota by selecting for antigen-specific RORγt⁺ T_reg cells and against T_H17 cells, establishing intestinal homoeostasis.

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.

An ABEmax-based screen identifies regulatory noncoding nucleotides in four loci that control erythroid fetal hemoglobin (HbF) expression. Targeting a repressor element raises HbF levels in cells from patients with sickle cell disease.

Leveraging independent gains and losses of eusociality, the authors identify complementary signatures of selection in sweat bee genomes, including two proteins that bind and transport juvenile hormone.

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.

Electrically insulating ligands and doping of colloidal semiconductor nanocrystals continue to be significant challenges for practical nanocrystal-based optoelectronics. Wheeler et al.demonstrate a new surface chemistry technique that confronts both of these challenges simultaneously.

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.

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.

Ru is one of the most active metals for oxygen evolution reaction, but it quickly dissolves in acidic electrolyte particularly in nanosized form. Here the authors show that coral-like solid-solution Ru‒Ir consisting of 3 nm-thick sheets with only 6 at% Ir is a long-lived catalyst with high activity

NanoLuc substrates with improved solubility and bioavailability, hydrofurimazine and fluorofurimazine, strongly enhance bioluminescence signals in vivo and enable bright dual-color bioluminescent imaging with AkaLuc and AkaLumine.

Iacobuzio-Donahue and colleagues use integrated transcriptomic, histologic and mutational data to analyze squamous features of pancreatic ductal adenocarcinoma (PDAC), further refining the understanding of heterogeneity and evolution in PDAC.