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The ferroptosis suppressor protein FSP1 has a critical role in ferroptosis protection of tumours across multiple in vivo models and is linked to worse prognosis in human lung adenocarcinoma, suggesting its potential as a therapeutic target in lung cancer.

The PAM specificity of SpCas9 can be altered with positive selection during directed evolution. Here the authors use simultaneous positive and negative selection to improve activity on NAG PAMs while reducing activity on NGG PAMs.

Targeting FSP1 in lymph nodes has considerable potential for blocking melanoma progression.

B. thuringiensis spores contain uncharacterized protein filaments that extend from the surface of the exosporium. Here, the authors show that these filaments feature conserved β-barrel neck domains and promote spore clustering through protein contacts and filament bundling, and reveal a mechanism for biofilm-like spore aggregation.

MGAT1 is a glycosyltransferase critical for the synthesis and maturation of complex N-glycans. Here, the authors show that MGAT1 modulation of CD73 glycosylation and function regulates tumor immune response in triple-negative breast cancer.

Ferroptosis has been connected to liver disease through unclear mechanisms. Here, the authors identify the terminal enzyme of cholesterol synthesis, 7-dehydrocholesterol reductase, as a regulator of ferroptosis in hepatocytes that suppresses ferroptosis through 7-dehydrocholesterol accumulation.

The manuscript uses an integrative approach to generate a comprehensive structure of the multisubunit endocytic TPLATE complex and to study its membrane targeting and its role in membrane deformation during the initial phase of plant endocytosis.

Understanding kinase action requires precise quantitative and spatial measurements of their activity in vivo. Here the authors develop a proteomic kinase activity sensor technique (ProKAS) enabling multiplexed spatial, kinetic, and screening analyses of kinase activities via mass spectrometry.

Thousands of recombinant antibodies enriched for specificity against defined targets are assembled in multivalent mixtures with enhanced therapeutic activity.

Cas9 DNA targeting is inherently sequence specific but not temporally controlled. Here, authors spatiotemporally couple Cas9 activity to target site transcription in eukaryotes and exploit this to preferentially edit the more highly transcribed of two alleles that harbor identical Cas9 targets.

Dietary n-6 PUFAs enhance adipose tissue expandability through the PPARγ–LPCAT3 membrane remodelling axis.

Molecular phylogenetics, ancestral sequence reconstruction and biophysical protein characterization are used to investigate the interaction between the orange carotenoid protein and its unrelated regulator, the fluorescence recovery protein (FRP). This interaction evolved when a precursor of FRP was horizontally acquired by cyanobacteria.

The secreted aminopeptidase Pseudomonas aeruginosa aminopeptidase (PaAP) is required for nutrient recycling in biofilms. Using the information from protein structure and kinetics, a potent cyclic peptide inhibitor for PaAP was designed that killed cells in late-stage biofilms.

Prokaryotes contain 17 types of histones, based on predictions from AlphaFold2. The histone groups differ from each other in the multimer structures that they form. Importantly, many prokaryotic histones can bridge DNA instead of wrapping DNA.

The bacterial plant pathogen genus Xanthomonas uses two distinct secretion systems for antibacterial competition. Here the authors show that some Xanthomonas lineages have switched from the ancestral X-T4SS state to T6SS-i4 despite the functional similarity of the systems, with X-T4SS gene clusters subject to degradation and loss and T6SS-i4-encoding sequences inserted through independent gains.

Ferritin, the cellular iron storage complex, binds NCOA4 and is trafficked to the lysosome for degradation and iron release. Here, authors present the cryo-EM structure of the NCOA4-Ferritin complex with biophysical and cellular characterization.

DNA transactions promote torsional constraints that pose inherent risks to genome integrity. Here the authors identify the macro-histone splice variant macroH2A1.1 as an epigenetic modulator of topoisomerase 1-associated genome maintenance. MacroH2A1.1 expression determines sensitivity to TOP1 poisons and may present a cancer vulnerability.

Our understanding on the humoral immunity induced by SARS-CoV-2 is still lacking. Here the authors analyze B cell responses at the single cell level to find that, in severe COVID-19 patients, plasmablasts shift from IFN to TGFβ instruction to produce IgA antibodies that are not specific to dominant SARS-CoV-2 antigens.

Interferon-α (IFN-α) is linked to type 1 diabetes (T1D), but how IFN-α impacts auto-antigen presentation is still unclear. Here the authors compare resting and IFN-α-treated islet β cells in vitro to find IFN-α inducing increased HLA-B expression, presentation of alternative epitopes, and activation of HLA-B-restricted T cells, thereby serving clues for T1D onset.

The global biodiversity decline might conceal complex local and group-specific trends. Here the authors report a quantitative synthesis of longterm biodiversity trends across Europe, showing how, despite overall increase in biodiversity metric and stability in abundance, trends differ between regions, ecosystem types, and taxa.

Using holistic and reductionist approaches, Karunakaran et al. identify a causal association between higher expression of RIPK1 (a central regulator of inflammatory cell function) and the risk of obesity. RIPK1 induces activation of proinflammatory signalling in adipose tissue, promoting the accumulation of macrophages that drive metabolic inflammation and obesity simultaneously.

The multicenter phase 3 trial of stem cell therapy for osteoarthritis (MILES) for knee pain revealed that cell therapies showed no significant difference in knee pain outcomes, compared to corticosteroid injections, 1 year following treatment.

The integration of liver and plasma quantitative lipidomic and proteomic data from 107 distinct mouse strains provides important insights into regulators of mammalian lipid metabolism.

Microtubule-associated proteins tau and MAP2 cooperatively form protein envelopes that compact the underlying tubulin lattice, revealing a novel role for these proteins in altering microtubule structure.

G protein-coupled receptors (GPCRs) enable cells to sense environmental cues and are indispensable for coordinating vital processes including quorum sensing, proliferation, and sexual reproduction. Here the authors, using heterologous GPCR expression and endogenous ligand production, enable synthetic mating in haploid yeast, and GPCR-mediated biosensing in diploid probiotic yeast.

Truong et al. developed a cell-based reporter system, EXSISERS, that enables non-invasive quantification of the protein expression levels of exon-specific isoforms via intein-mediated protein splicing.

Large DNA sequences are integrated into human cells using RNA-guided CRISPR-associated transposases.

Transancestral GWAS meta-analysis in 160,420 individuals identifies 139 loci associated with refractive error, including myopia. Newly identified genes implicate pathways involved in eye growth and light signaling cascades.

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

Savage and colleagues identify a population of CD4⁺ T cells within the endogenous repertoire that exhibit hallmarks of overt self-reactivity, spontaneously adopt a follicular helper T cell phenotype and are enriched in non-lymphoid organs following sustained T_reg cell depletion.

Cells and organisms requires proper membrane composition, which the cell must modulate as membrane lipids are primary acquired from the diet. Here, Ruiz et al. identify a conserved pathway connecting the fluidity regulators AdipoR1/2 with fatty acid desaturase SCD to mediate membrane homeostasis.

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.

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.

mRNA medicines hold enormous promise for drugging targets outside the reach of classic small molecules. Here, the authors develop a modular platform to design programmable mRNA therapeutics that act by modifying epigenetic state.

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.

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.

A cryo-EM structure of a stable, protease-resistant fibril formed by a fragment of the human prion protein shows two intertwined protofilaments with a tightly packed hydrophobic interface.

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.

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.

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.

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.

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.

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.

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.