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The dysregulation of the inositol-requiring enzyme 1 alpha (IRE1α) has been associated with multiple human diseases, so IRE1α-targeting small molecules present great therapeutic potential. Here, the authors report a series of substituted indoles as IRE1α inhibitors of good potency and selectivity, and show that the inhibitor IA107 allosterically inhibits IRE1α RNase activity via binding to the IRE1α kinase domain but without inhibiting the IRE1α dimerization.

Distinguishing glioblastoma and primary central nervous system lymphoma (PCNSL) remains challenging due to their overlapping pathology features. Here, the authors develop a computational tool, PICTURE, for differentiating similar pathological features enabling improved diagnosis of CNS tumours.

Plasma proteomic analysis of presymptomatic individuals with amyotrophic lateral sclerosis identifies novel disease-associated proteins and enables the development of an accurate diagnostic biomarker panel.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Long-term complications and persistent symptoms occur following COVID-19, but the nature and duration of the long-term symptoms are not fully characterised. Here the authors report the evolution of post COVID-19 symptoms using a validated self-reported questionnaire assessing 53 symptoms over time in the ComPaRe long COVID prospective e-cohort.

Neutrophils infiltrate the ischemic brain. Here, the authors show a disease-stage dependent neutrophil diversification in neonatal brain injury; neutrophils aggravating tissue damage in the acute phase while promoting regeneration in the later stage.

17β-oestradiol establishes an anti-ferroptotic state in female kidney tubules.

In a randomized, placebo-controlled, stepwise dose-escalation phase 1 trial evaluating a conjugate vaccine against both typhoid and invasive non-typhoidal Salmonella infections, the vaccine was found to be safe and immunogenic in healthy adults.

Here the authors present a computational method that expands the potential of multimodal single-cell analyses by delivering an accurate, fast, and user-friendly approach for normalizing and comparing surface protein expression across large and heterogeneous datasets.

Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.

Currently, there is an urgent need to evaluate the strengths and limitations of various probe-based full transcriptome methods for formalin-fixed paraffin-embedded tumor tissues. Here, the authors analyze three commonly used methods and highlight relative advantages and disadvantages of each method in the context of operational challenges, bioinformatic analyses and biological discoveries.

Visium spatial transcriptomics, single-nucleus RNA sequencing and co-detection by indexing are used to identify distinct spatial microregions in tumours and their microenvironment across six diverse solid cancer types.

The face reveals more than just emotion. Cazettes, Reato and colleagues show that subtle facial movements reveal hidden cognitive states, reflecting the brain’s ongoing computations and offering a noninvasive window into unexpressed thoughts and decisions.

Tanner’s law describes the spreading dynamics of droplets made of Newtonian viscous fluids. Here, the authors demonstrate that this law remains valid for phase-separated binary liquids close to their critical point, and thus for all the associated universality class.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer. Here, the authors develop a NLPHL specific model to identify 34 distinct cell states across 14 cell types that co-occur within 3 lymphocyte predominant ecotypes (LPEs) for 171 cases.

Galland et al. present soSMARt, a method for in-depth single molecule localisation microscopy using microfabricated devices, which enables single-objective light-sheet microscopy, adaptive optics correction, real-time registration, and axially extended volume reconstruction with nanometer precision.

Immune gene expression analysis can help differentiate between inflammatory skin diseases. Here the authors compare expression profiles between different human inflammatory skin diseases and identify gene modules such as cytokines or inflammatory mediators and a molecular map to assist in diagnosis and treatment.

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with few effective treatment options available. Here, the authors use dynamic BH3 profiling to measure drug-induced mitochondrial priming and identify AZD8055 and navitoclax as a pro-apoptotic drug combination in ex vivo and preclinical MPM models.

Here the authors perform a trans expression quantitative trait locus meta-analysis study of over 3,700 people and link a USP18 variant to expression of 50 inflammation genes and lupus risk, highlighting how genetic regulation of immune responses drives autoimmune disease and informs new therapies.

Dynamic Kerr microscopy enables the tracking of the two-step melting of a magnetic skyrmion lattice from a two-dimensional solid through an intermediate hexatic regime to an isotropic liquid and provides direct insights in the occurrence and dynamics of lattice dislocations, the defects that mediate melting.

Some cancer cells exhibit high loads of reactive iron in lysosomes, and this feature is exploited by using fentomycin-1, a newly developed small molecule, to induce ferroptosis.

An understanding of the molecular mechanisms promoting the generation of immunoregulatory and tumour-promoting monocytes and macrophages is key to breaking the cycle of tumour myelopoiesis and developing more effective myeloid-targeting therapies.

The authors estimate the damages associated with global temperature variability. They find that variability in temperature leads to substantial uncertainty about damages, which imposes costs equivalent to a large fraction of annual consumption today.

The loss of a dominant species in a community could have major impacts on ecosystem functioning. Here, a manipulative field experiment on ants shows that species functional redundancy mitigates multifunctionality declines due to suppression of dominant species.

This study examines the function of G-quadruplex DNA secondary structures in mammalian promoters, revealing that they represent core promoter elements contributing to gene regulation by nucleosome exclusion and by promoting RNA polymerase II pause–release.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

Reaction optimisation is a challenging yet essential process in chemistry. Here, authors develop a machine learning framework for automated and highly parallel multi-objective reaction optimisation, validated in pharmaceutical process development.

Transcriptomic analyses of 255 primary human microglial samples from 100 individuals highlight brain region, age, sex and disease states as sources of microglial heterogeneity. Molecular quantitative trait locus analyses implicate variants involved in neurological diseases through effects on gene expression and splicing.

This work presents CalicoST for inferring allele-specific copy numbers and reconstructing spatial tumor evolution by using spatial transcriptomics data.

The Mass Spectrometry Query Language (MassQL) is an open-source language that enables instrument-independent searching across mass spectrometry data for complex patterns of interest via concise and expressive queries without the need for programming skills.

Chronic brain infection and IL-1 exposure impair spatial memory by triggering DNA double-strand break signaling in hippocampal neurons. Blocking this pathway prevents memory deficits, suggesting new therapeutic prospects for various brain diseases.

Rizzollo et al. show that BDH2 participates in iron distribution between cellular compartments, which sets the threshold for the ferroptosis vulnerability of the melanoma cell phenotypes, ultimately affecting their metastatic capacity

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.

CRISPR-Cas systems protect bacteria by capturing viral DNA as genetic memories, known as spacers. Here, authors used deep mutational scanning to identify Cas1 and Cas2 variants that enhance spacer acquisition and phage immunity, with the potential to improve CRISPR-based applications.

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.

Iceberg calving can act as a submarine melt amplifier through excitation of transient internal waves.

Here they show that specialized filopodia are essential for steroid hormone secretion in fruit flies, highlighting a vesicle-mediated mechanism adjusted by filopodia dynamics that challenges a simple secretory diffusion model.

Gene expression topography analysis by GASTON portrays domain organization and spatial gradients of gene expression and cell type composition using spatially resolved transcriptomics data.

Meiotic crossovers enhance genetic diversity in sexually reproducing organisms. Here, the authors propose that the higher-order spatial organization of the meiotic chromosomes shapes sexual dimorphism in Arabidopsis thaliana.

Class A and B GPCR show differential downstream regulation and functions. Here, the authors show how their C-termini largely mediate GRK-specific β-arrestin N-domain conformational changes and co-internalization, while GPCR helix-bundles govern pERK.

Understanding ligated metal clusters’ reactivities is challenging. Now, a methodology has been developed to explore dynamic mixtures of metal clusters. Interrelated cluster populations are constructed through organometallic precursor chemistry. Structural information on mixed-metal systems is obtained with a bias-free computational framework, and reactivities towards CO₂ and alkynes are investigated in situ.

An analysis of habitat fragmentation using a dataset of more than 4,000 species worldwide shows that fragmentation reduces biodiversity at all scales, and that increases in β diversity do not compensate for the loss of α diversity.

Human diseases may evolve by migration or spread, but understanding these complex processes is challenging. Here, the authors leverage graph homomorphisms to reconstruct trees describing histories of metastatic migrations and viral host-to-host transmissions.

Upon emerging from their pupal case, insects swiftly deploy their wings from a compact origami-like structure to a fully extended blade. Here, authors use a combination of imaging and mechanical tests to model the kinematics and dynamics of wing deployment in Drosophila.

Land use intensification is a major driver of biodiversity change and ecosystem functioning. Here the authors identify thresholds of grassland plant community structure and stability in response to land use intensification.

Current tools for single-cell spatial omics still face barriers with regard to incomplete molecular profiling, tissue loss, and probe failure. Here, the authors use machine learning for the imputation of protein abundance in tissue-based cyclic immunofluorescence, showing that the spatial context can improve the accuracy of the imputation outputs.

Epistasis can be quantified using the chimeric formula, which mixes additive and multiplicative scales. Here, the authors show that this formula does not appropriately quantify higher-order epistasis.

Two broadly reactive and inhibitory human monoclonal antibodies against the malaria parasite Plasmodium falciparum have been characterized, providing insights into immunity, prevention and treatment of severe malaria.

The JAK inhibitor ruxolitinib has been used for treatment of myeloproliferative neoplasms (MPN) and its association with clonal evolution requires further investigation. Here the authors report accumulation of RAS pathway mutations in ruxolitinib-treated myelofibrosis patients, stemming from RAS clonal selection induced by JAK2 inhibition.

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.