Search

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.

Engineering polymerases to synthesize alternative genetic polymers remains a challenging problem in synthetic biology. Using DNA shuffling and droplet microfluidics, the current study provides a short evolutionary path from a DNA polymerase to one with robust RNA-synthesizing activity.

Here, the authors present the cryoEM structure of the sodium-translocating methyltransferase (Mtr) complex from Methanosarcina mazei. Along with providing catalytic insights, they identify MtrI, an unannotated small protein, bound to the Mtr complex in a redox-dependent manner.

Phylodynamic modelling shows how the changing antibiotic landscape and genetic determinants of resistance shape real-world gonococcal dynamics. Experiments validated that determinants with identical resistance phenotype differed in impact on fitness.

Viral ribonucleoprotein–viral protein networks form pre-replication centres that nucleate viral factories and drive respiratory syncytial virus replication.

Bacterial ribonucleoprotein bodies are dynamic biomolecular condensates that play roles in RNA metabolism. Here, Ortiz-Rodríguez et al. show that, under stress, these condensates shift from a liquid state to a rigid state and switch their function from mRNA decay to mRNA storage, thus enabling transcript preservation and rapid recovery upon nutrient replenishment.

Saturation genome editing of a cancer mutation hotspot in CTNNB1, the gene encoding β-catenin, reveals a gradient of effects of missense mutations on Wnt signaling.

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

In targeted protein degradation, a degrader molecule brings a neosubstrate protein proximal to a hijacked E3 ligase for its ubiquitination. Here, pseudo-natural products derived from (−)-myrtanol—iDegs—are identified to inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs prime apo-IDO1 ubiquitination and subsequent degradation using its native proteolytic pathway.

A library of 400 phage protein-coding genes is used to find a trove of antiphage systems, revealing systems that target tail fibre and major capsid proteins.

Analysis of Babesia divergens egress from host cells reveals druggable targets and identifies compounds for potential babesiosis treatment.

A combination of genome-wide functional screening, imaging and chromatin profiling identifies a new class of highly prevalent genomic elements that help retain extrachromosomal DNA copies in dividing cells and persist across generations.

Multi-omics profiling of the mucosal mycobiome in individuals with Crohn’s disease identifies C. sphaerospermum as a protective fungal species that counteracts intestinal inflammation and reinforces the intestinal barrier.

DIAL designs synthetic promoters for generation of heritable setpoints of gene expression across a range of cell types.

A study examines the effects of mutations that occur naturally in T cell cancers, reporting that such mutations can potentially be exploited to increase the potency of T cell therapies.

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.

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.

CRISPR-based transcriptional activation (CRISPRa) is a powerful tool for controlling gene expression. Here, Liang et al. show that commonly used CRISPRa systems are surprisingly toxic to cells due to their potent activation domains, informing the application and development of this technology.

CaBLAM is a bioluminescent genetically encoded calcium indicator that delivers high-contrast signals as shown in cell culture, in the in vivo mouse brain and in zebrafish larvae.

The reactivity and ligandability of arginine within the human proteome have been largely unexplored despite it being involved in various biological functions. Now, arginine reactivity and ligandability have been mapped across the proteome, revealing hyper-reactive sites and identifying residues that control liquid–liquid phase separation, protein activity and protein–protein interactions.

Using lipid nanoparticle delivery of mRNAs to the liver in aged mice, T cell function and declining immune cues can be restored.

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.

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.

Structural, genetic, functional and biochemical analyses of the complex flagellar motor of Campylobacter jejuni reveal structural adaptations with an ancient origin also found more widely across bacterial species, including elements exapted from the type IV pilus machinery.

The authors discover a homeostatic process termed interstasis, in which an increased concentration of proteins within RNA–protein condensates induces the sequestration of their own mRNAs.

The Panoptes antiphage system defends bacteria by detecting phage-encoded counter-defences that sequester cyclic nucleotide signals, triggering membrane disruption and highlighting a broader strategy of sensing immune evasion through second-messenger surveillance.

Bunel et al. show that mitochondria behave as asymmetric fate determinants in vertebrates in vivo. Forcing their unequal segregation during mitosis is sufficient to drive premature neural differentiation of the daughter inheriting the smallest pool.

Here, Santamaria de Souza et al. explore the context-dependent fitness effects of glpT-deficiency in Salmonella enterica, showing mutants thrive in the gut lumen but are counter-selected by macrophages, highlighting antagonistic pleiotropy and niche-dependent adaptation.

3-Hydroxypropionic acid (3HP) is a top Department of Energy value-added chemical and precursor to bioplastics, yet cost-effective microbial bioproduction remains elusive. Here the authors establish efficient 3HP production in an acid tolerant yeast and validate its financially viability.

A combined cryo-electron tomography and cryo-electron microscopy pipeline was developed to inflict axonal damage and monitor the cellular response induced by epothilone B, revealing that microtubule polymerization at and beyond the lesion site promote axon regeneration.

Nonstop extension mutations in cancer remain poorly characterized. Here, the authors test the impact of 2335 tumor-derived C-terminal nonstop extensions on protein expression and find the majority to be suppressive; they also analyze their biochemical properties and relation to evolutionary selection patterns.

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.

Whole-cell catalyst-based hydroxytyrosol production is low. Here, the authors increase the efficiency of its production in E. coli by de-bottlenecking two enzymatic steps catalyzed by monooxygenase and tyramine oxidase using structure-based enzyme redesign or in vivo-directed evolution with the aid of a newly developed biosensor.

Engineered DNA recombinases efficiently and specifically insert genetic cargos without the use of landing pads.

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.

In an effort to deorphanize G-protein-coupled receptors, a photo-cross-linking platform was established to capture ligands from complex samples. Little-LEN was identified as a ligand for GPR50, which coordinately regulates body metabolism.

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.

Cas12a3 nucleases constitute a distinct clade of type V CRISPR–Cas bacterial immune systems that preferentially cleave the 3′ tails of tRNAs after recognition of target RNA to induce growth arrest and block phage dissemination.

Leber hereditary optic neuropathy (LHON) is caused by mtDNA mutations. Here, authors generated a mouse model with the common LHON mutation and showed that optimized TALE-like deaminases restored both phenotype and genotype via high-fidelity mitochondrial base editing.

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.

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.

A DNA nanoruler platform enables precise measurement of the labeling radii of TurboID and APEX2, uncovering their contact-dependent mechanisms. These findings redefine the enzymology of proximity labeling and highlight the promise of DNA nanotechnology for spatially resolving enzyme reactivity with nanometer precision.

CRISPR-Cas9 is a powerful tool for genome editing; however, difficulties in generating pools of paired guide RNAs limit its applicability to large-scale screening experiments. Here the authors report a one-step method for rapid and efficient generation of pooled libraries of guide RNA pairs.

The majority of human genes can produce multiple isoforms, but studying their functional relevance requires tools to target specific isoforms. Here, the authors develop a CRISPR-based exon-exon junction-targeting strategy to achieve isoform-specific RNA knockdown.

Xenotransplantation of a genetically edited pig kidney with a thymic autograft into a brain-dead human for 61 days with immunosuppression resulted in stable kidney function without proteinuria, and xenograft rejection was treated and reversed by the end of the study.

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

Clb2 is a B-type cyclin essential for mitotic progression. Here, the authors found that the CLB2 mRNA localizes to the yeast bud via a cis-acting ZIP-code and She2/She3 transport machinery. This spatial regulation ensures proper cyclin protein levels, whereas its mislocalization perturbs division timing and bud size control.

RNA base-editors are often used in methods for RNA binding protein (RBP) target discovery. Here the authors present a new RBP target discovery method, PRINTER, and suggest optimal RNA base-editors for dual-RBP studies, emphasizing the importance of matching rBEs’ editing biases with RBPs’ binding preferences.