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Bicyclic azetidine inhibitors are promising antimalarials that target the Plasmodium cytosolic phenylalanine tRNAsynthetase (cFRS). Here, Sharma et al. provide the biochemical and structural basis of its mechanism using co-crystal structure of PvcFRS with BRD1389.

The structure of the Venezuelan equine encephalitis virus in complex with LDLRAD3 provides insights into the structural basis of alphavirus–receptor interactions.

Screening mutated proteins is a versatile strategy in protein research, producing massive datasets when combined with NGS. Here, authors present ACIDES to estimate mutated protein fitness and aid protein engineering pipelines in a range of applications, including gene therapy.

Development of live-cell target engagement approaches to query MEK-bound binary and ternary complexes reveals the distinct pharmacology of clinical MEK inhibitors at specific assemblies composed of MEK, RAF, KSR and 14-3-3.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

The metabolite methylthioadenosine (MTA) inhibits PRMT5. Therefore, MTA accumulation due to MTA phosphorylase (MTAP) deletion has been proposed as a vulnerability for PRMT5-targeted therapy in cancer. Here, the authors show that MTA does not accumulate in MTAP-deficient cancer cells but is secreted and metabolized by MTAP-intact cells in the tumour microenvironment.

Tropical aboveground biomass carbon is a crucial, yet complex, component of the terrestrial C budget. Here remote observations demonstrate that fire emissions and post-fire recovery in non-forested African biomes dominate the interannual variability of aboveground biomass carbon, which acts as a moderate net C sink.

A cryo-electron microscopy structure of human NLRP3 in complex with the mitotic kinase NEK7 provides insights into the interactions that mediate the activation of the NLRP3 inflammasome.

The structure of a complex containing calcitonin gene-related peptide, the human calcitonin gene-related peptide receptor and the G_s heterotrimer, determined using Volta phase-plate cryo-electron microscopy, provides structural insight into the regulation of G-protein-coupled receptors by receptor activity modifying protein 1.

Structural and functional studies of the sodium leak channel, non-selective (NALCN) in complex with a distinct auxiliary subunit reveal the structural basis of the channel function and pharmacology and the functional impact of mutations that cause NALCN channelopathies.

The use of atomic-level simulations reveals a molecular mechanism by which a ligand can achieve selectivity between nearly identical receptors, enabling the rational design of targeted drugs.

Software to model, pack and integrate biological structures at the scale of macromolecular complexes and cellular organelles is described. It is applied in several contexts, including hypothesis generation and testing.

IWS1 regulates multiple steps in RNA metabolism, including RNA elongation and alternative RNA splicing. Here the authors show that AKT3 phosphorylates IWS1, which alters U2AF2 RNA splicing and promotes growth of lung adenocarcinomas via a Sororin/ERK-dependent pathway.

Invertebrates are key components in the ecological functioning of tropical forests. Here, Ewers et al. show that, compared to primary forest, logging halves the contribution of invertebrate species to several key ecosystem processes, including litter decomposition.

The drug Xanomeline is progressing through clinical trials for the treatment of patients with schizophrenia. Here, the authors determine a cryo-EM structure of Xanomeline bound to its primary target revealing a dual binding mode mechanism.

‘Commercial fisheries have decimated keystone species, including oysters in the past 200 years. Here, the authors examine how Indigenous oyster harvest in North America and Australia was managed across 10,000 years, advocating for effective future stewardship of oyster reefs by centering Indigenous peoples.’

Pheochromocytomas and paragangliomas (PCPG) are rare neuroendocrine tumours. Here, the authors use single-nuclei and bulk-tissue RNA-seq to characterise PCPG tumours and their microenvironments and reveal molecular subtypes as well as expression patterns associated with metastasis.

Enzymes for poly(ethylene terephthalate) (PET) deconstruction are of interest for plastics recycling, but reports on their directed evolution are missing. Now, an automated, high-throughput directed evolution platform is described, affording HotPETase that effectively achieves depolymerization above the glass transition temperature of PET.

SAMHD1 is a cellular dNTPase proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting dNTP substrate supply; its anti-viral but not dNTPase function is downregulated by phosphorylation of T592. Here, Martinat et al. describe an additional SUMOylation at residue K595, which promotes the dNTPase-independent restriction activity.

The tripartite multidrug efflux pump MacA-MacB-TolC in Gram-negative bacterial pathogens is driven by the ATPase MacB, which belongs to the ATP-binding cassette (ABC) superfamily. Here the authors present the 3.4 Å resolution crystal structure of MacB, and compare it with other known ABC transporter structures.

The biological basis of brain aging is not well understood, but it has implications for human health. Here, the authors explore the genetic basis of human brain aging, finding genetic variants, genes and potential causal relationships with disease.

The link between neural development and tumourigenesis in adult glioma remains unclear. Here, the authors monitor the developmental stages of Sox2 + /− stem cells from a mouse model using single-cell RNA sequencing and suggest the acquisition of embryonic-like states in the adult glioma development.

β-amyloid (Aβ)-dependent neuronal hyperactivity is an early marker of Alzheimer’s Disease (AD). Here, the authors report that scavenging Aβ monomers by an Aβ-binding anticalin protein blocks the formation of Aβ oligomers and prevents hyperactivity in AD mice.

Using experiments in organoids and in vivo in mice, the authors show that Apc-mutant cells act as supercompetitors to initiate the formation of adenomas.

Crystal structures reveal the catalytic mechanism through which the radical S-adenosylmethionine enzyme MiaB adds a methylthio group onto tRNA.

The EMDataResource Ligand Model Challenge aimed at assessing the reliability and reproducibility of modeling ligands bound to protein and protein–nucleic acid complexes in cryo-EM maps determined at near-atomic resolution. This analysis presents the results and recommends best practices for assessing cryo-EM structures of liganded macromolecules.

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.

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.

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.

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.

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.

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.

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.

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.

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.