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BiP–glucose-regulated protein 94 chaperones are critical to the proper folding of secretory and transmembrane proteins. Brenner et al. provide biochemical and structural insight into a conserved mechanism of chaperone cooperation underlying this quality control process.

CRISPR-associated transposases represent a promising tool for precise, DSB-free genome editing. Here, authors investigate a CAST system active in human cells, improve activity via structure-guided engineering, and develop novel chimeras for improved modularity.

Many natural product biosynthetic gene clusters are found not to harbor a full set of necessary genes and must utilize enzymes encoded elsewhere (hidden) in the genome for biosynthesis. Here, the authors establish a global correlation network bridging the gap between lanthipeptide precursors and hidden proteases.

We show that gain-of-function cancer mutations in the KBTBD4 E3 ligase promote neodegradation of substrates via a shape-complementarity-based mechanism, which converges with the mechanism of action of the UM171 molecular glue degrader and can be blocked by HDAC1/2 inhibitors.

As well as being the substrate for the lipopolysaccharide transport protein complex comprising LptA–G, lipopolysaccharide binding to Lpt proteins promotes their assembly into a bridge linking the inner and outer membranes of Gram-negative bacteria.

To date, brain gene therapies require high vector doses. Here, authors devised an AAV capsid screen and found variants with unprecedented potency for transduction of deep brain and cortical neurons and human iPSC-neurons with cell tropism relevant for Huntington’s and Parkinson’s disease.

Single-cell comparison of developing bat and mouse limbs reveals conservation of cell populations and gene expression patterns, and suggests repurposing of genes involved in proximal limb development for wing evolution.

A metabolic system of engineered biocatalysts using the noncanonical cofactor nicotinamide mononucleotide is established for biomanufacturing in cell-free systems and in Escherichia coli without interference from nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate.

González-Delgado et al. developed retron-based editors termed multitrons, which can modify multiple sites on a single genome simultaneously. This technology is compatible with recombineering in prokaryotes and CRISPR editing in eukaryotes with applications in molecular recording, genome minimization and metabolic engineering.

PARP inhibitor treatment triggers histone release from the chromatin in cancer cells; consequently, targeting the histone chaperone NASP renders cells vulnerable to PARP inhibition.

Cellulose acetate sponges were fabricated by cryo-templating, without chemical crosslinking, from cellulose acetate nanofilms produced using a nonsolvent-induced phase separation (NIPS)-jet spinning technique. X-ray computed tomography (X-CT) revealed their open-cell, continuous microstructure. The sponges exhibited resilience, stability, and mechanical tunability via microstructural tailoring. Their viscoelasticity was attributed to the bending of the cell structure and the delamination and slippage of the uncrosslinked nanofilms.

Barcoding microbial ribosomal RNA creates a recording of gene transfer events without requiring translation.

Limited experimental platforms exist for assessing quantitative sequence-function relationships for multiple antibodies. Here, authors develop a deep-sequencing based technology called MAGMA-seq, that determines the quantitative properties of antibody libraries.

Cell movements are achieved by the spatio-temporal coordination of local membrane protrusions and retractions. Here, the authors identify a mechanism by which these protrusion and retraction events are coupled and how this affects the directionality of cell movements.

Pathological B-cell receptor (BCR) signaling is a key driver of mantle cell lymphoma tumorigenesis. Here, the authors discover that CEACAM1, an immunoglobulin-like transmembrane protein, is essential for a subset of mantle cell lymphoma through activation of the BCR.

Engineering mammalian cells with synthetic circuits drives innovation in next-generation biotherapeutics and industrial biotechnology. Here the authors use RNA-seq and computational biology to identify drugs that increase engineered cell productivity without genetic edits - Filgotinib proved enhanced gene expression across contexts, offering a powerful tool for biotech applications.

The actin methyltransferase SETD3, by virtue of its ability to interact with the viral 2A protein and independently of its enzymatic activity, is necessary for RNA replication of several enteroviruses in cell culture and in vivo.

BRCA2 is a well-characterized central player in homologous recombination in which it functions as the RAD51 loader. Here the authors identify an N-terminal region of BRCA2 that binds DNA and promotes efficient DNA repair.

Managing power exhaust in fusion reactors is a key challenge, especially in compact designs for cost-effective commercial energy. This study shows how alternative divertor configurations improve exhaust control, enhance stability, absorb transients and enable independent plasma regulation.

This work reports the metallothermic production of rare earth (RE) Nd metal using NaNdF₄ as an alternative fluoride salt, without HF use or generation, enabling safer, scalable production of critical RE metals for advanced technologies and industry

Host factors required for parechovirus entry are not well understood. Here, the authors identify MYADM as an essential host entry factor that directly binds human parechovirus 1 and that is required for PeV-A infection in cell lines and human gastrointestinal epithelial organoids.

Single-molecular microscopy shows that GAGA multimeric zinc finger transcription factor searches chromatin for cognate sites through rapid one-dimensional sliding on free DNA (which can be blocked by nucleosomes) and three-dimensional diffusion for nucleosomal targets.

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.

The endosomal retrieval subdomain organizes recycling of endocytosed proteins. Here, using proximity proteomics, the authors reveal that this recycling subdomain regulates switching of specific RAB GTPases, a feature likely important in neuroprotection.

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.

Human pathways acting on nuclear ncRNAs have been refractory to forward genetics. Here, the authors develop a forward genetic approach that identifies such pathways and show DDX59 is required for minor intron splicing, suggesting a mechanism for its association with Oral-Facial-Digital syndrome.

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.

A mutant-selective AKT inhibitor shows potential as a targeted therapy for breast cancer, enabling enhanced target engagement and avoiding the dose-limiting toxicity associated with pan-AKT inhibitors.

“Out of one, many”. The authors show that, despite binding to a common network of genes, two transcription factors each have their own set of direct targets (also known as their ‘regulon’). Thus, out of one bound network, many regulons are possible.

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.

Fine-tuning the expression of biosynthetic pathway genes is crucial to improve microbial production titres. Here, the authors present GEMbLeR, an optimization strategy to balance the expression of multiple genes simultaneously over a wide range.

The PAM specificity of SpCas9 can be altered with positive selection during directed evolution. Here the authors use simultaneous positive and negative selection to improve activity on NAG PAMs while reducing activity on NGG PAMs.

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.

The oncogene MYC plays a key role in cancer initiation and progression. Using thousands of CRISPR perturbations, the authors investigate regulators of MYC in six different cancers. These tumor-specific regulators suggest potential therapeutic targets for this oncogene.

Dietary n-6 PUFAs enhance adipose tissue expandability through the PPARγ–LPCAT3 membrane remodelling axis.

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.

Polyamines are essential metabolites linked to aging, cancer, and Parkinson’s disease. Here, authors develop a live-cell polyamine reporter and use a genome-wide CRISPR screen to uncover a link between mitochondrial respiration and polyamine import.

Metelev et al. use single-molecule tracking to study kinetics of translation directly in E. coli cells, and how it is affected by translation inhibitors and rRNA mutations. Their results support widespread 70S re-initiation on mRNAs.

The membrane insertion of C-terminal transmembrane helices is particularly challenging. Here, the authors describe the insertion mechanism, showing that a crucial protein sequence feature enables these helices to be inserted post-translationally by insertases.

Here the authors develop Splice-RUSH, a high-throughput screening method to map both proximal and distal splicing-regulatory sequences in a native sequence context. These sequences can also be targeted by ASOs to modulate splicing.

This study reveals how the pathogen Staphylococcus aureus adapts to the lung microenvironment, rich in host metabolites fumarate and itaconate, by using a key enzyme, FumC, to support its metabolic fitness, survival, and persistence.

Application of highly specific Cas9 variants can be restricted by the design of the guide RNA. Here the authors present DeepHF, a gRNA activity prediction tool built from genome-scale screens of 50,000 guides covering 20,000 genes.

Prime-editing mouse models enable the study of specific cancer mutations in vivo.

Agrobacterium-mediated transformation of plants and fungi is enhanced by plasmid copy number variants.

Köhler et al. present the crystal structure of fungal tRNA ligase Trl1-LIG bound to an activated RNA substrate, providing key insights into conserved substrate binding and activation, enzyme specificity and a tRNA substrate coordination model.