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Using cryo-EM, this study reveals the structures of amyloid fibrils from a patient with ALECT2 amyloidosis, uncovering structural polymorphism of full-length ALECT2 fibrils and identifying features that may inform future diagnostics and treatments.

Approach and avoidance behavior is disrupted in many psychiatric disorders, but the neural circuits that support this behavior are unknown. Here, the authors identify a theta-mediated limbic circuit that support approach and avoidance decision-making, contributing to a network understanding of psychiatric disorders, especially those characterized by maladaptive avoidance.

Magrinelli et al. link biallelic PSMF1 variants to phenotypes from parkinsonism to perinatal lethality, implicating proteasomal and mitochondrial dysfunction. PI31 loss in fly and mouse models causes age-dependent motor deficits and neurodegeneration.

A large-scale study on the replicability of claims from social and behavioural science journals reports that about half of the results replicate in the same patterns as the original study.

When 100 social and behavioural science claims were examined, 34% of reanalyses closely matched the original results, with 74% reaching the same conclusion, revealing limited robustness of single-path analyses and the need to address analytical uncertainty.

Recently, the dose escalation stage of the GLORIA trial investigating NOX-A12 (L-RNA aptamer-based CXCL12 inhibitor) in combination with radiotherapy in patients with glioblastoma was reported. Here, the authors report the preclinical rationale and an expansion arm of the GLORIA trial combining NOX-A12, radiotherapy and bevacizumab (anti-VEGF) in patients with newly diagnosed glioblastoma.

Desmoplastic small round cell tumor (DSRCT), a very rare and understudied sarcoma, presents serious challenges for both diagnosis and treatment. Here, the authors employ multi-omics profiling on 30 refractory DSRCT patients to improve the diagnosis and identify potentially actionable targets for individualized DSRCT treatment.

From 2014–2017, marine heatwaves caused global mass coral bleaching, where the corals lose their symbiotic algae. The authors find, this event exceeded the severity of all prior global bleaching events in recorded history, with approximately half the world’s reefs bleaching and 15% experiencing substantial mortality.

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.

Observations of a nearby type I superluminous supernova showing oscillating light-curve bumps provide evidence of a centrally located magnetar in the wake of the explosion, surrounded by an infalling accretion disk undergoing Lense–Thirring precession.

Here the authors compare genetic testing strategies in rare movement disorders, improve diagnostic yield with genome analysis, and establish CD99L2 as an X-linked spastic ataxia gene, showing that CD99L2–CAPN1 signaling disruption likely drives neurodegeneration.

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.

Cryo-EM analysis of fibrils from heart and liver of an ATTR amyloidosis patient with the V122Δ mutation reveals polymorphic single and double filaments, suggesting that fibril structural polymorphism may contribute to phenotypic variation in ATTR amyloidosis.

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.

Temporal profiling of central carbon metabolism during Kras^G12D-driven acinar-to-ductal metaplasia reveals that disruptions in NADPH-producing enzymes accelerate the formation of pancreatic precancerous lesions.

Current research focuses on enhancing the efficacy of immune checkpoint blockade combined with chemotherapy in HER2-negative gastrointestinal adenocarcinoma. This trial evaluates different first-line chemotherapy regimens in combination with immunotherapy.

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.

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 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.

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.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

Application of multiancestry and ensemble-based approaches yields improved polygenic risk prediction models for breast cancer and its subtypes among women of African ancestry.

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.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

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.

Biomolecular insights into significant cultural changes during the Central European Late Bronze Age (1300–800 BCE) have been limited by cremation. Here, the authors examine available inhumation burials with ancient DNA, stable isotopes, and osteoarchaeology to identify regional traditions and interconnectedness.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

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 general stereospecific glycosylation is developed that is applicable across a range of monosaccharides. A directing-group-on-leaving-group strategy allows mild donor activation and enables the complete inversion of anomeric configuration with excellent yields. This method can be applied in multistep oligosaccharide syntheses and automated glycan assembly.

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.

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.

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.

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.

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.

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).

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.

Integrating complex multi-omics data for individual patient decision making can be challenging. Here, the authors develop Knowledge Connector as a decision support system to generate and document Molecular Tumor Board recommendations and support medical decision-making.

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.

This study utilized a longitudinal cohort of adolescents to identify distinct brain signatures linked to ADHD symptom trajectories, revealing that specific cortical and subcortical changes correlate with symptom persistence, remission and emergence, enhancing predictive capabilities for ADHD outcomes.

Lithium-ion battery cathode lifetime is limited by large expansion and contraction during cycling. This study uses electrochemical activation to suppress collapse in LiNi_0.9Mn_0.1O₂ cathodes, achieving improved capacity and cycle life.

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.

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.