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RODEO, an algorithm developed for RiPP natural product discovery, was applied to map out the gene clusters that encode and tailor lasso peptides and led to the identification and characterization of several new lasso peptide topologies.

The human genome contains stretches of DNA sequence with unknown function. Peptidomics coupled to RNA-Seq now reveals a class of short open reading frames in human genomes that are translated into small peptides.

The ideal metal selection and atomic-level arrangement for catalysts in CO₂ hydrogenation are still uncertain. Here, copper is identified as the most effective promoter for enhancing ZnZrO_x catalysts when precisely structured into CuZn ensembles, offering new insights for designing superior catalysts for CO₂-based methanol synthesis.

Panzeri et al. use a Trim28^+/D9 mouse model with intrinsic developmental heterogeneity to show that ‘heavy’ and ‘light’ developmental morphs exhibit different timing, type and severity of cancer, linked to a relevant DNA hypomethylation signature.

Melanoma cells can switch between proliferative and invasive phenotypes. Here the authors show that the embryonic stem cell factor Sall4 is a negative regulator of melanoma phenotype switching where its loss leads to the acquisition of an invasive phenotype, due to derepression of invasiveness genes.

Here the authors show that Xist drives non-stoichiometric recruitment of SHARP/SPEN to the inactive X chromosome, including at regions not occupied by Xist, through concentration-dependent homotypic assemblies of SHARP, which is required for chromosome-wide silencing. This spatial amplification allows Xist to balance chromosome-wide silencing and specificity to the X thereby enabling Xist to silence the X, the whole X, and nothing but the X.

Glutamine metabolism is well known to support tumour growth. Here the authors show that cancer cells also utilize glutamine to promote invasiveness by converting it to glutamate, which upon secretion activates metabotropic glutamate receptors to stimulate matrix metalloproteases recycling to the cell surface.

Gene delivery to fibroblasts for liver fibrosis treatment remains challenging. Here the authors develop a combinatorial library of ligand-tethered lipidoids via a modular synthetic method and adopt a 2-round screening strategy to identify lipidoids for potent and selective gene delivery to fibroblasts.

This protocol provides structure-guided capsid library approaches to evolve new adeno-associated viral vectors for enhanced CNS gene delivery with altered tissue tropism, higher transduction efficiency and the ability to evade pre-existing humoral immunity.

A genetically encoded FRET-based optical sensor generated from a computational design approach can monitor hippocampal glycine levels in brain tissue to determine differences between spines and shafts and changes induced by high- and low-frequency stimulation.

Histones, proteins that bind DNA, are toxic for pathogens outside cells but can also cause multi-organ damage as seen in sepsis. Here the authors develop small negatively charged molecules that can be used as histone antidotes, and show that they improve the phenotype in mouse models with histone-related pathologies.

The authors report three palaeomagnetic poles from the North China craton and document a large round-trip true polar wander oscillation during 155−141 Ma that may have affected biotic evolution in East Asia and global extinction and endemism.

Astrocombs serve as precision calibrators for astrophysical spectrographs by providing a regular sequence of optical lines on a multi-GHz grid. Here, the authors report the first broadband astrocomb in the UV to blue-green spectral region, where stellar absorption lines are most abundant.

Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here, the authors present the largest FL study to-date to generate an automatic tumor boundary detector for glioblastoma.

The complete assembly of human chromosome 8 resolves previous gaps and reveals hidden complex forms of genetic variation, enabling functional and evolutionary characterization of primate centromeres.

Whole-genome sequencing of haematopoietic colonies from human fetuses reveals the somatic mutations acquired by individual progenitors, which are used as barcodes to construct a phylogenetic tree of blood development.

There is a pressing need to develop representative organ-like platforms recapitulating complex in vivo phenotypes to study human development and disease in vitro. Here the authors present a method to generate human heart organoids by self-assembly using pluripotent stem cells, compare these to age-matched fetal cardiac tissues and recreate a model of pregestational diabetes.

Functional brain imaging with two-photon microscopy is limited by a tradeoff between imaging area and acquisition speed. Here, the authors present Quadroscope, a flexible microscope which allows for simultaneous video rate acquisition of four independently targetable brain regions across 5 mm.

The natural antisense transcript MAPT-AS1 interferes with translation of mRNA transcript into tau protein in the brain and may represent a general mechanism for controlling levels of intrinsically disordered proteins, with particular relevance for neurodegeneration.

Transcriptomic analysis may provide information about the differentiation state and cell of origin of a cancer. Here, the authors assess mRNA signals in 1300 childhood and adult renal tumors and report a fetal origin of childhood tumors and no dedifferentiation of adult tumors.

Breaking down the endothelial barrier is a hallmark of systemic inflammatory response syndrome. Here the authors show that palmitoylation, a post-translational modification of proteins, plays a critical role in altering endothelial function during inflammation, and suggest the targeting of palmitoyl acyltransferase DHHC21 as potential disease therapy.

Heterogeneous geminal-atom catalysts, which pair single-atom sites in specific coordination and spatial proximity, offer a new avenue for the sustainable manufacture of fine chemicals.

Loss of PP2A activity is often associated with cancer but the underlying mechanism remains unclear. Here, the authors show that decreased methylation of PP2A catalytic C subunit caused by loss of LCMT-1 in prostate cancer abrogates the tumor suppressor activity of PP2A on AR/MED1-dependent gene expression, proposing decreased methyl-PP2A-C as a prognostic marker for prostate cancer progression.

Replacing the extracellular domains of heterodimeric cytokine receptors in chimeric antigen receptor T cells with two leucine zipper motifs leads to optimal JAK/STAT signalling and augments the effector function of the T cells.

Ameliorating or preventing signatures of aging in humans using natural compounds is an exciting area of research. Here the authors isolate a previously unknown phytochemical from carrots which activates defence mechanisms against oxidative stress and extends lifespan in worms, and improves glucose metabolism, promotes exercise capacity, and protects from frailty at higher age in mice.

Antibiotic-resistant bacteria are an urgent threat to human health. Here, Roberts et al. characterise and monitor an ongoing hospital outbreak of carbapenemase-producing Enterobacter hormaechei by integrating several technologies for whole-genome sequencing and shotgun metagenomics.

The Musashi family of RNA binding proteins are found in an oligomeric state in the brains of patients with Alzheimer’s disease. Here the authors show that Mushashi1 and Musashi2 interact with tau protein in patient tissue and in models of tauopathy.

Top-down proteomics can provide unique insights into the biological variations of protein biomarkers but detecting low-abundance proteins in body fluids remains challenging. Here, the authors develop a nanoparticle-based top-down proteomics approach enabling enrichment and detailed analysis of cardiac troponin I in human serum.

Advances in biofabrication technology enable 3D printed constructs to resemble real tissues, but it remains unclear how cell-generated forces deform these constructs. Here the authors investigate mechanical behaviours of 3D printed “microbeams” made from mixtures of living cells and extracellular matrix.

Systemically injected lipid–polymer nanoparticles encapsulating small interfering RNA for silencing genes in bone-marrow endothelial cells of mice improved the healing of the mice after myocardial infarction.

Though efforts toward electrically-pumped lasers based on simple organic light-emitting diode (OLED) structures have been reported, a comprehensive model is needed to elucidate key optoelectronic processes. Here, the authors report a model describing OLED operation under high current densities.

An apparent redundant role with EZH2 has rendered EZH1 as a secondary player in PRC2-mediated homeostasis regulation. Here, the authors report that gain- and loss-of-function variants in EZH1 cause neurodevelopmental disorders, highlighting its functional relevance.

The diversity of synchronized neuronal groups provides a challenge for brain theories. Here, the authors report that group size grows quadratically with duration in line with predictions for neuronal avalanches and brain dynamics being critical.

Fumarate metabolism regulates the innate immune response through a mechanism in which high levels of fumarate result in the generation of mitochondrial-derived vesicles and the release of mitochondrial DNA into the cytosol, which activates inflammatory pathways.

Detecting relevant odours from background odours is important for animal behaviour. Here the authors design a task to study this process in mice.

Newly formed endosomes mature into early endosomes by shedding one protein and acquiring another. Here, the authors describe a trigger-and-convert mechanism driven by endosomal collisions and fusions that govern timeliness in ensemble maturations.

Riffelmacher et al. show that immunization with a live vaccine strain leads to the expansion of two memory-like mucosal-associated invariant T cell lineages with distinct metabolic needs, effector programmes and protective capacities.

Anti-cancer treatment often results in a subset of the clonal cell population developing resistance to therapy, with resistant cells displaying a diversity of fate types resulting from the intrinsic variability among the clonal population before treatment.

Nucleotide analogs modified with a free 3′ hydroxyl, maintaining the interactions at the polymerase active site, and a cleavable linker, attaching a fluorescent dye and an inhibitor, are efficient at reading homopolymer runs in a single-molecule sequencing reaction.

Building crystal structures into the electron density is an important step in protein structure solution. Here, the authors recruit online game players, students, and experienced crystallographers to compete in a competition to solve a new structure, and find that crowdsourcing model-building works.

Ubiquitous in nature, hierarchical architectures are less commonly achieved in synthetic functional materials. Here, the authors design and carefully assemble block copolymer micelles into complex supermicelles using hydrogen bonding in orthogonal combination with other non-covalent interactions.

Uniform, hierarchical 2D nanostructures with controlled shapes can be prepared from homopolymers with charged end-groups using a crystallization-driven assembly process.

Achieving a high degree of control over the self-assembly process is a challenging task, but one that can give access to precisely defined structures. Here, the authors show the generation of hybrid materials with controlled morphology and hierarchy based on the assembly of block copolymers on silica cores.