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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.

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.

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.

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.

Many enzymes form homo-oligomers, but it is often not clear why. This study follows the evolution self-assembly in citrate synthases across their phylogeny and finds it to be variable and not obviously related to enzyme function.

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.

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.

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.

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.

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.

MERS-CoV ORF4b antagonizes host innate immune response, partially via blocking nuclear import adapter IMPα activity and preventing nuclear translocation of NF-κB. Here, Munasinghe and Edwards et al. biochemically and structurally define the interaction between ORF4b and IMPα-family members and find a non-canonical interaction between ORF4b NLS and IMPα2 and IMPα3.

The Mant-ATP assay is a simple and accessible means for rapid quantitative assessment of the ratio of super-relaxed myosin to disordered relaxed myosin. This protocol provides a standardized methodology to perform the assay across a range of systems.

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.

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.

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.

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.

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.

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.

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.

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 local X-ray-induced dynamics that occur in protein crystals during serial femtosecond crystallography (SFX) measurements at XFELs are not well understood. Here the authors performed a time-resolved X-ray pump X-ray probe SFX experiment, and they observe distinct structural changes in the disulfide bridges and peptide backbone of proteins; complementing theoretical approaches allow them to further characterize the details of the X-ray induced ionization and local structural dynamics.

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.

This Perspective reviews computational methods for cross-species knowledge transfer and introduces ‘agnology’, a data-driven concept of functional equivalence independent of evolutionary origin.

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.

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.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Measuring the bulk power laws of Luttinger liquids in semiconductors remains challenging. Here, the authors demonstrate the dominance of the end-tunneling effect in two fairly distinct Luttinger liquids coexisting in a single quantum wire.

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.

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.

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.

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.

Peptide design remains a challenge owing to the large library of amino acids. Rational design approaches, although successful, result in a peptide design bias. Now it has been shown that AI techniques can be used to overcome such bias and discover unusual peptides as efficiently as humans.

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.

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.

The response to hypoxia involves multiple genes regulated by the hypoxia inducible transcription factors (HIFs), whose stability is regulated by prolyl hydroxylation. Here the authors provide a molecular basis for the substrate selectivity of the HIF prolyl hydroxylases that can be altered in erythrocytosis and cancer.

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.

The multipass membrane transporter MFSD6 localizes to the plasma membrane and acts as a host entry factor for enterovirus D68 (EV-D68) by binding directly to EV-D68 particles through its extracellular, third loop, offering a potential target to combat infections by this emerging pathogen.

Combining structural, biochemical, cellular and in vivo assays, the authors uncover the mechanism for capture and multisite phosphorylation of lethal (2) giant larvae by the atypical protein kinase C and partitioning-defective protein 6, revealing the basis for their mutual antagonism underpinning cell polarity.

Diacylglycerol kinase is a small bacterial membrane-bound trimer that catalyses diacylglycerol conversion to phosphatidic acid. Here, the authors solve the crystal structure of the kinase bound to a lipid substrate and an ATP analogue, and show that the active site arose through convergent evolution.

AMPK regulates the metabolism and so drugs that activate AMPK might have potential for the treatment of metabolic disease. Here, the authors report the structure of AMPK bound to an activating compound, revealing two binding sites and indicating that dual therapy might be a good drug strategy.

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.

The host cell factor cyclophilin A (CypA) interacts with the HIV-1 capsid and regulates infectivity. Here the authors combine cryo-EM, solid-state NMR and all-atom MD simulations, identifying an interaction interface between CypA and the HIV capsid that stabilizes the viral capsid and regulates infectivity.

Efficient, large-scale genomic analysis is facilitated on the cloud by a computational tool with error-diagnosing and self-healing capabilities.

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.

The 2021 unprecedented Pacific Northwest heatwave broke temperature records by extraordinary amounts. Impacts included hundreds of deaths, mass-mortalities of marine life, increased wildfires, reduced crop and fruit yields, and river flooding.