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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.

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.

The authors analyze rare coding variants in 1990 individuals with congenital kidney anomalies, finding diagnostic variants in 14.1% of cases. They identify two new causal genes, ARID3A and NR6A1, along with 38 candidate genes, providing evidence for shared genetics with other developmental disorders.

In Sweden, dietary changes simulated under four food futures pathways reduced environmental impacts by 30 percent, but waste and fossil fuel emissions reductions are necessary to meet the climate target, according to an analysis that combines food items, nutrients, health, and environmental data.

The cause of abnormal alveolar regeneration in idiopathic pulmonary fibrosis is unknown. Here, the authors generated a temporo-spatial cellular map of the regenerating niche and, using unbiased mathematical methods, identified a spatial interaction between a subset of macrophages and aberrant alveolar epithelial cells across all stages of the disease.

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.

Primary angle-closure glaucoma is a leading cause of blindness. Here, the authors identify rare deleterious variants in UBOX5 as risk factors and implicate BIP ubiquitination as a potential disease mechanism.

Prediabetics have an increased risk of type 2 diabetes. In this parallel-design, randomized controlled trial, the authors show improvements in metabolic health in a prediabetes population consuming a legume-rich diet, which are mediated through favorable changes in gut microbiome.

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.

AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple triple-negative breast cancer models in vivo by triggering an involution-like process.

Without relying on any infrastructure-based vehicle detectors, the authors present a scalable traffic signal re-timing system that uses a small percentage of connected vehicle trajectories as the only input. Real-world tests demonstrate that the system decreases both delays and number of stops.

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.

Water thermodynamics drive changes in macromolecular assembly that rapidly restore intracellular water availability in response to physiological fluctuations in temperature, pressure and osmotic strength.

How synaptic vesicles (SVs) are clustered at the presynapse is suggestive of anchoring processes counteracting their diffusion. Here, the authors co-track recycling and reserve SVs in live neurons to find that Synapsin 2a tetramerization dynamically immobilizes reserve SVs at the presynapse.

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.

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.

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.

 A transcriptomic cell-type atlas of the whole adult mouse brain with ~5,300 clusters built from single-cell and spatial transcriptomic datasets with more than eight million cells reveals remarkable cell type diversity across the brain and unique cell type characteristics of different brain regions. 

A single-cell sequencing study using more than 30,000 tumour genomes from human ovarian cancers shows that whole-genome doubling is an ongoing mutational process that drives tumour evolution and disrupts immunity.

Antigen specific regulatory T cells (Treg) play key roles in the peripheral tolerance to suppress autoreactive immune cells and represent potential avenue for therapeutic intervention. Here the authors identify Smith specific Treg and engineer Treg based cell therapy showing suppression of inflammation in a murine model of lupus nephritis.

An optogenetic tool called Opto-OGT has been developed that enables researchers to probe pathways involving modifications with O-linked β-N-acetylglucosamine (O-GlcNAc) such as OGT, mTOR and AMPK signaling with high spatiotemporal precision. The method is based on fusing a photosensitive cryptochrome protein to an O-GlcNAc transferase and enables OGT to be reversibly activated with blue light.

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.

A comparison of fetal hemoglobin gene editing strategies using human sickle cell disease donor cells and in vivo transplantation finds that adenine base editing of the –175A>G site in the γ-globin gene promoters results in durable and potent expression.

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.

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.

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

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.

Epithelial tissue mononuclear phagocytes (MNP) can transmit HIV to CD4 T cells, but less is known about sub-epithelial cells. Here, the authors describe MNPs in human anogenital and colorectal tissues and find that CD14⁺CD1c⁺ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 preferentially take up and transmit HIV.

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.

Gender-based violence is widespread, affecting women and men worldwide. Stein et al. use a meta-analysis and the Burden of Proof methodology to evaluate associations between gender-based violence and eight health outcomes, including major depressive disorder, substance use and reproductive health.

Around the world, more than a billion children are regularly exposed to violence or neglect. Flor et al. systematically review evidence that links childhood physical violence, psychological violence and neglect to increased risks for 14 health outcomes.

We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M⁺ diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG.

Lee and colleagues demonstrate that actin depolarizing factor (ADF)/cofilin regulates, and is required for, the insertion of acetylcholine receptors (AChRs) into the postsynaptic membrane at neuromuscular synapses. ADF/cofilin also appears to stabilize membrane AChRs; it associates with AChR clusters and disappears before the clusters themselves disassemble.

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.

RNA sequencing data and tumour pathology observations of non-small-cell lung cancers indicate that the immune cell microenvironment exerts strong evolutionary selection pressures that shape the immune-evasion capacity of tumours.

Multi-modal analysis of genomically unstable ovarian tumours characterizes the contribution of anatomical sites and mutational processes to evolutionary phenotypic divergence and immune resistance mechanisms.

A survey of T cell repertoire evolution in the tumors, healthy tissue and blood of patients with early-stage untreated lung cancer offers an opportunity to monitor and identify neoantigen-specific T cells for personalized immunotherapy.

Medulloblastoma is the most common brain tumour in children; using exome sequencing of tumour samples the authors show that these cancers have low mutation rates and identify 12 significantly mutated genes, among them the gene encoding RNA helicase DDX3X.

By manipulating the rhythmicity of neural activity in entorhinal cortex and hippocampus, Quirk et al. show that memory is impaired by aberrant oscillatory activity during the encoding phase, but not during retention or retrieval phases.

There is a trade-off between increasing thickness of active layers in organic photovoltaic cells to be compatible with modern printing techniques and decreasing it to improve the device performance. Sun et al.report a nematic liquid crystalline molecular electron donor material used in thick layers.

An environmentally friendly, all-organic radical battery is demonstrated, in which redox-active polypeptides perform as both cathode and anode materials, with a metal-free organic electrolyte.

A consensus cell type atlas for the fly brain provides both an intellectual framework and open-source toolchains for brain-scale comparative connectomics.

Chromosomal instability enables the continuous selection of somatic copy number alterations, which are established as ordered events that often occur in parallel, throughout tumour evolution and metastasis.

Analysis of whole-genome doubling (WGD) by using cancer sequencing data combined with simulations of tumor evolution suggests that there is negative selection against homozygous loss of essential genes before WGD but not after.

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.

Circulating tumour DNA profiling in early-stage non-small-cell lung cancer can be used to track single-nucleotide variants in plasma to predict lung cancer relapse and identify tumour subclones involved in the metastatic process.

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.

Rodin and Dou et al. characterized genome-wide somatic mutation in autistic and control brains, revealing that even unaffected individuals may possess dozens of brain somatic mutations and providing insight into the role of somatic mutation in autism.