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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).

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.

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.

Evo 2 is an artificial intelligence-based biological foundation model trained on 9 trillion DNA base pairs spanning all domains of life that predicts functional properties from genomic sequences and provides a rich generative model for researchers in biology.

Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.

Breakdown of the blood–brain barrier in individuals carrying the ε4 allele of the APOE gene, but not the ε3 allele, increases with and predicts cognitive impairment and is independent of amyloid β or tau pathology.

The early genetic evolution of uveal melanoma (UM) remains poorly understood. Here, the authors perform genetic profiling of 1140 primary UMs, including 131 small early-stage tumours, finding that most genetic driver aberrations have occurred by the time small tumours are biopsied; in addition, the15-gene expression profile discriminant score can predict the transition from low- to high-risk tumours.

Neuroimaging and cerebrospinal fluid analyses in humans reveal that loss of blood–brain barrier integrity and brain capillary pericyte damage are early biomarkers of cognitive impairment that occur independently of changes in amyloid-β and tau.

. Androgen-receptor blockade can overcome immunotherapy resistance in prostate cancer by intrinsically enhancing T cell function and IFNγ responses. 

Variation in antibody levels elicited by the COVID-19 vaccine ChAdOx1 nCov-19 is linked to specific major histocompatibility complex class II alleles, providing insight into the breadth of immune response among vaccinated individuals.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

CRISPR–Cas9 genome editing is used to induce a DNA repair response and correct a disease-causing heterozygous mutation in human embryos with reduced mosaicism and preferential repair using the wild-type copy of the gene.

In a first-in-human phase 1/2 study in seven patients with sickle cell disease, autologous hematopoietic stem cell lentiviral gene therapy using reduced-intensity conditioning was considered feasible and safe, achieving >80% reduction in the frequency of vaso-occlusive events.

FLT3 is commonly mutated in acute myeloid leukaemia and treatment with FLT3 inhibitors often ends with relapse. Here, the authors perform exome sequencing of samples from patients treated with the FLT3 inhibitor, crenolanib, to show that resistance occurs due to diverse molecular mechanisms, not primarily due to secondary FLT3 mutations.

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.

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.

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.

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.

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.

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.

Co-infection with HIV and tuberculosis is a potent combination. Amy Maxmen investigates the impact of this deadly duo.

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

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.

Two doses of the coronavirus disease 2019 vaccine ChAdOx1 nCoV-19 boost antibody responses and functions in phase 1/2 trial participants.

Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.

Genome-wide ancient DNA data from individuals from the Middle Bronze Age to Iron Age documents large-scale movement of people from the European continent between 1300 and 800 bc that was probably responsible for spreading early Celtic languages to Britain.

A new discovery strategy, ‘reverse metabolomics’, facilitates high-throughput matching of mass spectrometry spectra in public untargeted metabolomics datasets, and a proof-of-concept experiment identified an association between microbial bile amidates and inflammatory bowel disease.

Neuroendocrine differentiation of epithelial tumor cells can contribute to cancer cell resistance and survival. Here, the authors show that dysregulated c-Myc promotes neuroendocrine differentiation in pancreatic ductal adenocarcinoma, leading to poor survival and chemoresistance.

Acute Myeloid Leukemia (AML) develops following multiple mutations of differing impact. Here, the authors show that activating mutations of CSF3R co-operate with loss-of-function mutations of CEBPA to promote AML development through an enhancer-dependent mechanism.

Mathematical tools can be used to help identify pathological features from images of diseased lungs. Here, the authors used mathematical tools combined with high resolution multiplex imaging mass cytometry to show an association between immature neutrophils, CD8 T cells and proliferating alveolar epithelial cells in areas of maximal alveolar damage in COVID-19 lungs.

Genome-wide meta-analysis of SARS-CoV-2 susceptibility and severity phenotypes in up to 756,646 samples identifies a rare protective variant proximal to ACE2. A 6-SNP genetic risk score provides additional predictive power when added to known risk factors.

Little is known about how hybrid taxa become established as new species. Studying floral morphology evolution in different Nicotiana allopolyploids shows transgressive shortening and broadening of the corolla accompanies hybrid species formation/hybridization.

SNP rs17713054 in the 3p21.31 COVID-19 risk locus is identified as a probable causative variant for disease association. Chromatin conformation and gene expression data indicate that LZTFL1 is impacted by rs17713054 in pulmonary epithelial cells.

Hedgehog signalling is known to be linked to oncogenic proliferation. Here, the authors identify structural events as a mechanism of Hedgehog activation in over one-third of driver unknown meningiomas.

The APOE4 allele is a major genetic risk factor for the development of late-onset Alzheimer’s disease (AD). In this manuscript, Butovsky and colleagues suggest that APOE4 impairs the microglial response in AD by inducing TGFβ-mediated checkpoints.

New delivery platforms are needed to allow broader application of biotherapeutics for CNS diseases. Here, the authors show enhanced CNS delivery with a transport vehicle engineered to bind CD98hc, a highly expressed target at the blood-brain barrier.

COVID-19-related travel restrictions were imposed in China around the same time as major annual holiday migrations, with unknown combined impacts on mobility patterns. Here, the authors show that restructuring of the travel network in response to restrictions was temporary, whilst holiday-related travel increased pressure on healthcare services with lower capacity.

Richard Trembath and colleagues report a meta-analysis of genome-wide association studies for psoriasis, including 2 cohorts genotyped on the custom Immunochip array, in a total of 10,588 cases and 22,806 controls. They identify 15 new susceptibility loci and refine signals in previously known loci, highlighting a role for innate host defense in susceptibility to psoriasis.

The MAGIC investigators report results of a large genome-wide association study meta-analysis to identify common variants influencing fasting glucose homeostasis. They further show that several of the newly discovered loci influencing glycemic traits are also associated with risk of type 2 diabetes.

A new GWAS of schizophrenia (11,260 cases and 24,542 controls) and meta-analysis identifies 50 new associated loci and 145 loci in total. The common variant association signal is highly enriched in mutation-intolerant genes and in regions under strong background selection.

DNA repair in response to DSBs in the preimplantation embryo is hard to analyze. Here the authors show that over 25% of pre-existing heterozygous loci in control single blastomere samples appeared as homozygous after whole genome amplification, therefore, they validated gene editing seen in human embryos in ESCs.

This study finds that sST2 is a disease-causing factor for Alzheimer’s disease. Higher sST2 levels impair microglial Aβ clearance in APOE4⁺ female individuals. A genetic variant, rs1921622, is associated with a reduction in sST2 level and protects against AD in APOE4⁺ female individuals.

A biodegradable pacemaker without external leads improves the safety of temporary cardiac pacing.

The Human Microbiome Project Consortium has established a population-scale framework to study a variety of microbial communities that exist throughout the human body, enabling the generation of a range of quality-controlled data as well as community resources.