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The CAG tract length influences Huntington’s disease onset but alone may not be sufficient to drive neuronal death. Here, the authors report that double strand breaks induce neuronal death, regardless of somatic expansion of the inherited disease allele.

Therapeutic antibodies represent a powerful tool for immunotherapy but to design their properties to make them functionally versatile but similar to naturally produced human antibodies is challenging. Here the authors engineer human B cells to express heavy chain only antibodies with mutations to avoid pairing with endogenous antibodies and to enhance effector function and durability.

N-desethyl-fluornitrazene is a µ-opioid receptor agonist derived from nitazenes that has supramaximal intrinsic efficacy that produces analgesia with minimal adverse effects in rodent models.

Genetically distinct neural circuits in the caudal brainstem receive feedback from the mouth and gut to regulate feeding behaviour on short and long timescales.

Genome-wide association meta-analysis identifies 58 independent risk loci for major anxiety disorders among individuals of European ancestry and implicates GABAergic signaling as a potential mechanism underlying genetic risk for these disorders.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Genetic mapping in mice identified Homer1a as a key modifier of attention. Developmental downregulation in the prefrontal cortex enhances inhibitory tone, neural signal to noise and adult attentional performance, revealing a new control mechanism and target.

Gene regulatory network architecture and complex dosage effects from paralogue diversification converge to shape phenotypic space, producing the potential for both strongly buffered phenotypes and sudden bursts of phenotypic change.

Microbial symbioses can help plants mitigate environmental stresses and plant microbiome compositions are influenced, for example, by drought stress. The investigated temporal shifts of the rice root microbiome under various durations of drought show the progression of microbiome composition in response to stress and a long-lasting effect of severe conditions.

Soil surface temperatures constrain the low-elevation extent of forests in the western United States through their direct effects on seedling mortality, according to analyses of the relationship between post-fire tree recruitment and soil surface temperature across this region.

Metabolites play an important role in physiology, yet the complexity of the metabolome and its interaction with disease and aging is poorly understood. Here the authors present a comprehensive atlas of the mouse brain metabolome and how it changes during aging.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

A slide-free, inexpensive and non-destructive microscopy technique rapidly provides high-resolution histology images that resemble those obtained from conventional haematoxylin-and-eosin-stained specimens.

Spontaneous traveling cortical waves shape neural responses. Using a large-scale computational model, the authors show that transmission delays shape locally asynchronous spiking dynamics into traveling waves without inducing correlations and boost responses to external input, as observed in vivo.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

Psychedelic alkaloids served as lead structures for the development of tabernanthalog, a non-hallucinogenic and non-toxic analogue that reduces alcohol- and heroin-seeking behaviour and produces antidepressant-like effects in rodents.

Treatment with neoadjuvant BRAF/MEK-targeted therapy results in higher rates of major pathological response in female compared with male patients with melanoma, and pharmacological inhibition of androgen receptor signalling improved the responses of male and female mice to BRAF/MEK-targeted therapy.

Samples of different body regions from hundreds of human donors are used to study how genetic variation influences gene expression levels in 44 disease-relevant tissues.

Dysregulation of mTORC1 function is linked to various pathological conditions, including addiction. In this study, the authors show that mTORC1 activation in the nucleus accumbens of mice consuming excessive alcohol triggers translational repression through microRNA machinery, which in turn suppresses glycolysis and increases alcohol intake.

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.

Analysing camera-trap data of 163 mammal species before and after the onset of COVID-19 lockdowns, the authors show that responses to human activity are dependent on the degree to which the landscape is modified by humans, with carnivores being especially sensitive.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

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.

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.

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.

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.

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.

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.

The authors show that rare genetic variants contribute to large gene expression changes across diverse human tissues and provide an integrative method for interpretation of rare variants in individual genomes.

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.

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.

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.

Directed evolution creates new compact Cas9 variants that target most single pyrimidine nucleotide PAMs.

Variation in inflorescence architecture in plants affects reproductive success and agricultural yield. Zachary Lippman and colleagues report that the phenotype of the terminating flower (tmf) tomato mutant, the only known tomato mutant with single-flower inflorescence, is caused by a mutation affecting a nuclear protein that regulates known floral meristem identity complex members AN and FA to repress floral termination.

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.

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.

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.

Resting and activated T cell states are established by context-specific regulators and dynamic gene circuits.

Distinct dopaminergic neurons in the ventral tegmental area respond to physiological fluid balance and nutrient cues at specific stages of ingestion, driving learning about the physiological effects of ingestion.

A subcortical circuit that regulates food consumption in mice is described, involving neurons in the ventromedial hypothalamus that are directly linked to motor centres that regulate feeding and jaw movements.