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Sprenger et al. find that cytosolic pyrimidine levels regulate the release of mitochondrial DNA and activation of cGAS–STING.

Puissant and colleagues identify a myeloid-restricted PIK3CG/p110γ–PIK3R5/p101 axis as a therapeutic vulnerability in acute myeloid leukemia and develop a proteolysis-targeting chimera to potently degrade PIK3CG and suppress AML progression.

The authors report that endothelial protocadherin FAT1 inhibits endothelial proliferation and angiogenesis by promoting degradation of the transcriptional cofactors YAP and TAZ by direct interaction with the E3 ubiquitin ligase Mind Bomb-2 (MIB2).

Targeting PML in acute promyelocytic leukaemia has changed the outcome of patients with this disease. Here, the authors demonstrated that PML is also a potential therapeutic target in breast cancer where it specifically regulates cancer initiating cells and tumour progression through the transcriptional regulation of SOX9.

Dynamic cytoskeletal regulation of lymphatic endothelial cell shape, induced by isotropic stretch and crucial for dermal lymphatic capillary function, is identified and found to result from continuous remodelling of cellular overlaps that maintain vessel integrity.

Sleeping sickness is caused by the parasite Trypanosoma brucei. This parasite outwits the human immune system by periodically changing its coat protein in a process known as VSG switching. Here, the first in vitro system that recapitulates VSG switching is established, indicating that a spontaneous double-stranded DNA break upstream of the gene encoding the code protein initiates the process.

The iconic image of ‘the public square’ typifies many cities in Europe and elsewhere, but they transcend spaces for socializing and public deliberation. Focusing on Munich, this study analyzes whether and how design features of public urban squares affect the broader biodiversity living there, finding that greenness matters but that different taxa respond differently to design elements.

Implementation of a genomics-informed prebreeding strategy in a global winter wheat collection enhances the use of genebank accessions and uncovers the value of genetic resources for wheat improvement.

A study of over 36,000 villages in Indonesia shows that palm oil eco-certification reduces poverty in market-oriented villages but increases it in subsistence villages.

Murthy et al. demonstrate that cancer-associated fibroblast-derived acetate regulates polyamine homeostasis via an ACSS2–SP1–SAT1 axis in pancreatic cancer cells, thus enabling cell survival and tumour development under acidosis.

Sequencing of individual human lymphocyte clones shows that they are highly prone to mutations, with higher burdens in memory cells than in naive cells arising from mutational processes associated with differentiation and tissue residency.

Modifications enhancing degradation resistance and albumin affinity enabled the delivery of an siRNA conjugate silencing MMP13 to guinea pig and murine arthritic joints, improving therapeutic outcomes following intravenous administration.

Arrestins terminate signaling from GPCRs, but several lines of evidence suggest that they are also able to transduce signals independently of G proteins. Here, the authors systematically ablate G proteins in cell lines, and show that arrestins are unable to act as genuine signal initiators.

Grankvist et al. combine global isotopic tracing and metabolic flux modelling to characterize metabolic networks in human intact liver tissue.

The authors report that neddylation is required for dendritic spine development and stability, and loss of neddylation in excitatory forebrain neurons leads to synaptic loss, impaired neurotransmission, and learning and memory deficits. The roles of neddylation in spine maturation and synaptic transmission could be attributed to neddylation of PSD-95.

A ChIP–exo method is used to define the genome-wide positional organization of proteins associated with gene transcription, DNA replication, centromeres, subtelomeres and transposons, revealing distinct protein assemblies for constitutive and inducible gene expression.

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.

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.

Cellular senescence plays a crucial role in cancer therapy, influencing how tumours respond to treatment. Here, the authors show that therapy-induced senescence in B-cell lymphoma leads to myeloid-like plasticity, enhancing T-cell recognition and improving patient outcomes.

Using multi-ancestry genome-wide association study and fine-mapping, 298 loci and 36 credible genes are identified in the aetiology of bipolar disorder.

Multi-scale spatial machine learning of soil carbon stocks in Australia’s terrestrial and coastal marine ecosystems reveals eight bio-regions and their underlying subregional drivers that can help inform strategies for conservation and climate change mitigation.

Tuft cells constitutively express IL-25 to sustain ILC2 homeostasis in the intestine, but mechanisms driving IL-25 secretion have been unclear. Here, Feng et al. find that tuft cells express IL-17RB, which is required to regulate the bioavailability of IL-25 and to restrain the activation of ILC2s during homeostasis.

Neoantigen-specific T cells recognise neoantigen-MHC complexes on target tumour cells. Here, the authors describe a molecular mechanism by which the neoantigen Hsf2 p.K72N is recognised by a corresponding high affinity Hsf2 p.K72N-reactive T cell receptor, 47BE7, from the mouse melanoma line B16F10.

The ability of the DEAD-box RNA helicase DDX5 to interact with master transcription factor RORγt is dependent on binding of the long noncoding RNA Rmrp; the DDX5–RORγt complex coordinates transcription of selective T_H17 genes and is required for the pathogenicity of T_H17 cells.

Solid organ transplant recipients are at increased risk of infectious disease and have unique molecular pathophysiology. Here the authors use host-microbe profiling to assess SARS-CoV-2 infection and immunity in solid organ transplant recipients, showing enhanced viral abundance, impaired clearance, and increased expression of innate immunity genes.

This work presents ORFtag that enables proteome-wide functional screens by tagging and overexpression of endogenously encoded proteins via randomly integrated cassettes.

This study examines the impact of herbivorous insects on biogeochemical cycling within forests. From a global network of 74 plots within 40 mature, undisturbed broadleaved forests, they show that background levels of insect herbivory are sufficiently large to alter both ecosystem element cycling and influence terrestrial carbon cycling.

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.

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.

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.