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Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Integration of GWAS and single-cell transcriptomic data from the entire nervous system systematically identifies cell types underlying brain complex traits and provides insights into the etiology of Parkinson’s disease.

Analysing 27 years of freshwater invertebrate biomonitoring data from European rivers, the authors show that although some commonly used biodiversity metrics can reflect anthropogenic impacts at broad spatial scales, there was little consistency among other metrics in accurately reflecting community responses.

Irradiation to condition hosts for bone marrow transplantation leads to alterations in intestinal microbiota. Reddy and colleagues demonstrate that these changes result in reduced butyrate production and breakdown of intestinal barrier function.

Specific gut microbiota constituents that affect the severity of malaria are unknown. Here, Mandal et al. identify specific Bacteroides species causing susceptibility to severe malaria in mice and correlate with the severity of malaria in Ugandan children.

Improvements in European freshwater biodiversity occurred mainly before 2010 but have since plateaued, and communities downstream of dams, urban areas and cropland were less likely to experience recovery.

Liquid-crystalline arrangements of complexes of DNA and antimicrobial peptides can lead to multivalent electrostatic interactions that drastically amplify TLR9-mediated immune responses.

This Review discusses multiomic approaches for the characterization and biological understanding of cellular senescence, including detailed case studies on skeletal muscle and adipose tissue that highlight current outstanding issues in the field.

Cytotoxic response is mediated by delivery of lytic molecules at the effector cell/target cell junction site, termed the immunological synapse. Here the authors find, using single cell biophysical measurements, that the during this process the αLβ2 integrin, LFA-1, helps focus lytic granule release via talin-dependent, pulling force-mediated spatial guidance.

The relationships that control seed production in trees are key to understand evolutionary pressures that have shaped forests. A global synthesis of fecundity data reveals that while seed production is not constrained by a strict size-number trade-off, it is influenced by taxonomy and nutrient allocation.

Metal-mediated base pairs expand the repertoire of nucleic acid structures and dynamics. Here, the authors prepared a metallo-DNA duplex including two C-Hg(II)-T base pairs separated by six normal Watson-Crick base pairs and investigated its solution structure and dynamics using NMR spectroscopy.

The emergence of relaxation in unitarily evolving systems can be seen as a paradox, but not once the distinction between local and global dynamics is considered. Here, the authors use photons in an integrated optical interferometer to show that, for a system evolving unitarily on a global level, single-mode measurements converge to those of a thermal state.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

TDP-43 controls an exon splicing event in UNC13A that results in the inclusion of a cryptic exon associated with frontotemporal dementia and amyotrophic lateral sclerosis.

The Pseudomonas aeruginosa lytic polysaccharide monooxygenase CbpD, prevalent in clinical isolates, has been proposed to act as a virulence factor. Here, the authors combine structural work, in silico simulations, enzymatic activity and in vitro and in vivo experiments to further delineate the role of CbpD and show that its deletion renders P. aeruginosa unable to establish a lethal systemic infection, leading to enhanced bacterial clearance in a mouse model of infection.

Senescent cells in fat and liver are shown to attract M1-like macrophages with increased expression of the NAD-consuming enzyme CD38, leading to their local accumulation and providing a mechanism for the age-associated decline in tissue NAD⁺ levels.

The ability to reversibly control monobody binding affinity would find use in biotechnology and research applications. Here the authors fuse the light-sensitive AsLOV2 domain to a monobody against the Abl SH2 domain to obtain a light dependent monobody and apply it in vitro and in mammalian cells.

Mutations in the Protein Phosphatase PPM1D are oncogenic in certain cancers including diffuse intrinsic pontine glioma (DIPG). Here, the authors show that PPM1D mutations in DIPG induce the silencing of the nicotinic acid phosphoribosyltransferase gene and display synthetic lethality with nicotinamide phosphoribosyltransferase inhibitors.

Uveal melanoma has a propensity to metastasise. Here, the authors report the whole genome sequence of 103 uveal melanomas and find that the tumour mutational burden is variable and that two subsets of tumours are characterised by MBD4 mutations and a UV exposure signature.

Polygenic Priority Score (PoPS) prioritizes candidate effector genes at complex trait loci by integrating genome-wide association summary statistics with other data types. Combining PoPS with methods that leverage local genetic signals further improves the performance.

Conventional wisdom suggests that it should be impossible for information to pass across a singularity. A study of the behaviour of air bubbles as they disconnect from a submerged nozzle suggests that this isn’t always the case.

Most confirmed susceptibility variants for epithelial ovarian cancer lie in non-protein-coding sequences. Here Permuth-Wey and colleagues investigate variants in 3′ untranslated regions (UTRs) and uncover a new susceptibility locus.

A possible kilonova associated with a nearby, long-duration gamma-ray burst suggests that gamma-ray bursts with long and complex light curves can be spawned from the merger of two compact objects, contrary to the established gamma-ray burst paradigm.

Associations between of omega-3 fatty acids and mortality are not clear. Here the authors report that, based on a pooled analysis of 17 prospective cohort studies, higher blood omega-3 fatty acid levels correlate with lower risk of all-cause mortality.

Finding causal variants and genes from GWAS loci results remains a challenge. Here, the authors train a model to predict if a variant affects nearby gene expression, and apply the method to identify new possible causal eQTLs and mechanisms of GWAS loci.

How climate change influences the lifecycle of stratospheric volcanic aerosols and the associated radiative forcing is unknown. Here, the authors present model experiments suggesting that climate change amplifies the forcing of large-magnitude tropical eruptions but reduces the forcing of moderate-magnitude tropical eruptions.

This Registered Report presents evidence from 87 countries and regions showing that brief emotion-regulation interventions consistently reduced negative emotions and increased positive emotions during the COVID-19 pandemic.

Optogenetically controlling the assembly of enzyme clusters enhances product formation and specificity during deoxyviolacein biosynthesis by decreasing concentrations of intermediate metabolites and reducing flux through competing pathways.

Hess and colleagues perform metabolic screens in B cells from patients with primary antibody deficiency and find that germline mutations in the succinate dehydrogenase subunit SDHA drive the expression of the cytokine IL-6 in patients with persistent polyclonal B cell lymphocytosis.

Lack of standardization between biofoundries limits their operational efficiency. In this perspective the authors advocate for a common framework to improve interoperability and reproducibility.

Paul Pharoah, Joellen Schildkraut, Thomas Sellers and colleagues report a meta-analysis of genome-wide association studies for epithelial ovarian cancer and genotyping using the iCOGS array in 18,174 cases and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. They identify three new ovarian cancer susceptibility loci, including one specific to the serous subtype, and their integrated molecular analysis of genes and regulatory regions at these loci suggests disease mechanisms.

An individual star at z = 1.49 is gravitationally lensed and highly magnified by a foreground galaxy cluster. Fluctuations in the star’s emission provide insight on the mass function of intracluster stars, compact objects and the presence of dark-matter subhaloes.

Massively parallel DNA sequencing allows entire genomes to be screened for genetic changes associated with tumour progression. Here, the genomes of four DNA samples from a 44-year-old African-American patient with basal-like breast cancer were analysed. The samples came from peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The findings indicate that cells with a distinct subset of the primary tumour mutation might be selected during metastasis and xenografting.

Peptide-based supramolecular assemblies are a promising class of nanomaterials with important biomedical applications, but their antibacterial properties can be overlooked. Here the authors show the antibacterial activity of self-assembled diphenylalanine, which emerges as the minimal model for antibacterial supramolecular polymers.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease.

Single-cell transcriptional profiling of primary human synovial sarcoma tumors suggests that combinatorial treatment with HDAC and CDK4/CDK6 inhibitors could enhance tumor immunogenicity.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

Exome-wide genetic analysis on >300,000 individuals identifies associations with plasma lipid traits. Loci significantly associated with cholesterol and triglycerides are examined together to determine the effects of alleles on type 2 diabetes and coronary artery disease risk.

Simulations of dwarf galaxies that include photoelectric grain heating and supernovae indicate that the former is the dominant means by which these galaxies regulate their star formation rate, because the latter are unable to account for the observed large gas depletion times.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.