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Targeted protein degradation has huge potential, but phenotype-specific degradation remains a difficulty. Here, a phase-separation biomolecular condensates as an intracellular degradation agent is developed, combining antibody-guided recognition with direct proteasome recruitment to enable phenotype-selective protein clearance.

Comprehensive benchmarking of computational methods for the prognostic significance of tumour-infiltrating lymphocytes (TILs) in breast cancer remains elusive. Here, the authors perform multi-centric validation and evaluation of multiple cTILs methods in a large cohort of triple negative and HER2+ breast cancer patients.

The cryo-EM study of RSV polymerase during early-stage RNA elongation reveals four key nucleotide addition states, providing the first comprehensive insights into orchestrated macrodomain rearrangements and micro-motif changes that drive catalysis.

This study reveals that glycogen metabolism is crucial for the sensory activation of POMC neurons, which is necessary for proper feeding behaviour and metabolic health in mice.

An analysis of diet-induced obesity using MouseMapper—a suite of foundation-model-based deep-learning algorithms—identifies structural alterations of the infraorbital branch of the trigeminal ganglia.

Multi-ancestry and ancestry-stratified genome-wide analyses identify genetic variants associated with refractive error and enable construction of an enhanced polygenic predictor incorporating functional annotations.

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.

Classical understanding of aromaticity has been challenged by its emergence in rings featuring only metal atoms. Now, diuranium and dithorium inverse sandwich complexes featuring a central cyclo-Bi₃³⁻ unit have been synthesized. These tribismuth rings exhibit exalted diamagnetism and are σ-aromatic, in contrast to the π-aromaticity in analogous tricarbon rings, providing benchmark data for comparisons between organic and inorganic aromaticity.

Robustness checks and reproduction of analyses with existing and updated data based on 110 articles in economics and political science journals with data and code-sharing requirements found high levels of robustness and reproducibility and determined that robustness was not dependent on author characteristics or data availability.

In this study, the authors show that the monoclonal antibody, FNI9, potently inhibits neuraminidases across H5N1 viruses spanning almost 30 years of evolution, protects mice from lethal challenge, and targets an H5N1-conserved NA epitope predicted to have low mutational escape and high fitness cost.

It remains unclear why some BRCA-deficient high-grade serous carcinomas (HGSC) do not respond to platinum-based therapy. Here, multi-omic analysis of BRCA1- and BRCA2-deficient HGSC attributes co-occurring mutations, DNA repair deficiency and tumor microenvironment features to short survival in these patients.

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.

ATF6α activation in human and preclinical models of hepatocellular carcinoma is significantly associated with an aggressive tumour phenotype characterized by reduced survival, glycolytic reprogramming and local immunosuppression.

Decreased brain volumes and increased NfL levels can be observed earlier than disease diagnosis in short-tandem-repeat-associated neurological diseases.

The mechanisms of increased EPAS1 transcription in clear cell renal cell carcinoma remain to be explored. Here, the authors propose a regulatory circuitry of EPAS1 expression which is dependent on HIF and lineage-specific transcription factors.

Machine learning upscaling analyses of global FLUXNET carbon and water flux measurements indicate that dryland vegetation productivity showed a negligible increase between 1982–2000 and 2001–2022, whereas humid-region vegetation productivity exhibited a nearly constant increase.

TnpB endonucleases are engineered for improved genome editing.

An in-depth analysis of tissue biopsies from patients with multiple myeloma and CAR T cell therapy-associated immune-related adverse events (CirAEs) after treatment with commercial BCMA-targeted CAR T cell therapy shows that CD4⁺ CAR T cells mediate off-tumor toxicities and that high CD4:CD8 ratio at apheresis, robust early CAR T cell expansion, ICANS and ciltacabtagene autoleuce treatment are independently associated with the development of CirAEs.

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.

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.

Gut microbial changes promoted by weaning in mice result in epigenetic modification in intestinal stem cells with long-lasting impact on host immunity.

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.

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.

Three endoplasmic reticulum luminal mannosyltransferases ALG3, ALG9 and ALG12 catalyze the synthesis of the branched mannose core in N-glycans in four distinct steps. Now, cryo-electron microscopy structures and characterization of ALG3, ALG9 and ALG12 reveal the molecular logic of oligomannose core assembly.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

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.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

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.

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

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.

The longevity of leaves determines the overall duration of photosynthesis for plants. This study suggests that climate change drives leaf longevity convergence toward intermediate ranges, which, by altering leaf traits and enhancing photosynthetic capacity, strengthens ecosystem stability and is closely linked to vegetation diversity.

Topological superconductivity is a promising concept for generating fault-tolerant qubits. Here, the authors report surface superconductivity at 5 K in a topological semimetal—trigonal PtBi₂.

Gene fusion products involving protein kinases are known drivers in human cancers and actionable targets for personalized therapy. Here, the authors uncover the structural and molecular determinants that control the mechanism of autoactivation of the CCDC6-RET oncogenic fusion protein revealing a dual ATP and ADP dependent activity, with implications in cancer signaling.

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.

As Nature Chemical Biology approaches its third decade we asked a collection of chemical biologists, “What do you think are the most exciting frontiers or the most needed developments in your main field of research?” — here is what they said.

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.

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.

Navigation involves perception, cognition, and movement. Here, the authors use computational modelling to show that different navigation behaviors, their errors, and variability arise from interactions of spatial uncertainties in optimal feedback control under uncertainty.

How landscapes are arranged affects soil pathogenic fungi worldwide. The authors reveal the global pattern and pronounced scale-dependency of landscape complexity and land-cover quantity on soil pathogenic fungal diversity.

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).

Here authors identify GluN2D-containing NMDA receptors on interneurons as a specific target for rapid antidepressant action. Blocking GluN2D restores stress-impaired plasticity and mimics the effects of ketamine with fewer side effects.

Geospatial estimates of the prevalence of anemia in women of reproductive age across 82 low-income and middle-income countries reveals considerable heterogeneity and inequality at national and subnational levels, with few countries on track to meet the WHO Global Nutrition Targets by 2030.

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.

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.

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.