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Results from a comprehensive evaluation of the function of BRCA2 variants, particularly variants of uncertain significance, provide a useful resource to improve the clinical management of individuals who carry such genetic variants.

Mussels produce a dynamic bio-interface between their living tissue and their non-living byssus attachment, relevant for design of implant devices. Here, authors discover a mechanoresponsive protein that may mediate mechanosensing at the 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.

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.

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.

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.

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.

Pcm1 bridges centrosome asymmetry and polarized endosome trafficking to regulate radial glia progenitor fate decisions, balancing self-renewal and differentiation in zebrafish and human cortical organoids.

Nixon-Abell et al. show that ANXA11 condensation on lysosomal membranes causes a coupled phase transition of the underlying lipids and mechanical stiffening of the overall ensemble involved in RNP granule-lysosome tethering and co-trafficking.

RUVBL1 and RUVBL2 are AAA+ ATPases that are involved in transcriptional regulation. Here, the authors discover that RUVBL1/2 regulation of KLF5 modulates both classical and basal-like transcriptional lineage programs in pancreatic cancer.

Controlling nanoscale interfaces is key for ensuring stable plasmonic and catalytic function yet remains difficult to achieve under operando conditions. Now it has been shown that transient Au–Cl adlayers function as redox-active Au(I) intermediates, modulating interfacial electrostatics. This modulation stabilizes gold nanogaps and directs ligand rebinding, thereby enabling reproducible regeneration of subnanometre architectures.

Precise control over the energy of atomic metal sites is key to unlocking novel reaction pathways. Here, the authors achieve selective oxygen activation by the isolated copper site on ceria, due to its reduced 3d orbital energy via cerium induced electron withdrawing effect.

Analysis of 4,041 single-nucleotide variants (SNVs) linked to 13 cancers performed in primary human cell types identifies 380 potentially regulatory SNVs and their putative target genes. Editing one SNV, rs10411210, revealed that the risk allele increases RHPN2 expression and stimulus-responsive RhoA activation.

The ability to assemble weakly-interacting subsystems is a prerequisite for implementing quantum-information processing. In recent years, molecular nanomagnets have been proposed as suitable candidates for qubit encoding and manipulation, with antiferromagnetic Cr₇Ni rings of particular interest. It has now been shown that such rings can be chemically linked to each other and the coupling between their spins tuned through the choice of chemical linker.

Gene activation may involve the formation of a DNA loop that connects enhancer-bound transcription factors with the transcription apparatus at the core promoter. But this process is not well understood. Here, two proteins, mediator and cohesin, are shown to connect the enhancers and core promoters of active genes in embryonic stem cells. These proteins seem to generate cell-type-specific DNA loops linked to the gene expression program of each cell.

Structures of mu-opioid receptor (mOR) in complex with morphine derivatives have been determined; but the structural basis of mOR activation by fentanyl-like synthetic opioids remains unclear. Here, authors use state-of-the-art simulation techniques and discover a secondary binding mode which is only accessible when the conserved His297 adopts a neutral HID tautomer state.

Artificial reefs provide important ecosystem services in marine environments. Accurate knowledge of the area covered by such reefs can help evaluate benefits and risks of such structures. This study describes the physical footprint of artificial reefs deployed in coastal waters of the United States.

Mutations in the BAF SWI/SNF complex subunits are frequent in cancers but selective therapeutic approaches are not available yet. Here, the authors demonstrate that defects ofARID1Aand other subunits sensitizes cancer cells to the DNA checkpoint kinase inhibitor ATR in a synthetic lethal manner.

IL-33, released by epithelial cells in response to stress, is a potent activator of inflammation. Here Cohenet al. show that secreted IL-33 is rapidly inactivated by disulfide bond formation that prevents binding to its receptor, and that IL-33-related cytokines are susceptible to similar oxidation.

Chromothriptically produced pieces of a micronucleated chromosome are shown to be tethered together in mitosis by a protein complex consisting of MDC1, TOPBP1 and CIP2A, thus enabling their inheritance by a single daughter cell.

This work presents GōMartini 3, an improved coarse-grained protein model combining physics- and structure-based approaches. It boosts computational efficiency and accuracy for structured soluble and membrane as well as disordered peptides/proteins.

In this work, the authors advance the viewpoint that powder alloys yield better processability and final properties, when they are designed from materials science principles to sinter quickly and with controlled microstructure evolution.

How the necroptosis executioner, MLKL, converts to a killer form has been mysterious. Here, authors show RIPK3-mediated phosphorylation of human MLKL is the cue for pseudokinase domain dimerization before assembly of pro-necroptotic MLKL tetramers.

GPAT1 is a mitochondrial outer membrane protein that catalyzes the first step of glycerolipid biosynthesis. Cryo-EM structures and functional studies of human GPAT1 uncover the molecular architecture and mechanism of this important acyltransferase.

Intervertebral disc degeneration is a natural consequence of ageing and involves a loss of tissue structural integrity, which can lead to various pathological states. In this Primer, Hammoor et al. review the epidemiology, pathophysiology, diagnosis and treatment of the various pathologies. They also discuss the effects of disc pathology on patient quality of life and highlight emerging and future therapies to improve outcomes.

Chromosomal instability (CIN) is widespread in human tumours and drives cancer evolution. Here, the authors present a computational cell-cycle model that generates CIN patterns from end-joining repair and replication after DNA double-strand breaks, contributing to a framework for investigating the processes underlying CIN.

De novo designed interleukin-4 mimetics were engineered that induce biased signaling activation and exhibit high thermal stability. These mimetics offer insight into cytokine signaling and can be directly incorporated into 3D-printed biomaterials

The pseudokinase MLKL is activated by the upstream kinase RIPK3 in the necroptotic pathway but the structural basis of MLKL activation is not well understood yet. Here, the authors present the crystal structures of the human RIPK3:MLKL complex and human RIPK3 kinase alone, which reveal structural differences between human and murine RIPK3 and they discuss mechanistic implications.

The synaptic vesicle protein 2 family are essential membrane proteins found in the brain that bind synaptotagmin and are targeted by anti-seizure medications. Structures reveal common features found in transport proteins, and the basis of ligand binding and selectivity.

Here, Kropp et al. use cryo-electron microscopy and structural modeling to show that the enzyme [MoCu]-CO dehydrogenase interacts with its partner, the membrane-bound quinone-binding protein CoxG, to facilitate electron transfer from atmospheric CO oxidation to the respiratory chain. This interaction is conserved across diverse bacteria and archaea.

Melnick and colleagues show that the cohesin complex exhibits dose-dependent regulation of chromatin remodeling that accompanies the transition of germinal center B cells to plasma cells, which is necessary to prevent lymphomagenesis.

Jiang et al. developed a computational method to design repeat proteins with multiple structured loops that are buttressed by extensive hydrogen bond networks. The designs were further functionalized into high-affinity peptide-binding proteins.

City pedestrians must look out for road traffic, especially at busy intersections. This study finds that New York City’s leading pedestrian interval program gives people a head start over turning traffic that improves safety.

H2A.Z is implicated in genome stability across species. Acetylation of this histone variant in S. pombe is now found to be involved in maintaining condensed chromosomes during mitosis, with premature dissociation of condensin occurring in its absence.

Insights from structural biology lead to the development of mini-Ins—a human des-octapeptide insulin analog that is monomeric and has receptor binding affinity and in vitro and in vivo activities comparable to those of human insulin.

Chimeric antigen receptor (CAR) T cell anti-cancer therapies might result in toxic side effects. Here the authors present a strategy based on the modulation of CAR T cells via administration of a bispecific adapter that target them to cancer cells, resulting in diminished CAR-T cells toxicity and enhanced solid tumor eradication.

AspH catalyses hydroxylation of asparagine and aspartate residues in epidermal growth factor-like domains (EGFDs). Here, the authors present crystal structures of AspH with and without substrates and show that AspH uses EFGD substrates with a non-canonical disulfide pattern.

Store-operated Ca²⁺channels (CRAC) are involved in several cellular functions. Here the authors identify a hydrophobic gate in the CRAC pore and show that CRAC activation by STIM1 involves rotation of the pore helix that hydrates this region to allow ion passage through the pore.