Search Results (30,666)

Inflammatory and immune alterations are increasingly recognized as components of ALS pathology, yet whether they arise as a direct consequence of TDP-43 dysfunction or as a downstream response to neurodegeneration remains unresolved. To address this question, we profiled adult head transcriptomes of Drosophila lacking TBPH, the fly homolog of TDP-43, and identified marked overactivation of the conserved Toll/Imd/NF-κB (Relish) innate immune pathway, including increased expression of antimicrobial effector genes and inflammatory genes. We further found that TDP-43/TBPH regulates the NF-κB homolog Relish by associating with its mRNA and that its loss permits Relish-dependent immune overactivation. Genetic reduction in Relish in TDP-43-deficient flies suppressed inflammatory signaling and ameliorated neurological defects in vivo, indicating that immune dysregulation contributes to TDP-43 loss-associated phenotypes. Full article

Background/Objectives: Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia, dyslipidemia, and oxidative stress, leading to severe systemic complications. Medicinal plants rich in polyphenolic compounds have gained increasing attention as complementary therapeutic agents. This study aimed to comparatively evaluate the chemical composition, as well as the antidiabetic, hypolipidemic, and antioxidant effects of Polygonum persicaria and Vaccinium myrtillus in a streptozotocin-induced diabetic model. Although Vaccinium myrtillus has been more extensively investigated for its antidiabetic potential, the pharmacological relevance of Polygonum persicaria in diabetes remains insufficiently characterized, particularly in direct comparison with a recognized phytotherapeutic comparator. Methods: Hydroalcoholic tinctures prepared from Polygonum persicaria L. herb and Vaccinium myrtillus L. leaves were subjected to phytochemical analysis using High-Performance Thin-Layer Chromatography (HPTLC) for the identification of flavonoids and phenolcarboxylic acids, alongside spectrophotometric determination of total polyphenol and flavonoid content. Experimental diabetes was induced in CD1 mice by streptozotocin administration. Animals were treated orally for 35 days, and glycemic parameters, lipid profile, body weight, food and water intake, and oxidative stress markers (MDA, SOD, TAC, and GPx) were evaluated. Results: HPTLC/CSS screening indicated the presence of rutin, chlorogenic acid, and caffeic acid in Polygonum persicaria, while Vaccinium myrtillus showed stronger densitometric signals for phenolcarboxylic acid-type compounds, particularly chlorogenic and caffeic acids. Total polyphenol and flavonoid content were also higher in Vaccinium myrtillus (433.89 ± 8.67 mg/L GAE; 154.38 ± 3.08 mg/L QE) compared to Polygonum persicaria (269.28 ± 5.25 mg/L GAE; 132.75 ± 2.65 mg/L QE). Functionally, Vaccinium myrtillus demonstrated a significant antihyperglycemic effect from day 14 (p = 0.009) and improved lipid parameters, while Polygonum persicaria showed a delayed glycemic effect, significant only at day 35 (p = 0.014), without significant hypolipidemic activity. In contrast, Polygonum persicaria exerted a marked antioxidant effect, significantly increasing GPx activity (p = 0.025) and reducing MDA levels (p = 0.053). Conclusions: Vaccinium myrtillus showed stronger antihyperglycemic and hypolipidemic effects, while Polygonum persicaria was mainly associated with antioxidant-related biochemical changes. These differences may be influenced by phytochemical composition, but they cannot be attributed solely to total polyphenol or flavonoid content. Full article

Background: In rodent models of intracranial tumor development, evaluating the actual burden experienced by animals beyond procedural severity is essential for ethical and legal compliance. This study examined whether voluntary wheel running (VWR) could serve as a sensitive indicator of post-surgical burden following subcutaneous transmitter implantation, tumor cell injection, and tumor resection. It also assessed whether VWR supports the detection of humane endpoints. VWR outcomes were compared with body weight, clinical scores, heart rate, and activity levels recorded via telemetry. Methods: Fourteen male BDIX rats were housed individually in cages equipped with a running wheel. Under general anesthesia, telemetric devices to monitor heart rate and activity were subcutaneously implanted. After recovery, glioblastoma BT4Ca cells were stereotaxically injected into the right frontal cortex. Eight days later, the resulting tumors were microsurgically resected. Body weight, VWR, heart rate, and general activity were continuously monitored until the animals reached humane endpoint criteria, indicated by sudden weight loss and clinical deterioration. Results: On average, body weight and VWR declined significantly after all surgical procedures, with tumor resection causing the most pronounced effect. As animals approached the endpoint, a marked drop in these parameters was observed, along with an increased clinical score (p < 0.05). Activity measures supported these findings, though less consistently than weight and VWR. Conclusions: Monitoring body weight and VWR enables an effective assessment of the actual postoperative burden experienced by rats undergoing surgeries of different procedural complexity. Moreover, VWR is a valuable supplementary tool for identifying humane endpoints alongside body weight and clinical scoring. Full article

Selenium (Se) is an essential micronutrient required for redox regulation and metabolic homeostasis. Altered biomarkers of Se status have been linked with obesity and metabolic syndrome, yet its role in these conditions, particularly in a sex-specific context, is not well defined. This study investigated the impact of suboptimal Se intake on metabolic risk profiles in male and female mice with pre-existing diet-induced obesity. C57BL/6N mice were fed either a standard diet with adequate Se (SD-ASe), a Western diet with adequate Se (WD-ASe), or WD-ASe followed by a Western diet containing suboptimal Se levels (WD-SOSe). Metabolic parameters, adipokine profiles, tissue Se distribution, and gene expression in visceral white adipose tissue (vWAT) were assessed. Both sexes exhibited increased weight gain and adiposity in response to a Western diet; however, only males developed hypertension and elevated non-fasted blood glucose levels. Suboptimal Se intake elicited marked sex-dependent effects. In females, it induced elevated non-fasted blood glucose levels and circulating leptin, and further dysregulated circulating adipokine profiles, accompanied by pronounced alterations in selenoprotein expression and redox-related pathways in vWAT. In contrast, male mice exhibited a partial adaptation, including reduced glucose levels and minimal alterations in gene expression. Tissue Se distribution also appeared to be influenced by biological sex. These findings demonstrate that suboptimal Se intake may exacerbate obesity-related metabolic dysfunction in a sex-specific manner, with females showing greater susceptibility, underscoring the importance of micronutrient status and sex differences in metabolic disorders. Full article

Background/Objectives: Ursodeoxycholic acid (UDCA) is a bile acid widely used for the treatment of cholestatic liver diseases; however, its poor aqueous solubility represents a major limitation for the development of oral liquid formulations, particularly in pediatric patients requiring accurate and flexible dosing. This study aimed to develop and characterize a fully solubilized extemporaneous UDCA oral formulation using the ready-to-use vehicle Wagner, with particular emphasis on the role of hydroxypropyl-β-cyclodextrin (HP-β-CD) as a solubilizing excipient. Methods: Phase-solubility studies, Job’s plot analysis, and ¹H NMR spectroscopy were performed to investigate the host–guest interaction between UDCA and HP-β-CD, confirming the formation of a stable 1:1 inclusion complex responsible for a marked increase in drug solubility. The aqueous solubility of UDCA increased from approximately 0.02 mg/mL in water to 31 ± 1 mg/mL in the Wagner base containing HP-β-CD, compared to ~10 mg/mL in the corresponding cyclodextrin-free vehicle. Chemical stability was evaluated using an HPLC method adapted from the European Pharmacopoeia, employing dual detection (refractive index and photodiode array detector) to ensure specificity and stability-indicating capability. Results: The UDCA solution (20 mg/mL) remained chemically stable for at least 4 months under refrigerated (4–8 °C) and room temperature (25 °C) conditions, with only moderate degradation observed at 40 °C. Physical stability studies confirmed the absence of precipitation, phase separation, or significant pH variations under all storage conditions. Conclusions: Wagner-based formulation enabled the development of a stable and homogeneous UDCA oral solution, providing a complementary formulation strategy to conventional suspension-based preparations. This approach represents a robust and patient-oriented strategy for extemporaneous compounding, particularly suitable for pediatric use. Full article

Background/Objectives: The toxic side effects and resistance-associated limitations of conventional chemotherapeutic agents necessitate the development of more effective and selective combination strategies incorporating naturally derived compounds. In this study, the cytotoxic, apoptotic, oxidative stress-associated, and immunomodulatory effects of thymoquinone (TQ), a bioactive compound derived from Nigella sativa, and docetaxel (Dos), a taxane-based chemotherapeutic agent, were investigated alone and in combination in OVCAR3 ovarian cancer cells using integrated two-dimensional (2D) and three-dimensional (3D) experimental models. Materials and Methods: Cell viability was evaluated following treatment with TQ (10–500 µM), Dos (1–500 nM), and the TQ + Dos combination, and synergistic interactions were assessed by IC₅₀⁻ and combination index-based analyses. Apoptosis and cell cycle distribution were analyzed by flow cytometry. Cytokine levels were determined using ELISA, whereas apoptosis- and cell cycle-associated gene expression profiles were evaluated by RT-qPCR. Active caspase-3 expression was assessed by immunocytochemistry. Intracellular reactive oxygen species (ROS) accumulation was examined using DCFH-DA-based fluorescence imaging and antioxidant rescue experiments using N-acetyl-L-cysteine (NAC). In addition, the antitumor activity of the combination was further evaluated in OVCAR3-derived 3D tumor spheroid models using spheroid morphology, ATP-based viability, and live/dead fluorescence imaging analyses. Results: The TQ + Dos combination demonstrated enhanced cytotoxic and apoptotic activity in OVCAR3 cells compared with single-agent treatments and induced marked G2/M cell cycle arrest. Combination treatment increased pro-apoptotic gene expression and was associated with reduced expression of anti-apoptotic markers and modulated inflammatory cytokine profiles. Fluorescence-based analyses demonstrated marked intracellular ROS accumulation following TQ + Dos treatment, whereas NAC pretreatment partially attenuated oxidative stress and restored viability, suggesting partial involvement of ROS-associated mechanisms in treatment-induced cytotoxicity. Importantly, the combination maintained stronger cytotoxic and growth-inhibitory effects than either monotherapy in 3D ovarian cancer spheroids, where combination treatment induced pronounced spheroid shrinkage, viability loss, and structural disruption. Relatively lower toxicity observed in HaCaT cells suggested partial selectivity toward cancer cells. Conclusions: Collectively, these in vitro findings suggest that the TQ + Dos combination produces greater cytotoxic, apoptotic, and growth-inhibitory effects than either agent alone in ovarian cancer models and is associated with alterations in apoptosis-, cell cycle-, and oxidative stress-related responses. The observation of these effects in 3D spheroid models supports further investigation of this combination in more advanced preclinical systems. Full article

From the perspective of process, time may be viewed as that which marks the occurrence of change, as previously proposed by this author. In contrast, spatial distinctions may be viewed as enabling the individuation and counting of events generated by processes. Following a conceptual discussion of Whitehead’s process theory, temporal distinctions, and spatial distinctions, a formal model of spacetime as history is presented based upon process actionsas generators of spacetime, and a new geometric concept of `thereness’ is introduced. Each process action propagates information to the next generation (time) and to a particular `there’ (space). This generates a mixed multigraph where the directed subgraph represents the timelike component (causal propagation of information) and the undirected subgraph represents the spacelike component (informational correlations arising from common causes). A spatial position is an equivalence class of generated events; thus, it is emergent. Each spacetime is local to its generating process, consistent with the concept of local becoming proposed by Arthur. If the set of process actions forms a commutative monoid, then the resulting spacetime takes the form of a discrete lattice. It is speculated that the intransitivity and incompleteness of the spacelike subgraph may be linked to the presence of contextuality. Full article

Machine learning (ML) has substantially advanced text classification by enabling automated understanding and categorization of complex unstructured textual data. However, accurately capturing nuanced linguistic patterns and contextual variations that are inherent in natural language, particularly within consumer complaints, remains a challenge. This study addresses these limitations by incorporating human-experience-trained algorithms that effectively recognize subtle semantic distinctions that are crucial for assessing consumer relief eligibility. Specifically, we propose synthetic data generation methods that leverage generative adversarial networks refined through expert labeling, complemented by featurization approaches for extracting textual representations. By combining expert-trained classifiers with high-quality synthetic data, this research demonstrates marked improvements in ML classifier performance, reduced dataset acquisition costs, and enhanced robustness across evaluation metrics in text classification tasks. Full article

Background/Objectives: Chronic pain is a significant clinical challenge, in part due to the absence of reliable objective biomarkers for its evaluation and treatment. Growing evidence indicates that immune cells, including natural killer (NK) cells, are involved in the regulation of pain processes. NK cells are innate cytotoxic lymphocytes whose functional status may mirror underlying pathological pain states. In this study, we investigated μ-opioid receptor (MOR) expression and functional alterations of NK cells in a murine model of neuropathic pain induced by chronic constriction injury (CCI). Methods: Mice were divided into three groups: Sham (sciatic nerve exposure without ligation), CCI 14-day, and CCI 21-day groups. At the respective time points, animals were sacrificed and spleens were collected for analysis. Splenocytes were isolated by mechanical dissociation followed by centrifugation and erythrocyte lysis. Lymphocytes were analyzed by flow cytometry to evaluate MOR expression in NK cells and their degranulation activity (CD107a assay). Cells were incubated with fluorochrome-conjugated antibodies against NK cell markers (NK1.1, CD3, Ly49A, Ly49C/I) in combination with anti-MOR and anti-Interferon γ antibody (IFN-γ). Immunofluorescence and confocal microscopy analyses were performed to assess MOR localization and granzyme localization, supporting CD107a-mediated degranulation. Results: Flow cytometry analysis revealed a significant reduction in surface MOR expression on total NK cells from CCI mice compared with sham controls at 14 and 21 days post-injury, a finding corroborated by immunofluorescence evidence of MOR cellular internalization. Functionally, CCI induced a marked decrease in CD107a expression and impaired IFN-γ production both under basal conditions and following PMA/ionomycin stimulation, indicating a hyporesponsive state of NK cells. Consistently, confocal microscopy revealed extracellular release of Granzyme A following CCI, suggesting dysregulated degranulation. Conclusions: Neuropathic pain is associated with a remodeling of NK cell phenotype and effector functions, characterized by impaired cytotoxic activity and cytokine production, along with modulation of inhibitory receptor expression. Notably, MOR-reduced surface expression in NK cells emerges as a potential biomarker of neuropathic pain. Further studies are needed to elucidate the molecular mechanisms regulating MOR expression and its relationship with NK cell hyporesponsiveness and degranulation in chronic pain conditions. Full article

This study examines income convergence among EU NUTS-2 regions from 2000 to 2023 using a combination of Phillips-Sul (PS) club convergence methodology, $\beta$-convergence, and spatial econometric models. The results reveal that regional convergence in Europe is heterogeneous and nonlinear: four stable convergence clubs emerge, while overall convergence is rejected. Convergence was faster before 2012 and weakened afterward. A single income threshold and two structural breaks (2005 and 2012) mark shifts in growth dynamics. Spatial models reveal that neighboring regions affect each other’s growth, indicating that regional development in Europe depends on both local conditions and interactions across regions. Full article

Mitochondrial dysfunction in colonic smooth muscle cells (SMCs) is closely associated with impaired gut motility in functional constipation (FC), but the underlying molecular mechanisms remain incompletely understood. The mitochondrial unfolded protein response (UPR^mt) is a critical pathway for maintaining mitochondrial proteostasis, and heat shock factor 1 (HSF1) acts as an important upstream regulator of this response. In the present study, we employed a loperamide-induced FC mouse model, combined with single-cell transcriptomic, molecular, and functional analyses to characterize the HSF1-UPR^mt pathway in colonic SMCs and to investigate its role in FC. Single-cell transcriptomic analysis of colon tissue from FC mice revealed marked downregulation of UPR^mt-associated genes in colonic SMCs. Immunofluorescence, Western blotting, and RT-qPCR analyses of colonic tissue confirmed that HSF1 expression was reduced in colonic SMCs, along with the downregulation of the UPR^mt components, including HSP60, mtHSP70, and LONP1. These molecular changes were accompanied by mitochondrial structural damage, seen by transmission electron microscopy, and by functional impairments, including reduced mitochondrial membrane potential, elevated mtROS production, decreased ATP levels, and diminished activities of respiratory chain complexes I–V. AAV9-mediated overexpression of HSF1 reactivated the UPR^mt pathway, improved mitochondrial function, and ameliorated constipation, whereas shRNA-mediated knockdown of HSF1 further suppressed UPR^mt activity and aggravated mitochondrial damage, indicating that HSF1 bidirectionally regulates this pathway. Complementary experiments in primary colonic SMCs confirmed that this regulatory mechanism operates in a cell-autonomous manner, as modulation of HSF1 expression produced corresponding changes in the UPR^mt pathway, in the expression of mitochondrial respiratory chain complex subunits (ATP5A, NDUFA9, COX1, SDHA, UQCRC1), and in ATP production, mirroring the in vivo findings. Collectively, these results demonstrate that HSF1 plays a pivotal role in maintaining mitochondrial homeostasis in colonic SMCs through regulation of the UPR^mt pathway and that HSF1 dysfunction is closely associated with slowed gut motility in FC. These findings offer a new mechanistic perspective on FC and point to the HSF1–UPR^mt axis as a potential therapeutic target. Full article

Background/Objectives: Graves’ disease (GD) is a prevalent autoimmune thyroid disorder marked by thyrotoxicosis, goiter, and Graves’ orbitopathy (GO). Recent studies highlighted its association with dysbiosis. This systematic review aims to update the current literature and clarify the distinctive microbial signatures and dysbiosis associated with GD/GO. Methods: A systematic search for relevant studies was conducted across multiple databases (2000–2023), employing appropriate keywords. Relevant data were extracted from 25 eligible studies. Results: Microbiota analysis from 19 GD studies (713 patients, 546 controls) and eight GO studies (356 patients, 187 controls), primarily conducted in China (21/25), were examined. The gut microbiota richness and evenness were reduced in GD patients compared to controls in 62.5% of fecal samples. No consistent pattern in alpha diversity was observed in GO. Significant taxonomic divergence was observed between GD/GO and controls. At the phylum level, the Firmicutes to Bacteroidetes ratio was consistently decreased in GD patients (66.7%). Most GO patients also exhibited a similar disequilibrium in their gut and orbital adipose microflora. At the genus level, Prevotella (11 studies), genera within the Lactobacillaceae family (three studies), and Streptococcus (three studies) consistently showed an increase. Genera from the families Lachnospiraceae (nine studies), Ruminococcaceae (six studies), and Veillonellaceae (five studies), as well as the genus Bacteroides (three studies), were decreased. Conclusions: GD/GO-associated dysbiosis is characterized by reduced microbial richness and evenness and alterations in gut phyla balance (↓ Firmicutes, ↑ Bacteroidetes, ↑ Proteobacteria). Specific genera—including Lactobacillus, Prevotella, Bacteroides, and members of the Lachnospiraceae family—may plausibly act as contributors to the onset or progression of GD/GO by influencing the Th17/Treg balance, although their exact roles remain uncertain and largely hypothetical. Systematic review registration: PROSPERO identifier CRD42024512007. Full article

Artificial intelligence has become constitutive of smart city governance, yet data and algorithmic challenges remain analytically separated in existing scholarship, obscuring their recursive coupling and consequences for the built environment. This review synthesises 82 peer-reviewed studies (2020–2025) drawn from a deduplicated corpus of 876 records, combining PRISMA-guided methodology with VOSviewer and CiteSpace bibliometric mapping. Annual output rose from 78 publications in 2020 to 224 in 2024, with ten leading countries contributing roughly 84% of the corpus. The keyword network organises into five thematic clusters spanning AI technical foundations, data governance, algorithmic governance, sustainability, and built-environment governance; emerging 2023–2025 couplings between digital twin and SDG 11, and between generative AI and SDG 11, mark a shifting research frontier, while the algorithmic governance → SDG 16 linkage constitutes the strongest single ribbon in the synthesis. The study advances a double-helix coupling mechanism specifying directional propagation, reverse modulation, and structural cross-linking between data and algorithmic strands, reframing building energy management, digital-twin operation, and smart infrastructure as governance arrangements whose sustainability legitimacy depends on the simultaneous integrity of both strands. Full article

India exhibits substantial variation in neonatal mortality across regions and socioeconomic groups. This study used nationally representative survey data (2019–2021) to examine wealth-based inequalities in neonatal mortality. Socioeconomic disparities were assessed using Erreygers’ Normalized Concentration Index (ECI) and concentration curves, with subgroup analyses by residence, state development status (Empowered Action Group (EAG) vs. non-EAG), district typology, and region. Inequality was further decomposed using the Wagstaff method. Analysis of 176,843 most recent live births revealed marked rural–urban disparities, with neonatal mortality in rural areas (18.3 per 1000 live births) 1.6 times higher than in urban areas (11.5). Neonatal mortality was significantly concentrated among poorer households (ECI: −0.0123; p < 0.001), with greater inequality in urban areas, EAG states, and non-aspirational districts. Regional variation was evident, with the highest inequality in the Western and Central regions. Decomposition analysis showed that inequality was primarily driven by adverse household conditions and maternal risk factors concentrated among poorer populations. Key contributors included unclean cooking fuel, higher parity, large family size, normal delivery and inadequate antenatal care. These findings highlight the need for equality-focused strategies addressing both social determinants and gaps in access to quality maternal and newborn care. Full article

In 2021, the SM9 identity-based cryptographic algorithm became an ISO/IEC international standard, marking a significant advancement in China’s commercial cryptography technology and international standardization capabilities. The SM9 key exchange protocol, a component of the SM9 algorithm suite, provides secure communication by establishing a shared symmetric key between two parties. However, in a group of n users, directly applying this key exchange protocol requires each user to perform O(n) encryption operations and transmit an O(n)-sized ciphertext to ensure confidentiality, which becomes highly inefficient for large groups. To enable efficient secure group communication, we first develop a batch multi-signature algorithm based on SM9, and then we propose a dynamic asymmetric group key agreement (SMDAGKA) protocol based on this method. Our protocol reduces the required encryption operations and ciphertext size to O(1), significantly improving efficiency. Security proofs demonstrate that our scheme achieves a high level of security, and performance analysis shows that it incurs relatively lower computational overhead than related protocols. Full article