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Newly developed mouse models that enable cell-specific analyses of proteostasis dynamics across the lifespan of the mice reveal key aspects of neuronal proteostasis with ageing.

Engineered mucus-tethering bispecific nanobodies neutralize and entrap viruses to enhance mucosal immunity, preventing influenza infection and limiting SARS-CoV-2 transmission.

The impact of variants of uncertain significance (VUS) on protein function and cancer risk remain unclear. Here, the authors focus on the functional impact of VUS of the PALB2 gene and identify defects in DNA damage repair by homologous recombination associated with increased risk of breast cancer.

The distinct architecture of the Escherichia coli membrane transporter LetA mediates lipid trafficking across the bacterial envelope in partnership with the tunnel-like complex LetB.

Post-translational modifications (PTMs) are important for the stability and function of many therapeutic proteins. Here, the authors develop a high-throughput workflow combining cell-free gene expression with AlphaLISA to rapidly characterize and engineer PTMs on both proteins and peptides.

Cost-effective, environmentally sustainable and energy-efficient ways to address rising atmospheric CO₂ levels are urgently needed. Here the authors combine electrochemical reduction of CO₂ to formate with biosynthetic conversion of formate to the universal building block acetyl-CoA using a synthetic metabolic pathway called ReForm.

Allosteric transcription factors (aTFs) are promising tools for environmental and human health monitoring. Here the authors develop a multi-objective, machine learning-guided method to engineer an aTF-based portable diagnostic for environment sensing of lead in drinking water at the legal limit.

Therapeutic gene editing in vivo is an ongoing challenge. Here, authors demonstrate Cas9 nickase guided DNA ligation as a nonviral method for installing permanent genomic corrections with favorable on target edit profiles in model animal cell types and adult mice.

The biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs) involves binding of the N-terminal leader region of precursor peptides to peptide modifying enzymes and subsequent modification of the C-terminal core. Here, the authors describe the intermolecular protein-protein interactions that guide the post translational modification of atypically large and structured RiPP precursor peptides.

The study shows that nitrogenase enzymes have maintained stable isotope signatures over billions of years, revealing how ancient microbes shaped Earth’s nitrogen cycle and offering a new experimental framework for probing early life.

Arrayed CRISPR libraries with each plasmid encoding an array of four non-overlapping single-guide RNAs allow for the efficient genome-wide ablation, activation and epigenetic silencing of human protein-coding genes.

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.

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.

Antibody discovery is bottlenecked by the individual expression and evaluation of antigen specific hits. Here, the authors build an antibody screening workflow leveraging cell-free protein synthesis that enables expression and evaluation of hundreds of antibody fragments in less than 24 h.

Transforming model heterotrophs into autotrophs is usually accomplished by engineering one carbon assimilation pathway and/or employing laboratory evolution. Here, the authors report the engineering of cyanobacterial endosymbionts in yeasts to achieve photosynthetic growth, carbon assimilation and natural products production.

Silencing of transgenes such as Cas9 limits gene editing and CRISPRa applications. Here, the authors show that adding intronic sequences reduces silencing and boosts transgene expression, enabling improved CRISPRa-mediated gene activation and more stable expression of the transgene over time.

Structurally diverse natural products are a promising source of antibiotics. Here, the authors report the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners and discover a compound active against both drug-sensitive and drug-resistant Staphylococcus aureus.

Genetic, biochemical and structural studies provide insights into the function of Escherichia coli CapRel^SJ46 as a fused anti-phage toxin–antitoxin system that binds SECΦ27 Gp57 capsid protein.

Together with a companion paper, molecular details of immune responses in a pig-to-human xenotransplantation are identified through dense longitudinal multi-omics profiling of the xenograft and the host recipient, across the 61-day procedure.

The antiphage defence protein CapRel^SJ46 in Escherichia coli can directly bind and sense two completely unrelated and structurally different proteins using the same sensory domain, with overlapping but distinct interfaces.

It is unclear how new lysosomal proteins are properly delivered in polarized neurons. Here, the authors developed a method combining the synchronization of protein release from the endoplasmic reticulum with proximity labeling-based proteomics to study lysosomal protein trafficking in neurons.

Directed evolution is a powerful method to optimize protein fitness. Here, authors develop an active learning workflow using machine learning to more efficiently explore the design space of proteins.

While machine learning shows promise in expanding protein engineering efforts, its potential is limited by the challenge of gathering large datasets of sequence-function relationships. Here, authors introduce a platform that integrates cell-free DNA assembly and gene expression to accelerate enzyme engineering.

Ribosome engineering is an emerging powerful approach for synthetic protein synthesis. Here the authors invert the Ribo-T system, using the engineered ribosome to translate the proteome while the native ribosome translates specific mRNA.

PRPS enzymes are crucial for making nucleotides needed to build DNA, RNA, and proteins. This study shows how gene duplications and emergent innovations evolved an ancestral PRPS enzyme into a multi-protein complex in mammals, allowing fine-tuned metabolic regulation vital for growth and adaptation.

Nagano et al. identify the third mitotic cohesin complex, STAG3–cohesin, which, with its unique biophysical properties, weakens insulation and rewires regulatory interactions of spermatogonial stem cells, shaping the male germline nucleome.

The GlycoSCORES method, which involves cell-free protein expression and substrate-site profiling of glycosyltransferase enzymes by SAMDI–MS, enables the identification of glycosylation tags for glycoengineering efforts.

Here, the authors provide molecular insight into the remarkable ability of Tardigrades to withstand high levels of radiation by demonstrating that their Dsup protein interacts with multiple surfaces of the nucleosome to protect the genome from oxidative DNA damage.

Using a multi-OMICS approach, Haas et al identify 54 human genes and 16 host-targeting chemical compounds that regulate influenza A virus infection in lung epithelial cells, including AHNAK and COBP1 which are also essential for SARS-CoV-2 infection.

Mathematical modelling and experimental tests reveal principles that govern displacement of a resident strain by an invader in microbial communities.

Khan et al. report a non-catalytic function of the methyltransferase SETD2 in regulating nuclear morphology and genome integrity. The SETD2 amino terminus functions as a scaffold helping CDK1 associate with lamins during nuclear-envelope disassembly

Glycosylation of human IgG antibodies in bacterial hosts has proven challenging. Here, the authors identify a bacterial enzyme enabling E. coli to glycosylate IgGs at native sites, thereby advancing therapeutic antibody development in this host.

Ribo-T is a tethered ribosome complex capable of orthogonal ribosome-mRNA functionality, but has low activity. Here the authors evolve new tether designs that support faster growth and increased protein expression.

Live-cell fluorescence microscopy and polymer simulations in human HCT116 cells show similar cohesin density, residence times and extrusion speed across multiple genomic regions.

Sperm–egg adhesion is crucial for mammalian reproduction. Here, authors report the human Izumo1:Juno complex, a key regulator of sperm-egg adhesion, forms an unusually strong bond through a secondary binding site, which is impaired in an infertility-associated Juno mutant.

Here, Peters et al. report that Pseudomonas fluorescens protects Caenorhabditis elegans against pathogen infection via polyketide synthase-derived sphingolipids, uncovering a non-canonical bacterial sphingolipid synthesis pathway that modulates host metabolism.

Precise and scalable regulation of gene expression in mammalian cells is challenging. Here, the authors created a highly tunable CRISPR-based synthetic transcription system for programmable control of mammalian gene expression and cellular activity.

In glioma, malignant synapses hijack mechanisms of synaptic plasticity to increase glutamate-dependent currents in tumour cells and the formation of neuron–glioma synapses, thereby promoting tumour proliferation and progression.

Mecp2 deficiency underlies Rett syndrome, a genetic disorder presenting with chronic low-grade inflammation of unknown origin. Here, the authors show that Mecp2 is a central regulator of the onset, breadth and nature of nucleic acid immunity.

Bacteria of the phylum Bacteroidota move by gliding and export proteins using a type-9 secretion system. Here, Liu et al. show that these two processes use a shared mechanism in which outer membrane proteins are covalently attached by disulfide bonds to a moving track structure inside the cell.

Thousands of recombinant antibodies enriched for specificity against defined targets are assembled in multivalent mixtures with enhanced therapeutic activity.

Somatic mutations in blood cells (CHIP) are linked to diseases like heart disease, but the mechanisms are unclear. Here, the authors show that different CHIP driver genes alter unique sets of plasma proteins, some of which are validated in mouse models.

This study highlights a unique drug target for trypanosomatid parasitic protozoa and a new chemical tool for investigating the function of their divergent kinetochores.

Engineering enzymes to perform new-to-nature reactions can address long-standing challenges in synthetic chemistry. Now a ketoreductase has been evolved to undergo a photoinduced single-electron-transfer pathway, thereby achieving an enantioselective Giese-type radical conjugate addition that yields α-chiral esters.

A method that exploits the double-stranded DNA-targeting capability of the bacterial toxin-derived cytosine deaminase, DddA, can map DNA–protein interactions in bacteria in vivo at genome-wide scale.

Multiple types of cell elongation have been described in bacteria, but little is known about how these strategies vary across species. Here, the authors use fluorescent D-amino acids to track the spatiotemporal dynamics of bacterial cell elongation, revealing unsuspected diversity of elongation modes among closely related species of the family Caulobacteraceae.

Endoplasmic reticulum (ER)-interorganelle membrane contact sites have emerged as key regulators of organelle dynamics. Here, the authors report that the ER-resident protein SNX19 mediates ER-endolysosome membrane contacts to maintain the perinuclear distribution of endolysosomes and restrict their motility.

Despite effective vaccines against SARS-CoV-2, therapeutic options such as anti-virals and neutralizing antibodies are critical in treating disease, especially given the breakthrough infections of emerging VOCs. Here, Peng et al. generate two potent monoclonal antibodies and a bispecific antibody with two antigenrecognition variable regions targeting SARS-CoV-2 spike, provide CryoEM structures and show in vitro and in vivo efficacy of a humanized antibody against wildtype virus and delta variant.