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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.

Huang and colleagues identify that EAG2 and Kvβ2 physically interact to form a potassium channel complex in glioblastoma and develop a designer peptide that disrupts their interaction and induces tumor regression.

In this study, Cheng et al. show that ammonia released from glutaminolysis disrupts the SCAP–Insig association, thus activating SREBP-1 and promoting lipogenesis to support tumour growth

Eps15-homology domain containing proteins comprise a family of dynamin-related ATPases. Here, Melo et al. use cryo-electron tomography to determine the membrane-bound EHD4 structure, therefore clarifying the membrane binding and oligomerization mode.

Tracking data from 17 marine predator species in the Southern Ocean are used to identify Areas of Ecological Significance, the protection of which could help to mitigate increasing pressures on Southern Ocean ecosystems.

Elevated inorganic phosphate levels promote excessive parathyroid hormone secretion, which contributes to the aetiology of secondary hyperparathyroidism. Here, the authors show that phosphate directly inhibits the calcium-sensing receptor, the main regulator of parathyroid hormone secretion.

The RNA binding protein MUSASHI-2 (MSI2) is a potential therapeutic target for acute myeloid leukemia. Here the authors identify a small molecule inhibitor of MSI2 and characterize its effects in a murine leukemia model.

TRPV3 mediates cutaneous sensations such as itch and pain. Here authors present the cryo-EM structure of TRPV3 bound with local anesthetic which binds the channel in membrane portals that connect the membrane environment to the channel pore.

Using large-scale screening and structure-guided mutagenesis, fast and sensitive GCaMP sensors are developed and optimized with improved kinetics without compromising sensitivity or brightness.

A compound previously identified as a dopamine D2 receptor allosteric modulator was found to be a bitopic ligand that binds the orthosteric and allosteric sites to allow binding to one D2 protomer and allosteric modulation of the associated protomer.

Gain of function mutations in isocitrate dehydrogenase 1 (IDH1) have been detected in cases of acute myeloid leukemia (AML). The application of an allosteric IDH1 inhibitor in AML cells promotes blast differentiation and restores DNA cytosine methylation patterns.

Cryo-EM structures of the heat-activated TRP channel TRPV3 in lipid nanodiscs at different temperatures reveal a conformational wave involved in the gating process.

The gains made in life expectancy and against infant mortality in low-income nations are being accompanied by increases in mental-health-related problems.

Several studies have recently demonstrated the role of the MSI2 RNA binding protein in normal and malignant haematopoietc stem cells. In this study, the authors show that MSI2 is required for maintaining myelodysplastic syndrome stem cells in mice and that MSI2 expression predicts poor prognosis in patients affected by this disease.

New research finds future rock fertiliser use as a contributor towards food security in Sub-Saharan Africa can be achieved with both sustainability-driven and fossil-fuel-driven economic growth.

Somasekar Seshagiri, James Brugarolas and colleagues report the mutational landscape of 167 non–clear cell renal cell carcinomas (nccRCCs) from multiple subtypes. They identify subtype-specific driver mutations and gene fusions, including ones involving MITF, which result in expression of the anti-apoptotic protein BIRC7 and might thus indicate candidates for treatment with BIRC7 inhibitors.

Here the authors report structures of pendrin, an anion exchanger, in complex with its substrate Cl⁻, I⁻, or HCO₃⁻, which reveal two anion binding sites in each protomer. The authors also identify binding sites of a pendrin inhibitor, niflumic acid.

OxLight1 is a genetically encoded sensor for the orexin neuropeptides. It has been applied in fiber photometry recordings and two-photon imaging in mice during a variety of behaviors.

Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. In the largest study to date, we report the results of DNA methylation profiling, RNA-Seq and genomic sequencing of 32 RIG tumors, and an in vitro drug screen in two RIG cell lines.

The structure of the human NALCN channelosome and a model of the gating mechanism are determined.

The authors report the structure of human oncochannel TRPV6 in complex with the plant derived phytoestrogen genistein. The structure provides insights into genistein binding in the channel pore, and how it acts as blocker and gating modifier, suggesting a mechanism of inhibition that can be explored for the structure-based drug design.

Neuberger et al. report the structure of human channel TRPV6 in complex with a cannabinoid inhibitor tetrahydrocannabivarin (THCV) and explore the pathway taken by the drug to reach binding sites in the portals that connect the membrane environment to the central cavity of the ion channel pore.

Small molecules targeting transient receptor potential (TRP) channels might be used to control pain. Here, Neuberger et al. report cryo-EM structures of human TRPV1 in the absence of added ligands or in the presence of the TRPV1-specific antagonist SB-366791, providing insights for the design of new promising analgesics.

Nadezhdin et al. present structures of human TRPV4 in complex with the GTPase RhoA, in the apo, agonist 4α-PDD and antagonist HC-067047 bound states, uncovering the mechanisms of channel activation, inhibition and disease-causing mutations.

A randomized trial in patients hospitalized with COVID-19 showed no benefit and potentially increased harm associated with the use of convalescent plasma, with subgroup analyses suggesting that the antibody profile in donor plasma is critical in determining clinical outcomes.

A venture capitalist gives his perspective on the outlook for life sciences ventures amid the perfect storm of the current economic downturn.

Niemann–Pick disease is characterized by the cellular accumulation of sphingomyelin. Blumberg and colleagues use both mouse models and materials from patients with Niemann–Pick disease to show that sphingomyelin accumulation inhibits CD1d-restricted NKT cell activation and development.

NF-κB signalling involves the scaffold protein NEMO, which can be bound by the oncoprotein vFLIP to promote cell survival and oncogenic transformation. Here the authors rationally engineer a tertiary protein mimic of NEMO to disrupt the vFLIP-NEMO interaction to induce cell death.

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.

The bacterial ABC transporter MsbA is essential for lipopolysaccharide biogenesis. Here, the authors apply native mass spectrometry, X-ray crystallography, cryo-EM and biochemical approaches to characterize the structural basis and functional roles of MsbA binding to copper and specific lipids.

Structural and functional characterization of the full-length TRPV1 channel from the thirteen-lined ground squirrel reveal the architecture of the extracellular cap domain and the intracellular C-terminus, and suggest a role of the cap domain in TRPV1 conductance and ion selectivity.

Online matching platforms are increasingly used for applications with positive social impact such as matching blood donors with recipients, where matching algorithms need to balance fairness with an efficiency objective. The authors demonstrate, both in computational simulations and using real data from the Facebook Blood Donations tool, that introducing a simple online matching policy can substantially increase the likelihood of donor action.

The GLASS Consortium studies the evolutionary trajectories of 222 patients with a diffuse glioma to aid in our understanding of tumour progression and treatment failure

Cross-species genetic screens reveal that decreased mitogen-activated protein kinase signalling reduces polyglutamine-expanded ataxin 1 levels and toxicity in models of spinocerebellar ataxia type 1.

Genome-wide association study for osteoarthritis using data from UK Biobank identifies loci for knee- and hip-specific disease. Functional analyses of chondrocytes provide further insight into candidate causal genes.

Adars are adenosine deaminases that act on RNAs, including those encoding proteins involved in neuronal transmission and also Adar RNA. Here, Savvaet al. engineered knock-in Drosophila mutants with altered Adar autoediting and found that this changed the spectrum of adenosine deamination and Drosophilabehaviour.

Cryo-electron microscopy of the tripartite MacA–MacB–TolC multidrug transporter.

The envelope glycoprotein (Env) trimer is the only antigenic target for broadly neutralizing antibodies on the surface of the HIV-1 virus. Here the authors show that two related monoclonal antibodies bind between gp41 protomers and neutralize HIV-1 by accelerating Env trimer decay.