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Chemically induced protein degradation is a powerful alternative to classical inhibition, but some proteins have deeply masked binding pockets that make the development of degrader molecules difficult. Here, the authors discover an alternate site on nuclear receptors that can be targeted by degraders.

In this work, Beyer and colleagues have utilized display screening technologies to comprehensively chart RAS proteins “druggability” and in doing so unravel a targetable ligand-induced pocket in RAS opening unprecedented anti-RAS targeted opportunities.

Loss of epigenetic information is a hallmark of cellular aging. Here, authors examine changes in the epigenetic landscape at three stages of Huntington neurodegenerative disease (HD) in two mouse models and demonstrate accelerated de-repression of developmental genes in HD striatal neurons.

Here the authors provide a deep tissue analysis of patients with autoimmune kidney diseases, identifying a conserved spatiotemporal immune program for the development of glomerular crescents and sclerosis.

Glioblastoma (GBM) is rich in tumor-associated vasculature and it remains to be understood how GBM is supported by vascular endothelial cells. Here, the authors identify that endothelial-secreted proteoglycan endocan acts as a ligand of PDGFR alpha receptor to promote GBM progression and induce therapy resistance.

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.

In young mice, antigens from the gut microbiota are trafficked by CX3CR1⁺ dendritic cells from the gut to the thymus, where they induce the expansion of T cells that are specific to commensal microorganisms.

Different functional variants in ADH1B (and elsewhere) in Europeans and Africans strongly affect risk for alcohol dependence. Dependence only partly genetically correlates with consumption, with strong correlations to other psychiatric disorders.

Optogenetics is applied to the entire mouse spinal cord.

In membranous nephropathy autoantibodies target podocytes of the kidney filter resulting in injury. Here the authors show that the ensuing proteostatic disturbances and proteinuria relate to aberrant interactions of non-functional UCH-L1 enzyme with the proteasome, curtailing its capacity.

The validation and analysis of X-ray crystallographic data is essential for reproducibility and the development of crystallographic methods. Here, the authors describe a repository for crystallographic datasets and demonstrate some of the ways it could serve the crystallographic community.

Complete sequences of chromosomes telomere-to-telomere from chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan and siamang provide a comprehensive and valuable resource for future evolutionary comparisons.

Flow cytometry allows the simultaneous quantification of many markers in and on a cell, but the analysis of such data is complicated. Here, the authors propose AutoSpill, a framework that facilitates the analysis of such data by automating parts of the analysis and requiring fewer controls.

Bassani-Sternberg and colleagues perform multiregion immunopeptidomics, genomics and spatial transcriptomics in patient lung cancer samples, demonstrating heterogeneity in the immunopeptidome associated with degrees of immune cell infiltration.

The neoantigen discovery pipeline NeoDisc incorporates mass spectrometry immunopeptidomics data.

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.

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.

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.

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.

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.

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.

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

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.

Tumor neoantigens versus tumor-associated antigens may have different functions in antitumor immunity depending on the strength of antigen recognition. Here the authors characterize CD8 T cell clones specific for TAA, neoantigens or viral antigens isolated from tumor and blood and show that neoantigen-specific clones have a higher structural avidity than TAA-specific ones and preferentially infiltrate tumors.

California’s farmworkers require 2–32 min of rest per hour depending on season and work shift to mitigate health risks from extreme heat, according to a study using high-resolution model outputs to translate exceedances of Wet Bulb Globe Temperature thresholds into rest break requirements.

Endogenous retroviruses (ERV) can induce immune responses and the control of these viruses uses immune mechanisms also involved in autoimmunity. Here, the authors characterize the control of ERVs in mice and show age-associated B cell control and nucleic acid sensing TLR pathway involvement.

The protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccine expressing the SARS-CoV-2 spike protein in non-human primates is demonstrated.

Macrophages and neutrophils release catecholamines after exposure to lipopolysaccharide or immune complex stimulation, and phagocyte-derived catecholamines contribute to acute lung injury.

Exhausted T cells are associated with inefficient viral clearance, tumor immunity and response to immunotherapy. Here the authors show CD8⁺ T cells in the pancreatic islets have a LAG3-promoted ‘restrained’ phenotype resembling exhausted cells but maintain effector functions, and LAG3 expression limits pathology in the nonobese diabetic mouse model of type 1 diabetes.

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.

It is generally thought that complement activation in human membranous nephropathy (MN) occurs predominantly via the lectin or alternative pathway. Here, the authors show that the classical pathway is the dominant form of complement activation in MN and a pathogenic driver of the disease.

DNA methyltransferase 3 A (DNMT3A) is involved in DNA methylation, and genetic variants in the DNMT3 locus have been associated with inflammatory bowel disease. Here the authors report that DNMT3A controls intestinal epithelial barrier function and restoration of the gut barrier function after intestinal epithelial perturbation.

HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation.