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A high-throughput chemical–genetic screening approach for the discovery of targets and chemicals to treat Mycobacterium tuberculosis yields tenfold more hit compounds than conventional whole-cell screening methods.

A foundation model trained on neural activity of visual cortex from multiple mice accurately predicts responses to video stimuli and cell types, dendritic features and connectivity within the MICrONS functional connectomics dataset.

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.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

Cancer cells in culture are often grown in media conditions containing unphysiological metabolite levels. Here, the authors grow cells under physiological metabolite levels to further understand the reliance of cells on serine and find that when grown under these conditions the cells are less sensitive to serine withdrawal.

Elucidation of the bacterial ceramide biosynthetic pathway reveals that it likely evolved independently from the eukaryotic pathway, as bacteria lack homologs for many of the eukaryotic enzymes and the reactions occur in a different order.

Deletion of PC-TP has many beneficial effects, mostly ascribed to its role in regulating THEM2. Here, the authors show a novel interaction between PC-TP and PPARδ that explains aspects of the beneficial metabolic phenotype associated with PC-TP deletion.

Cell fate choices, including developmental cell death, are often driven by asymmetric cell division, though what determinants drive these choices remain unclear. Here they show that the evolutionarily conserved CMG complex, best known for its role in unwinding DNA during chromosome replication, is also required for cell fate divergence during asymmetric cell divisions in C. elegans development.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

A foundation model learns transcriptional regulatory syntax from chromatin accessibility and sequence data across a range of cell types to predict gene expression and transcription factor interactions, with generalizability to unseen cell types.

A protocol is described for predicting the structures and functions of multi-domain proteins using the freely available deep-learning-based web platform I-TASSER-MTD.

Combined hepatocellular-cholangiocarcinomas (cHCC-CCA) are challenging to diagnose, as they exhibit features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICCA). Here, the authors use deep learning to re-classify cHCC-CCA tumours into HCC or ICCA based on histopathology images.

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.

The NF-κB complex is a core regulator of inflammatory gene expression and activates transcription of many different target genes. Fu et al. show that NF-κB promoter specificity can be tuned by Sam68, which is required for targeting NF-κB to the CD25 promoter during T cell activation.

Macrophages are abundant in atherosclerotic plaques and are a pivotal cell type in plaque formation and progression. But how do they get there? Filip Swirski and his colleagues show that, contrary to most previous work that has emphasized the importance of monocyte recruitment from the blood, most macrophages in established lesions are generated by local macrophage proliferation, which depends on the SR-A scavenger receptor.

The goal of the 1000 Genomes Project is to provide in-depth information on variation in human genome sequences. In the pilot phase reported here, different strategies for genome-wide sequencing, using high-throughput sequencing platforms, were developed and compared. The resulting data set includes more than 95% of the currently accessible variants found in any individual, and can be used to inform association and functional studies.

Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

PetaKit5D offers versatile processing workflows for light sheet microscopy data including performant image input/output, geometric transformations, deconvolution and stitching. The software is efficient and scalable to petabyte-size datasets.

Radiotherapy has an established role in the treatment of many patients with cancer, with evidence suggesting that this modality can also have immunostimulatory effects in certain scenarios. More recently, evidence has emerged supporting a role of the microbiome in influencing the incidence and severity of toxicities in patients receiving radiotherapy as well as in mediating possible synergy with other therapeutic interventions, including immunotherapy. In this Review, the authors explore the clinical potential of these emerging relationships.

Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance.

Premature termination codons can cause early translation termination and lead to disease. Here the authors perform a screen to identify compounds with readthrough activity and show that these reduce eRF1 levels to suppress premature termination associated with cystic fibrosis.

Federated learning (FL) has emerged as a potential solution to train machine learning models in multiple clinical datasets while preserving patient privacy. Here, the authors develop an MRI-based FL platform for pediatric posterior fossa brain tumors—FL-PedBrain—and evaluate it on a diverse multi-center cohort.

Near infrared energy remains untapped toward the maneuvering of entire solar spectrum harvesting for fulfilling nuts and bolts of solar hydrogen production. Here, the authors report the use of Au@Cu₇S₄ yolk@shell nanocrystals for hydrogen production from untapped near infrared energy.

Cyanobacterial nitrogen fixation supplies bioavailable nitrogen to marine ecosystems, but the mechanisms governing iron and phosphorus co-limitation in elevated CO₂remain unknown. Here, the authors show a complex cellular response to co-limitation characterized by changes in growth, cell size, and the proteome.

A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

This study finds that sST2 is a disease-causing factor for Alzheimer’s disease. Higher sST2 levels impair microglial Aβ clearance in APOE4⁺ female individuals. A genetic variant, rs1921622, is associated with a reduction in sST2 level and protects against AD in APOE4⁺ female individuals.

Point-defect metamaterials have the property of concentrating vibration energy at the defect location. We design an environmental monitoring node based on this property, which can efficiently convert wave kinetic energy into electrical energy for real-time monitoring of the ocean environment.

Altered mechanotransduction has been proposed as a mechanism for disease pathophysiology, yet evidence remains scarce. Here, the authors show that antibodies from patients with bleeding disorders bind to integrins and modulate platelet cell contraction force, and this correlates with clinical symptoms.

Metabolomics data from germ-free and specific-pathogen-free mice reveal effects of the microbiome on host chemistry, identifying conjugations of bile acids that are also enriched in patients with inflammatory bowel disease or cystic fibrosis.

Using the unique valley properties of a twisted MoTe₂ bilayer, measurements of the degree of circular polarization of trion photoluminescence reveal optical signatures of a zero-field composite Fermi liquid.

While recognized as the first effective immunotherapy for human cancer, IL-2 based immunotherapy still encounters several limitations in the clinic. Here, the authors design a cytokine receptor-masked IL-2 mutein prodrug that is selectively activated by matrix metalloproteinases in the tumor microenvironment, promoting anti-tumor immune response while minimizing systemic toxicity.

Several studies have demonstrated that IFN-I administration can boost anti-tumor immune response against solid tumors. Here, to overcome the limitations of systemic IFN-I therapy (side effects, short half-life), the authors design a masked IFN-I prodrug activatable by tumor-associated proteases, showing preserved anti-tumor activity but reduced toxicity.

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