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The Panoptes antiphage system defends bacteria by detecting phage-encoded counter-defences that sequester cyclic nucleotide signals, triggering membrane disruption and highlighting a broader strategy of sensing immune evasion through second-messenger surveillance.

TREM2 is an important AD risk factor playing essential roles in the microglial response to amyloid pathology. Here, authors show using a TREM2 reporter mouse that TREM2 levels are critical for efficacy of TREM2 agonism informing current clinical efforts.

Structural, genetic, functional and biochemical analyses of the complex flagellar motor of Campylobacter jejuni reveal structural adaptations with an ancient origin also found more widely across bacterial species, including elements exapted from the type IV pilus machinery.

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.

Engineered DNA recombinases efficiently and specifically insert genetic cargos without the use of landing pads.

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.

Long-term follow-up of participants in the ADVENT trial, which compared pulsed field ablation to conventional thermal ablation in patients with paroxysmal atrial fibrillation, shows preserved effectiveness of pulsed field ablation over the course of 4 years.

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.

Nudt21-mediated 3′UTR regulation orchestrates tissue regeneration through dose-dependent control of stem cell differentiation and multiprotein complex assembly, revealing alternative polyadenylation as essential for organismal survival.

RNA base-editors are often used in methods for RNA binding protein (RBP) target discovery. Here the authors present a new RBP target discovery method, PRINTER, and suggest optimal RNA base-editors for dual-RBP studies, emphasizing the importance of matching rBEs’ editing biases with RBPs’ binding preferences.

Leber hereditary optic neuropathy (LHON) is caused by mtDNA mutations. Here, authors generated a mouse model with the common LHON mutation and showed that optimized TALE-like deaminases restored both phenotype and genotype via high-fidelity mitochondrial base editing.

The impact of variants of uncertain significance (VUS) on protein function and cancer risk remain unclear. Here, the authors focus on the functional impact of VUS of the PALB2 gene and identify defects in DNA damage repair by homologous recombination associated with increased risk of breast cancer.

Xenotransplantation of a genetically edited pig kidney with a thymic autograft into a brain-dead human for 61 days with immunosuppression resulted in stable kidney function without proteinuria, and xenograft rejection was treated and reversed by the end of the study.

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 emergence of resistant subpopulations often underlies the development of resistance to cancer therapy. Here, using a DNA barcoding approach, the authors demonstrate EGFR TKI treatment in non-small cell lung cancer enriches for resistant subpopulation which can be prevented by treatment with the multikinase inhibitor sorafenib via inhibition of MKNK, STAT3 and MCL1.

Together with a companion paper, molecular details of immune responses in a pig-to-human xenotransplantation are identified through dense longitudinal multi-omics profiling of the xenograft and the host recipient, across the 61-day procedure.

A combined cryo-electron tomography and cryo-electron microscopy pipeline was developed to inflict axonal damage and monitor the cellular response induced by epothilone B, revealing that microtubule polymerization at and beyond the lesion site promote axon regeneration.

The discovery that DNA methylation of different CpG sites can serve as digital barcodes of clonal identity led to the development of EPI-Clone, an algorithm that enables single-cell lineage tracing through cellular differentiation at scale.

Silencing of transgenes such as Cas9 limits gene editing and CRISPRa applications. Here, the authors show that adding intronic sequences reduces silencing and boosts transgene expression, enabling improved CRISPRa-mediated gene activation and more stable expression of the transgene over time.

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.

Directed evolution is a powerful method to optimize protein fitness. Here, authors develop an active learning workflow using machine learning to more efficiently explore the design space of proteins.

The majority of human genes can produce multiple isoforms, but studying their functional relevance requires tools to target specific isoforms. Here, the authors develop a CRISPR-based exon-exon junction-targeting strategy to achieve isoform-specific RNA knockdown.

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.

Saturation mutagenesis screening examines 11,520 point mutations in the kinase domains of FGFR1, FGFR2, FGFR3 and FGFR4, identifying their activating and resistance properties to the FGFR inhibitors pemigatinib and futibatinib.

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.

Cardiac fibrosis arises from persistent myofibroblast activity. This study reveals how chromatin factors control scar-forming cells in the heart and shows that inhibiting KAT5 can reduce harmful cardiac fibrosis.

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.

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.

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

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.

STING is an intracellular sensor of pathogen- or host-derived DNA. In this study, the authors identify an ESCRT complex that regulates STING degradation, thus acting as a homeostatic regulator of STING signalling and type-I interferon responses.

Despite their great diversity, human languages are shaped by recurring grammatical universals. Verkerk et al. show that about one-third of the proposed universals hold cross-linguistically through analyses of the Grambank database.

In an effort to deorphanize G-protein-coupled receptors, a photo-cross-linking platform was established to capture ligands from complex samples. Little-LEN was identified as a ligand for GPR50, which coordinately regulates body metabolism.

The STAR experiment at the Relativistic Heavy Ion Collider at Brookhaven National Laboratory demonstrates evidence of spin correlations in \(\Lambda \bar{\Lambda }\) hyperon pairs inherited from virtual spin-correlated strange quark–antiquark pairs during QCD confinement.

Murphy et al. reveal a unifying pathogenetic mechanism according to which diverse mutations in the muscle-specific ribosomal protein RPL3L cause severe neonatal dilated cardiomyopathy, establishing a framework for interpreting the growing spectrum of RPL3L variants.

Nagano et al. identify the third mitotic cohesin complex, STAG3–cohesin, which, with its unique biophysical properties, weakens insulation and rewires regulatory interactions of spermatogonial stem cells, shaping the male germline nucleome.

3-Hydroxypropionic acid (3HP) is a top Department of Energy value-added chemical and precursor to bioplastics, yet cost-effective microbial bioproduction remains elusive. Here the authors establish efficient 3HP production in an acid tolerant yeast and validate its financially viability.

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.

Sensory neuron population expansions are common in evolution but of unclear function. Here, the authors show that, in drosophilid olfactory systems, increased sensory neuron number impacts interneuron dynamics, but not sensitivity, to promote olfactory-guided behaviour.

DNA damage threatens genome stability, but its dynamics in living systems remain difficult to track. Here, the authors engineer MCPH1-based protein probes that specifically recognize γH2AX, enabling real-time visualization and mapping of DNA damage across diverse cellular and organismal contexts.

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.

Tendons exhibit limited healing capacity and the role of lymphatic vessels in tendon regeneration is largely overlooked. Here they compare control and injured tendon cells from both neonatal and adult mice and identify lymphatic vessels as key regenerative niche elements.

This study demonstrates that the extracellular matrix (ECM) of the developing brain stabilizes recently born synapses. The authors identify a microglial metalloprotease that digests the ECM to increase the plasticity of these newborn synapses.

Smargon et al. show that small nuclear RNAs can improve the cellular safety and efficacy of endogenous protein-mediated RNA base editing, enhancing nuclear RNA editing and the rescue of premature termination codon disease.

Ribosome engineering is an emerging powerful approach for synthetic protein synthesis. Here the authors invert the Ribo-T system, using the engineered ribosome to translate the proteome while the native ribosome translates specific mRNA.