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Bacterial antigens, such as lipopolysaccharides, are complex structures which remain difficult to synthesise or purify for antibody generation. Here, authors present a platform technology using Citrobacter rodentium - an enteric mouse pathogen - to both produce and present complex antigens for antibody generation.

Engineering an immune receptor improves resistance to bacterial and fungal pathogens in a variety of plants.

Enfortumab vedotin (EV) is the current standard treatment for advanced bladder cancer, but resistance typically develops within a year, highlighting the need for new therapies. This study demonstrates that NECTIN4-targeting CAR T cells are effective against bladder cancer, including EV-resistant cells, and their potency can be further enhanced by using rosiglitazone to boost NECTIN4 expression.

TUG protein localizes to the endoplasmic reticulum-Golgi intermediate compartment, forms biomolecular condensates, and organizes and stabilizes these membranes to support their function in diverse secretory and degradative trafficking pathways.

Here Schwämmle et al. develop CRISPR reporter screens to map transcription-factor-regulatory element interactions at the Xist locus, revealing a two-step mechanism integrating developmental and X-dosage signals to initiate X-chromosome inactivation.

In this study, the authors assess the global response to the toxic aldehyde glyoxal (GO) in Pseudomonas aeruginosa, suggesting that GO controls quorum sensing during infection through a mechanism involving a novel protein, ArqI.

This work presents Perturb-tracing, integrating CRISPR screening with barcode readout and chromatin tracing for loss-of-function screens, enabling the identification of chromatin folding regulators at various length scales.

While machine learning shows promise in expanding protein engineering efforts, its potential is limited by the challenge of gathering large datasets of sequence-function relationships. Here, authors introduce a platform that integrates cell-free DNA assembly and gene expression to accelerate enzyme engineering.

Gut bacteria digest dietary fiber and release molecules as energy for the host. Here, Yu et al. find that the ability of certain gut bacteria to digest different fibers influences host consumption of food containing these fibers.

Insoluble protein expression continues to be a bottleneck for biotechnology. Here, Chilkoti and colleagues report a method for generating and identifying hypersoluble intrinsically disordered protein fusion tags to improve soluble protein expression and rescue protein function.

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 bacteria use the second messenger cyclic diguanylate (c-di-GMP) to control motility, biofilm production and virulence. Here, the authors identify a thermosensitive enzyme that synthesizes c-di-GMP and modulates temperature-dependent motility, biofilm development and virulence in the opportunistic pathogen Pseudomonas aeruginosa.

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.

Here the authors define an inter-protomeric mechanism of deglycosylation of human IgG antibodies for corynebacterial IgG-specific ENGases and demonstrate that in vivo CU43 treatment preserve the neutralizing capacity of anti-influenza IgG antibodies.

Upon target RNA recognition, type III CRISPR-Cas systems produce cyclic oligoadenylates that activate effectors such as Csm6 ribonucleases. Here, Garcia-Doval et al. show that Enteroccocus italicus Csm6 degrades its cyclic hexa-AMP activator, and report the crystal structure of the protein bound to an activator mimic.

To date, experimental induction of hair cell regeneration in mammals leads to immature and poorly differentiated hair cells. Here the authors show that the transcription factor prdm1a plays a crucial role in specifying sensory hair cell types with loss of prdm1a in zebrafish leading to misspecification of hair cells in the sensory lateral line system into ear hair cells.

pOXA-48 plasmids have emerged as key vectors of carbapenem resistance within Enterobacteriaceae. In this study, the authors use a transposon sequencing (Tn-seq) approach to identify genetic determinants critical for plasmid stability and conjugative transfer.

Li et al. discovered that the cytotoxic synthetic small molecule BRD1732 is directly ubiquitinated in cells. Ubiquitination of BRD1732 is E3 ligase dependent and leads to inhibition of proteasomal degradation.

ZF5.3 is a mini-protein that escapes endosomes efficiently. Work to understand the underlying mechanism now reveals that ZF5.3 unfolds at pH values lower than 5.5 through protonation of Zn(II)-bound His residues. Unfolding promotes pH-dependent interactions with a unique lipid present in late endolysosomal membranes and is essential for endosomal escape.

Cryo-EM structures of the full-length Junin virus and Machupo virus spike glycoprotein complexes stabilized in the prefusion conformation. Analyses reveal features that regulate glycoprotein pH-dependent membrane fusion activity.

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

The multipass membrane transporter MFSD6 localizes to the plasma membrane and acts as a host entry factor for enterovirus D68 (EV-D68) by binding directly to EV-D68 particles through its extracellular, third loop, offering a potential target to combat infections by this emerging pathogen.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Here, the authors provide cryo-EM structures of mature and immature Spondweni virus, defining the furin recognition site at high resolution, and identifying a lipid that binds E upon capsid maturation and is also present in Zika and Dengue virions.

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.

Cas7-11—the fusion of a putative Cas11 domain and four Cas7 subunits—cleaves RNA without detectable non-specific activity and, when optimized for RNA knockdown and editing in mammalian cells, has no effects on cell viability.

B. subtilis is valuable both as a model for cell biology and as an industrial organism. Here the authors use genetic code expansion to enable functional tools for exploring cell division dynamics.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Matched ribosome profiling and RNA sequencing data quantify translation efficiency patterns across 140 human and mouse cell lines.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Programmable addition via site-specific targeting elements (PASTE) combines the specificity, efficiency and cargo size benefits of site-specific integrases with the programmability of prime editing for precise and efficient integration of large DNA sequences into mammalian genomes.

Actin is crucial for nervous system function yet the role of microexons in its modulation is unclear. Here, the authors show that a microexon in DAAM1 has a role in actin dynamics, neuronal function and memory formation in mice.

Characterization of bacterial auxin degradation loci and their regulators reveals two distinct types across plant microbiome species, where only one, exemplified in Variovorax species, can interfere with root growth inhibition in a complex synthetic microbial community.

Large sequences are integrated site specifically into the human genome without double-strand DNA cleavage.

The bacterial plant pathogen genus Xanthomonas uses two distinct secretion systems for antibacterial competition. Here the authors show that some Xanthomonas lineages have switched from the ancestral X-T4SS state to T6SS-i4 despite the functional similarity of the systems, with X-T4SS gene clusters subject to degradation and loss and T6SS-i4-encoding sequences inserted through independent gains.

The authors use a machine-learning algorithm to predict the spectrum of CRISPR–Cas9-nuclease-mediated DNA repair outcomes at human genomic target sites.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Autonomous hypermutation yeast surface display (AHEAD) mimics the process of somatic hypermutation in animals to enable the rapid in vitro evolution of antibodies, including nanobodies targeting the RBD of SARS-CoV-2.

Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

CRISPR-associated protein Csm6 is activated by a cyclic oligoadenylate second messenger generated by Cas10 activity in the CRISPR type III interference complex, representing a novel mechanism of CRISPR interference.

Zeinert et al. provide cryo-EM structures of the E. coli Mg²⁺ importer MgtA: unexpectedly, this P-type ATPase is a dimer with an uncommon transmembrane ion-binding site and knotted N-terminus, which are functionally important features.

Myddosomes, in which MyD88 forms barrel-like scaffold structures for effector protein recruitment and activation, contain proteins that act at all stages and regulate all effector responses of the TLR signalling pathways.

BURP domains within lyciumin precursor peptides serve as autocatalytic peptide cyclases, enabling the discovery of other BURP-domain-derived products and development of a bioinformatic method to mine plants for precursor-peptide-encoding genes.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

iGluSnFR variants with improved signal-to-noise ratios and targeting to postsynaptic sites have been developed, enabling the analysis of glutamatergic neurotransmission in vivo as illustrated in the mouse visual and somatosensory cortex.

Single cell analysis of histologic variant bladder tumors detects a shared CA125+ tumor cell state associated with aggressive clinical features and reveals enriched expression of TM4SF1, a membrane protein that can be targeted with CAR T cells.

Engineered living materials (ELMs) are emerging as a field at the intersection of materials science and synthetic biology. Here, the authors describe a photosynthetic ELM composed of genetically engineered cyanobacteria in a hydrogel matrix, capable of bioremediation and inducible cell death.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.