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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.

Hydrogen peroxide is a signaling molecule that can also cause damage if its levels are too high. Here, the authors report HyPerFLEX, a fluorescent sensor with tenable colors, to track very low peroxide levels in cellular organelles, even in low-oxygen or highly oxidizing environments.

Peng et al. show that DLL1-expressing muscle myoblasts not only regulate NOTCH signaling in neighbor cells but also send a retrograde signal to themselves via the DLL1 intracellular domain.

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.

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 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.

Rapid discovery of functional resistance genes is enabled by a high-expression signature and high-throughput transformation. This approach identified 31 new resistance genes for wheat and can be applied across crops to support food security.

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 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.

Thermal lepton pairs are ideal probes for the temperature of quark-gluon plasma. Here, the STAR Collaboration uses thermal electron-positron pair production to measure quark-gluon plasma average temperature at different stages of the evolution.

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.

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.

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.

Append editing of ADP-ribosyl to thymine is used for precise modifications in bacteria and eukaryotes.

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.

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.

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.

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.

Synthetic receptors are a powerful approach for engineering cell-based therapies that can sense and respond to their environment. Here cytokine receptor domains have been repurposed to develop engineered T cells that can sense and respond to cues associated with cancer or immune dysfunction.

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.

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.

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.

BindCraft, an open-source, automated pipeline for de novo protein binder design with experimental success rates of 10–100%, leverages AlphaFold2 weights to generate binders with nanomolar affinity without the need for high-throughput screening.

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.

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.

Fine-tuning expression of pathway genes allows pathway flux optimisation and reduces cell stress. Here, the authors develop a CRISPR-mediated method for transcriptional fine-tuning which allows simultaneous targeting of eight pathway genes, demonstrating optimised squalene and heme production in Saccharomyces cerevisiae.

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.

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.

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.

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.

Moroidins are plant ribosomally-synthesized and posttranslationally-modified peptides with anticancer activity. Here, the authors generate a searchable database of publicly available plant RNAseq data and identify a moroidin analog with higher cytotoxic activity.

Pioneer neurons extend their axons to provide a track for follower neurons to follow, whether these neurons differ in other ways has not been clear. Here they show that pioneer and follower neurons are transcriptionally distinct and that RA signaling is required for pioneer axon targeting.

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

TCR-TRANSLATE, a deep learning framework adapting machine translation to immune design, demonstrates the successful generation of a functional T cell receptor sequence for a cancer epitope from the target sequence alone.

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.

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.

Cell cycle control depends on phosphorylation of many proteins by the kinase Cdk1. Here, the authors show that phosphorylation of Cdk1 substrates is influenced by a phosphate-binding pocket on the surface of the cyclin regulatory subunit.

The epigenetic and transcriptional roles of Nucleoporin 98 (NUP98) fusion oncoproteins in driving pediatric acute myeloid leukemia (AML) remain to be explored. Here, the authors identify a core set of genes regulated by NUP98::KDM5A and suggest CDK12 as a potential therapeutic vulnerability.

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.

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.

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.

Newly evolved Xanthomonas citri pv. malvacearum isolates triggers recent bacterial blight outbreaks in cotton. Here, the authors show that a recently evolved TALE, Tal7b, activates host susceptibility genes GhSWEET14a and GhSWEET14b rather than GhSWEET10 to confer pathogenicity in these new isolates.

LaccID, an engineered laccase, enables hydrogen-peroxide-free proximity labeling and electron microscopy (EM) in mammalian cells. Notably, LaccID is selectively active at the cell surface, enabling the mapping of the dynamic T cell–tumor surfaceome and its use as a genetically encodable EM tag, expanding the toolkit for cell-based imaging and proteomics.

Here, the authors show that a modular deregulation strategy in Saccharomyces cerevisiae boosts xylose conversion to 3-HP by engineering central carbon metabolism with five strategies, achieving a 4.7-fold productivity increase over an initially optimized strain using xylose.

Systematic base-editing and computational screens identify specific cysteine residues on VPS35 in the retromer complex as key sensors that decrease mitochondrial translation in response to reactive oxygen species signals.

Autophagy is initiated by the Unc-51-like kinase protein kinase complex (ULK1C) and class III phosphatidylinositol 3-OH kinase complex I (PI3KC3-C1). Here, the authors reveal the structure of the 2:1:1 core of ULK1C and its complex with PI3KC3-C1. ULK1C transitions to a 2:2:2 complex in the presence of PI3KC3-C1, suggesting a mechanism for autophagy induction.