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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.

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.

Genome-wide association meta-analysis identifies 58 independent risk loci for major anxiety disorders among individuals of European ancestry and implicates GABAergic signaling as a potential mechanism underlying genetic risk for these disorders.

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.

Single-particle tracking experiments in intact cells reveal dynamic co- and post-translational interactions of the TRiC–PFD chaperonin complex with client proteins during in vivo protein folding.

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.

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.

Tau phosphorylation was found to hinder the formation and protective functionality of tau envelopes against microtubule-severing enzymes, providing a potential explanation for microtubule destabilization observed in neuropathology.

GABA_B receptors are the G-protein-coupled receptors for γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. Here, functional proteomics is used to show that GABA_B receptors in the brain are complexes of GABA_B1, GABA_B2 and members of a subfamily of KCTD proteins. The KCTD proteins increase the potency of agonists and markedly alter the G-protein signalling of the receptors, suggesting that they determine the pharmacology and kinetics of the receptor response.

A histone ubiquitin-dependent regulatory hub governs stimulus-dependent heterochromatin propagation, with important implications for understanding mechanisms governing rapid changes in the epigenetic landscape in physiology and disease.

A tension-modulated DNA origami-based nanosensor, compatible with bulk biochemical analysis in cell lysates, is used to assess the force-induced interaction of proteins involved in cellular mechanotransduction.

Stepp and colleagues present hybrid-EDA, an event-driven acquisition (EDA) that enables gentle investigation of rare mitochondrial events. This approach combines continuous, low-phototoxicity phase-contrast surveillance with event-triggered fluorescence imaging, powered by dynamics-aware machine-learning event detection.

Microhomology-mediated end joining (MMEJ) and mitotic DNA synthesis (MiDAS) are critical DNA repair pathways in mitosis. Here the authors show that CIP2A–TOPBP1 coordinate mitotic DNA repair through the regulation of factors required for MiDAS and MMEJ.

The cell death effector Gasdermin A is only known to be activated by Streptococcus pyogenes. This work discovers a mechanism for its activation by Staphylococcus aureus, and shows a conserved role in immunity against invasive skin pathogens

The T-cell receptor (TCR) activation mechanism has remained uncertain. Here, the authors present molecular structures for the apo and ligand-bound human TCR–CD3 complex in lipid nanodiscs, revealing large conformational changes during activation.

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.

Roßmann and colleagues report a simple strategy to generate a panel of fluorescent HaloTag Ligands that enable visualisation of cell surface proteins at low concentrations and with brief incubation times. They use these probes to label neuromodulatory receptors in neurons, allowing for the distinction of surface versus internal receptors of the presynaptic terminal.

The authors report on engineering metazoan fatty acid synthase variants with tunable selectivity to obtain short- and medium-chain fatty acids, alcohols and aldehydes. Pairing these optimized enzymes with a yeast strain designed for efficient β-oxidation yields high production levels of medium-chain fatty acids.

AvrPm4 is a chimeric powdery mildew effector that is recognized by the wheat kinase fusion resistance protein Pm4. The pathogen can evade Pm4 recognition by expressing the suppressor SvrPm4, an RNase-like effector with multiple roles.

The alveolate alga Chromera velia is a close relative of parasitic apicomplexans that possesses an unusual Photosystem I. Here, the authors present the cryo-EM structure of this complex, revealing several novel subunits, including a bound superoxide-dismutase heterodimer.

Moral-Sanz, Fernández-Carrasco and colleagues identify senolytic properties of sea anemone-derived pore-forming toxins, with selectivity mediated by senescence-associated lipid profiles. An optimized senotoxin improves the efficacy of chemotherapy in mouse models.

This study demonstrates the capability of deep learning protein design models in generating functionally validated β-strand pairing interfaces, expanding the structural diversity of de novo binding proteins and accessible target surfaces.

Synovial sarcoma (SyS) is a cancer driven by a fusion oncoprotein, SS18::SSX, but the mechanism underlying the oncoprotein-mediated tumorigenesis remains unclear. Here, the authors employ transgenic mouse models and multi-omics to show how SS18:SSX modifies the activity and recruitment of BAF-family chromatin remodeling complexes to drive SyS tumorigenesis.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

How do bacteria control formate flow, essential for microbial life? Researchers detected specialized molecular checkpoints that fine-tune small-molecule transport by combining cryo-electron microscopy with in silico, in vitro and in vivo approaches.

The authors reveal that the C-terminal tail anchors of BCL-2 family proteins control BH3 binding and cell survival by allosteric regulation at the mitochondrial membrane, involving BAX recruitment and complex disruption upon BH3 mimetic antagonism.

Haines et al. developed an MEK–RAF molecular glue called IK-595 that blocks MAPK pathway activation in RAS-mutant and BRAF-mutant cancer cells. IK-595 exhibited high tolerability and strong antitumor effects in preclinical models across cancer types.

This study shows that high-molecular weight tau has enhanced seeding capacity, and seeding differences can define molecular subtypes of progressive supranuclear palsy, underpinning the disease’s heterogeneity.

Elevated intracellular Cu converts CTR1 trimers to monomers at Rab5⁺ sites prior to endocytosis, rapidly halting Cu uptake; an endocytosis-deficient mutant fails to mount this response.

Some transcription factors can organize into different structural states, from small nanoscale clusters to macrophases. Here authors show that NHA9 undergoes differential conformational expansion across these states and exhibits micelle-like organization with non-fixed stoichiometry.

Kozai, Fernandez-Martinez et al. use high-speed atomic force microscopy to study the permeability barrier of yeast nuclear pore complexes. They show that karyopherins remodel a central plug that shapes barrier dynamics and disorder within the pore.

Npm1 promotes tumor formation via attenuating the integrated stress response and p53 activation in mouse WNT-driven intestinal and liver tumorigenesis.

Pathogenic BRCA2 truncating variants in heterozygosis drive distinct cancer-linked mechanisms. Here the authors show that one causes PARPi sensitivity and HR loss via haploinsufficiency, while another expresses a truncated protein that rewires transcription by hijacking PCAF, reducing H4 acetylation and NF-κB activity.

Researchers find that whether a person is first vaccinated or first infected with COVID-19 influences their antibody and T-cell responses, offering new insights into how hybrid immunity develops and protects over time.

In this work, fragments identified by 19F-NMR are optimized into submicromolar binders of the MITF transcription factor. These results support direct targeting of bHLH-LZ DNA binding domains and provide a foundation for the development of new melanoma therapies.

Here the authors report that brown adipocyte-derived vaspin reduces heat-producing activity in brown fat by blocking adrenergic signals, helping to regulate energy expenditure and maintain metabolic balance.

We show that FOXF2 maintains cerebrovascular function through Tie2 signaling, and that pharmacological activation of Tie2 with AKB-9778 rescues deficits in cerebral small vessel disease and stroke.

The oomycete Phytophthora infestans is a damaging crop pathogen. Here, the authors show that a group of P. infestans secreted enzymes play roles in penetration and colonization of host plants by oxidising fragments of the polysaccharide pectin in the plant cell wall.

Inhibitor-induced kinase degradation is a common event that positions supercharging of endogenous degradation circuits as an alternative to classical proximity-inducing degraders.

Mitochondrial translational activators (TAs) facilitate transcript-specific translation. Using selective ribosome profiling and cryo-electron microscopy, the authors show that TAs bind to the 5′ untranslated region of their target transcript to position mitoribosomes for initiation.

PARP enzymes play key roles in human biology, but their regulation remains poorly understood. This study shows that PARP15 is activated through dimerization of its catalytic domain and reveals how this event primes the domain for ADP-ribosyl transfer.

Many protein–protein interactions depend on Short Linear Motifs (SLiMs). In this study, the authors use large-scale binding assays, deep mutational scanning, and structural analysis to map SLiMs recognised by human cyclins and uncover the rules that determine their specificity and affinity.

Pseudomonas aeruginosa survives extreme acidity by importing lysine through the LysP transporter to regulate acid-resistance genes. Here, authors reveal the cryo-EM structure of LysP and show how specific hydrogen bonds enable lysine recognition.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

BPTF is a scaffolding subunit of the nucleosome remodeling factor (NURF) complex. Here the authors show that BPTF is upregulated in prostate cancer cells, increases chromatin accessibility at Androgen Receptor (AR)-binding sites, and stabilizes the AR-FOXA1 complex.

Tracers are fluorescent protein ligands required for various displacement assays. Here, the authors announce a curated database named tracerDB, which will make essential tracer data, contributed by the worldwide research community, easily available and searchable.

Molecular glues are monovalent compounds that can recruit a protein of interest to an E3 ligase so the protein of interest can be targeted for degradation. Here, Hughes et al. identify a molecule that selectively and potently degrades BRD9.

Targeting two distinct steps of the transcription process yields synergistic antibiotics that kill non-replicating Mycobacterium tuberculosis and reduce drug resistance.