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Here the authors show that endogenous or therapeutically delivered GDF-15 activates brainstem neurons that trigger splenic β-adrenergic signaling. This, in turn, suppresses autoreactive T cells and reduces neuroinflammation, identifying a possible target for multiple sclerosis treatment.

Lipid nanoparticle based mRNA vaccines are known to induce robust CD4 + T cell responses. Here the authors establish a role of endogenously derived antigen processing in the optimal priming of CD4 + T cell responses to mRNA lipid nanoparticle vaccines.

A natural circular RNA termed ciRS-7 is shown to function as a negative regulator of microRNA; ciRS-7 acts as an efficient sponge for the microRNA miR-7, and is resistant to the usual microRNA-mediated degradation pathway of exonucleolytic RNA decay.

The hierarchy of DNA repair pathways at stalled replication forks is not fully understood. Here, the authors isolate two mutations in yeast RAD51 with defects in binding to duplex DNA and stalled replication forks, suggesting a role of Rad51 duplex DNA binding in fork stabilization and postreplication repair.

Cystine levels in pancreatic ductal adenocarcinoma (PDAC) tumour microenvironment are deficient, despite its crucial role for cancer cell maintenance. Here, the authors show that adaptation to cystine limitation stress promotes PDAC growth through induces metabolic reprogramming to promote PDAC tumor growth, while conferring a vulnerability in lipid metabolism targetable by lomitapide.

The microbial metabolite trimethylamine (TMA), the precursor of TMAO, which is associated with adverse cardiometabolic outcomes, is shown to have beneficial metabolic and anti-inflammatory effects in the host in the context of obesity.

A proteotoxic stress response specific to exhausted T cells, governed by AKT signaling and accompanied by increased protein translation, represents a mechanistic vulnerability and a new therapeutic target to improve cancer immunotherapies.

RNA nanotechnology creates structural and functional RNA architectures for biomedicine, synthetic biology and beyond. Here, the authors introduce pyFuRNAce, an intuitive browser-based RNA design tool. With pyFuRNAce, they realize the largest cotranscriptionally folded RNA nanostructures to date.

Microgravity triggers carotid artery aging via SREBP1. This lipid regulator remodels chromatin by boosting acetyl-CoA, silencing contractile genes while activating aging pathways. Targeting SREBP1 blocks senescence, revealing a therapeutic strategy for spaceflight-associated vascular remodeling.

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.

Engineering polymerases to synthesize alternative genetic polymers remains a challenging problem in synthetic biology. Using DNA shuffling and droplet microfluidics, the current study provides a short evolutionary path from a DNA polymerase to one with robust RNA-synthesizing activity.

Streptococcus equi subsp. zooepidemicus imports glucose via the bacterial mannose phosphotransferase system (PTS_man), which inhibits stringent response, supports growth in cerebrospinal fluid and promotes brain damage during meningitis.

How the complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth is explored.

RAS-driven cancers depend on SHOC2–PP1C. Here, the authors reveal that KRAS forms a low-affinity SHOC2–PP1C complex with fewer contacts than MRAS and show that dual inhibition of KRAS- and MRAS-dependent assemblies strengthens SHOC2 suppression and may overcome resistance.

Myeloid derived suppressor cells (MDSC) use different metabolic mechanisms to adapt to the tumour microenvironment. Here the authors show that 6-phosphogluconate dehydrogenase (6PGD) is important for MSDC function and that blockade of 6PGD impaired MDSC function and suppresses tumour growth leading to metabolic and functional changes in the MDSC and a more pro-inflammatory phenotype.

The endoplasmic-reticulum (ER) transmembrane protein IRE1 mitigates ER stress through kinase-ribonuclease and scaffolding activities. However, a significant nonenzymatic IRE1 dependency has been shown in cancer. Here, the authors design a proteolysis-targeting chimera (PROTAC) to fully disrupt cellular IRE1 protein, selectively blocking growth of IRE1-dependent cancer cells.

Small regulatory RNAs can act on target mRNAs to control their translation and stability. Here, the authors present evidence that this riboregulation can potentially regulate by pairing to a target site within translation initiation complex and translation-transcription assemblies.

CFAP20 has a key role in rescuing RNA polymerase II complexes that have arrested during DNA transcription, limiting the accumulation of R-loops and preventing collisions between the transcription and replication machinery.

Mislocalized and aggregated TDP-43 drives neurodegeneration in several diseases. The current work shows that RAD23A contributes to TDP-43 toxicity by driving pathological re-distribution of key proteins into an insoluble fraction of cells and thereby leading to loss of function phenotypes.

Importin β, the prototypical eukaryotic nuclear import receptor, transports a wide variety of cargos into the nucleus. Ko et al. used cryogenic electron microscopy to reveal an unexpected allosteric regulation of Importin β’s affinity for FG-nucleoporins, triggered by Ran-GTP.

Mutations in the insulin receptor cause severe insulin resistance, but their functional impact is often unclear. Here, the authors map ~14,000 receptor variants, linking molecular defects to disease and highlighting variants responsive to therapeutic activation.

AI decision support system non-homogenously influences clinical decisions in dynamic treatment regimen, as it depends on several factors including prior knowledge, preference, disease type, treatment modality, and AI’s learned behavior and inherent biases.

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.

Here authors show loss of AKAP11, a strong genetic risk factor for bipolar disorder and schizophrenia, disrupts PKA proteostasis and signaling, leading to widespread transcriptomic alterations across the brain, particularly in striatal neurons, as well as altered behavior.

A study finds that a protease called granzyme K can activate the entire complement cascade, explaining how it can drive destructive inflammation in inflammatory diseases such as rheumatoid arthritis.

Saito et al. identify sphingosine kinase 1 as a critical regulator of physiological ductus arteriosus closure and pathological supravalvular aortic stenosis through its role in smooth muscle cell proliferation and propose potential therapeutics.

Information has been encoded into the quantum wavefunctions of a two-dimensional electron gas using electronic holograms constructed from single molecules. The information is stored in two spatial dimensions and one energy dimension and is read with a scanning tunnelling microscope, to enable information densities exceeding 20 bits nm⁻².

Human antibodies DENV-290 and DENV-115 are ultrapotent against dengue virus 3 strains with differing particle morphologies. CryoEM shows both bind across two protomers at the center of the envelope protein dimer, defining a new class of epitope.

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.

A forward genetic screen in Caenorhabditis elegans reveals that decreased levels of the ferredoxin FDX2 suppress the loss of frataxin in worms and in mice by relief of FDX2 inhibition of frataxin-stimulated NFS1 activity.

After spinal cord injury, lesion-remote astrocytes acquire heterogeneous, spatially restricted reactivity states that shape neuroinflammation, neural repair and neurological recovery.

Maintenance and quality control of the mitochondrial respiratory chain complexes responsible for bulk energy production are unclear. Here, the authors show that the mitochondrial protease ClpXP is required for the rapid turnover of the core N-module of respiratory complex I, which happens independently of other modules in the complex.

The evolutionary diversification of an exocyst subunit was enabled by electrostatic shifts leading to its dissociation from the ancestral complex.

Cells can sense mitochondrial damage through signalling via an unimported mitochondrial targeting sequence.

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.

Measles virus and canine distemper virus (CDV) are still causing health impairments in humans and animals. Here, the authors develop a synthetic antibody protecting ferrets from lethal CDV infections, providing a roadmap for antiviral drug design.

DNAJC12 variants cause parkinsonism. Here, the authors show that DNAJC12 stabilizes tyrosine hydroxylase, a crucial enzyme in dopamine synthesis, and identify key structural motifs for this interaction, explaining the pathogenesis of truncated variants.

N¹-Methylpseudouridine enhances the translation of synthetic mRNAs, independently of innate immunity.

Using human iPSC-derived motor and cortical neurons as well as Drosophila models, the authors have identified a dysregulated Ku80–p53–SIRT1 axis downstream of DNA damage repair as a common pathogenic mechanism in both sporadic ALS and familial FTD.

Treekitkarnmongkol, Katayama, Sankaran et al. identify RASH3D19 as a downstream target for KRAS signalling through miR-301a, which in turn leads to RAS activation and tumorigenesis. Targeting RASH3D19 inhibits growth of KRAS-mutant tumour cells in vivo.

Using a combination of antibody- and LC–MS/MS-based methods, Zhang et al. reveal lysine l-lactylation as the key lactylation isomer in cellular histones, responding dynamically to glycolysis and positively correlating with lactyl-CoA levels, providing insights into the Warburg effect.

Tailed bacteriophages package their DNA into symmetric protein shells, called “capsids”, that use a common subunit fold. Here, authors visualize such a capsid at the molecular level and identify a key structural motif involved in regulating its size.

Silencing of endogenous retroviral elements (ERVs) is mediated by KAP1. Here, the authors describe the molecular mechanism by which KAP1 induces structural reorganization and multimerization of HP1α and maintains inaccessible chromatin at ERVs in mouse embryonic stem cells.

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.

Mitochondria depend on phospholipids supplied by the endoplasmic reticulum. Here, using biochemical assays and molecular dynamics simulations, authors identify VDAC as a scramblase-type lipid transporter that catalyze lipid entry.

Here the authors demonstrate that the assembly of mitochondrial respiratory supercomplex (III₂–IV) from Toxoplasma gondii is critical for parasite fitness. They reveal the basis for cytochrome b inhibition by atovaquone and improved ELQ inhibitors.

To bypass the limitations of detergents, Ren et al. developed peptide scaffolds that extract membrane proteins directly into lipid nanodiscs, preserving the native environment for structural and functional studies of previously inaccessible membrane protein complexes

A generative artificial intelligence-powered method enables de novo design of highly active enzymes based on information about the geometry of residues in the active site, without requiring protein backbone or sequence information.