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This study shows how the bacterial retron Eco2 defends against viruses. Phage nucleases trigger activation of Eco2, which cuts RNAs, shuts down protein production and stops phage replication.

Phosphatidylinositol phosphates together with cholesterol bind at the interface between STING dimers, directly promoting high-order oligomerization.

Here, the authors develop Q4ddPCR, a high-throughput assay to quantify genetically intact HIV reservoirs by targeting four regions, and demonstrate that it reduces assay dropout to 5%, tracks reservoir decay, and closely correlates with viral outgrowth.

Thermal imaging lenses are typically made from expensive materials such as germanium and silicon. Here, the authors synthesise a sulfur-based polymer with high mid-wave infrared and long-wave infrared transparencies, presenting a high-performing, low-cost alternative to traditional thermal imaging lens materials.

A Gifsy-1 prophage–encoded higher eukaryotes and prokaryotes nucleotide-binding protein, HepS, senses Siphoviridae infection, activates abortive defence by cleaving host transfer RNAs, blocks rival phages and avoids self-targeting via tail-tip variation.

Native top-down proteomics reveals epidermal growth factor receptor–estrogen receptor-alpha (EGFR–ER) signaling crosstalk in breast cancer cells and dissociation of nuclear transport factor 2 (NUTF2) dimers to modulate ER signaling and cell growth.

Mouse models show that lymphoedema caused by impaired lymphatic drainage is ameliorated by removal of cholesterol deposits, which promotes the regeneration of lymphatic vessels.

This study provides new insights into the role of endoglin (ENG) as a co-receptor in endothelial cells and addresses a gap-in-knowledge on how ENG could be involved in both TGF-β and BMP9 signalling. Such knowledge greatly facilitates therapeutic targeting of ENG-related pathways.

Nitrate sensing by NLP7 engages a MEKK–MAPK cascade to phosphorylate the circadian clock protein CCA1, establishing a positive-feedback loop that stimulates auxin signalling to drive root foraging for nitrate.

Chang et al. found that nuclear reactive electrophile stress suppresses translation through HNEylation at C436 of NCBP1, triggering alternative splicing of S6K1, a key regulator of translation.

Jacquemyn et al. identify key lipid determinants controlling ectosome shedding from neurons. They find that ectosomes are a major route for the intercellular transport of misfolded α-synuclein, with relevance to Parkinson’s disease pathology.

Cryo-electron microscopy structures of nucleotide excision repair complexes reveal the roles of the constituent proteins XPA, XPB, XPC, XPD, XPF, XPG and RPA in DNA bubble formation and excision of the lesion strand.

Despite high morbidity and mortality, there are currently no approved vaccines for protection against Middle East respiratory syndrome (MERS) coronavirus. Here the authors develop a ferritin nanoparticle-based MERS-CoV vaccine that elicits high levels of neutralizing antibodies in mice, non-human primates, and alpacas and prevents infection in an alpaca challenge model.

This study investigates whether genetic predisposition to systemic inflammation affects cortical thinning trajectories and the risk for psychopathology in adolescents, using data from the Adolescent Brain Cognitive Development Study.

In this study, the authors present optimization and efficacy testing of apolipoprotein-based lipid nanoparticles for delivering various nucleic acid therapeutics in vivo to immune cells and their progenitors in the bone marrow.

Patients with myelodysplastic syndromes (MDS) have limited therapeutic options. Here the authors show that functionally impaired NK cells contribute to immune escape of pre-malignant clones in early stage MDS and that NK adoptive cell therapy can be considered to prevent or delay the development of MDS.

Highly pathogenic avian influenza H5N1 viruses are of global concern. This study shows that a low-dose H5N1 clade 2.3.4.4b Alum/CpG-adjuvanted vaccine elicits broad, durable antibody and T cell responses and protects female mice against lethal homologous and heterologous H5N1 challenges.

The PCRCR complex of Plasmodium spp. binds basigin on the erythrocyte surface. While Rh5 of the complex is restricted to P. falciparum, PTRAMP, CSS and Ripr orthologs are present across the genus, for which the authors report common features.

How cellular metabolism influences tissue-resident macrophage survival is currently unknown. The authors here demonstrate that SerpinB2 regulates mitochondrial function to promote tissue-resident macrophage survival.

Langstein-Skora, Schmid, Huth et al. propose that intrinsically disordered region functionality can be driven by the interplay between linear binding motifs and contextual chemical characteristics such as charge and hydrophobicity.

Molecular glue degraders have consistently been discovered retrospectively, despite their increasing importance. Herein, a high-throughput approach is described that modifies existing ligands into molecular glue degraders.

Epstein–Barr virus (EBV) is a widespread herpesvirus linked to cancer and autoimmune disease. The authors in this work design and characterize a stabilized prefusion form of gB, an essential viral fusion protein, advancing EBV vaccine and therapeutic development.

Here, the authors report recent updates to the ENCODE data portal including a redesigned home page, an improved search interface, custom-designed pages highlighting biologically related datasets and an enhanced cart interface for data visualisation plus user-friendly data download options.

Taniuchi and colleagues show that differential phosphorylation of the terminal Y residue in Runx proteins connect MHC restriction with the helper versus cytotoxic T cell lineage choice.

Polyamines prevent the action of kinases on acidic phosphorylatable motifs in spliceosomal proteins, thus providing a mechanism for metabolite-mediated regulation of alternative splicing in cells.

The relative contribution of lipid catabolism on fasting-induced longevity was unknown. Authors showed lifespan extension from fasting depend on silencing lipid catabolism upon nutrient replenishment through phosphorylation of NHR-49 by KIN-19.

In targeted protein degradation, a degrader molecule brings a neosubstrate protein proximal to a hijacked E3 ligase for its ubiquitination. Here, pseudo-natural products derived from (−)-myrtanol—iDegs—are identified to inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs prime apo-IDO1 ubiquitination and subsequent degradation using its native proteolytic pathway.

Circadian clock in adipocytes maintains metabolic health by regulating mitochondrial complex I respiration.

Polyamides (PAs) or nylons are types of plastics with wide applications, but due to their accumulation in the environment, strategies for their deconstruction are of interest. Here, the authors screen 40 potential nylon-hydrolyzing enzymes (nylonases) using a mass spectrometry-based approach and identify a thermostabilized N-terminal nucleophile hydrolase as the most promising for further development, as well as crucial targets for progressing PA6 enzymatic depolymerization.

Becker et. al developed a proteomic proximity labeling platform named POCA, which makes use of a photosensitizer for singlet oxygen production and protein capture in the presence of amine, enabling profiling of interactomes of proteins and lipids in living cells.

Taveneau et al. leverage artificial-intelligence-driven protein design to create inhibitors that control RNA-targeting enzymes in cells, revealing a strategy to rapidly design off-switches for RNA-editing systems.

Donahue et al. show that ageing is associated with changes in ER morphology. ER-phagy drives age-associated ER remodelling through tissue-specific factors.

In this work, authors show how the enterotoxigenic Escherichia coli (ETEC) protease EatA cleaves the human mucus protein MUC2 at a C-terminal site, allowing bacteria to cross the intestinal mucus, reach epithelial cells, and promote infection, as demonstrated using a human MUC2 transgenic mouse model.

Bacteria use diverse defence systems against phages, including a 164-residue prophage-encoded protein, Rip1, which senses conserved phage assembly rings to form membrane pores that block virion maturation and trigger premature host cell death.

Chen et al. show that PEX39 cooperates with PEX7 in the peroxisomal import of proteins containing a PTS2 site and uncover an (R/K)PWE motif in PEX39 and PEX13 that binds to PEX7 and facilitates the import of PTS2-containing proteins.

Functional studies of O-GlcNAcylation have often focused on individual modifications. Now, a systems-level approach has identified simultaneous O-GlcNAcylation events that coordinate cellular activities and tissue-specific functions.

Self-DNA has been implicated in the activation of cGAS/STING/IFN-I responses in autoimmunity and inflammatory diseases. Here the authors show that macrophage uses a process termed ‘nucleocytosis’ to extract nuclear DNA from lysosome-impaired, dying target cells, thereby activating downstream cGAS-STING signaling and IFN-I production.

In this work, the authors reveal that three non-ribosomal peptides targeting a common protein quality system differentially alter the Mycobacterium tuberculosis proteome, providing new insight into the molecular mechanisms behind their antimycobacterial activity.

Phosphatidylinositol 3,5-bisphosphate is a ligand of STING and, together with cGAMP, induces STING activation and innate immune responses.

Vassy, Dornisch and colleagues developed a genomics-based prostate cancer risk model to support a randomized clinical trial of precision screening in a national healthcare system.

A rationally designed assay detects granzyme A activity by integrating peptide-based GzmA-targeted inhibitors and probes with chemiluminescent reporters to monitor inflammatory bowel disease.

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

Viral ribonucleoprotein–viral protein networks form pre-replication centres that nucleate viral factories and drive respiratory syncytial virus replication.

The xylosyltransferase isoenzymes XT1 and XT2 catalyze the first glycosylation step in the biosynthesis of proteoglycans. Now, bump-and-hole engineering of XT1 and XT2 enables substrate profiling and modification of proteins as designer proteoglycans to modulate cellular behavior.

Here the authors present NCATS-SM0225, a small molecule that inhibits ERAD and selectively kills cancer cells by binding VDACs, disrupting calcium homeostasis, and triggering the PERK-STIM1 pathway to degrade ERAD regulators.

Membrane ion channels can be responsive to a variety of stimuli such as pressure, temperature, or pH. Here, the authors show that simply shining 365 nm light activates a native potassium channel in rodent pain-sensing neurons, delivering powerful analgesia without drugs or genetic manipulations.

Rearrangement of the B cell receptor is sequential, and pairing of the successfully assembled heavy chain with the surrogate light chain proteins VpreB and λ5 to form the pre-B cell receptor is an important checkpoint signal for continued B cell development. Here, the authors show that λ5 plays a key role in the multi-step assembly process involving association-induced folding reactions.

Structure-specific endonucleases play an important role in several DNA repair pathways. Here the authors present structures of the endonuclease XPF-ERCC1 in complex with SLX4, SLX4IP, and DNA. Combined with functional analysis, these results provide insight into the mechanisms of XPF-ERCC1 recruitment and activation during DNA repair.

Polygenic risk scores can help identify individuals at higher risk of type 2 diabetes. Here, the authors characterise a multi-ancestry score across nearly 900,000 people, showing that its predictive value depends on demographic and clinical context and extends to related traits and complications.

Crystal structures of HIV Env trimer with native glycosylation in complex with neutralizing antibodies reveal a glycan shield of high-mannose and complex-type N-glycan and indicate a path for germline-targeting vaccine design.