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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.

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

Smc5/6 association with DNA junctions can support genomic functions. Here, the authors show that Smc5/6 junction polarity preferences, targeting, and dwell times are determined by its structural modules as well as the RPA and PCNA genomic factors.

In bacteria, many small regulatory RNAs (sRNAs) associate with the RNA chaperone Hfq to modulate gene expression at the post-transcriptional level. Here, the authors identify global Hfq-mediated RNA-RNA interactions in Caulobacter crescentus and uncover a sponge RNA that antagonizes four homologous sRNAs in response to carbon starvation.

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.

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.

CELLFIE, a CRISPR platform for optimizing cell-based immunotherapies, identifies gene knockouts that enhance CAR T cell efficacy using in vitro and in vivo screens.

The bacterial anti-phage toxin–antitoxin–chaperone defence system CmdTAC senses capsid proteins via CmdC, enabling dissociation from the CmdTAC complex of the RNA ADP-ribosyltransferase CmdT, which targets single-stranded RNAs, inhibiting viral replication.

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.

Kathiriya et al. identify a cardiac progenitor lineage with expression of Tbx5 and anterior heart field-specific expression of Mef2c that bisects the intraventricular septum during development and show that alterations in this lineage lead to congenital heart defects in mice.

Multiplexed assays of variant effect can resolve clinical variants but are incompatible with secreted proteins. Here Popp et al. develop MultiSTEP, a generalizable surface-tethering method to assess variant effects in secreted proteins at scale.

The bacterium Borrelia burgdorferi, which causes Lyme disease and is transmitted by ticks, has a linear chromosome and multiple plasmids. Here, Takacs et al. show that the pathogen is polyploid, the number of genome copies decreases during stationary phase, and chromosome copies are regularly spaced along the cell’s length.

Here the authors characterize a single-domain antibody that broadly neutralizes SARS-CoV-2 variants with high potency by targeting the heptad repeat 2 (HR2) coiled coil, conserved in sarbecoviruses. Binding to its quaternary epitope blocks membrane fusion, by locking HR2 in its prefusion conformation.

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.

Streptococcus thermophilus phages circumvent host CRISPR defences via AcrIIIA2, which complexes with enolase, a highly abundant glycolysis enzyme, to block phage RNA binding.

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

A two-component system, DbfRS, regulates biofilm formation in Vibrio cholerae. Here, Nguyen et al. identify a small periplasmic protein that controls the activity of the system’s receptor, and show that DbfRS responds to membrane stress and regulates additional processes such as metabolism and cell envelope biosynthesis.

The ferroptosis suppressor protein FSP1 has a critical role in ferroptosis protection of tumours across multiple in vivo models and is linked to worse prognosis in human lung adenocarcinoma, suggesting its potential as a therapeutic target in lung cancer.

Coagulase-negative staphylococci secrete natural products that prevent pathogen colonization. Here, the authors identify hominicin, a daptide bacteriocin produced by Staphylococcus hominis that has antimicrobial activity against a skin pathogen.

Ring deconvolution microscopy leverages symmetry to provide fast and straightforward spatially varying deblurring and offers improved speed and image quality compared to standard approaches across diverse microscopy modalities.

Here, the authors developed a novel high-throughput, DNA barcoded overexpression platform, BOBA-seq, to uncover new gene functions among gut anaerobes involved in carbon utilization and stress tolerance.

The ExoSloNano system facilitates nanogold probe-based labeling of specific proteins of a wide range of sizes in live cells for cryo-electron tomography and correlative light and electron microscopy studies.

Many diseases are caused by single-nucleotide polymorphisms. Here, the authors present CRISPR base editors that use the base excision machinery for single-base transversions.

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

Cryptosporidium is an important threat to public health, yet it lacks a robust genetic toolkit. Here, Watson et al. introduce a targeted CRISPR-based screening method to identify parasite genes that are essential for its survival within the intestine.

Ultrasound imaging with acoustic reporter genes has been limited to a single ‘tone’, restricting the types of experiments that can be achieved. This work introduces two acoustic reporter genes that enable multiplexed imaging in vitro and in mice.

CRISPR screens reveal Toxoplasma’s GRA12 as a strain- and mouse species-transcendent virulence factor. GRA12 protects parasites from IFNγ-activated macrophage clearance and parasitophorous vacuole collapse.

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.

An engineered RNA A-to-I deaminase (rABE) offers low sequence bias, high activity and low background for REMORA (RNA-encoded molecular recording in adenosines) and enables improved molecular recording of RNA–protein interactions.

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.

A study of retrotransposon activity repurposes a retroelement called R2Tocc to create a programmable system called STITCHR that enables diverse genome edits including efficient, scarless large payload insertions.

Epigenome editing programs gene silencing without inducing DNA breaks but challenges in delivery into human cells limit its broader use. Here, the authors present the RENDER platform, which uses virus-like particles to enable CRISPR-based epigenome editing for durable gene silencing in human cells.

Here, using a mouse model, the authors show that a lysine-restricted diet counteracts obesity via the enrichment of Parabacteroides goldsteinii and its metabolite MIAA, which in turn leads to suppressed fat accumulation by modulating the FTO-YTHDC1-SLC2A4 pathway.

Gene variants can affect folding and stability of the encoded protein. Here, the authors apply deep mutational scanning to provide genotype-phenotype information for 99% of the possible PRKN variants and reveal mechanistic details on how some variants cause loss-of-function and Parkinsons disease.

Santos et al found that the ubiquitin ligase adaptor Fbxo42 is a critical regulator of terminal Unfolded Protein Response signaling through its control of Ataxin-2 granules containing Xbp1 mRNA.

Using cryo-EM, Schmidt, Schulz, et al. solve the structure of the iron nitrogenase complex, which shows a unique architecture of alternative nitrogenases and suggests the G subunit to be involved in substrate channeling, stabilization of the cofactor and determining specificty among nitrogenase components.

Radical Fe^II/α-ketoglutarate-dependent halogenases are powerful biocatalysts for C–H functionalization. Here, the authors reveal the mechanistic basis for chemoselectivity in a lysine halogenase.

Animal models of drug use require specialized technical expertise and often differ from how humans consume drugs. Here, the authors establish a robust method which allows mice to self-administer intranasal cocaine, greatly improving face validity and ease of use.

Here the authors report asperigimycins, fungal ribosomally synthesized and post-translationally modified peptides with a heptacyclic scaffold. After chemically modifying them for nanomolar anticancer activity, CRISPR screening identifies SLC46A3 as a key transporter for their uptake in cells.

Engineering mammalian cellular functions requires a toolkit of orthogonal and well-characterized genetic components. Here the authors develop COMET: an ensemble of transcription factors, promoters, and accompanying models for the design and construction of genetic programs.

Here, the authors identify mechanisms of glycosylation of intrinsically disordered regions present in streptococci membrane proteins, uncovering a functional role for glycosylation in Streptococcus mutans chaperone PrsA.

Rashan, Bartlett and colleagues show that mammalian 4-hydroxy fatty acids are primarily catabolized by ACAD10 and ACAD11 (atypical mitochondrial and peroxisomal acyl-CoA dehydrogenases, respectively) that use phosphorylation in their reaction mechanisms.

Combinatorial CRISPRi screening was used to map genetic interactions in DNA damage response pathways, revealing known and new connections, including the roles of WDR48 and USP1 in preventing under-replication and SMARCAL1 and FANCM in remodelling persistent cruciform DNA structures.

Kraft, Murphy, Jones et al. identify extrachromosomal DNA (ecDNA)-interacting elements (EIEs) enriched for transposable elements within ecDNA in colorectal cancer cells. They show that EIE 14 integrated within ecDNA acts as an enhancer to promote cancer fitness.

Context-dependent, responsive synthetic promoters are crucial for a wide range of applications, yet currently available options are limited. Here, authors develop a library of thousands of candidate promoters based on binding motifs of hundreds transcription factors for use in mammalian cells.

A large-scale mouse study reveals that while existing epigenomic data detect many developmental enhancers, a substantial fraction is missed - highlighting the need for expanded resources to fully annotate enhancers genome-wide.