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Parkinson’s disease is managed through co-treatment with levodopa and tolcapone, with tolcapone altering the microbiome to increase its capacity to metabolize levodopa, implicating the gut microbiome in drug–drug interaction.

Borneol has repelled mosquitoes for millennia, but how it worked was unknown. Here, the authors show the sensory pathway mosquitoes use to detect and avoid this ancient plant compound, opening the door to improved natural repellents.

Robustness checks and reproduction of analyses with existing and updated data based on 110 articles in economics and political science journals with data and code-sharing requirements found high levels of robustness and reproducibility and determined that robustness was not dependent on author characteristics or data availability.

Mutational rates of bacterial evolution are increased using an error-prone orthogonal system.

The high-plasticity cell state (HPCS) is a critical hub that enables reciprocal transitions between cancer cell states, and targeting the HPCS may suppress cancer progression and eradicate treatment resistance.

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.

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.

REXER, a new method that allows long sections of DNA to be inserted or replaced in the genome of the bacterium Escherichia coli, is used to investigate codon replacement schemes for the generation of synthetic genomes.

DNA in many bacteriophages contains unusual chemical modifications. Here, the authors discover that carboxymethylcytosine is a natural DNA base and reveal its role as an intermediate enabling further DNA hypermodification.

Donahue et al. show that ageing is associated with changes in ER morphology. ER-phagy drives age-associated ER remodelling through tissue-specific factors.

Genetic predictors of health outcomes often drop in accuracy when applied to people dissimilar to participants of large genetic studies. Here, the authors investigate the root causes and highlight open questions underlying this problem.

Florfenicol amine hijacks intrinsic resistance in Mycobacterium abscessus, highlighting that antimicrobial resistance mechanisms can be harnessed for antibiotic activation.

Non-canonical amino acids can be incorporated into proteins through translation of orthogonal mRNAs. Now, automating the design of orthogonal mRNAs—which are more selectively and efficiently translated—in combination with compact orthogonal aminoacyl-tRNA synthetase/tRNA expression systems, enables the incorporation of four distinct non-canonical monomers via a 68-codon genetic code.

Enzymes are highly selective and sustainable catalysts for chemical synthesis, but their optimization is often limited by the difficulty of identifying functional starting points. This study shows that using the GenSLM protein language model to design TrpB variants can yield stable, active enzymes with broad substrate promiscuity, outperforming natural and evolved counterparts and demonstrating the potential of generative models to accelerate biocatalyst discovery.

Engineered Escherichia coli strains expressing a colibactin antitoxin, ClbS, on the surface prevent the genotoxic effects of colibactin released by genotoxin-producing bacteria in the mouse gut.

Development of a generalized method for dual site-specific incorporation of nonnatural photocaged and photoreactive amino acids into proteins expressed in live cells enabled engineering of a photoreactive photoactive antibody fragment.

Here, the authors show that two residues in FDX1 control both protein lipoylation and copper-induced cell death, suggesting these roles are interconnected. They also identify DLD as an upstream regulator that strengthens FDX1’s link to the lipoylation pathway.

Thermal imaging lenses are typically made from expensive materials such as germanium and silicon. Here, the authors synthesise a sulfur-based polymer with high mid-wave infrared and long-wave infrared transparencies, presenting a high-performing, low-cost alternative to traditional thermal imaging lens materials.

Torrens-Spence et al. reveal how plants in the cabbage family uniquely accelerate production of salicylic acid, a key defense hormone, through evolution of a specialized enzyme called EPS1. This finding could help enhance disease resistance in other crops.

Pcm1 bridges centrosome asymmetry and polarized endosome trafficking to regulate radial glia progenitor fate decisions, balancing self-renewal and differentiation in zebrafish and human cortical organoids.

Genetic code expansion and reprogramming require orthogonal tRNAs. Methods have now been developed for the automated generation of chimeric orthogonal tRNAs and discovery of their cognate synthetases. These approaches have been used to discover new orthogonal pairs for efficient non-canonical amino acid incorporation.

The authors describe how three types of cis-element (CTCF sites, active TSSs and TTSs) regulate cohesin trafficking along chromosomes. They uncover that this cohesin traffic pattern is genetically linked to gene regulation and RNA processing.

A newly engineered phosphoserine synthetase/tRNA pair allows quantitative insertion of phosphoserine or, when coupled with metabolic rewiring, a non-hydrolyzable analog into protein sequences, leading to high yields of modified constructs for functional analysis.

A survey of the cellular RNA-binding proteins (RBPs) that interact with dengue virus and Zika virus genomic RNA identifies ribosome-binding protein 1 and vigilin as bona fide RBPs able to promote viral RNA translation, replication and stability.

FAM72A differentially controls mutation rates by regulating uracil processing at different stages of the cell cycle, thereby regulating somatic hypermutation and class-switch recombination in B cells.

Bacteroides strains have multiple operons for biosynthesis of diverse capsular polysaccharides, but most cells express only one operon at a time due to tight regulation of transcription elongation by locus-specific UpxY and UpxZ proteins. Here, Saba et al. provide insight into the mechanisms by which UpxY distinguishes among cognate operons and how UpxZ inhibits only noncognate UpxY proteins.

Computationally designed genetically encoded proteins can be used to target surface proteins, thereby triggering endocytosis and subsequent intracellular degradation, activating signalling or increasing cellular uptake in specific tissues.

Cryo-EM shows SSNA-1 forms anti-parallel coiled-coils with a triple-helical junction for microtubule binding. Disrupting self-assembly or deleting SSNA-1 reduces C. elegans embryonic viability and disrupts spindles, revealing its role in cell division.

Here the authors describe a functional screening platform in human stem cells to identify and optimize protein-based gene editing additives that increase homologous directed recombination and have potential to improve gene therapy workflows.

A rapidly inducible, autoinhibited SpCas9 and quantitative assessment of double-strand cleavage and indel formation allow insights into Cas9 kinetics in cell lines.

Hiʻiaka is the largest moon of the distant dwarf planet Haumea. Here, the authors report the first multi-chord stellar occultations of Hiʻiaka, revealing its size, shape, and density, suggesting an origin from Haumea’s icy mantle.

In this work, authors show that the nucleoside prodrug obeldesivir has potent antiviral activity across respiratory syncytial virus (RSV) clinical isolates with a high resistance barrier. Once-daily obeldesivir treatment was efficacious against RSV in a non-human primate model.

Gammaherpesviruses are DNA viruses that result in lifelong latent infections. Here Owens and colleagues show that intrinsic activation of p53 restricts gammaherpesvirus-linked germinal centre B cell expansion during the establishment of latency in a murine model.

Surveying targets by APOBEC-mediated profiling identifies binding sites of RBPs by C-to-U RNA editing. STAMP is isoform specific, can be multiplexed and enables detection of ribosome association in single cells.

Chemotherapy resistance in recurrent gliomas is a large hurdle for successful therapy. Here, the authors show that some recurrent gliomas harbour O-6-methylguanine-DNA methyltransferase (MGMT) genomic rearrangements, and in vitro and in vivo these contribute to temozolomide resistance.

Binding-activated optical sensors are powerful tools, but their development can be slow and laborious. Here, authors introduce a platform to expedite biosensor discovery and evolution using genetically encodable fluorogenic amino acids.

Melanoma is a cancer that responds relatively well to immunotherapy but resistance does ensue. Here, the authors show that loss of IFNGR2 or JAK1 in a melanoma cell line enhances T cell mediated lysis, however these cells are paradoxically more sensitive to immune-mediated tumor control in vivo due to the loss of PD-L1.

A framework combining combinatorial CRISPR knockout in breast, lung and oropharyngeal cancer in vitro models with public data identifies synthetic lethal interactions, such as perturbed KDM5C sensitizing cells to PARP7 inhibition.

Malaria mosquitoes use their ears to detect the flight tones of mating partners in the swarm as part of the courtship ritual. Here, the authors describe the auditory role of octopamine as a modulator of auditory plasticity in malaria mosquitoes and identify the main receptors involved in this process.

The most recent class of base editors utilize DddAtox, a deaminase domain that can act upon double-stranded DNA. Here the authors target DddAtox fragments and a FokI-based nickase to the human CIITA gene by fusing these domains to arrays of engineered zinc fingers; they also identify a variety of DddAtox orthologues.

Non-canonical amino acids (ncAAs) can be incorporated into proteins in cells using orthogonal aminaocyl–tRNA synthetase/tRNA pairs; the most widely adopted system is based on a pyrrolysyl–tRNA synthetase (PylRS)/tRNA pair. Now, three new PylRS/tRNA pairs have been developed that are mutually orthogonal and can be used together to site-specifically incorporate three distinct ncAAs into a single protein.

Spirulina is used to manufacture a therapeutic antibody against campylobacter.

KLHDC2 is a promising E3 ligase for targeted protein degradation (TPD). In this study, the authors demonstrate that heterobifunctional degraders induce cooperative ternary complexes with KLHDC2 and BRD3. They highlight exit vector, neo-substrate, E3 ligase selectivity, and prodrug choice can effectively leverage C-degron E3s for TPD.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

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.

Li, Burgos-Bravo and colleagues report that NDF phase separation regulates FACT condensation, which enhances transcription by generating a localized biochemical environment that promotes nucleosome disassembly while preserving chromatin integrity by retaining histones.

RNA-guided CRISPR-associated transposases (CAST) are natural systems with broad potential in biotechnology. Here, the authors report compact type V-K CAST discovered from genome-resolved metagenomics and demonstrate targeted integration of a large transgene to a safe-harbor site in the human genome.

The natural product nimbolide covalently reacts with a functional cysteine of the E3 ubiquitin ligase RNF114, resulting in impaired substrate recognition and degradation, enabling the use of nimbolide for targeted protein degradation.

While targeted lipid nanoparticles might allow partial delivery of genetic materials to non-hepatic cells, the selectivity of this approach is still unsatisfying. Here the authors functionalize their lipid nanoparticles with a targeting moiety that recognizes a protein conformation specific to gut-homing leukocytes, inducing gene silencing exclusively in this cellular subset and providing a potential therapeutic strategy for inflammatory bowel disease.