Search Results (643)

Cognitive impairment in schizophrenia remains insufficiently addressed by existing treatments. Current FDA-approved therapies primarily modulate neurotransmitter systems, resulting in incomplete symptom control and substantial adverse effects. There is therefore a critical need for therapeutic strategies that more directly address the intracellular signaling mechanisms underlying synaptic dysfunction and cognitive deficits in schizophrenia. Protein phosphatases represent an essential but historically underexplored class of signaling enzymes that regulate phosphorylation-dependent control of synaptic receptor trafficking, plasticity, and neuronal circuit function. Although multiple phosphatases have been implicated in schizophrenia through genetic, post-mortem, and functional studies, their therapeutic targeting has been limited by challenges related to selectivity, cellular permeability, and pleiotropy. Here, we review the etiology of schizophrenia and limitations of current pharmacological approaches, synthesize evidence linking specific protein phosphatases to schizophrenia pathophysiology, and discuss emerging strategies, including allosteric modulation and targeted protein degradation, that may enable selective intervention in phosphatase-driven signaling pathways. We highlight the striatal-enriched tyrosine phosphatase STEP (PTPN5) as a case study illustrating how selective phosphatase modulation can restore synaptic signaling in schizophrenia-relevant models. Full article

Time synchronization is a fundamental requirement for the reliable operation of Control and Data Acquisition Systems (CODASs) in large-scale fusion experiments such as the Divertor Tokamak Test (DTT). Distributed diagnostics, sensors, and control subsystems must share a unified time reference to guarantee deterministic data acquisition and stable plasma control. This paper presents the FPGA-based implementation and evaluation of a synchronization system that combines the IEEE 1588 Precision Time Protocol (PTP) with Pulse Per Second (PPS) generation. The proposed platform is built on Zynq UltraScale+ Kria KR260 System-on-Modules (SOMs) running a customized PetaLinux distribution with LinuxPTP utilities. Hardware timestamping is enabled through the integrated Timestamping Unit (TSU) in the Gigabit Ethernet MAC, while a hardware logic module generates PPS signals from the synchronized PTP clock. Experimental validation demonstrates nanosecond-level synchronization with an RMS timing accuracy of approximately 8.5 ns. A detailed analysis of PPS offset, network path delay, and servo adjustments confirms stability of the timing system. The proposed design offers a low-cost, flexible, fully customizable and controllable solution for distributed diagnostic and control systems in fusion facilities. Full article

By investigating the conditions for the C–C coupling reaction of p-terphenyls, we successfully synthesized C–C coupled dimeric p-terphenyls for the first time using a reaction system involving air, silica gel, and B(OH)₃. Additionally, we developed a novel method to synthesize furan-fused p-terphenyl dimers through solvent-free reactions by creatively applying rotary evaporation and heating. Compounds 6–12, 16, 20, and 22 demonstrated DPPH radical scavenging activity that was either stronger than or comparable to the positive control (vitamin C), with IC₅₀ values ranging from 0.14 to 4.61 μM. Compounds 4–22 also exhibited significant activity against α-glucosidase, with IC₅₀ values ranging from 0.37 to 17.9 μM, exceeding the efficacy of the positive control, acarbose. Moreover, compounds 6–14, 16–18, 21, and 22 demonstrated greater inhibitory activity against PTP1B compared with the positive control, oleanolic acid, with IC₅₀ values between 0.30 and 9.17 μM. These findings highlight their potential as promising leads or dietary supplements for the treatment and prevention of diabetes, as well as possible application as oxidative agents in food preservation. Full article

Receptor protein tyrosine phosphatases (RPTPs) are transmembrane enzymes that counterbalance protein tyrosine kinase activity by catalyzing the removal of phosphate groups from tyrosine residues on target proteins. Despite their critical roles in regulating cellular proliferation, adhesion, differentiation, and survival, RPTPs remain significantly understudied compared to their kinase counterparts. Contrary to early assumptions that PTPs function as constitutive housekeeping enzymes, emerging evidence demonstrates that RPTPs exhibit highly context-dependent roles in cancer, functioning as tumor suppressors or tumor promoters, or displaying dual activities depending on tissue type, cellular environment, and the specific signaling networks involved. This review provides a comprehensive analysis of RPTP structure, catalytic mechanisms, regulatory processes, and interactions with signaling effectors in cancer. Through a systematic examination of RPTP expression patterns across ten cancer types using Clinical Proteomic Tumor Analysis Consortium (CPTAC) and International Cancer Proteogenome Consortium (ICPC) datasets, we identify subfamily-specific and cancer-type-specific expression alterations that correlate with established functional classifications. PTPσ and PTPμ emerge as uniformly downregulated tumor suppressors across diverse malignancies, whereas PTPα and PTPε display oncogenic potential by activating Src family kinases. Context-dependent RPTPs, such as LAR and DEP-1, exhibit variable expression patterns that reflect their complex, multifaceted signaling roles. These findings establish RPTPs as critical regulators of cancer signaling with significant therapeutic potential while underscoring the need to understand tissue-specific signaling architectures when developing RPTP-targeted interventions. Full article

Adaptive Neuro-Fuzzy Inference System (ANFIS)-based inverse kinematics (IK) is highly accurate for trained poses but often yields approximations for unseen inputs due to non-standardized training data. This research addresses these limitations through two novel contributions designed for any generic Degrees of Freedom (DoF) serial revolute robotic arm. First, A structured training methodology is introduced using workspace decomposition and cubic path planning. Instead of random sampling, the workspace is partitioned into cubic regions where 28 unique trajectories (12 edges, 12 face diagonals, four space diagonals) connect the eight vertices using cubic polynomial interpolation. This ensures physically consistent data mirroring real world point to point (PTP) movements. Even though validated on an ABB IRB-1200 robotic arm, this modular design is inherently scalable, allowing the local cubic expertise to be extended to cover the entire reachable workspace. Second, a two-stage hybrid IK framework is proposed, where an initial ANFIS approximation is refined via Jacobian-based iterative methods. Three Hybrid Frame works were evaluated, Framework-1 (ANFIS + Jacobian Gradient), Framework-2 (ANFIS + Jacobian Pseudoinverse/Newton–Raphson), and Framework-3 (ANFIS + Damped Least Squares). The results show that all three hybrid IK frameworks achieve reliable convergence, while the DLS-based hybrid provides the best trade-off between accuracy, convergence speed, and numerical stability. This generic, analytical free architecture provides a computationally efficient solution even in a hybrid scenario, bridging the gap between offline structured training and online, real-time refinement for digital twin synchronization and industrial automation. Full article

Background/Objectives: This study aimed to evaluate the antidiabetic potential of five extracts/sub-extracts and five known cycloartane saponins [astragalosides (AST) I, II, III, IV, and cyclocanthoside E] from Astragalus noeanus (AN), using four specific diabetes-related molecular targets. Methods: Four diabetes-associated in vitro and in silico targets—protein tyrosine phosphatase 1B (PTP1B), dipeptidyl peptidase IV (DPP IV), α-amylase, and advanced glycation end-products (AGEs)—were employed to obtain comprehensive antidiabetic activity profiles. Additionally, the antioxidant and prebiotic capacities of the extracts/sub-extracts were assessed in vitro. A cycloartane saponin was isolated and structurally characterized. Quantitative analyses of total flavonoids, total saponins, and high-performance thin-layer chromatography (HPTLC) were performed to profile the chemical constituents of the plant material. Results: Among the extracts/sub-extracts, the aqueous extract (ANW) exhibited the highest inhibitory effects against all four diabetes-related targets, with inhibition percentages ranging from 83.70% to 93.49%. The methanol extract (ANM) demonstrated significant prebiotic activity comparable to standard controls on two Lactobacillus strains. The chloroform extract (ANC) showed the highest flavonoid content and exhibited the strongest antioxidant activity across all assays. ANM yielded the highest saponin content (3250 mg escin equivalent/g). HPTLC quantification revealed that AST IV was the predominant saponin in ANM (14.28 μg/mg) after cyclocanthoside E (117.27 ± 6.71 μg/mg). Among the saponins, AST IV displayed the most potent inhibition in diabetes-related enzyme assays, surpassing reference drugs acarbose and vildagliptin at equivalent concentrations. AST III also demonstrated considerable activity, ranking just below AST IV. Molecular docking studies identified AST II and AST III as the most promising ligands, exhibiting superior binding affinities and stronger hydrogen bonding and hydrophobic interactions with target proteins. Cyclocanthoside E was isolated from A. noeanus and evaluated for its antidiabetic effects for the first time, with its structure confirmed by NMR and LC-HRMS analyses. Conclusions: This study highlights Astragalus noeanus as a promising source for safe and effective antidiabetic agents. The potent activity of the aqueous extract, along with AST IV and AST III, warrants further investigation through clinical trials to validate their therapeutic potential in diabetes management. Full article

Background: Streptococcus pneumonia is the primary etiological agent of community-acquired pneumonia (CAP). Pneumococci promote severe lung injury through the release of virulence factors, including pneumolysin (PLY). Obesity/diabetes increases pneumonia-associated mortality, but the mechanisms remain elusive. We found that obese db/db mice have increased pulmonary barrier disruption to PLY. Previously we showed that upregulation of NOX1 in endothelial cells (EC) of db/db mice drives endothelial dysfunction, but a role for NOX1 in PLY-induced lung injury, especially in diabetic conditions, has not yet been described. Results: Increased NOX1 in lung ECs dose-dependently increased superoxide and EC barrier disruption (p < 0.05). Even at low activity levels, NOX1 greatly potentiated PLY-induced EC barrier disruption, whereas loss of NOX1 activity, either pharmacological or genetic, reduced barrier disruption (p < 0.05). Blockade of calcium entry protected the EC barrier from combined PLY and NOX1, indicating a key role for calcium. Hyperglycemia amplified PLY-enduced EC barrier disruption and intracellular calcium and these effects were mitigated by NOX1 inhibition and silencing (p < 0.05). NOX1-enhanced calcium entry was reduced by knockout of calcium sensor STIM1, and PLY-induced barrier disruption was reduced by STIM1 inhibition. Levels of STIM1, Orai1, TRPV4, or TRPC4 were unchanged by HG, but TRPC1 significantly increased (p < 0.05). NOX1 and HG promoted increased STIM1 and TRPC1 binding, and silencing TRPC1 ameliorated PLY-induced barrier disruption (p < 0.05). Increased calcium promoted mitochondrial permeability transition pore (MPTP) opening and PPIF inhibition protected EC barrier function (p < 0.05). Conclusions: These results suggest that elevated glucose levels in obesity primes EC barrier disruption by amplifying PLY-induced calcium influx via a novel NOX1, STIM1, TRPC1 and MPTP signaling axis. Full article

Mitochondria are central regulators of cardiac homeostasis, integrating energy production, redox balance, calcium handling, and innate immune signaling. In cardiovascular disease (CVD), mitochondrial dysfunction acts as a unifying mechanism connecting oxidative stress, metabolic inflexibility, inflammation, and structural remodeling. Disturbances in mitochondrial quality control—encompassing fusion–fission dynamics, PINK1/Parkin- and receptor-mediated mitophagy, biogenesis, and proteostasis—compromise mitochondrial integrity and amplify cardiomyocyte injury. Excess reactive oxygen species, mitochondrial DNA release, and calcium overload further activate cGAS–STING, NLRP3 inflammasomes, and mPTP-driven cell death pathways, perpetuating maladaptive remodeling. Therapeutic strategies targeting mitochondrial dysfunction have rapidly expanded, ranging from mitochondria-targeted antioxidants (such as MitoQ and SS-31), nutraceuticals, metabolic modulators (SGLT2 inhibitors, metformin), and mitophagy or biogenesis activators to innovative approaches including mtDNA editing, nanocarrier-based delivery, and mitochondrial transplantation. These interventions aim to restore organelle structure, improve bioenergetics, and reestablish balanced quality control networks. This review integrates recent mechanistic insights with emerging translational evidence, outlining how mitochondria function as bioenergetic and inflammatory hubs in CVD. By synthesizing established and next-generation therapeutic strategies, it highlights the potential of precision mitochondrial medicine to reshape the future management of cardiovascular disease. Full article

The genus Phanerotoma Wesmael, 1838 (Hymenoptera, Braconidae, Cheloninae, Phane- rotomini) is distributed across all six major zoogeographical regions, with the highest species diversity recorded in the Palaearctic Region. DNA barcoding provides a robust method for species identification, yet its effectiveness for the genus Phanerotoma is limited by the scarcity of reliable, species-level data from specific regions in public databases. This gap makes it essential to contribute comprehensive genetic resources to advance taxonomic research. This study presents a comprehensive COI dataset of 92 sequences for the genus Phanerotoma, employing both the Automatic Barcode Gap Discovery (ABGD) method for species delimitation and the bPTP model for phylogenetic inference. The integrated analytical approach revealed 18 distinct species, including five new species; all species new to science are described and illustrated, and updates of the most recent key to the Chinese species are included. Full article

Schizophrenia is a severe neurodevelopmental disorder with a complex and largely unresolved pathogenesis. Accumulating evidence indicates that mitochondrial dysfunction is a consistent pathological hallmark of schizophrenia, suggesting that impaired mitochondrial homeostasis may represent a convergent mechanism underlying disease vulnerability. BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) is a critical regulator of mitochondrial integrity and apoptosis. However, its role in schizophrenia has not yet been elucidated. Human endogenous retroviruses W family envelope (ERVWE1) has been implicated as a potential risk factor in schizophrenia, but the molecular mechanisms by which it contributes to neuronal pathology remain poorly understood. In this study, we investigated whether ERVWE1 induces mitochondrial dysfunction and neuronal apoptosis through the regulation of BNIP3. Bioinformatic analysis of the public dataset GSE53987 revealed significantly elevated BNIP3 expression in the brain tissues of patients with schizophrenia, accompanied by enrichment of mitochondria-related pathways. Consistently, BNIP3 expression was also increased in the peripheral blood of schizophrenia patients and positively correlated with ERVWE1 levels. Mechanistically, ERVWE1 upregulated BNIP3 expression by suppressing miR-27b-3p, a microRNA that directly targets BNIP3. The resulting increase in BNIP3 led to marked mitochondrial structural and functional impairment, characterized by reduced mitochondrial aspect ratio, enhanced mitochondria permeability transition pore (mPTP) opening, and decreased mitochondrial DNA (mtDNA) copy number. These mitochondrial defects subsequently triggered cytochrome c release into the cytosol, activating the intrinsic mitochondrial apoptotic pathway. Collectively, this study provides the first evidence that the ERVWE1/miR-27b-3p/BNIP3 axis contributes to mitochondrial dysfunction and neuronal apoptosis in schizophrenia. Our findings identify a previously unrecognized molecular pathway linking endogenous retroviral activity to mitochondrial pathology, offering novel insights into the mechanisms and potential therapeutic targets for schizophrenia. Full article

Diabetes mellitus is a major global health burden, and plant-derived polyphenols are increasingly explored as adjuncts for metabolic control. Hence, the hypoglycaemic potential of Pinus nigra bark extract from Serbia was evaluated using complementary in silico and in vivo approaches. Major constituents reported for P. nigra bark (catechin, epicatechin, taxifolin, caffeic, ferulic, p-coumaric, protocatechuic, and syringic acids) were docked against selected metabolic targets (LXRα, LXRβ, PTP1B, and SUR1) as hypothesis-generating screening due to the frequent PAINS behaviour of small polyphenols. For in vivo assessment, normoglycaemic and alloxan-induced diabetic Wistar rats received a 7-day oral treatment with ethanol bark extract (100 mg/kg) alone or combined with metformin (100 mg/kg) or gliclazide (10 mg/kg), and fasting glycaemia, oral glucose tolerance, lipid profile, and body weight were assessed. The ethanol extract reduced glycaemia, improved glucose tolerance, and favourably modulated dyslipidaemia, with additive effects observed in combinations with metformin or gliclazide. These findings suggest activity relevant to hypoglycaemic-relevant activity of P. nigra bark extract in vivo; however, comprehensive chemical profiling, mechanistic confirmation, and safety evaluation are required before translational consideration. Full article

The kelp genus Eisenia Areschoug is represented by two species in the Southeast Pacific: Eisenia cokeri, distributed in Peru and Chile, and E. gracilis, endemic to Peru. However, the taxonomic distinction between these species has long been questioned, and it remains unclear whether E. cokeri is conspecific with the Northeast Pacific species E. arborea. To address these issues, we conducted an integrative taxonomic assessment combining morphological analyses, molecular phylogenetics, and molecular species delimitation approaches. Sampling for morphological and molecular analyses was carried out in subtidal zones at five localities along the Peruvian coast, and an additional locality in Chile was included for molecular analyses where E. cokeri was documented. Peruvian Eisenia species exhibited consistent morphological differentiation, including differences in thallus size, holdfast diameter, stipe modifications (e.g., longitudinal division and pseudostipe formation), frond division, frond margins, and surface roughness, as supported by morphometric analyses. Phylogenetic reconstructions based on mitochondrial and chloroplast markers, together with concordant results from multiple species delimitation methods (ABGD, GMYC, and bPTP), consistently recovered three independent evolutionary lineages corresponding to E. cokeri, E. gracilis, and a distinct lineage of Eisenia from the Desventuradas Islands (Chile). Our results confirm the taxonomic distinctiveness of E. cokeri and E. gracilis, demonstrate that E. cokeri is genetically distinct from E. arborea, and reveal the presence of a previously unrecognized lineage of Eisenia in the Southeast Pacific. These findings refine species boundaries within the genus and provide a robust framework for the management and conservation of these endemic, foundation, habitat-forming species. Full article

Myocardial ischemia represents a state of reduced coronary perfusion with oxygenated blood, insufficient to meet the metabolic demands of the myocardium. Both acute and chronic ischemia trigger a cascade of cellular events that lead to disturbances in ionic balance, mitochondrial function and energy metabolism. During ischemia, cardiomyocytes (CMs) shift from aerobic to anaerobic metabolism, resulting in adenosine triphosphate (ATP) depletion, loss of ionic homeostasis and calcium (Ca²⁺) overload that activate proteases, phospholipases and membrane damage. Reperfusion restores oxygen supply and prevents irreversible necrosis but paradoxically initiates additional injury in marginally viable myocardium. The reoxygenation phase induces excessive production of reactive oxygen species (ROS), endothelial dysfunction and a strong inflammatory response mediated by neutrophils, platelets and cytokines. Mitochondrial dysfunction and opening of the mitochondrial permeability transition pore (mPTP) further amplify oxidative stress and inflammation and trigger apoptosis and necroptosis. Understanding these intertwined cellular and molecular mechanisms remains essential for identifying novel therapeutic targets aimed at reducing reperfusion injury and improving myocardial recovery after ischemic events. Full article

Renal ischemia–reperfusion injury (IRI) is a leading trigger of acute kidney injury (AKI), a syndrome with high incidence and mortality worldwide. The kidney is among the most energy-demanding organs; its mitochondrial content is second only to the heart, rendering renal function highly contingent on mitochondrial integrity. Accumulating evidence places mitochondria at the center of IRI pathogenesis. During ischemia, ATP depletion, ionic disequilibrium, and Ca²⁺ overload set the stage for injury; upon reperfusion, a burst of mitochondrial reactive oxygen species (mtROS), collapse of the mitochondrial membrane potential (ΔΨm), aberrant opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA (mtDNA) damage, and release of mitochondrial damage-associated molecular patterns (mtDAMPs) further amplify inflammation and drive regulated cell-death programs. In recent years, the centrality of mitochondrial bioenergetics, quality control, and immune signaling in IRI-AKI has been increasingly recognized. Building on advances from the past five years, this review synthesizes mechanistic insights into mitochondrial dysfunction in renal IRI and surveys mitochondria-targeted therapeutic strategies—including antioxidant defenses, reinforcement of mitochondrial quality control (biogenesis, dynamics, mitophagy), and modulation of mtDAMP sensing—with the aim of informing future translational efforts in AKI. Full article

Deep reinforcement learning (DRL) with self-play has emerged as a promising paradigm for solving combinatorial optimization (CO) problems. The recently proposed Gumbel AlphaZero Plan-to-Play (GAZ PTP) framework adopts a competitive training setup between a learning agent and an opponent to tackle classical CO tasks such as the Traveling Salesman Problem (TSP). However, in complex and multi-constrained environments like the Electric Vehicle Routing Problem (EVRP), standard self-play often suffers from opponent mismatch: when the opponent is either too weak or too strong, the resulting learning signal becomes ineffective. To address this challenge, we introduce Two-Stage Self-Play GAZ PTP (TSS GAZ PTP), a novel DRL method designed to maintain adaptive and effective learning pressure throughout the training process. In the first stage, the learning agent, guided by Gumbel Monte Carlo Tree Search (MCTS), competes against a greedy opponent that follows the best historical policy. As training progresses, the framework transitions to a second stage in which both agents employ Gumbel MCTS, thereby establishing a dynamically balanced competitive environment that encourages continuous strategy refinement. The primary objective of this work is to develop a robust self-play mechanism capable of handling the high-dimensional constraints inherent in real-world routing problems. We first validate our approach on the TSP, a benchmark used in the original GAZ PTP study, and then extend it to the multi-constrained EVRP, which incorporates practical limitations including battery capacity, time windows, vehicle load limits, and charging infrastructure availability. The experimental results show that TSS GAZ PTP consistently outperforms existing DRL methods, with particularly notable improvements on large-scale instances. Full article