Search

Here the authors show that inhibition of host N-myristoyltransferase by IMP1088 reduces SARS-CoV-2, VSV and RSV infection across lung and nasal cells, through a Golgi-bypassing virion egress that disrupts spike maturation and yields less infectious progeny, supporting host-directed antivirals.

Authors solve structures of in vitro Aβ40:medin mixtures to show three fibril populations and association within co-assemblies. Results support two non-exclusive mechanisms: transient interactions redirecting Aβ folding or partial medin incorporation into fibril assembly.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

ZY19489 is a potent antimalarial candidate, which shows a low resistance liability, mediated by a fitness-compromising mutation in PfCRT that restores Plasmodium falciparum susceptibility to the licensed drug piperaquine by blocking its efflux.

Mizrak et al. use single-molecule tracking to dissect mechanisms of protein targeting to lipid droplets. They show that nanodomain-based confinement drives selective protein accumulation on lipid droplets.

It remains unclear why some BRCA-deficient high-grade serous carcinomas (HGSC) do not respond to platinum-based therapy. Here, multi-omic analysis of BRCA1- and BRCA2-deficient HGSC attributes co-occurring mutations, DNA repair deficiency and tumor microenvironment features to short survival in these patients.

Chromatin dynamics govern search times between DNA elements. Using integrated MINFLUX imaging, Mazzocca, Narducci, Grosse-Holz and colleagues track chromatin dynamics over seven orders of magnitude in time, revealing two dynamics classes and providing bounds on search times.

When 100 social and behavioural science claims were examined, 34% of reanalyses closely matched the original results, with 74% reaching the same conclusion, revealing limited robustness of single-path analyses and the need to address analytical uncertainty.

The assessment of their functional neuroanatomy in healthy older adults highlights differences between event-based and time-based prospective memory including a differential modulation in the context of performance incentives.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

Mache, Kerber, et al. conduct nationwide integrated genomic, epidemiological, and virological surveillance of SARS-CoV-2 variants in Germany. They identify sequential variant replacements, age-specific infection patterns, clinical risk factors, and phenotypic evidence of continued adaptation to the human respiratory tract.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Deep learning-based modeling of interphase DNA-FISH images enables accurate detection of extrachromosomal DNA (ecDNA) across cell lines, xenografts, and patient tissues, overcoming the traditional requirement for mitotic cells in metaphase spreads.

Heinen et al. show that the mitochondrial import complex recruits lipid droplets to the mitochondrial outer membrane. The mitochondrial import complex binds to the lipid metabolism enzyme Ayr1 and contributes to lipid-droplet biogenesis and homeostasis.

IκBζ is a rather unknown transcriptional co-factor of NF-κB. Here, the authors show that constitutive IκBζ expression in a subgroup of patients with melanoma drives immunotherapy resistance and enhanced tumor growth.

Atherosclerosis is the major driver of mortality worldwide and recent studies provide first insights at single cell resolution. Here, the authors show that integrating all available studies enables coherent automatic cell type annotation, optimal experimental design and bulk deconvolution.

Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Lamin A/C in the nuclear lamina is identified as a regulator of cysteine catabolic flux, necessary for cell fate decisions and function.

Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.

The authors synthesize bee assemblage data from 681 crop fields across three continents, finding that local pesticide hazards and decreasing adjacent semi-natural habitats both negatively affected wild bee abundance and species richness in crop fields, while pesticides also reduced functional diversity.

Genome-wide association studies (GWAS) have become a key tool to discover genetic markers for complex traits; however, environmental factors that interact with genes are rarely considered. Here, the authors conduct a GWAS of obesity traits, and find that smoking may alter genetic susceptibilities.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

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.

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.

DNA methylation and copy number variant analyses across a large number of genetic mouse models of pediatric brain tumors reveal subtype-specific molecular alterations shared with the corresponding human diseases.

HippoMaps provides an open-source resource for studying the human hippocampus at different scales and with different modalities such as histology, fMRI, structural MRI and EEG.

Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index. Gene-based meta-analysis and functional studies implicate 13 genes, eight of which are novel, and neuronal pathways as factors in human obesity.

Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

Mammalian genomes are scattered with repetitive sequences, but their biology remains largely elusive. Here, the authors show that transcription can initiate from short tandem repetitive sequences, and that genetic variants linked to human diseases are preferentially found at repeats with high transcription initiation level.

Molecular analyses of longitudinal kidney biopsies from a phase 2 trial testing an anti-CD38 antibody for kidney transplant rejection show temporary suppression of antibody-mediated rejection during treatment, with molecular recurrence at 52 weeks.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

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.