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Khawaja et al. show sex-specific differences in neuronal-activity regulation by chaperone-mediated autophagy and that loss of chaperone-mediated autophagy leads to defective neuronal physiology and increased seizure susceptibility, linking chaperone-mediated autophagy to neuronal excitability.

Creative experiences such as dance, music, drawing, and strategy video games might preserve brain health. The authors show that regular practice or short training in these activities is linked to brains that look younger and work more efficiently.

Brain age gaps (BAGs) highlight deviations from healthy brain aging, yet their biophysical underpinnings in aging and dementia are not well understood. Here, the authors use EEG connectivity and generative modeling across diverse populations to reveal that BAGs are influenced by geography, income, sex and education, with implications for understanding accelerated aging and dementia.

The authors analyze rare coding variants in 1990 individuals with congenital kidney anomalies, finding diagnostic variants in 14.1% of cases. They identify two new causal genes, ARID3A and NR6A1, along with 38 candidate genes, providing evidence for shared genetics with other developmental disorders.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Systematic analysis from the Global Burden of Disease study reported that, despite global improvements from 1990 to 2021, dietary iron deficiency-associated disease burden remains high in women, children and residents in low socio-demographic index countries.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Using large cohorts from published clinical trials involving more than 8,000 patients with multiple sclerosis, a probabilistic machine learning model reconstructs the transition probabilities from data-derived diseases statuses, showing patterns that suggest how progression to severe stages occur and potential inversion of the process.

NNC2215 is an insulin conjugate that can reversibly adjust its bioactivity in response to a diabetes-relevant glucose range in vivo.

Bacterial two-component systems (TCSs) consist of a sensor histidine kinase (HK) and a response regulator that modulate gene expression. Here, the authors generate phosphatase-deficient HK mutants, with constitutive TCS activation, to characterise the regulatory networks of 14 TCSs in the human pathogen Streptococcus agalactiae.

Oncofetal (OnF) reprogramming, driven by YAP and AP-1, induces phenotypic plasticity and therapy resistance in WNT-dependent colorectal cancer (CRC). Targeting the OnF state in combination with chemotherapy substantially attenuates tumor growth in mouse models and patient-derived CRC tumoroids.

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.

Analysis of HbA1c and FPG levels across 117 population-based studies demonstrates regional variation in prevalence of previously undiagnosed screen-detected diabetes using one or both measures and suggests that use of elevated FPG alone could underestimate diabetes prevalence in low- and middle-income countries.

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.

Toll-like receptor 7 (TLR7) normally recognizes exogenous single-stranded RNA for the activation of innate immunity. Here the authors show that TLR7 may also contribute, via the modulation of mast cell functions, to experimental, cigarette smoke-induced mouse models of emphysema, thereby hinting TLR7 as a potential therapeutic target for human lung inflammation.

Combining human proteome and transcriptome analyses and Mendelian randomization on a large genetic dataset of HFpEF and HFrEF cases, Rasooly et al. identified 58 potential therapeutic targets specific for either HEpEF or HFrEF and created their therapeutic target profiles.

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.

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 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.

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

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.

From 1980 to 2018, the levels of total and non-high-density lipoprotein cholesterol increased in low- and middle-income countries, especially in east and southeast Asia, and decreased in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe.

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.

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.

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.

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.

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.

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.

Low threshold lasing is widely required, especially for portable systems. Here the authors design a circular subwavelength metallic aperture in a QCL to shape its phase front and control diffraction losses, which in turn allows a lower threshold dissipation power, enabling the fabrication of shorter cavities.

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.

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.

Using single-cell and spatial transcriptomics in chicken hearts, here, the authors generate a census of cellular interactions from early to late four-chambered heart stage, identifying a distinct epicardial-mesenchymal cell population with a migratory phenotype.

Analyses of neuroimaging datasets from 5,306 participants across 15 countries found generally larger brain-age gaps in Latin American compared with non-Latin American populations, which were influenced by disparities in socioeconomic and health-related factors.

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.