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DNA origami may enable more versatile gene delivery applications through its ability to create custom nanoscale objects. Here the authors show that genes folded in DNA origami with custom scaffolds express efficiently when delivered to mammalian cells and can be assembled into multimeric arrays to deliver and express defined ratios of multiple genes simultaneously.

Targeting the glycolytic PFKFB3 enzyme is being studied as a therapeutic strategy against cancer. Here the authors identify PFKFB3 as being involved in homologous recombination (HR) repair of DNA double strand breaks (DSBs) and present a PFKFB3 inhibitor.

HIV vaccine candidates often have limited capacity to induce broadly neutralizing antibodies (nAbs). In this study, the authors show that stabilized Clade C HIV-1 Env protein trimers decorated on CoPoP liposomes induce nAbs against 18 of 20 multiclade tier 2 HIV-1 strains in immunized rabbits.

DNA strands can self-assemble into tetrahedral nanoparticles that can deliver small interfering RNA molecules to cells and suppress genes in tumours.

Enterococci enhance the fitness and pathogenesis of Clostridioides difficile in the gut by altering the amino acid composition and providing signals that increase its virulence towards the host.

Intraepithelial lymphocytes expressing γ and δ T cell receptor subunits protect Paneth cells from cell death caused by viral infection or Crohn's disease.

Membrane lipid composition is a key factor for bacterial stress adaptation. Here, authors show that ViaA and AAA+ ATPase RavA, alter lipid composition and modulate E. coli aminoglycoside sensitivity.

Stehlik and colleagues show that NLRP11 is an essential component of the NLRP3 inflammasome in human macrophages.

Lassa virus can cause haemorrhagic fever for which no specific treatment currently exists. Here the authors have cloned 113 monoclonal antibodies from the survivors of Lassa infection and show that the majority of neutralizing antibodies target a complex of GP1 and GP2 viral proteins.

Platelets express negatively charged phosphatidylserine (PS) on their plasma membrane when propagating coagulation within a developing thrombus. Here the authors show that an adaptor protein 14-3-3 regulates mitochondrial function and PS exposure and thus platelet procoagulant activity, promising a new therapy to reduce thrombosis.

Meiotic recombination enables reciprocal exchange of genetic material between paternal and maternal homologous chromosomes. Here Luo et al.show that MEIOB, a novel meiosis-specific factor identified in a proteomics screen, forms complexes with RPA2 and SPATA22, and is required for meiotic recombination.

A conserved network of bacteria and fungi underpins cadaver decomposition despite selection effects of location, climate and season.

Experimental deletion of the furin cleavage site of the SARS-CoV-2 spike protein highlights an important role for this site in infection and the need to consider this site when evaluating the neutralization activities of antibodies.

Polymyositis (PM) is a chronic inflammatory myopathy characterized by progressive muscle weakness. Here the authors showed that muscle fibers in PM undergo necroptosis and aggravate inflammation via releasing pro-inflammatory molecules such as HMGB1.

Escherichia coli form pili structures in order to initiate infection of the urinary tract. Here, Thanassi et al., have solved the structures of pili assembly intermediates and provided insights into their biogenesis and assembly.

The biological roles of deubiquitinating enzymes (DUBs) in pancreatic ductal adenocarcinoma (PDAC) are not fully explored. Here the authors perform activity based proteomics with a loss of function genetic screen and identify that USP25 promotes PDAC growth and survival through HIF-1 protein stability and transcriptional activity.

The cytoplasmic Xrn1 protein has long been established as the predominate 5′ to 3′ exoribonuclease that cleaves RNAs with an unprotected 5′ monophosphate end. Here the authors demonstrate Xrn1 can also degrade RNAs harboring the noncanonical nicotinamide adenine diphosphate (NAD) 5′ cap by removing the NAD cap and degrading the RNA.

Actin polymerization provides force for vital processes of the eukaryotic cell, but our understanding of actin dynamics and energetics remains limited due to the lack of high-quality probes. Here authors identify a family of highly sensitive fluorescent nucleotide analogues which bind to actin and provide energy to power actin-based processes.

The tumor suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF) and itself a target for ubiquitylation. Here, the authors show that TRIP12 mediates branched K11-linked ubiquitylation of FBW7, to regulate its stability and thus abundance of a subset of SCF^FBW7 substrates.

In a randomized controlled trial, Schleider et al. show that single-session online interventions are able to reduce depression symptoms up to three months later in adolescents.

Snaebjornsson et al. explore a selective vulnerability in cancer elicited by targeting aldolase A, which causes energy imbalance and prevents further metabolic adaptations.

Enveloped viruses employ the maturing environment of endosomes to promote endosomal escape. Here, authors generate a pseudo-atomic model of the BUNV envelope using sub-tomogram averaging and AlphaFold, and identify ionic cues for fusion events.

Macrocyclic peptides are promising scaffolds for chemical tools and potential therapeutics, but their synthesis is currently difficult. Here, the authors report the characterization of Ulm16, a peptide cyclase of the penicillin-binding protein (PBP)-type class of thioesterases, that catalyzes head-to-tail macrolactamization of nonribosmal peptides of 4–6 amino acids in length.

A common genetic cause of Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is expansion of the intronic hexanucleotide repeat (GGGGCC)_n in C9orf72. Here the authors reveal that the RNA (GGGGCC)_n expansion repeat associated with ALS/FTD can generate condensates in the absence of proteins, highlighting the potential relevance of targeting RNA-structures to treat neurodegenerative diseases.

Bacterial Rhs proteins constitute a diverse family of secreted toxins. Here, the authors present a cryo-electron microscopy structure of an Rhs protein from Pseudomonas aeruginosa and provide insights into the mechanisms by which the protein delivers its encapsulated pore-forming toxin fragment to the bacterial membrane.

Diverse microbial polyphenol transformations in thawing permafrost refute the theory that these compounds stabilize soil carbon across Arctic landscapes.

There is growing need for ways to slow or prevent Alzheimer’s disease (AD). Here, the authors demonstrate that a low protein diet can protect against metabolic dysfunction, slow AD progression, and preserve cognitive function in a mouse model of AD.

The pathogen Staphylococcus aureus releases several pore-forming toxins, termed leukocidins, that kill immune cells. Here, Zheng et al. show that the retention of a leukocidin on bacterial cells and its release are modulated by lipoteichoic acid and a membrane lipid, which also control the sorting of other surface-associated proteins.

Histone H2AX is a central regulator in DNA repair. Here, the authors show that the H2AX C-terminal linker mediates recruitment of 53BP1, a mechanism which evolved to function independently of the canonical phospho-ubiquitin axis important for DNA repair regulation.

ACKR3 is a critical regulator of platelet-mediated thrombosis and organ injury following ischemia/reperfusion. Platelet ACKR3 surface expression is independently associated with all-cause mortality in patients with cardiovascular diseases.

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.

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.

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.

Recombination is essential for life. Here, the authors characterize FLIP as a novel regulator of the key recombination protein RAD51’s functions. FLIP loss caused marked sensitivity to DNA damage, increased DNA breakage and defective replication.

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.