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Using a mouse model with a macrophage-specific DNA repair defect, Niotis, Arvanitaki et al. identify DNA damage-induced autophagy in macrophages as a link from aging to autoimmunity.

The contribution of ether lipid species in cancer cell fate has not been fully understood yet. Here the authors show that malignant cancer cells employ ether lipids to modulate membrane biophysical properties, enhancing iron endocytosis and ferroptosis susceptibility.

Reduced fitness of the tumor microenvironment is mediated by a long non-coding RNA expressed in tumors.

Estimates from the Global Burden of Disease study reveal declines in chronic respiratory disease mortality between 1990 and 2023—especially during the COVID-19 pandemic—but the burdens on people affected remain substantial.

Proxy records from Lake Baikal show that rapid cooling coincided with Northern Hemisphere ice sheet expansion 2.7 million years ago, a change accompanied by a transition to open steppe ecosystems.

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.

An RNA-binding protein on leukemia cells provides an effective target in mouse models.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

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).

Ultraviolet light damages DNA and drives skin cancer. Here, the authors show that the DNA replication factor And-1 coordinates with DNA polymerase δ to repair UV-induced lesions, and that loss of And-1 phosphorylation impairs repair and promotes skin tumorigenesis.

Intracellular redox state orchestrates a self-reinforcing circuit connecting hypoxia inducible factor 1α-dependent signalling with post-translational regulation of the metabolic enzyme isocitrate dehydrogenase 1 to govern intestinal stem cell fate.

RNAi therapy has huge potential but effective delivery to target location is a major issue. Here, the authors report on the delivery of RNAi to tumors using self-agglomerating nanohydrogels that can overcome the different delivery barriers and supply multiple RNAi payloads.

The identification of synthetic essential genes of PTEN is of therapeutic potential for PTEN-deficient prostate cancers. Here, the authors show that ARID4B is a synthetic essential gene in these cancers in which deficiency of PTEN prompts the AKT-ARID4B feedback loop required for activation of the PI3K-AKT signaling pathway.

PCNA is essential for DNA replication and cellular proliferation. Here, the authors reveal that PCNA ubiquitination protects stalled replication forks from DNA2-mediated degradation via regulation of Okazaki fragment maturation and chromatin assembly.

Results of the phase 1/2 TACTOPS trial show that autologous T cell therapy targeting PRAME, SSX2, MAGEA4, Survivin and NY-ESO-1 in patients with pancreatic ductal adenocarcinoma is feasible and safe, and leads to encouraging clinical responses and evidence of antigen spreading in responders.

Recent MPXV outbreaks underscore the need for better vaccines and treatments. Here, the authors isolate and structurally characterize potent antibodies interacting with A28 that they identify as a key viral surface protein essential for viral entry and that induces strong, protective antibody response in mice.

How the complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth is explored.

How signaling pathways recruit SWI/SNF chromatin remodeling complexes is not known. Here the authors suggest a ubiquitin directed mechanism targeting SWI/SNF for Wnt pathway dependent transcription, important for development and cancer.

How co-receptors Gas1 and Boc interact with Ptch1/2 receptors and regulate Hh signalling is unclear. Here, the authors demonstrate that the spatiotemporal expression of Gas1 and Boc determines how Hh signalling affects the dynamic migration of murine primordial germ cells.

ssDNA gaps have emerged as structures which may mediate cytotoxicity of chemotherapeutic agents such as cisplatin. Here, the authors show that the mono-ADPribosyltransferase PARP10 promotes the repair of ssDNA gaps by recruiting RAD18 to initiate PCNA ubiquitination-mediated translesion synthesis.

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.

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

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 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.

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.

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.

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.

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.

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.

Although the gain in chromosome 17q21-ter is commonly associated with neuroblastoma, it is not clear which gene of this region mediates tumorigenesis. Here, the authors are showing that JMJD6, which locates in that region, is a neuroblastoma tumorigenic factor.

Caspase 8 protein expression is largely absent in small cell lung cancer (SCLC) patients. Here, the authors generate a caspase 8 deletion SCLC mouse model and show that it promotes a neuronal progenitor-like cell state and pre-tumoral immunosuppression triggered by necroptosis that promotes metastasis.

Understanding the mechanisms underlying the survival of drug tolerant persister cells following chemotherapy remains elusive. Here, multi-omics analysis and experimental approaches show that the germ-cell-specific H3K4 methyltransferase PRDM9 promotes metabolic rewiring in glioblastoma stem cells.

Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.

Here the authors identify that C16orf72 regulates BRCA1/Senataxin to promote replication fork recovery. These proteins act together in a pathway parallel to PARP1 to suppress R-loop accumulation in response to replication stress and confer resistance to PARP inhibitors.

Protection of replication forks against nucleolytic degradation is crucial for genome stability. Here, Dhoonmoon et al identify PARP14 and the KU complex as essential regulators of fork degradation by MRE11 and EXO1 nucleases in BRCA-deficient cells.