The excessive activation of sympathetic nerve is closely related to cardiovascular diseases (CVDs). In this study, we developed a novel MIL-100(Fe)@Ag surface-enhanced Raman scattering (SERS) substrate for the simultaneous and effective detection of plasma norepinephrine (NE) and adenosine-two pivotal sympathetic hormones. The microscopic morphology and crystal structure of the substrate were characterized using techniques such as transmission electron microscope (TEM) and X-ray diffraction (XRD). Mechanistically, the HOMO-LUMO energy levels of the detection molecules were calculated using Gaussian. The substrate realized a dual SERS enhancement mechanism through the synergistic effect of localized surface plasmon resonance and interfacial charge transfer. Consequently, the MIL-100(Fe)@Ag platform exhibited high-sensitivity quantitative detection capabilities for NE and adenosine: the detection limit for NE is 0.596 nmol/L; the detection limit for adenosine is 0.24 nmol/L. Crucially, when applied to patients with pheochromocytoma-a neuroendocrine tumor characterized by plasma catecholamine surges, this method achieved robust and stable detection of plasma NE. It offered comparable diagnostic accuracy to conventional mass spectrometry while significantly reducing analysis complexity. Therefore, this innovative strategy may hold great promise for the long-term, decentralized monitoring of sympathetic nerve activity in populations at risk for CVDs or related clinical disorders.

Extracellular Adenosine 5'-triphosphate (eATP) is a damage-associated molecular pattern in both plants and animals, playing an important role as a danger signal in response to various environmental stresses. eATP works both independently and in coordination with other signaling pathways. Here, we identify a previously uncharacterized proline-rich extensin-like receptor kinase 15 (PERK15), which interacts with the plant eATP receptor P2K1 and integrates eATP and salicylic acid (SA)-mediated pathogen defense responses. perk15 mutant plants display reduced eATP responses and compromised pathogen resistance, whereas ectopic overexpression of PERK15 triggers autoimmunity. eATP treatment enhances PERK15-P2K1 interaction. P2K1-mediated phosphorylation of a Ser/Thr cluster in the PERK15 kinase domain is essential for its activation. PERK15 transcript levels are upregulated by SA, and PERK15 overexpression promotes the protein accumulation of the SA receptor NPR1. Data show that eATP and SA act synergistically to regulate plant defense responses in a PERK15-dependent manner. Together, the findings identify PERK15 as a key node linking eATP and SA signaling, providing insights into how plants integrate extracellular danger signals and defense hormone signals to mount effective immune responses.

Overcoming oxidative stress resulting from reactive oxygen species (ROS) overload in the microenvironment of bone injury is crucial for bone repair. This study developed a multifunctional composite scaffold composed of zein, adenosine-calcium phosphate (ACP), and epigallocatechin gallate (EGCG) for enhanced bone regeneration through antioxidant activity. For the preparation of the Zein/ACP/EGCG (Z/A/E) composite scaffold, ACP nanoparticles were first synthesized using an enzymatic reaction and characterized by SEM, EDS, FTIR, and XRD. ACP nanoparticles showed great biocompatibility and osteoinductivity within a certain dose range in vitro. A three-dimensional (3D) porous Zein/ACP (Z/A) composite scaffold was fabricated by compression molding and particulate leaching, followed by the adsorption of EGCG onto its surface. The final Z/A/E composite scaffold exhibited enhanced surface hydrophilicity, which facilitated the adhesion, proliferation, and differentiation of osteoblasts. Mechanistically, the Z/A/E composite scaffold promoted osteogenesis while concurrently inhibiting osteoclastogenesis, primarily through its ROS-scavenging capability. The bidirectional regulation of bone remodeling by the Z/A/E composite scaffold was demonstrated by significant repair of hydrogen peroxide-induced calvarial defects in ex vivo cultured explants from neonatal mice, confirmed by μ-CT and histological evaluation. Collectively, this Z/A/E composite scaffold, which leverages antioxidant activity to rebalance bone homeostasis, represents a promising strategy for bone regeneration.

B cells can suppress anti-tumor T cell responses, representing a potential mechanism of resistance to immunotherapy. Multiple Breg subsets have been described in humans and mice. Bregs inhibit anti-tumor immunity through cytokine secretion, immune checkpoint expression, and potentially adenosine generation, which collectively suppress effector T cells, and strengthen immunosuppressive signaling. Hypoxia is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to immune dysregulation within the tumor microenvironment (TME); however, the effects of hypoxia on B cell subsets remain poorly defined. In this study, we investigated how hypoxic stress shapes regulatory B cell phenotype using murine PDAC models. We show that nearly half of intratumoral B cells are hypoxic, which also increased across systemic B cell compartments with tumor burden. Hypoxic B cells were enriched for CD39 and CD73 ectonucleotidases and suppressed T cell activation via adenosine receptor-dependent mechanisms. Hypoxia preferentially induced CD39[+]CD73[+] expression in peritoneal-derived B cells, indicating tissue-specific regulation, while splenic B cells showed limited responsiveness ex vivo. Conversely, hypoxia reduced IL-35 production by splenic Bregs through decreased Ebi3 expression and reduced activation marker levels. Within tumors, hypoxia correlated with CD11b[+] and CD39[+]CD73[+] B cells but not IL-35-producing subsets. Mechanistically, Ebi3 loss enhanced CD39 expression under hypoxia, whereas recombinant IL-35 suppressed CD39[+]CD73[+] induction, suggesting reciprocal regulation between IL-35 and adenosine pathways. These findings reveal hypoxia-driven plasticity in immunosuppressive B cell programs in PDAC, characterized by suppression of IL-35-producing Bregs and promotion of adenosine-generating CD39[+]CD73[+] B cells, highlighting potential therapeutic targets to modulate tumor-associated immunosuppression.

Increased pre-osteoblast cell density within bone resorption areas is a key factor in promoting osteoblast differentiation; however, the molecular mechanisms underlying this process remain poorly understood. In this study, we investigated the role of ATP release and purinergic receptor P2X4 signaling in osteoblast differentiation using the murine pre-osteoblastic cell line MC3T3-E1. Under high cell density conditions, which were essential for the induction of osteoblast differentiation, we observed a significant accumulation of extracellular ATP released via the hemichannel Pannexin 3 (Panx3). This ATP accumulation subsequently activated the P2X4. Pharmacological inhibition and siRNA-mediated knockdown Panx3 markedly reduced extracellular ATP levels and decreased expression and activity of alkaline phosphatase (ALP), an osteoblast differentiation marker. Similarly, pharmacological inhibition and siRNA-mediated knockdown of P2X4 suppressed ALP expression and activity. Functional analyses using calcium imaging and whole-cell patch-clamp recording revealed that P2X4 activity was enhanced during osteoblast differentiation. Notably, this functional upregulation correlated with enhanced localization of P2X4 to the plasma membrane. Moreover, pharmacological inhibition of Panx3 or P2X4 impaired the endochondral ossification of isolated mouse metatarsal bone. These findings suggest that Panx3-mediated ATP release and the subsequent activation of P2X4 signaling constitute a crucial pathway linking cell density to osteoblast differentiation. Our study provides new insights into the purinergic signaling mechanisms underlying bone formation and identifies potential molecular targets for promoting osteogenesis.

Neonatal hypoxic-ischemic brain damage (HIBD) is the leading cause of neonatal death and long-term neurological dysfunction. Dexmedetomidine (DEX) has been shown to have neuroprotective effects, but its mechanisms in HIBD remain incompletely understood. This study aimed to explore whether DEX inhibits neuroinflammation and pyroptosis via activating adenosine monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) axis, thereby reducing HIBD. A HIBD model was established. Histological staining observed the pathological changes and neuronal survival. Primary cortical neurons were cultured to establish an oxygen-glucose deprivation/reoxygenation (OGD/R) model. DEX was used for intervene, and siAMPK was transfected to knock down AMPK expression. Inflammatory and oxidative stress indicators within brain tissue and neuronal cells were measured using enzyme-linked immunosorbent assay (ELISA) and biochemical kits. The AMPK/SIRT1 pathway and pyroptosis protein expressions were evaluated using fluorescence staining and Western blot. DEX dose-dependently reduced cerebral infarction volume, improved cerebral cortex pathological damage, enhanced neuronal nuclei (NeuN) positive neurons, decreased interleukin (IL)-6 and malondialdehyde (MDA) contents, enhanced superoxide dismutase (SOD) activity, and inhibited terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)/cleaved Caspase-1 double positive cells and N-terminal domain of Gasdermin D (GSDMD-N) protein expressions. DEX significantly upregulated p-AMPK and SIRT1 expression, whereas the AMPK inhibitor Compound C reversed the neuroprotective effect of DEX. In vitro experiments confirmed that DEX increased neuronal cell viability, reduced lactate dehydrogenase (LDH) release and propidium iodide (PI)-positive cell rate, reduced oxidative stress, and inhibited inflammatory factor release and pyroptosis-related protein expression. AMPK knockdown significantly reversed this axis activation by DEX and attenuated the neuroprotective effect of DEX. In conclusion, DEX improved neurological function in HIBD rats via the activating AMPK/SIRT1 pathway, reducing neuroinflammation and inhibiting neuronal pyroptosis.

Tryptophan codon-specific mistranslation, in the form of ribosomal frameshifting and tryptophan-to-phenylalanine (W > F) codon reassignments (substitutants), is induced in cancer cells by the limiting level of tryptophan imposed by anti-tumour immunity. While the oncogenic mitogen-activated protein kinase pathway drives frameshifting, whether substitutants are genetically regulated remains unknown. Here we screened for genes that control W > F substitutants following interferon-γ-mediated tryptophan shortage. This screen identified ADAR1, an enzyme that converts adenosine to inosine in double-stranded RNA molecules, and FTSJ1, an enzyme that 2'-O-methylates the anticodon region of several tRNAs. We demonstrate that ADAR1 sustains expression of key players in the ribosome quality control pathway, which in turn is essential for mistranslation events. FTSJ1, in contrast, specifically drives W > F mistranslation by methylation of tRNA[Trp] to promote its binding to WARS1 loaded with phenylalanine instead of tryptophan. As ADAR1 and FTSJ1 levels are elevated in many cancer types, we propose that cancer cells deploy global and specific mechanisms to promote mistranslation in response to anti-tumour immunity.

ADAR-mediated A-to-I RNA editing is crucial for proper neuronal function. However, its spatial signatures in the cerebral cortex remain largely unexplored. To address this, we developed SRDRE, an analysis framework for identifying RNA editing sites in spatial transcriptomics data. By analyzing over 40 million cells across 142 spatially annotated cortical regions in the adult macaque cortex, we uncovered laminar and cell-type-specific RNA editing landscapes. Notably, neuronal RNA editing levels correlated with cortical hierarchy in the visual and somatosensory systems. Parvalbumin neurons exhibited the highest editing activity in most regions. Furthermore, we identified primate-enriched sites within ion channel genes, specifically in excitatory neuronal subtypes of the prefrontal cortex. Finally, in a preliminary exploratory analysis, we observed altered RNA editing in deeper layers of the dorsolateral prefrontal cortex in macaques exhibiting depressive-like behaviors, suggesting a potential link that warrants further investigation. These findings underscore the role of RNA editing and its potential contributions to cortical specialization, brain evolution, and neuropsychiatric disorders.

Inborn errors of immunity (IEI) are no longer defined solely by recurrent infection, and up to two-thirds of patients present with immune dysregulation affecting virtually all organs and systems. This article elucidates the cardinal noninfectious red flags of IEI, categorizing them by medical specialty to aid the generalist clinician. We highlight distinct phenotypes-from the atopy plus of STAT3 loss-of-function to the neurovascular strokes of deficiency of adenosine deaminase 2-that warrant immunologic investigation. Recognizing these patterns is imperative as early molecular diagnosis unlocks targeted, mechanism-based therapies, preventing irreversible organ damage and improving long-term survival.

Cyclic adenosine 3',5'-monophosphate (cyclic AMP; cAMP) has emerged as a bona fide signalling molecule in plants. Although its regulatory roles in diverse cellular processes are increasingly recognised, the transient nature of cAMP signalling has limited our understanding of its systemic functions at the whole-plant level. In this study, we engineered Arabidopsis thaliana plants to constitutively express adenylate cyclase (AC) activity, thereby enabling sustained elevation of endogenous cAMP levels. The AC transgenic lines exhibited a 1.3- to 1.8-fold increase in endogenous cAMP content relative to wild-type plants. Elevated cAMP promoted accelerated growth and developmental progression, enhanced photosynthetic performance, increased cellular metabolic activity, and improved productivity, as evidenced by 13-14% greater plant height, 12-17% higher 1000-seed weight, and 36-41% greater seed yield per plant. However, these growth advantages were accompanied by increased susceptibility to salinity stress, pathogen infection, and exogenous ethylene treatment compared with wild-type plants. Collectively, our findings establish cAMP as a central regulator of plant physiology that coordinates growth, development, metabolism, and stress responsiveness. While sustained elevation of endogenous cAMP enhances plant growth and productivity, it also increases sensitivity to environmental stimuli, highlighting the importance of precise spatiotemporal regulation of cAMP signalling in maintaining optimal plant performance.

TheThe colonization of the gastric epithelium with Helicobacter pylori elicits a robust nuclear factor kappa-light chain enhancer of activated B cells (NF-κB)-dependent inflammatory response. The bacterial effector molecule adenosine diphosphate-glycero-β-D-manno-heptose (ADP-heptose) triggers both the classical and alternative NF-κB pathways almost simultaneously leading to activation of the transcription factor heterodimers p50/RelA and p52/RelB. Previous studies have demonstrated that the COP9 signalosome complex (CSN) plays an important role in regulating the classical NF-κB pathway through deneddylation of the E3 ligase Skp1-Cullin1-F-Box-β-TRCP (SCF[β-TRCP]), while the influence of the CSN on the alternative NF-κB pathway remains unclear. Here, we show that CSN-dependent deneddylation of Cullin-1 controls via the classical NF-κB signaling pathway the upregulation of RelB mRNA and protein expression, enhancing the nuclear translocation of RelB. These findings are supported by the fact that ADP-heptose induces RelB expression in 2D mucosoids derived from 3D organoids from gastric antral glands of the stomach. Blocking neddylation and the activity of SCF[β-TRCP] by treatment with the NEDD8-activating enzyme inhibitor MLN4924 prior to H. pylori infection, stabilized IκBα as well as p100 and suppressed RelA and RelB nuclear translocation. Therefore, our data show that CSN-dependent regulation of SCF[β-TRCP] controls classical NF-κB signaling and consequently contributes to RelB nuclear translocation and alternative NF-κB activity. For the termination of alternative NF-κB activity, the CSN serves as a hub between constitutively associated c-Cbl and nuclear RelB, allowing c-Cbl-mediated ubiquitinylation of nuclear RelB following H. pylori infection.

Chromatin remodeling governs how eukaryotic genomes are accessed and interpreted by dynamically modulating nucleosome architecture. Adenosine triphosphate (ATP)-dependent remodeling complexes are highly conserved molecular machines built around Snf2-family ATPases that use the energy of ATP hydrolysis to slide, evict, or restructure nucleosomes, thereby shaping transcription, replication, and DNA repair. Their importance is such that their malfunctioning is linked to different diseases, including cancer. Recent discoveries reveal that chromatin remodelers are far more dynamic than previously appreciated: they undergo continual motion, rapid exchange, and transient nucleosome engagement, underscoring a highly fluid regulatory landscape. To capture this emerging view, we invoke Heraclitus' aphorism panta rhei (ancient Greek: πάντα ῥεῖ, 'everything flows, moves'), which aptly reflects the intrinsic dynamism of remodeling processes. Advances in single-molecule imaging and high-resolution structural approaches now illuminate how remodelers search the genome, transition between functional states, and remodel nucleosomes in real time. This review synthesizes recent developments, with emphasis on SWItch/Sucrose Non-Fermentable (SWI/SNF) complexes and comparative insights across remodeler families, highlighting how integrating structural, biochemical, and biophysical perspectives is reshaping current models of chromatin regulation.

Traditional metabolic inhibitors have limited clinical efficacy, with issues such as narrow window periods, and compensatory effects. These barriers indicate that effective metabolic therapy requires spatially restricted, temporally coordinated, cell-context-aware, and clinically stratifiable intervention. This review examines how glucose-lactate, lipid-redox, amino acid-immune checkpoint, and nucleotide-adenosine circuits drive tumour progression, immune suppression, and therapeutic escape. We then define the engineering advantages that distinguish nanomedicine from free metabolic drugs, including spatiotemporal control, smart and responsive release, multi-target co-delivery, and organelle targeting. Representative nanomedicine strategies are discussed according to the immunometabolic circuits they modulate, with emphasis on their ability to overcome metabolic compensation, restore immune cell function, and address tumour heterogeneity. Finally, we evaluate key translational challenges, including chemistry, manufacturing and control (CMC), regulatory obstacles, and biomarker selection. This review proposes clinically actionable design principles of nanomedicine for immunometabolic reprogramming.