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The response to infectious and inflammatory challenges differs among people but the reasons for this are poorly understood. Here the authors explore the impact of variables such as age, sex, and the capacity for controlling inflammation and maintaining immunocompetence, linking this capacity to favourable health outcomes and lifespan.

Kuhm et al. reveal how human guanylate-binding protein 1 (GBP1) dimers self-associate to coat bacterial pathogens and uncover a guanosine triphosphate hydrolase-dependent membrane-remodeling activity of GBP1 that is crucial for intracellular immunity

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.

The effects of chaperones on the aggregation of different tau variants are examined in a large-scale study. Among other findings, the work reveals that DnaJA2 can inhibit tau aggregation, a role that is supported by analysis of samples from human brains.

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.

Phenotype variation is higher in mutants than wild types. Examining a range of mutant severities, this study unexpectedly found that variation decreases in severe conditions. A quadratic trend best fits the relationship between severity and variation.

Prefrontal cortex can be flexibly engaged in many different tasks. Yang et al. trained an artificial neural network to solve 20 cognitive tasks. Functionally specialized modules and compositional representations emerged in the network after training.

The native anaplastic lymphoma kinase (ALK) oncofetal protein is expressed in neuroblastoma and in multiple pediatric and adult solid tumors. Here, the authors show an ALK-directed antibody-drug conjugate with therapeutic efficacy in ALK-expressing preclinical models.

Effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8⁺ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Reductions in precipitation and water storage increased fire emissions in pan-tropical forests by 133% during and following El Niño events (1997–2016). Fires follow a predictable cascade across tropical continents that may improve seasonal fire forecasts.

Influenza B viruses are linked to significant morbidity and mortality, and yet their immunobiology is comparatively poorly understood. Here Menon et al identify influenza B virus-specific CD8⁺ T cell epitopes and characterise these in adults, children and the elderly.

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.

cfDNA fragmentomics is a potential clinically applicable method for identifying cancer. Here, the authors assess fragmentomics analysis methods and their application to commercial targeted sequencing panels.

The multi-subunit SWR1C remodeler deposits histone variant H2A.Z at nucleosomes flanking protein-coding genes. Here the authors use single-molecule and ensemble methodologies to identify three ATP-dependent phases in the H2A.Z deposition reaction.

Amyloid self-assembly is linked to type 2 diabetes and Alzheimer’s disease. Here the authors designed constrained peptides which are nanomolar amyloid inhibitors of the key polypeptides IAPP and Aβ42 and act via supramolecular nanofiber co-assembly.

Bilateral vestibular schwannomas (VS) are the main feature of NF2-related schwannomatosis, but the immunological landscape of VS is poorly understood. By performing imaging mass cytometry, the authors assess the cellular heterogeneity in VS tumours and reveal niche-dependent modes of T-cell regulation in these neoplasms.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, the authors identify pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through allosteric inhibition of its primary RND transporter.

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.

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.

Crystal structures of two complexes of the angiotensin II receptor AT₂R with distinct tightly bound ligands reveal an active-like state of the receptor, in which helix VIII adopts a non-canonical position that blocks binding of G proteins and β-arrestins.

Structural, computation and kinetics approaches reveal the energy landscape of catalysis by adenylate kinase and show that the cofactor Mg²⁺ activates two distinct molecular events in the reaction cycle: phosphoryl transfer and lid opening.

Co-occurring mutations in the tumor suppressor LKB1 are frequent in KRAS-mutant lung cancers. Here, the authors show that LKB1 regulates JNK-dependent stress signaling apoptotic dependencies of KRAS-mutant tumors, making LKB1-deficient cells vulnerable to MCL-1 inhibition.

Data on geographically restricted SARS-CoV-2 variants is lacking in some regions. In this nationwide effort including 18 public health labs, the authors used genomic epidemiology and travel data to understand the origin and spread of 2 variants of interest that predominated during the second wave of the pandemic in Nigeria.

A ‘smart’ toilet that uses pressure and motion sensors, biometric identification, urinalysis strips, a computer-vision uroflowmeter and machine learning longitudinally tracks biomarkers of health and disease in the user’s urine and stool.

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.

There has been a great deal of interest in single-atom heterogeneous catalysis recently. Here, the authors show that industrially relevant lanthanum oxide-doped alumina supports are capable of stabilizing atomically dispersed palladium species, which are evaluated for low-temperature carbon monoxide oxidation.

Jayavelu, Samaha et al., apply machine learning models on hospital admission data, including antibody titers and viral load, to identify patients at high risk for Long COVID. Low antibody levels, high viral loads, chronic diseases, and female sex are key predictors, supporting early, targeted interventions.

Trees come in all shapes and size, but what drives this incredible variation in tree form remains poorly understood. Using a global dataset, the authors show that a combination of climate, competition, disturbance and evolutionary history shape the crown architecture of the world’s trees and thereby constrain the 3D structure of woody ecosystems.

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.

An atlas of the substrate specificities for the human tyrosine kinome reveals diversity of motif specificities and enables identification of kinase–substrate relationships and kinase regulation in phosphoproteomics experiments.

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.

To mature, dendritic cells collect and synthesize cholesterol to construct lipid nanodomains on their membranes. Obstructing this process impairs their ability to prime T cells.

Nucleosome flipping mediates a proofreading and processive mechanism of histone exchange driven by the chromatin remodeller SWR1.

The causative agent of sea star wasting disease has been elusive. This study used genetic datasets and experimental exposures to demonstrate that a strain of the bacterium Vibrio pectenicida caused disease and mortality in sea stars.

Microbial communities provide protection to their hosts by excluding colonizing pathogens. Here the authors study plasmid transfer and plasmid-mediated effects on host colonization and persistence of Enterococcus faecalis in the intestinal tract of mice.

The receptor tyrosine phosphatase CD45 has an important role in T cell activation. Davis and colleagues resolve the structure of CD45 and provide molecular insights into how it contributes to productive T cell receptor triggering.

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.

The covalent insertion of fluorophore-labeled DNA adaptors by Tn5 transposase into open chromatin allows its imaging and subsequent analysis by sequencing from exactly the same samples.

A multi-modal analysis of pre-metastatic liver biopsies from patients with localized pancreatic cancer with a minimum of 3 years of follow-up shows that immunological, proliferative and metabolomic features distinguish patients who develop metastases from disease-free survivors and can be used to predict outcomes.

Individuals with malignant hyperthermia susceptibility (MHS) suffer from lifethreatening responses to heat. Here the authors demonstrate that adaptive thermogenesis from brown adipose tissue contributes to this heat sensitivity in a preclinical mouse model of MHS

Recent experience can only provide limited information to guide decisions in a volatile environment. Here, the authors report that the choices made by a monkey in a dynamic foraging task can be better explained by a model that combines learning on both fast and slow timescales.

Impaired musical rhythm abilities and developmental speech-language related disorders are biologically and clinically intertwined. Here, the authors explore the correlation between the two traits, finding evidence of epidemiological associations and genetic overlap.

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.

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.

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.