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Most patients with B-cell leukemia respond to chimeric antigen receptor T cell (CAR T) therapy, yet many relapse due to loss of CAR T function. Here, the authors show that the metabolism of CAR T from short- and long-term responders is different, which may explain why CAR T lose functionality.

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.

GDF15 has been associated with cancer-associated cachexia. Here, the authors show that STK11/LKB1 loss-of-function mutations in non-small cell lung cancer result in an exaggerated integrated stress response culminating in the tumor cell secretion of the cytokine GDF15 promoting cachexia.

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.

Convergent mutations in hot spots of the spike proteins of currently circulating SARS-CoV-2 Omicron variants increase the binding affinity for the host receptor and promote more efficient fusion with host cell membranes.

Cryo-electron microscopy structures of three large ornate natural bacterial RNA molecules reveal their quaternary structures and intra- and intermolecular interactions that stabilize them.

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

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.

Spatial multi-modal data analysis using embeddings from diverse foundation models (spEMO) represents a transformative approach that unifies embeddings from pathology foundation models with those from large language models to advance spatial multi-omics research.

Liu et al. report Chinese normative lifespan brain charts showing later neurodevelopmental milestones than those detected in Western cohorts. Individual deviations from these norms are valuable in assessing clinical risk and outcomes.

Observations over a decade at the Sheshan Station in the Yangtze Estuary support pre-landfall erosion, highlighting the necessity to consider such erosion and sediment stratification in predictions of storm-induced coastal alterations, according to analysis of morphodynamic observations and sediment dynamics of Typhoon Fung-wong.

Ribas and colleagues report the results of a phase 2 clinical trial of neoadjuvant PD-1 blockade in patients with surgically resectable desmoplastic melanoma.

Transcriptomic and clinical data analyses from multiple cohorts of patients with cancer receiving immunotherapy find that PD-1 blockade potentiates tumor-specific IgG1 plasma cell responses that complement cellular immunity and contribute to clinical benefit.

MAGPIE is a computational framework for co-registering spatially-resolved transcriptomics, metabolomics and tissue morphology for integrated downstream analysis. Case studies across lung, brain and breast reveal coordinated cross-modality molecular changes.

Engineered mucus-tethering bispecific nanobodies neutralize and entrap viruses to enhance mucosal immunity, preventing influenza infection and limiting SARS-CoV-2 transmission.

This work developed an all-fibre-coupled THz reflection single-pixel imaging system capable of real-time, in vivo, and in situ imaging. It achieves a five-fold improvement in throughput over the state of the art, reaching 30,000 pixels per second.

A multiancestry phenome-wide analysis of copy number variants in the UK Biobank genomes increases power to detect genetic associations with complex traits across human populations.

Liang et al. estimate the prevalence of text modified by large language models in recent scientific papers and preprints, finding widespread use (up to 17.5% of papers in computer science).

Air lasing offers a direct route to ultraviolet structured light in air using cylindrical-vector beam pumping. The authors generate both radially and azimuthally polarized N2+ lasing, yet azimuthal pumping yields no second-harmonic signal, favoring an amplified spontaneous emission mechanism over second-harmonic self-seeding.

Several recent publications have attempted to detect novel unannotated microproteins using mass spectrometry proteomics. Here, the authors reassess these claimed microprotein detections, finding that many are poorly supported, while a subset represents likely genuine discoveries of novel proteins.

Early life RSV infection contributes to risk of childhood asthma. Here, the authors develop a statistical model to predict age at first RSV infection in the United States based on birthdate, demographics, and RSV surveillance data which could be used to identify groups at risk of chronic respiratory sequalae like asthma.

Woven lattices offer a pathway to highly compliant and tunable mechanical metamaterials. Here, authors present a geometric design framework for woven lattices that encodes topology and compliance, allowing for arbitrary complexity and enabling programmable large-deformation and failure responses.

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.

CD27 is a key T-cell costimulatory receptor, but efforts to target CD27 have been limited by the poor clinical efficacy of first-generation anti-CD27 antibodies. The authors here engineer higher-valency antibodies by more effectively engaging CD27 and selectively binding to FcγRIIB, which enhance anti-tumor activity.

The anterior cingulate cortex encodes affective pain behaviours modulated by opioids; targeting opioid-sensitive neurons through a new chemogenetic gene therapy replicates the analgesic effects of morphine, providing precise chronic pain relief without affecting sensory detection.

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 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.

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.

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.

Many studies assess which jobs risk automation, but less is known about how skill demands shift within surviving jobs. Here the authors show that U.S. lower-skilled occupations face the steepest upskilling requirements, especially in small firms and labor markets.

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.

Data on immune response to the SARS-COV-2 AZD1222 vaccine are limited in African populations. Here, the authors show immunogenicity of the AZD1222 vaccine in two independent cohorts from West Africa, including seroprevalence levels prior to vaccine rollout in January 2021.

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).

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.

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.

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.

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.

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.

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.

Here the authors perturb genes linked to schizophrenia risk in human neurons. They find that single perturbations share common downstream effects on gene networks, while joint perturbations result in downstream effects being saturated.

Upfront and lifetime costs often prevent EV adoption. Vaishnav and colleagues find that using EV batteries to shift the time of electricity purchases for other household uses can cut both owners’ electricity costs and greenhouse gas emissions.