Search

Although antiretroviral therapies (ART) have expanded the life expectancy of patients with HIV, they are not curative due to the presence of latently infected cells. Here, the authors present IMC-M113V, a bispecific soluble TCR targeting the HIV peptide Gag_77-85 complexed to HLA-A*02:01 as an approach for targeting HIV reservoirs and test safety, tolerability and pharmacodynamics in a first-in-human clinical trial on 12 HLA-A*02:01-positive male individuals on ART.

Estimates from the Global Burden of Disease study reveal declines in chronic respiratory disease mortality between 1990 and 2023—especially during the COVID-19 pandemic—but the burdens on people affected remain substantial.

There is a lack of effective therapies for patients with non-V600E BRAF mutant cancer. Here, the authors report limited response in a phase II trial investigating the combination of binimetinib (MEK inhibitor) and encorafenib (BRAF inhibitor) for the treatment of non-V600E BRAF mutant cancer and subsequently investigate resistance mechanisms and combination therapeutic strategies in patient-derived models.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

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.

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.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Superconducting-qubit quantum annealers have served as platforms for simulating condensed-matter phenomena. Sathe et al. use a quantum annealer to probe critical phenomena in classical magnets by reliably sampling thermal distributions, revealing universal signatures of phase transitions without classical slowdowns.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

Andrew Robinson reviews five of the best science picks.

A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

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.

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

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.

This study maps chromatin accessibility in neurons and glia in schizophrenia, revealing fetal-like regulatory patterns in adult neurons enriched for genetic risk variants, linking early brain development to schizophrenia pathogenesis

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.

As Nature Aging celebrates its fifth anniversary, the journal asks some of the researchers who contributed to the journal early on to reflect on the past and the future of aging and age-related disease research, the impact of the field on human health now and in the future, and what challenges need to be addressed to ensure sustained progress.

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

A large-scale multi-ancestry whole-genome sequencing study of Alzheimer’s and related dementias identifies novel potential disease-causing variants, genetic risk and resilience factors, and offers a platform for advancing global research.

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.

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.

Microflora Danica—an atlas of Danish environmental microbiomes—reveals that although human-disturbed habitats have high alpha diversity, species reoccur, revealing hidden homogeneity.

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.

TEAD transcription factors are critical effectors and druggable sites of the Hippo pathway in cancer, however, the development of small molecule inhibitors and degraders remains underexplored. Here, the authors identify and characterize bifunctional IAP-based degraders targeting TEAD1 via a lipid pocket and recruit different members of the inhibitor of apoptosis proteins (IAPs) family, offering a comprehensive toolkit for structural, biophysical and cellular profiling.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

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.

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 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.

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.

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.

Head and neck squamous cell carcinoma (HNSCC) frequency and risk factors vary considerably across regions and ancestries. Here, the authors conduct a multi-ancestry genome-wide association study and fine mapping study of HNSCC subsites in cohorts from multiple continents, finding susceptibility and protective loci, gene-environment interactions, and gene variants related to immune response.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

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.

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.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

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.

Results from the phase ELAD 2 trial reveal that liraglutide is safe and well tolerated in people with mild to moderate Alzheimer’s disease but does not significantly slow brain metabolism decline.