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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.

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.

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.

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.

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.

In multiple sclerosis, smoldering inflammation contributes to clinical progression. Using multi-omics data, here the authors link chronic inflammation to senescence-like processes and cellular network changes, suggesting a potential therapeutic target.

EGFR inhibitors are standard of care in patients with EGFR-mutant non-small cell lung cancer (NSCLC) but resistance often develops. Here the authors report that the evolution of EGFR inhibitor resistance in EGFR-mutant NSCLC results in a sensitivity to the compound, MCB-613, and investigate the underlying mechanism of action.

Here the authors unveil the essential role of MCL-1 for adult hair follicle regeneration and inhibition of proliferation stress-induced apoptosis in mice. They also identify a P53/MCL-1/BAK axis balancing proliferation and death of activated hair follicle stem cells to ensure proper hair growth.

Skull bone marrow expands during adult life, exhibits lifelong vascular growth and increases its haematopoietic potential during ageing.

Pucella, Maqueda-Alfaro and colleagues distinguish three developmentally related subsets of mouse plasmacytoid dendritic cells that differ in their ability to produce type I interferon and their susceptibility to virus.

Starczynowski and colleagues show that overexpression of TRAF6 in HSCs induces ubiquitination of the RNA-binding protein hnRNPA1 and alternative splicing of Arhgap1, which accounts for the hematopoietic defects in myelodysplastic syndromes.

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.

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.

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.

In JAK2V617F mutant myeloproliferative neoplasms (MPN), inflammation impacts clinical outcomes. This study uncovers that the NLRP3 inflammasome drives thrombocytosis, granulocytosis, HSPC expansion, splenomegaly, and bone marrow fibrosis in MPN

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.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

As an interface between maternal and fetal tissues, decidua hosts immune cells specialized in fostering a successful pregnancy. Here the authors carry out high-dimensional characterization of function, morphology and surface markers of human decidual innate lymphoid cells (ILCs), identifying subsets with features distinct from blood ILC.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

HIV-1 infection is associated with persistent inflammation that can contribute to a variety of comorbidities. Luban and colleagues demonstrate that HIV-1 infection results in permanent depletion of innate lymphoid cells, leading to breakdown of gut barrier function and a feed-forward inflammation loop, which includes skewing of NK cells toward an inflammatory/memory phenotype.

Inspired by dynamic textural modulation in cephalopod skin, polymer films whose colour and surface texture can be dynamically and independently controlled are developed and demonstrated using standard electron-beam patterning tools.

Human milk oligosaccharides (HMOs) have highly diverse and branched structures that present a significant challenge for chemical synthesis. Here, the author reports that masking the amino group in glucosamine with a p-nitrobenzyloxycarbonyl (pNZ) group enhances coupling and deprotection efficiency during the automated glycan assembly (AGA) of homogeneous HMOs.

MCL1 is an anti-apoptotic protein associated with cancer and therapy resistance. Here, the authors show that MCL1 regulates mTORC1 signalling and metabolism, explaining MCL1-inhibition reported cardiotoxicity, which can be mitigated by dietary leucine supplementation.

When damaged by excess light the core proteins of photosystem II are repaired by selective degradation by the protease FtsH. Increased degradation after removal of outer subunits, suggests that protease accessibility identifies proteins as damaged.

Vijayanand and colleagues show highly suppressive CD4⁺CTLA-4⁺PD-1⁺ follicular regulatory T (T_FR) cells reside within tumor microenvironments. Depleting T_FR cells or blocking their activity with CTLA-4-depleting antibodies before anti-PD-1 checkpoint blockade therapy improved the efficacy of anti-PD-1 treatment in mouse tumor models and was also associated with better survival outcomes in a large cohort of patients with melanoma.

The role of structural variants (SVs) in Mycobacterium tuberculosis has been understudied. In this study, the authors leverage 859 high-quality, diverse, long-read assemblies to construct pangenome reference graphs (PRGs).

BCL6 corepressor (BCOR) is recurrently mutated in acute myeloid leukaemia and myelodysplastic syndrome. Here, the authors use mouse models to show the mechanism of how inactivation of BCOR in haematopoietic stem cells contributes to the development of leukaemia.

Group 3 innate lymphoid cells (ILC3s) promote T cell activation in the spleen but suppress it in the gut. Here, the authors show that this distinct regulation is mediated by gut microbiota-induced IL-23 and IFN-γ, respectively, and, along with the article by Rao et al, this work elucidates how cytokines set context specificity of ILC-T cell crosstalk by regulating ILC antigen presentation.

Somatic mutations in blood cells (CHIP) are linked to diseases like heart disease, but the mechanisms are unclear. Here, the authors show that different CHIP driver genes alter unique sets of plasma proteins, some of which are validated in mouse models.

The phase 3 STEER trial showed that a single intrathecal dose of onasemnogene abeparvovec significantly improved motor function in children and adolescents with spinal muscular atrophy versus sham, with a similar and acceptable safety profile.

A multigenerational single-cell tracking approach provides a framework to dissect phenotypic plasticity at the single-cell level, offering insights into cellular processes that may resemble early events during cancer development.

Association analyses in over 1 million individuals identify 535 new loci influencing blood pressure traits. The results provide new insights into blood pressure regulation and highlight shared genetic architecture between blood pressure and lifestyle exposures.

Homologous recombination is essential for DNA repair. Here, the authors present cryo-EM structures capturing five distinct intermediates of the RAD51 filament during strand exchange. These findings suggest a spatially coordinated, stepwise mechanism where the NTD guides DNA bending, while the L2 loop and S2 sites promote strand separation and product stabilization.

Mirchandani and colleagues show that tissue hypoxia alters the number and phenotype of circulating monocytes and their differentiation into lung macrophages, with important implications for the resolution of inflammation in the lung.

Cyclization provides a general strategy for improving peptide proteolytic stability, cell membrane permeability and target binding affinity. Here the authors develop a cyclopropenone-based proximity-driven chemical linker for the site-specific cyclization of phage-displayed peptides.

Haematopoietic stem cells (HSCs) are very sensitive to energetic and oxidative stress, and modulation of the balance between their quiescence and proliferation is needed to respond to metabolic stress while preserving HSCs' long term regenerative capacity. Here the tumour suppressor Lkb1 is shown to have a crucial role in maintaining energy homeostasis in haematopoietic cells — an effect largely independent of AMPK and mTOR signalling.

Gerber, Russ et al. show that the H3.3 chaperone Daxx, which represses endogenous retroviral and retrotransposable elements, acts as an epigenetic barrier to control haematopoietic progenitor plasticity and protect against PU.1-mediated inflammation.

BRCA1 and BRCA2 are well known breast cancer predisposition genes, however, many variants have not yet been classified for their pathogenicity. Here, the authors analyse a large combined cohort to provide evidence of variant pathogenicity.

Type 2 innate lymphoid cells (ILC2 cells) contribute to early immune responses directed against helminths and fungi. Paul and colleagues identify distinct inflammatory IL-25-responsive and natural IL-33-responsive ILC2 cells in lung tissues.

Cyclin-dependent kinases are deregulated in blood cancers. Here, the authors show that CDK8, independent of its kinase activity, regulates mTOR signalling for the maintenance of BCR-ABL1⁺ leukemia, and that the dual inhibition of CDK8 and mTOR signalling induces apoptosis in these cells.

Exploiting the intrinsic response of magic-angle twisted bilayer graphene to resonant terahertz radiation, the interplay between electron interactions and quantum geometry is studied in such flat-band systems.