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Crystal structures of human CB₁ bound to two cannabinoid agonists reveal key features, including a twin toggle switch and binding pocket reduction, advancing understanding of receptor dynamics and guiding cannabinoid drug design.

This article shows that different oil types are not easily substitutable, raising costs and reducing productivity in refining for the EU market.

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.

Determining dynamics of Fe–CO bond breaking in heme proteins is essential to understand the interplay between protein function and dynamics. Here, the authors report the first experimental proof for the two-step CO photodissociation, involving the previously unknown slower ~15 ps process.

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.

This paper reports integrative molecular analyses of urothelial bladder carcinoma at the DNA, RNA, and protein levels performed as part of The Cancer Genome Atlas project; recurrent mutations were found in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways; chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far.

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.

New agonists of the serotonin 5-HT_2A receptor (5-HT_2AR) confer high brain permeability and antidepressant activity and—in contrast to classic 5-HT_2AR agonists—lack psychedelic activity.

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.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

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.

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.

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.

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.

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.

Together with a companion paper, the generation of a transcriptomic atlas for the mouse lemur and analyses of example cell types establish this animal as a molecularly tractable primate model organism.

The cryo-EM structure and functional analyses of oxytocin bound to its receptor reveal a Mg²⁺ coordination complex in the binding pocket and find that the identity of a single residue determines whether a vasopressin/oxytocin family receptor requires Mg²⁺ as a cofactor.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

A recent study has examined potential predictive markers of Alzheimer disease (AD) and stroke. The results challenge some current assumptions, suggesting that stroke might often follow a decade of deterioration in brain structure and function, and that cognitive and MRI markers of AD differ in older and younger individuals.

G protein-coupled receptors (GPCRs) are critical drug targets that undergo conformational changes upon ligand binding. Here, authors developed photochemical switches for the adenosine A2A receptor and followed ligand dissociation using time-resolved crystallography.

The apelin receptor (APJR) is a drug target for cardiovascular and metabolic health. Here, authors reveal how ligand binding, receptor dimerization, and G protein coupling cooperate to regulate APJR signaling pathway, providing insight for drug discovery.

Here, the authors perform large trans-ancestry fine-mapping analyses identifying large numbers of association signals and putative target genes for colorectal cancer risk, advancing our understanding of the genetic and biological basis of this cancer.

Detailed analyses of the serotonin receptor 5-HT_1A and the psychedelic 5-methoxy-N,N-dimethyltryptamine reveal the differences in receptor structural pharmacology that mediate signalling specificity, efficacy and potency, findings that may facilitate the development of new neuropsychiatric therapeutics.

Bitopic functionalized ligands based on fentanyl can target the sodium ion-binding site of the mu-opioid receptor and selectively modulate downstream signalling pathways, potentially leading to safer analgesics.

The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies.

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

Agonists of the orexin receptor 2 (OX₂R) show promise in the treatment of narcolepsy. Cryo-EM structures of active-state OX₂R bound to an endogenous peptide agonist and a small-molecule agonist suggest a molecular mechanism that rationalizes both receptor activation and inhibition.