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Periventricular heterotopia (PH) is associated with neurodevelopmental delay. Here authors report patient-derived organoids with FAT4 and DCHS1 mutations mimic PH features, showing hyperactivity, synaptic changes and cell morphological alterations.

A national prospective study of patients requiring hospitalization for COVID-19 demonstrates global cognitive deficits at 1 year, associated with elevated brain injury markers and reduced gray matter volume.

Urban soils are exposed to numerous human-driven stressors that can interact in unpredictable ways. This study concludes that the impact of adding one factor does not correspond to the impact of removing it from a set of interacting stressors.

In vitro propagation of the pathogenic bacterium Coxiella burnetii, the causative agent of Q fever, leads to attenuated virulence and lipopolysaccharide (LPS) truncation. Here, Long et al. show that a strain considered to be avirulent (NMII) can be recovered from infected animals, and these isolates display increased virulence and an elongated LPS due to reversion of a 3-bp mutation in a gene.

Natural products inspire the development of pseudo-natural products through combinations of fragments of compound classes that are chemically and biologically distinct. Here, the authors report a library of 244 pseudo-natural products, evaluate them in the cell painting essays and identify the phenotypic role of individual fragments.

Microglial states throughout remyelination are incompletely understood. Here, the authors show that microglia form several states during the early stages of remyelination that coalesce into a partially resolved state that is dysregulated with age.

Blocking peptidoglycan synthesis kills bacteria. The authors show that the E. faecium PBP5 peptidoglycan binding site is distal to the active site, which could be the focus of antibiotic strategies that hinder substrate recruitment.

The xylosyltransferase isoenzymes XT1 and XT2 catalyze the first glycosylation step in the biosynthesis of proteoglycans. Now, bump-and-hole engineering of XT1 and XT2 enables substrate profiling and modification of proteins as designer proteoglycans to modulate cellular behavior.

Taveneau et al. leverage artificial-intelligence-driven protein design to create inhibitors that control RNA-targeting enzymes in cells, revealing a strategy to rapidly design off-switches for RNA-editing systems.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

In this work, researchers address a key question for maternal group B Streptococcus (GBS) vaccine assessment: What newborn antibody concentrations protect against invasive infant GBS disease? They present serologic thresholds by age at onset and serotype based on a large U.S. case-control study.

The affected cellular populations during Alzheimer’s disease progression remain understudied. Here the authors use a cohort of 84 donors, quantitative neuropathology and multimodal datasets from the BRAIN Initiative. Their pseudoprogression analysis revealed two disease phases.

The ρ-type GABAA receptors are potential therapeutic targets in several neurological conditions. Here, authors elucidate interactions of it with three therapeutic drugs, offering mechanistic insights and a prospective basis for further pharmaceutical development.

Authors demonstrate that four distinct heterodimeric complexes catalyze chondroitin sulfate chain polymerization in humans. The synthase proteins possess catalytic activity, while the polymerization factors are essential for complex formation.

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

Coagulation factor IX (FIX) contributes to hemostasis through both plasma activity and binding to extravascular collagen IV. Here, the authors show that collagen binding of albumin-fused hyperactive FIX can be engineered to tailor the pharmacokinetics, distribution, and functional properties in mice for tailored short- or long-term hemophilia B therapy.

This study associates p53 loss and brain metastasis in breast cancer. Mechanistically, p53-null tumors recruit astrocytes that provide substrates for enhanced fatty acid synthesis via upregulated SCD1 expression, representing a targetable axis in the disease.

Transfer RNA-derived small RNAs (tsRNAs) emerge as crucial players in biological processes but their disease relevance is unknow. Here, the authors show that tsRNA-Glu-CTC is the most abundant hepatic tsRNA that plays a key role in regulating cholesterol homeostasis and atherosclerosis development.

A combination of high-resolution spatial imaging, spatial proteomics and transcriptional data reveals sparse and heterogeneous bacterial signals in gliomas and brain metastases.

Metabolomic profiling of 581 mother–child pairs revealed patterns associated with neurodevelopmental disorders (NDD). Maternal metabolomic profiles at gestational week 24 showed the strongest predictive value, with quinolinate consistently associated with NDD across time points and linking maternal inflammation to NDD risk.

Murphy et al. reveal a unifying pathogenetic mechanism according to which diverse mutations in the muscle-specific ribosomal protein RPL3L cause severe neonatal dilated cardiomyopathy, establishing a framework for interpreting the growing spectrum of RPL3L variants.

Using a large multi-center neuroimaging dataset, Fu, Antoniades et al. reveal that major depressive disorder is characterized by two neuroanatomical dimensions exhibiting distinct treatment response to placebo and selective serotonin reuptake inhibitor medications.

Here, the authors generated and analyzed run-on sequencing data to observe transcription in species across the tree of life to uncover the origins of the promoter-proximal pause.

In this work, functional antibodies against the cancer-related GPCR NTS1 were generated by immunizing chickens with in silico-designed 3D peptides, offering a strategy for GPCR targeting with potential diagnostic and therapeutic applications.

BPTF is known to regulate chromatin accessibility and self-renewal in mammary epithelial stem cells. Here, the authors discover that BPTF inhibition delays tumor formation, re-activates ERα expression, increases sensitivity to tamoxifen treatment, and inhibits metastatic development.

Induced proximity by molecular glues is a strategy that leverages the recruitment of proteins to facilitate their modification or degradation. Here the authors present unbiased quantitative proteomic, biochemical and computational workflows that uncover hundreds of CRBN molecular glue targets using recombinant protein and cell lysate.

UCHL5 is a deubiquitinating enzyme that cleaves Lys-48-linked polyubiquitin chains. Here, the authors discover through in-vivo CRISPR-Cas9 screens that Uchl5 is involved in immune evasion and modulation of extracellular matrix deposition in head and neck squamous cell carcinoma.

Researchers analyzed 5,279 plasma proteins in 40 people undergoing feminizing gender-affirming hormone therapy over 6 months, revealing significant changes in 299 proteins. Such changes could have implications for reproductive capacity, immune regulation and long-term health.

Human astroviruses are a leading cause of diarrhea worldwide. Lentz et al. report the structure of the astrovirus capsid spike bound to the human neonatal Fc receptor, revealing detailed insights into how astroviruses infect human cells.

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.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

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.

Luster and colleagues report that lung-resident ST2⁺ regulatory T cells secrete the IL-1 antagonist IL-1Ra to suppress neutrophils and early innate immune responses to influenza virus infection.

In this study, the authors develop a flavivirus vaccine strategy by introducing mutations into envelope glycoproteins resulting in structural changes that conceal the ADE-prone fusion loop epitope. They show that the Zika virus-specific construct protects mice against viral challenge and prevents ADE by Dengue virus.

Birth season has been associated with differences in epigenetic, developmental and health outcomes, but associations to developing metabolome are unclear. Here the authors report a secondary exploratory analysis of The Early Life Interventions for Childhood growth and development in Tanzania (ELICIT) trial showing that in rural Tanzania, an infant’s birth season shapes their metabolism up to 18 months of life, linked to rainfall, food insecurity and breastmilk composition.

Computational methods are becoming an increasingly important part of biological research. Using the Rosetta framework as an example, the authors demonstrate how community-driven development of computational methods can be done in a reproducible and reliable fashion.

How the brain controls pain perception remains elusive. Here, authors show that layers 5 and 6 of the somatosensory cortex suppress or enhance nociception through cell-type-specific cortical and corticothalamic interactions.

Padi and Godek et al. solve cryo-electron microscopy structures of protein phosphatase 2A (PP2A):B55 bound to p107 and Eya3, which, together with nuclear magnetic resonance dephosphorylation experiments, show how PP2A:B55 recruits specific substrates and how it achieves efficient dephosphorylation of phosphosites with high cellular fidelity.

Starble, Sun, and colleagues identify an epigenetic priming mechanism that promotes oncogene amplification in acquired resistance to tyrosine kinase inhibitors and establishes a role of METTL7A in this process.

Using several complementary models, including human iPSC-derived trophoblasts, trophoblast organoids, and placenta explants, the authors find cytotrophoblasts and syncytiotrophoblasts to be susceptible to Oropouche virus (BeAn19991) infection.

Here, the authors screen for sex differences in the common genetic architecture of over 1000 neuroanatomical phenotypes, showing overall concordance between female and male individuals.

By enriching productive mutational paths, a Kemp eliminase that speeds up proton abstraction >10⁸-fold was developed in only five evolution rounds. Recombining it with a variant differing by 29 substitutions revealed the underlying fitness landscape.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

Borgs are large extrachromosomal elements of anaerobic methane-oxidizing archaea. Here, via in silico protein structure prediction of ~10,000 Borg proteins, the authors reveal that Borgs share numerous features with giant eukaryotic viruses, suggesting that Borgs have a viral-like lifestyle and evolutionary convergence of large extrachromosomal elements across the Domains of Life.

The assembly of the genome of the koala provides insights into its adaptive biology and identifies gene expansions that contribute to its ability to detoxify eucalyptus-derived compounds and perceive plant secondary metabolites.

cAMP export by ABCC4 is critical for localized signaling. Here, the authors revealed that PKA activation drives ABCC4 to the plasma membrane and organizes a PDZ-dependent protein network with actin cytoskeleton and scaffolds, like SCRIB, that stabilize the transporter and optimize cAMP efflux. Furthermore, the authors show that the potent ABCC4 inhibitor Ceefourin 2 disrupts this network, revealing a non-canonical mechanism of ABCC4 inhibition.

In this study, Uldrich and colleagues describe the crystal structure of the Vγ9Vδ2 T cell antigen receptor (TCR) interacting with BTN2A1 and demonstrate the existence of a second ligand that co-binds to a distinct epitope on Vγ9Vδ2 TCR. Using these data, the authors suggest a model of Vγ9Vδ2 TCR activation in which BTN2A1 and BTN3A1 are tethered to each other at the steady state, and must disengage to allow TCR binding.

The authors identify pathogenic variants in the SMARCA1 gene as the cause of a variable neurodevelopmental disorder. Mouse studies suggest diverse genetic mechanisms related to NURF complex composition mediate the phenotype.