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The high-plasticity cell state (HPCS) is a critical hub that enables reciprocal transitions between cancer cell states, and targeting the HPCS may suppress cancer progression and eradicate treatment resistance.

Activity-based protein profiling identifies covalent small molecules that potentiate the activity of the METTL5:TRMT112 complex through binding to a complexoform-restricted allosteric pocket absent in other TRMT112:methyltransferase complexes

Light represses biofilm formation and production of virulence factors in the pathogenic bacterium Pseudomonas aeruginosa. Here, Manias et al. identify a periplasmic microprotein that regulates this process by activating the degradation of a component of the light-sensing pathway.

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.

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.

Lymphatics maintain lipid transport, immunity, and fluid balance. Kim J and Chaudhary S et al. reveal an AIBP-driven cholesterol efflux mechanism that regulates lymphangiogenesis via VEGF signaling.

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.

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.

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.

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.

Fast panoramic rotational ultrasound tomography and photoacoustic tomography are integrated for hybrid rotational ultrasound and photoacoustic tomography, for three-dimensional dual-contrast imaging of soft tissue and vasculature across the human body.

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.

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.

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.

TDP-43 dysfunction in ALS/FTD causes faulty splicing of the KCNQ2 ion channel, leading to toxic protein buildup, neuron hyperactivity and a potential new biomarker and treatment target using RNA-based therapies.

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.

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.

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.

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.

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.

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.

The P2X4 receptor, an ATP-activated ion channel, plays a role in chronic pain, inflammation, and cancer. Authors in this work discover an extracellular allosteric binding site that interacts with anthraquinone derivatives, and is narrowed by ionic lock formation.

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.

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.

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.

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

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.

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.

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.

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

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.

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

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

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.

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.

Here, by integrating faecal metabolomics, metagenomics, and habitual dietary data of two large human cohorts, the authors show that faecal metabolites reflect diet and gut microbiome interactions, predict dietary patterns, and indicate cardiovascular risk, offering insights for diet-based health interventions.

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.

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.

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.

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.

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.

Synthetic gene circuits regulated by small molecules have been used to fine-tune glycosyltransferase expression in CHO cells, providing a method to produce therapeutic monoclonal antibodies with precise glycosylation states.

In a mouse model of progeria, an adenine base editor delivered with adeno-associated virus corrects the pathogenic mutation in LMNA, rescues vascular pathology and markedly extends the lifespan of the mice.

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.

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.

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.

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.