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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 APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

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.

Global landings of wild-caught seafood have plateaued in recent years. Analysing trends in global fisheries catches, Watson et al.find that distance between sourcing and consumption has increased steadily since the 1950s, with ocean productivity unlikely to meet current consumption rates by 2100.

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.

Metformin may serve as a non-toxic intervention to inhibit mitochondrial metabolism and slow DNMT3A-R882 clonal haematopoiesis expansion, thus delaying or averting progression to acute myeloid leukaemia.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

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.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

An epitaxial heterostructure of a perovskite and rocksalt is stable up to 1,100 °C in air. Based on mechanistic and computational analyses, hundreds of potential cubic oxide pairs with similar properties are identified for applications in nanophotonics.

Swanton and colleagues present a clonal expression signature, ORACLE, which, in combination with clinicopathological and molecular risk factors, can predict survival of patients with lung adenocarcinoma, and they prospectively validate its prognostic value.

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

In this work, researchers address a key question for maternal group B Streptococcus (GBS) vaccine assessment: What newborn antibody concentrations protect against invasive infant GBS disease? They present serologic thresholds by age at onset and serotype based on a large U.S. case-control study.

The goal of the 1000 Genomes Project is to provide in-depth information on variation in human genome sequences. In the pilot phase reported here, different strategies for genome-wide sequencing, using high-throughput sequencing platforms, were developed and compared. The resulting data set includes more than 95% of the currently accessible variants found in any individual, and can be used to inform association and functional studies.

Patient-derived xenografts are important tools for cancer drug development. Here, the authors develop models from 22 non-small cell lung cancer patients. They show genomic differences between models created from different spatial regions of tumours and a bottleneck on model establishment.

Immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS) infers B cell and T cell fractions from whole-genome sequencing data. Applied to the 100,000 Genomes Project datasets, circulating T cell fraction provides sex-dependent and prognostic insights in patients.

The TRPM7 channel enables endosomal acidification, which is vital for the entry of many enveloped viruses. Here, the authors show that loss of TRPM7 protects cells from various pandemic-threat viruses, pointing to a new strategy for broad-spectrum antiviral drugs.

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.

By coupling robotic cell culture systems with artificial intelligence–powered image analysis, Schiff et al. identify previously unseen characteristics of Parkinson’s disease in patient skin cells that distinguish them from healthy controls.

Analyses of the TRACERx study unveil the relationship between tissue morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk of lung adenocarcinomas.

Experiments in mouse and hamster models show that monoclonal antibody combinations, using antibodies that correspond to products in clinical development, largely retain their efficacy in protecting against currently prevailing variant strains of SARS-CoV-2.

Results of the TRACERx study shed new light into the association between body composition and body weight with survival in individuals with non-small cell lung cancer, and delineate potential biological processes and mediators contributing to the development of cancer-associated cachexia.

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.

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 Cancer Genome Atlas Research Network reports an integrative analysis of more than 400 samples of clear cell renal cell carcinoma based on genomic, DNA methylation, RNA and proteomic characterisation; frequent mutations were identified in the PI(3)K/AKT pathway, suggesting this pathway might be a potential therapeutic target, among the findings is also a demonstration of metabolic remodelling which correlates with tumour stage and severity.

A longitudinal evolutionary analysis of 126 lung cancer patients with metastatic disease reveals the timing of metastatic divergence, modes of dissemination and the genomic events subject to selection during the metastatic transition.

Major histocompatibility complex (MHC) loss of heterozygosity, allele-specific mutation and measurement of expression and repression (MHC Hammer) detects disruption to human leukocyte antigens due to mutations, loss of heterogeneity, altered gene expression or alternative splicing. Applied to lung and breast cancer datasets, the tool shows that these aberrations are common across cancer and can have clinical implications.

In the TRACERx cohort of 171 patients with lung cancer, the ultrasensitive detection of ctDNA improves preoperative patient stratification, also in early-stage disease.

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.

TH1760 is a first-in-class, potent, selective and cell-active inhibitor against human NUDT15, which sensitizes cells to 6-thioguanine treatment. TH1760 represents a valuable tool for deciphering the enigmatic functions of NUDT15.

Measurements of subclonal expansion of ctDNA in the plasma before surgery may enable the prediction of future metastatic subclones, offering the possibility for early intervention in patients with non-small-cell lung cancer.

An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes.

Analyses of multiregional tumour samples from 421 patients with non-small cell lung cancer prospectively enrolled to the TRACERx study reveal determinants of tumour evolution and relationships between intratumour heterogeneity and clinical outcome.

The Impact of Genomic Variation on Function Consortium is combining single-cell mapping, genomic perturbations and predictive modelling to investigate relationships between human genomic variation, genome function and phenotypes and will provide an open resource to the community.

Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.

Observations from the JWST show the presence of a spectral absorption feature at 4.05 μm arising from SO₂ in the atmosphere of the gas giant exoplanet WASP-39b, which is produced by photochemical processes and verified by numerical models.

Observations from the JWST MIRI/LRS show the detection of SO₂ spectral features in the 5–12-μm transmission spectrum of the hot, Saturn-mass exoplanet WASP-39b, suggesting that photochemistry is a key process in high-temperature exoplanet atmospheres.

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

When an extrasolar planet passes in front of its star (transits), its radius can be measured from the decrease in starlight and its orbital period from the time between transits. This study reports Kepler spacecraft observations of a single Sun-like star that reveal six transiting planets, five with orbital periods between 10 and 47 days plus a sixth one with a longer period. The five inner planets are among the smallest for which mass and size have both been measured, and these measurements imply substantial envelopes of light gases.

In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.

The olfactory receptors and neurons that recognize the insect repellent DEET have been identified in Drosophila melanogaster, enabling identification of new insect repellents in a chemical screen and offering another research avenue against diseases transmitted by insects.

Computational and machine-learning approaches that integrate genomic and transcriptomic variation from paired primary and metastatic non-small cell lung cancer samples from the TRACERx cohort reveal the role of transcriptional events in tumour evolution.

The addition of a Notch signaling inhibitor to both mouse and human keratinocytes bypasses the use of oncogenes and p53 to increase transcription factor mediated–pluripotent stem cell reprogramming through blocking p21 expression.