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Robustness checks and reproduction of analyses with existing and updated data based on 110 articles in economics and political science journals with data and code-sharing requirements found high levels of robustness and reproducibility and determined that robustness was not dependent on author characteristics or data availability.

Independently folding domains can be seen as the functional and evolutionary structural units of proteins. Here, the authors assess effects of >7000 mutations in a model PDZ domain, to quantify how two small extensions to a protein domain reshape its energetic and allosteric landscape.

Analysis of Babesia divergens egress from host cells reveals druggable targets and identifies compounds for potential babesiosis treatment.

The distinct architecture of the Escherichia coli membrane transporter LetA mediates lipid trafficking across the bacterial envelope in partnership with the tunnel-like complex LetB.

In this work, authors show that β-lactamase enzymes not only confer antibiotic resistance but also increase susceptibility to other antibiotics.

By experimentally sampling from sequence spaces larger than 10¹⁰ and using thermodynamic models, the genetic structure of at least some proteins can be well described, indicating that protein genetics is simpler than anticipated.

Hybridomas are widely used for antibody screening and production due to their genetic stability and rapid proliferation. Here the authors demonstrate the rapid reprogramming of antibody specificity in hybridomas using CRISPR-Cas9.

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).

Africa-specific genetic variation on chromosome 1 near CHD1L is associated with HIV replication in vivo.

Actin is crucial for nervous system function yet the role of microexons in its modulation is unclear. Here, the authors show that a microexon in DAAM1 has a role in actin dynamics, neuronal function and memory formation in mice.

Here, by integrating faecal metabolomics, metagenomics, and habitual dietary data of two large human cohorts, the authors show that faecal metabolites reflect diet and gut microbiome interactions, predict dietary patterns, and indicate cardiovascular risk, offering insights for diet-based health interventions.

A main challenge for the use of CAR-T in solid tumours is the identification of surface proteins as feasible targets. Here, the authors show TYRP1 as a target for CAR-T cell therapy in preclinical models of cutaneous, acral and uveal melanoma.

The authors describe a new crosstalk between a globally disseminated carbapenem resistance plasmid and clinical enterobacteria clones. This crosstalk provides a fitness advantage to the plasmid-carrying bacteria, promoting the spread of resistance.

The design of prime editing guide RNAs is optimized by deep learning.

Comparison of genome-wide association studies of HTT CAG repeat expansion in blood to expansion-driven clinical traits in Huntington’s disease identifies shared and distinct modifiers implicating DNA mismatch repair with tissue and cell-type specificity.

Synchronizing gene expression across eukaryotic communities presents complex challenges. Here the authors construct a compact synthetic system inspired by bacteria response to antibiotics that robustly converts chemical rhythms into synchronized gene expression across populations.

The lack of control over Cas13 activity has limited its utility. Here the authors report Control of RNA with Inducible SpliT CAs13 Orthologs and Exogenous Ligands (CRISTAL), controlled by orthogonal split inducible Cas13 effectors that can be turned ON or OFF, providing precise temporal control.

Transcription factors are rich in intrinsic disorder and therefore hard to drug. The authors improve an experimental drug for castration-resistant prostate cancer by learning how the activation domain of the androgen receptor activates transcription.

The Global Flourishing Study provides a comprehensive view of the distribution and determinants of well-being by assessing domains such as health, happiness, meaning, character, relationships and financial security. Initial findings reveal significant variations in flourishing across countries and demographic groups, with factors such as age, marital status and religious service attendance showing strong associations with well-being.

Bialowolski et al. analyse financial well-being across 22 countries using data from the Global Flourishing Study. They find that demographic factors (for example, age) and early-life conditions (for example, childhood finances) correlate with financial outcomes.

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.

Roquin targets are known to contain two types of sequence-structure motifs, the constitutive and the alternative decay elements (CDE and ADE). Here, the authors describe a linear Roquin binding element (LBE) also involved in target recognition, and show that Roquin binding affects the translation of a subset of targeted mRNAs.

Movement of small RNA between cells is critical to plant development and stress responses. Here the authors uncover a gate-keeping mechanism that can restrict small RNA movement at cell-cell interfaces, providing selectivity in long-distance signalling and limiting the scope of local mobility.

RNA-guided CRISPR-associated transposases (CAST) are natural systems with broad potential in biotechnology. Here, the authors report compact type V-K CAST discovered from genome-resolved metagenomics and demonstrate targeted integration of a large transgene to a safe-harbor site in the human genome.

Chemical profiling in hyponeddylated cells coupled with multi-omics target deconvolution led to the identification of molecular glue degraders of cyclin K that function by inducing proximity between the CRL adaptor DDB1 and a CDK12–cyclin K complex.

Hoyer et al. establish that selective autophagy mechanisms are needed to remodel the ER and its proteome during in vitro neurogenesis across neuronal subcompartments and decode the substrate selectivity of ER-phagy receptors.

Happ et al. uncover an unusual regulatory mechanism in the Hedgehog signaling pathway, which enables a G protein-coupled receptor to physically block the enzymatic activity of a major cellular kinase.

Mitochondrial protein synthesis requires charging a mitochondrial tRNA with its amino acid. Here, the authors describe pathogenic variants in the GatCAB protein complex genes required for the generation of glutaminyl-mt-tRNA^Gln, that impairs mitochondrial translation and presents with cardiomyopathy.

Kalluri and colleagues use mammary carcinoma models to study the causes of metastatic organotropism and find an organ-specific role for angiopoietin 2 in driving lung metastasis through the suppression of the tight junction protein Claudin 5.

Combining experimental and within-patient evolution analyses, the authors show that the widespread conjugative plasmid pOXA-48 promotes bacterial evolution through the transposition of plasmid-encoded insertion sequence IS1 elements.

Effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8⁺ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Structural analysis of a protein complex in the circadian clock of Drosophila reveals how a light-sensing cryptochrome recognizes and engages its target.

Llorente, Blasco, Espuny and colleagues show that MAF regulates the genomic distribution of ERα and modulates the expression of metastasis genes via KDM1A, thereby driving metastatic spread in breast cancer.

Enkler et al. show that a pool of Arf1 at lipid droplets is implicated in mitochondrial ATP production control through regulation of fatty acid metabolism and acetyl-CoA transfer to mitochondria.

Reovirus endocytosis depends on junctional adhesion molecule A (JAM-A) and β1 integrin binding. Here, Koehler et al. use single-virus force spectroscopy and confocal microscopy to demonstrate a direct interaction between reovirus and β1 integrins via viral capsid protein λ2, which promotes clathrin recruitment to cell-bound reovirus.

Binding of the small molecule BI-3802 to the oncogenic transcription factor B cell lymphoma 6 (BCL6) induces polymerization of BCL6, leading to its ubiquitination by SIAH1 and proteasomal degradation.

Activity-based protein profiling (ABPP) was used to identify and optimize bioactive, selective pharmacological enzyme activators of the serine hydrolase LYPLAL1, which improved the metabolic defects of diet-induced obese mice.

Solinger et al. show that FERARI is a conserved tethering platform that mediates Rab11-dependent recycling at sorting endosomes.

The p38α protein kinase is an attractive druggable target for many human diseases. Here, the authors show how the structural plasticity of p38α can be leveraged to selectively inhibit a subset of the functions regulated by this kinase and aid in the development of therapeutic compounds.

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.

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.

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.

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.

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.

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.

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.