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Here the authors apply machine learning approaches to Alzheimer’s genetics, confirm known associations and suggest novel risk loci. These methods demonstrate predictive power comparable to traditional approaches, while also offering potential new insights beyond standard genetic analyses.

Bennu comprises components of intra- and extra-Solar System origins. The parent bodies of Bennu, Ryugu and CI chondrites likely formed from a shared but heterogeneous reservoir in the outer parts of the solar protoplanetary disk.

This Review discusses the effects of three age-associated stressors—loss of proteostasis, oxidative damage and dysregulated nutrient sensing—on global protein synthesis and highlights how altered translation is used by the cell as a stress sensor.

The cell-wall peptidoglycan in model bacteria typically includes 4,3- and 3,3-crosslinks, catalysed by DD- and LD-transpeptidases, respectively. Here, the authors identify and characterise the activity and structure of an LD-transpeptidase that generates a new type of crosslink (1,3).

Cellular niches are highly heterogenous in triple negative breast cancer. Here, the authors utilise imaging mass cytometry and spatial transcriptomics to characterise the microenvironment in Black American and White American patients.

Intestinal tuft cell subtypes represent successive stages of differentiation that is driven by crypt-villus signaling gradients. Here, the authors show that applying these gradients to organoids generates mature immune-related chemosensory tuft cells suitable for experimental studies.

Body size and composition are complex traits that are challenging to characterize due to environmental and genetic influences. Here, Arehart et al. disentangle shared and distinct genetic signals underlying body size and composition.

This study identifies a unique multiple sclerosis lesion, the broad rim lesion, which is associated with rapid disease progression and marked by a distinct inflammatory profile involving innate inflammation, cellular stress, unfolded protein response and apoptosis.

In a phase 3 trial for Huntington’s disease, pridopidine did not meet its primary endpoints but was safe and favored in some prespecified subgroup analyses.

A high-bandwidth neuromotor interface offers performant out-of-the-box generalization across people.

How changes in brain blood vessels lead to a chronic reduction in blood flow and, consequently, to vascular dementia is poorly understood. Here, the authors show that venous endothelial dysfunction driven by EPAS1 promotes abnormal vascular remodeling and contributes to cognitive decline.

The heterogeneity of HSPCs in response to IR stress remains poorly characterized. Here, the authors provide insights into the molecular intricacies of IR-induced BM injury and reveal the roles of BMP4-BMPR2 signaling in radiation resistance of HSCs.

Here, the authors characterize the tempo and mode of lemur speciation with a phylogenomic dataset that also includes lorisiforms. They find that lemurs exhibited multiple bursts of diversification (without subsequent decline in diversification rate) with the highest diversification rates accompanied by high introgression rates.

In this genomic analysis of peripheral blood samples of the phase 3 CheckMate-067 trial of ipilimumab (IPI) versus nivolumab (NIVO) versus ipilimumab and nivolumab (IPI-NIVO) in melanoma, the status of certain mitochondrial haplogroups in patients was associated therapeutic resistance to NIVO or IPI-NIVO, a finding validated in an independent cohort.

Graphene oxide membranes have great potential in separation processes, but small ions rejection needs improvement for large scale applications. Here the authors manipulate the membrane’s surface charge to control selective ion transport, achieving high rejection for A2B and AB2 type salts and maintaining high water permeance.

LaccID, an engineered laccase, enables hydrogen-peroxide-free proximity labeling and electron microscopy (EM) in mammalian cells. Notably, LaccID is selectively active at the cell surface, enabling the mapping of the dynamic T cell–tumor surfaceome and its use as a genetically encodable EM tag, expanding the toolkit for cell-based imaging and proteomics.

In Drosophila, coherent slow-wave activity between sleep-promoting and locomotion-promoting neural networks provides a brain state structure that allows for quiescent behaviours.

Artificial molecular machines have captured the imagination of researchers, given their clear potential to mimic and influence human life. Here, the authors use a DNA cube framework for the design of a dice device at the nanoscale to reproduce probabilistic events in different situations such as equal probability, high probability, and low probability.

Dense calcium imaging combined with co-registered high-resolution electron microscopy reconstruction of the brain of the same mouse provide a functional connectomics map of tens of thousands of neurons of a region of the primary cortex and higher visual areas.

The fetal globin gene repressors BCL11A and ZBTB7A directly bind γ-globin gene promoter regions. Repressor binding is disrupted by naturally occurring point mutations located upstream of the transcriptional start site that are associated with hereditary persistence of fetal hemoglobin.

Analysis of whole genomes and life-history data of male black grouse shows that deleterious mutations, especially those in promotors, reduce lifetime reproductive success.

Toxoplasma gondii RNA triphosphatase, the first enzyme in mRNA capping machinery, is essential and has a completely different structure and mechanism compared to the human RNA ortholog, making RNA triphosphatase a promising therapeutic target for toxoplasmosis.

The homeostasis of myelin in the central nervous system is highly regulated, but the underlying mechanisms are unclear. Here, the authors show that the FBXW7 protein has a role in constraining myelin growth in the developing and adult central nervous system, preventing the accumulation of myelin abnormalities. FBXW7 acts in part through targeting the MYRF transcription factor for degradation.

Robust bioanalytical and modeling methods are needed for covalent drug discovery. Here, the authors demonstrate a mass spectrometry (MS) assay to measure target engagement of any drug-target protein complex, a universal PK/PD model for covalent drugs, and a decision tree to guide research.

Pocock et al. reveal that transient activation of 5′ AMP-activated protein kinase and estrogen-related receptor drives robust maturation of multicellular human cardiac organoids, enabling modeling of desmoplakin cardiomyopathy dysfunction, which could be rescued using the bromodomain and extra-terminal inhibitor INCB054329.

Major Depressive Disorder (MDD) is a heritable psychiatric disorder whose biological basis remains poorly understood. This large-scale postmortem brain study identified extensive gene expression changes associated with genetic risk, highlighting disrupted glutamatergic signaling and synaptic vesicle function in MDD.

The lateral prefrontal cortex (LPFC) is thought to maintain goal-relevant representations that promote cognitive control, but causal evidence has been limited. By targeting action-goal representations in LPFC with transcranial magnetic stimulation and fMRI, the authors found that LPFC promotes goal oriented behaviour during emotional processing. Reviewer recognition:

Immunotherapy has yet to demonstrate efficacy for patients with glioblastoma. Here, the authors employ human single-cell RNA-seq, spatial transcriptomics, and a preclinical mouse model to show that glioblastoma cell-derived synaptogenic factor Thrombospondin-1 promotes neuronal circuit remodeling and regional immunosuppression, highlighting a potential therapeutic target.

Tuberculosis is a major global health threat. Here, the authors develop a single-cell drug discovery approach and identify a compound that tunes bacterial phenotypic variation. This enhances the activity of anti-tubercular drugs against the pathogen.

The complexity of epithelial cell states in the fibrotic niche in the context of chronic kidney disease remains incompletely understood. Here the authors integrate snRNA and ATAC-seq with high-plex single-cell molecular imaging to generate a spatially-revolved multiomic atlas of human kidney disease.

A computational method called Ortho-Marker Gene Groups (OMGs) was developed to enable cell-type identification and comparison across plant single cell data. The OMG method revealed 14 conserved cell-type groups and is accessible via the OMG browser.

Simulations of the SARS-CoV-2 proteome that include over 0.1 s of aggregate data are reported. Spike opening was observed, revealing cryptic epitopes that differ between variants, explaining differential interactions with antibodies and receptors that determine pathogenicity. The cryptic pockets described provide new targets for antivirals and a wealth of mechanistic insight.

Plants encounter high temperatures concomitantly with intense sunlight during the daytime. Here, the authors reveal a concerted chloroplast and nucleus high-temperature signaling framework that gates daytime thermomorphogenesis in Arabidopsis.

Imidazole propionate produced by gut microbiota is associated with atherosclerosis in mouse models and in humans, and causes the development of atherosclerosis through activation of the imidazoline-1 receptor in myeloid cells.

Two new methodologies for automated cell tracking allow rapid analysis of cellular-scale behaviors across diverse samples with minimal errors.

Collagen VI microfibril cryo-EM structure resolves a cysteine-rich coiled-coil important for heterotrimerization and microfibril assembly, reveals a hotspot of collagen VI muscular dystrophy mutations and provides a template for therapeutic design.

Preparation of well-defined N-glycans is very demanding, which hampers progress in glycoscience. Now, a biomimetic synthetic approach has been developed in which a readily available bi-antennary glycan can be converted in ten or fewer steps into multi-antennary N-glycans. This approach enables each arm to be uniquely extended by glycosyltransferases to give complex branched N-glycans.

Excised signal circles are circular DNA by-products of V(D)J recombination that form a complex with the V(D)J recombinase, and when increased in abundance, result in increased mutagenesis, causing adverse outcomes in cancer.

Here, the authors present fossilized neural traits from the lower Cambrian euarthropod Jianfengia multisegmentalis, including structured eyestalks and compound eyes, that resolve multiple phylogenetic relationships within Euarthropoda.

This work introduces an accurate liquid identification strategy by integrating droplet mechanics and solid–liquid interface contact electrification in a ZnO–PDMS superhydrophobic solid–liquid sensor.

Brain-machine interfaces are hindered by neuroinflammation. Here, the authors found that bacterial sequences invade the brain post-microelectrode implantation. Antibiotic-treated mice showed reduced bacterial presence and altered neuroinflammatory profile, temporarily improving recording performance.

A versatile nano-adaptor is used to construct multi-specific nano-antibodies for treatment of tumours in mice.

The present main-stream medical ultrasonic nebulizers contain a usually overlooked health risk of lead exposure as their key components are made of lead-containing piezoceramics. Here the authors introduce a lead-free medical ultrasonic nebulizer, which eliminates lead exposure risk in nebulization therapy and offers a healthy solution for patients.

Alzheimer’s disease (AD) drug discovery has been hampered by patient heterogeneity, and the lack of sensitive tools for precise stratification. Here, the authors show an AI-guided model enhances patient stratification, improving outcomes and increasing efficiency in the AMARANTH trial.

In a mouse model, maternal obesity during pregnancy can lead to fatty liver disease in the offspring, driven by aberrant developmental programming of Kuppfer cells.

GO monolayers are presumed to invariably contain a large density of nanoscale pinholes. Here the authors present gas and proton transport measurements which show that GO monolayers can be pinhole-free over micrometer-scale areas.