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A method for de novo design of peptide macrocyles called RFpeptides has been developed. RFpeptides is an extension of RoseTTAFold2 and RFdiffusion and combines structure prediction and protein backbone generation for rapid and custom design of macrocyclic peptide binders.

Rhine et al. find that neuronal aging leads to widespread dysregulation of RNA biology, including mislocalization of splicing proteins like TDP-43, chronic cellular stress and reduced resiliency.

This work identified cyclic peptide inhibitors of a mammalian N-terminal cysteine oxidase, ADO, through mRNA display, one of which was used as a scaffold to graft substrate moieties, allowing key interactions to be assessed through structural and biochemical approaches.

Utilizing single-cell RNA sequencing, the authors here find that IL1B gene expression in peripheral blood monocytes associates with smaller HIV-1 reservoir size in people treated during acute infection, suggesting IL1B may be a natural latency reversing factor decreasing the reservoir via NF-κB activation.

The choroid plexus (ChP) provides molecular cues for brain development. However, the underlying mechanisms are unclear. This study identifies an apocrine secretion mechanism in the ChP that modulates the CSF protein composition and instructs cortical development.

X-ray synchrotron measurements reveal heterogeneities at electrode|electrolyte interfaces of lithium metal batteries operating at high potentials. Here the authors demonstrate the rearrangement of ionically conductive phases in polymer electrolytes that lead to battery performance degradation.

MGAT1 is a glycosyltransferase critical for the synthesis and maturation of complex N-glycans. Here, the authors show that MGAT1 modulation of CD73 glycosylation and function regulates tumor immune response in triple-negative breast cancer.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

The APC/C ubiquitylates histones to regulate gene expression in pluripotent cells. Here, the authors pair cryo-EM and biochemical and biophysical assays to show that instead of modifying nucleosome-incorporated histones, the APC/C ubiquitylates extranucleosomal histone complexes through a mechanism that bypasses canonical substrate degrons.

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.

Inhibition of haem synthesis is shown to lead to the accumulation of branched-chain amino acids in the brown adipose tissue of mice, which reduces UCP1 levels and impairs thermogenesis.

Enantioconvergent reactions convert both enantiomers of a racemic starting material into a single enantioenriched product. All currently known enantioconvergent processes necessitate the loss or partial loss of the racemic substrate’s stereochemical information. Now, an alternative approach has been developed that proceeds with full retention of the racemic substrate’s configuration.

Structural and single-molecule analyses show the CTPase, KorB, is a sliding DNA clamp that interacts with a clamp-locking protein KorA to inhibit gene expression over distances of more than 1 kb in the multi-drug resistance RK2 plasmid.

Here, the authors leverage whole-genome sequencing from >88,000 diverse individuals to uncover 18 BMI-related genetic signals, including novel variants in participants of African genetic ancestry, highlighting the value of diversity in genetic discovery.

T cell antigen receptor stimulation by the ligand antigen triggers multiple downstream pathways that affect CD4 + T cell function. Here authors show that activation of the downstream WNK1 kinase causes water entry into the cells, which is essential for CD4⁺ T cell proliferation.

Shape transformation without the need for external devices or wires is desirable for soft robotics, but challenging to achieve. Here, the authors report the development of actuators capable of shape changes by polymerization and depolymerization of DNA activator sequences.

Here the authors conduct a multi-ancestry meta-analysis of telomere length, used diverse approaches to identify genes underlying association signals, and experimentally validated POP5 and KBTBD6 as regulators of telomere length in human cells.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Garbincius et al. show that the mitochondrial protein TMEM65 is required to mediate NCLX-dependent mitochondrial calcium efflux, thus fine-tuning mitochondrial function and cellular homeostasis

Elasticity is ubiquitous in everyday life, but the molecular origin of the restoring force remains elusive. Here the authors use a series of density functional theory calculations to understand how interaction energies change as a result of the bending of molecular crystals.

Hydrocarbon selectivity in photoelectrochemical CO₂ reduction has been limited due to a lack of low-overpotential catalysts and high-photovoltage semiconductors. Here Cu nanoflowers are interfaced with perovskite light absorbers for bias-free conversion of CO₂ to ethane and ethylene coupled to water or glycerol oxidation.

Joshua Bis, Christopher O'Donnell and colleagues report a meta-analysis of genome-wide association studies from the CHARGE Consortium that identifies loci associated with carotid intima media thickness and plaque. These are established measures of subclinical atherosclerosis that predict future cardiovascular disease events.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Analysis of large-scale CRISPR screening data, combined with experiments in patient-derived tumour organoid models, identifies PELO as a potential therapeutic target in chromosomal 9p21.3-deleted cancers and microsatellite-unstable cancers harbouring specific mutations.

The creation of biomaterials which are resorbable and have biomimetic mechanical properties is key to successful tissue engineering. Here the authors report on the creation of a new biopolymer where the mechanical properties can be tuned by changing the ratios of cis:trans double bonds in the backbone.

Here, the authors use passenger mutations to quantify expansion rate in ~6,000 people with mosaic chromosomal alterations in the NHLBI TOPMed cohort, finding associations between growth rate and blood counts along with germline genetic modulators of growth rate.

Xu and colleagues show that the transcription factor Hand2 promotes pdgfra expression during early cardiogenesis and that it can do so independently of direct DNA binding by interacting with Tcf3.

A thin liquid coating on a fibre can break up into droplets due to the Plateau–Rayleigh instability, as for instance on a spider web. Here, Haefner et al. show that the growth rate of the droplet undulations strongly depends on the fibre–liquid boundary condition and slip accelerates the instability.

Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.

Extrachromosomal DNA makes cancerous tumours resistant to treatment, but this research demonstrates that increasing transcription–replication conflict allows for targeted elimination of cancer cells containing extrachromosomal DNA, and thus sustained tumour regression in mice.

Assembled helical maquettes have been used to mimic basic oxidoreductase activities, but the requisite design symmetry limited advanced functions. Construction of a single-chain protein now enables intra- and interprotein electron transfer and complex cofactor interactions at rates comparable to those of natural proteins.

The medicinal plant Catharanthus roseus is a source of leading anticancer drugs. The monoterpene indole alkaloid (MIA) biosynthetic pathway in C. roseus has now been analyzed using a complementary, multi-omics, single-cell approach. This identified clusters of genes involved in MIA biosynthesis and cell-type-specific partitioning in the MIA biosynthetic pathway.

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.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

Network structures can be examined at different scales, and subnetworks in the form of motifs can provide insights into global network properties. The authors propose an approach to decompose a network into a set of latent motifs, which can be used for network comparison, network denoising, and edge inference.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

Graphene sheets used to build electronic devices have defects that limit performance. As a possible bottom-up route towards better devices, Diez-Perez and co-workers build large polyaromatic molecules with precisely defined structures which show good performance as field-effect transistors.

Alternative algorithms exploiting advantages of multidimensional mass spectrometry in untargeted metabolomics are needed. Here, the authors develop and demonstrate PeakDecoder for confident and accurate metabolite profiling in 116 microbial sample runs and using a library built from 64 standards.

Tai et al. show that Hem25p—a mitochondrial glycine transporter required for haem biosynthesis—is also needed for isopentenyl pyrophosphate (IPP) transport into mitochondria and coenzyme Q synthesis in Saccharomyces cerevisiae.

This study uses single-base tiled screens, bioinformatics, comprehensive mutagenesis and proteomics to provide a high-resolution view of RNA silencing with PspCas13b. It reveals design principles for potent silencing without collateral effects.

The environmental and geopolitical problems associated with fossil fuels might be alleviated if it were possible to produce synthetic multicarbon fuels efficiently from single-carbon feedstocks; here, a molybdenum compound supported by a terphenyl–diphosphine ligand is used to convert carbon monoxide into a metal-free C₂O₁ fragment, with the ligand both serving as an electron reservoir and stabilizing the different intermediate species.

The in-tissue architectures of β-amyloid and tau pathology in a postmortem Alzheimer’s disease donor brain are determined, showing fibril heterogeneity is spatially organized by subcellular ___location and suggesting applications to a broad range of neurodegenerative diseases.

Time-resolved cryo-EM captured transient intermediates during E. coli RNAP promoter melting, revealing conformational changes affecting stepwise transcription bubble opening. Results inform how DNA sequence controls bacterial transcription initiation.

Clonal hematopoiesis of indeterminate potential (CHIP) was found to be associated with a protective effect from Alzheimer’s disease (AD) in large population-based cohorts.

Understanding virus assembly could identify potential drug targets. Here the authors use a safe and efficient method to solve pathogenic flavivirus structures, revealing two lipid-like ligands within highly conserved pockets of the stem region of envelope protein that are important for virus maturation.