Search Results (8,138)

Natural products (NPs) have historically provided the foundational scaffolds for drug development, yet traditional bioprospecting faces critical limitations: high rediscovery rates, laborious isolation workflows, and substantial attrition during clinical translation. The emergence of big data technologies is fundamentally transforming this landscape, enabling a shift from serendipity-based discovery toward systematic, data-driven approaches. This review examines how the integration of artificial intelligence (AI), machine learning (ML), and multi-omics datasets is accelerating natural product research across three key domains: (1) genome mining for biosynthetic gene cluster identification using platforms such as antiSMASH, (2) cheminformatics-driven prediction of structure–activity relationships and ADMET properties, and (3) metabolomics-guided dereplication to prioritize novel bioactive scaffolds. We evaluate the convergence of genomics, metabolomics, and computational chemistry in enabling in silico lead optimization and the discovery of cryptic metabolites from previously inaccessible microbial taxa. While challenges in data standardization and scalability persist, the synergy between big data and NP research is accelerating clinical translation. Despite persistent challenges in data standardization, scalability, and equitable benefit-sharing, the convergence of big data and NP research is poised to redefine drug development. These advances position computational NP research as a cornerstone of next-generation drug development. Full article

Virtual vitality has become an important complementary dimension for describing urban vitality; however, the identification and formation mechanisms of its stable, high-vitality state during dynamic change remain insufficiently explored. Taking five urban districts of Harbin as the study area, this study uses TikTok short-video data from July to August 2024 (summer) and December 2024 to January 2025 (winter), together with Gaode Map POI data, as the core dataset. Kernel density differences between adjacent weeks are used to measure the dynamic changes in virtual vitality. Bivariate local spatial autocorrelation is applied to identify high-vitality stable zones, and a Random Forest model is employed to examine the nonlinear influence of physical vitality spatial structures. The results show the following: (1) Dynamic change patterns of virtual vitality differ significantly across seasons, and when online attention content points to specific physical spatial structures, a stable high-vitality state is more likely to be maintained. (2) Bivariate local spatial autocorrelation analysis indicates that high-vitality stable zones (HH zones) exhibit significant spatial clustering, with vitality-enhancing zones (LH zones) distributed around them and showing spillover effects, while vitality-declining zones (HL zones) are more scattered. (3) The Random Forest results show that the stable maintenance of high virtual vitality depends more on combinations of spatial structural characteristics with high recognizability, among which distance to activity center (tourism), functional composition dissimilarity (culture), and functional composition dissimilarity (shopping) have the strongest influence. These findings reveal a nonlinear relationship between the stable high-vitality state and the structure of physical vitality space, providing insights for guiding online attention to support physical spatial development. Full article

Elaeocarpus sylvestris (Lour.) Poir., an evergreen tree native to East and Southeast Asia, has gained increasing scientific attention owing to its broad pharmacological properties. Traditionally used in East Asian medicine to treat inflammation, fever, and infectious diseases, modern research has revealed diverse bioactivities, including potent antioxidant, anti-inflammatory, antiviral, anticancer, antidiabetic, and immunomodulatory effects. This therapeutic potential is primarily attributed to its rich phytochemical composition, particularly polyphenols such as geraniin, 1,2,3,4,6-penta-O-galloyl-β-D-glucose and quercetin. This review particularly focuses on the chemistry of E. sylvestris, summarizing structurally elucidated compounds, including hydrolysable tannins, flavonoids, and triterpenoids, along with recent insights into the structure–activity relationships that underpin these antiviral, antioxidant, and anticancer activities. Recent studies have demonstrated substantial antiviral efficacy of E. sylvestris extracts and isolated compounds against major human pathogens, including herpesviruses, influenza A virus, and SARS-CoV-2, supported by in silico, in vitro, in vivo, and early-phase clinical evaluations. Its cosmeceutical applications, including antioxidant, skin-whitening, and blue-light protective effects, further highlight its multifunctional potential. To our knowledge, this is the first comprehensive review summarizing the phytochemistry, pharmacological activities, therapeutic potential, and cosmeceutical applications of E. sylvestris. Despite these promising findings, challenges remain in elucidating precise molecular mechanisms, pharmacokinetics, and clinical validation. This review identifies current research gaps and future directions necessary to advance E. sylvestris as a scientifically validated natural therapeutic resource. Full article

Oxidative stress generates oxidized phospholipids (OxPLs) that alter membrane structure and inflammatory lipid signaling, yet the underlying biophysical mechanisms remain poorly understood. Here, we examine how two structurally distinct truncated oxidized phosphatidylcholines (OxPCs), 1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC), remodel membrane lateral organization and regulate secretory phospholipase A₂ (sPLA₂) activity. Large unilamellar vesicles composed of sphingomyelin, cholesterol, and either monounsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) or polyunsaturated 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (PDPC) were used to reconstitute the liquid-ordered/liquid-disordered (L_o/L_d) phase coexistence characteristic of eukaryotic plasma membranes. Fluorescence spectroscopy revealed that OxPLs modulate lipid packing and nanodomain organization in a structure- and composition-dependent manner. POVPC promoted pronounced membrane ordering and L_o domain stabilization compared with PGPC, particularly in monounsaturated membranes with low cholesterol content. In contrast, PDPC-containing membranes, especially at elevated cholesterol, exhibited enhanced structural resilience to OxPL-induced perturbations. These biophysical changes were associated with distinct functional outcomes. Notably, the relationship between membrane structural parameters and sPLA₂ activity was not linear, indicating a decoupling between bulk membrane properties and enzymatic response. sPLA₂ activity was linked to membrane lateral organization: the size of L_o domains modulate hydrolysis by influencing the physicochemical properties of L_o/L_d interfaces, which may represent preferential sites for enzyme activation. Consistent with this, POVPC reduced sPLA₂ activity through stabilization of ordered domains at both low and high cholesterol, while PGPC enhanced hydrolysis at high cholesterol. Importantly, PDPC-containing membranes attenuated sPLA₂ activity and exhibited a protective effect against OxPC-induced enzymatic activation. Together, these findings identify membrane lateral organization as a key regulator of sPLA₂ function and provide mechanistic insight into how oxidative stress can differentially modulate inflammatory lipid signaling depending on membrane composition. This work highlights membrane organization as an active determinant of enzyme activity and a potential target in pathologies associated with oxidative stress, including atherosclerosis, neuroinflammation, and metabolic disease. Full article

Digital government is widely regarded as a catalyst for sustainable development, yet the mechanisms by which e-government adoption translates into progress on the SDGs remain poorly understood, particularly in high-income contexts where governance is already mature. This study addresses that gap using a balanced panel of all 27 EU member states over 2015–2023. Applying two-way fixed-effects estimation with formal Baron–Kenny mediation and country-block bootstrap inference, we identify three findings that collectively reframe the relationship between digital government and sustainable development in the European context. First, the widely assumed governance reform pathway is not empirically supported in the EU27: e-government adoption is not associated with measurable improvement in institutional quality, consistent with structural saturation rather than policy failure. Second, the benefits of digital government are unevenly distributed across the EU: old member states (EU15) exhibit significant positive effects on SDG 9: Innovation and Infrastructure, whereas new member states (EU13) do not, challenging the assumption that digital strategies yield symmetric returns across the Union. Third, and most importantly, the EU15 effect appears to be fully channelled through household internet access, consistent with a digital co-investment mechanism in which e-government uptake and broadband infrastructure co-evolve as expressions of a shared national digital transformation strategy. These findings inform the policy debate: the question for EU15 is not whether to invest in e-government, but how to sustain the joint infrastructure investment that makes it effective; for EU13, the priority is to establish the digital and institutional foundations that enable the mechanism to be activated. Full article

Cardiac and hemodynamic conditions such as myocardial infarct, cardiomyopathy, hypertension, and aortic valve disease can impair conduction within the Purkinje fiber network and compromise left ventricular (LV) pump function. We developed a computational framework that couples electrical propagation in a structurally organized Purkinje fiber network with LV electromechanics to analyze the impact of conduction abnormalities on cardiac performance. A baseline simulation reproduced physiological activation patterns and pump indices consistent with healthy human data. Conduction block was then introduced at different locations within the Purkinje fiber network. LV pump function was strongly dependent on block location: left bundle branch block (LBBB) produced the largest reduction in ejection fraction (EF) (59% to 46%) and peak pressure (119 to 97 mmHg), whereas left anterior fascicle block caused smaller functional changes. Across simulations, myocardial activation delay and systolic dyssynchrony index (SDI) exhibited a nonlinear relationship with EF and myocardial strain. A threshold behavior was identified at a simulated LV activation duration of approximately 240 ms and an SDI of 8.4%, beyond which EF and strain decreased by about 5% relative to baseline. These findings provide a mechanistic framework to investigate how Purkinje fiber network conduction abnormalities influence LV pump dysfunction. Full article

Background/Objectives: Protein kinases play a crucial role in cancer initiation, progression, and therapeutic resistance by regulating signalling pathways involved in tumour growth and survival. Consequently, they represent major targets in anticancer drug discovery. Among heterocyclic scaffolds explored in kinase inhibitor design, benzimidazole has emerged as a privileged structure due to its strong hydrogen-bonding capability and structural resemblance to purine moieties. Triazole motifs are also widely incorporated into bioactive molecules because of their metabolic stability, favourable electronic properties, and ability to establish key interactions within kinase active sites. This review aims to summarise and critically discuss benzimidazole- and triazole-based kinase inhibitors, both as individual scaffolds and as hybrid systems, with emphasis on their kinase targets and multitarget potential. Methods: The relevant literature was surveyed from major scientific databases focusing on studies describing the synthesis, biological evaluation, and molecular modelling of benzimidazole- and triazole-containing kinase inhibitors. Results: Numerous studies demonstrate that both benzimidazole and triazole scaffolds exhibit significant kinase inhibitory activity against oncogenic targets, including EGFR, cyclin-dependent kinases (CDKs), and components of the PI3K/Akt/mTOR signalling pathway. Hybrid molecules combining these pharmacophores frequently enhance binding interactions and facilitate the development of multitarget kinase inhibitors. Structure–activity relationship trends indicate that pharmacophore accessibility, substitution patterns, and linker architecture influence inhibitory potency and selectivity. Conclusions: Overall, benzimidazole- and triazole-based scaffolds represent promising platforms for developing next-generation multitarget anticancer agents and provide valuable insights for the rational design of improved kinase inhibitors. Full article

Background: Organic cation transporter 2 (OCT2) mediates the renal uptake of cisplatin and is a principal contributor to its dose-limiting nephrotoxicity. Despite reports of OCT2 inhibition by various phytochemicals, the structure–activity relationships (SARs) governing inhibition and their functional implications remain poorly understood. Methods: We systematically evaluated OCT2 inhibitory activity across a structurally diverse library of 146 phytochemicals, including anthraquinones, flavanols, stilbenes, and isoflavones, using Madin–Darby canine kidney (MDCK) cells stably overexpressing OCT2. Structure–activity relationships were analyzed using non-parametric statistics and multivariate logistic regression, and functional relevance was assessed via cisplatin-induced cytotoxicity assays. Results: Inhibitory activity varied widely across the library, with potent inhibitors identified across multiple chemical scaffolds. Non-parametric statistical analyses revealed no significant differences in overall activity distributions among scaffold classes. Notably, chemical substituent patterns, rather than core scaffold identity, were the primary drivers of OCT2 inhibitory potency. Methoxylation was consistently associated with enhanced OCT2 inhibition, particularly within isoflavones, although its impact varied across structural scaffolds. The selected OCT2 inhibitors markedly reduced cisplatin-mediated cell death in OCT2-expressing cells but not in mock-transfected controls, confirming an OCT2-dependent mechanism of protection. Conclusions: This study establishes a structure-guided framework linking phytochemical OCT2 inhibition to nephroprotective potential and identifies methoxylation as a major determinant of OCT2-targeted intervention strategies. Full article

Marine biofouling remains a major challenge for maritime industries, affecting submerged structures and vessels worldwide. The long-standing reliance on biocidal coatings, together with their documented environmental impacts, has led to increasingly restrictive regulations and an urgent demand for environmentally compatible antifouling (AF) solutions. This study evaluates the AF potential and toxicological profile of two nucleoside analogues, hypoxanthine arabinoside (1′) and 2′-deoxyinosine (2′), selected based on the previously reported non-lethal AF activity of the naturally occurring nucleosides adenosine and 2′-deoxyadenosine from cyanobacteria. Both analogues inhibited the growth of Navicula sp. by approximately 60% without inducing mortality and significantly reduced settlement of Mytilus galloprovincialis plantigrades, with EC₅₀ values of 5.50 µM (1′) and 8.54 µM (2′), and no lethality detected (LC₅₀ > 200 µM). At near-EC₅₀ concentrations, both compounds increased acetylcholinesterase and tyrosinase activities, supported by molecular docking results, suggesting involvement of neurotransmission- and byssal formation-related pathways. Proteomic analysis revealed compound-specific molecular responses. No lethal effects were observed in non-target organisms (LC₅₀ > 32 µM for A. amphitrite and LC₅₀ > 50 µM for A. salina), and environmental fate modelling predicted low bioaccumulation and rapid degradation. Overall, substitution of the amino group by a carbonyl group preserved AF efficacy without increasing toxicity, highlighting nucleosides as promising low-toxicity AF agents. Full article

This study develops a semiparametric causal inference framework to quantify the effect of Artificial Intelligence (AI) adoption on enterprise labor structure under high-dimensional confounding. We employ the Double Machine Learning (DML) estimator proposed , which combines Neyman orthogonality and cross-fitting to achieve reliable causal identification in settings where conventional regression methods are prone to bias from high-dimensional controls and nonlinear confounding. Nuisance functions are estimated using Lasso and Random Forests, enabling flexible modeling of complex relationships between control variables and outcomes. Using an unbalanced panel of Chinese A-share listed companies spanning 2006 to 2023, we identify a significant positive average treatment effect of AI adoption on the share of high-skilled labor (estimate: 0.118; 95% CI: [0.073, 0.163]), indicating that complementarity between AI and skilled workers dominates substitution at the firm level. Heterogeneity analysis reveals that the effect is stronger in manufacturing (0.183) than in services (0.071), and more pronounced in Eastern China (0.142) than in Central and Western regions (0.079). Quantile regression further shows that the complementarity effect intensifies at higher skill quantiles. A Panel Smooth Transition Regression (PSTR) model identifies a digitalization threshold beyond which AI–skill complementarity further strengthens. Mediation analysis confirms that productivity enhancement, digital transformation, and innovation activities together account for the majority of the total effect, with productivity improvement alone contributing approximately 34%. Placebo tests and propensity score weighting validate the robustness of our findings. Full article

Well-defined, small-molecule, platinum-centered coordination compounds are of continued interest in both basic and applied research, particularly in medicinal chemistry and pharmaceuticals (i.e., cisplatin). Organoplatinum(IV) complexes have been reported to exhibit substantial in vitro cytotoxicity across a range of cancer cell lines. Compared with coordinatively unsaturated platinum(II) species, electronically and coordinatively saturated platinum(IV) complexes are generally more inert, reducing undesirable side reactions in plasma and cellular environments and potentially improving their safety profiles as chemotherapeutic agents. In addition, the presence of organic ligands can enhance lipophilicity, facilitating passive diffusion across cell membranes. Here, we report the synthesis, structural characterization, and in vitro anticancer activity of a series of organoplatinum(IV) complexes of the general formula Pt(CH₃)₂I₂{n,n′-dimethyl-2,2′-bipyridine} (n,n′ = 4,4′; 5,5′; 6,6′). The 5,5′- and 6,6′-dimethyl isomers were characterized by single-crystal X-ray diffraction. All three dimethyl-substituted complexes, along with the parent compound, Pt(CH₃)₂I₂{2,2′-bipyridine}, were evaluated for cytotoxic activity against a panel of 60 human cancer cell lines. Whereas Pt(CH₃)₂I₂{2,2′-bipyridine} and the 4,4′- and 5,5′-dimethyl derivatives displayed limited cytotoxicity, the 6,6′-dimethyl isomer exhibited notable activity, particularly against the colon cancer cell line HCT-116 (LC₅₀ = 8.17 μM) and the ovarian cancer cell line OVCAR-3 (LC₅₀ = 7.34 μM). The enhanced cytotoxicity of the 6,6′-dimethyl derivative is attributed, at least in part, to the relatively facile dissociation of the 6,6′-dimethyl-2,2′-bipyridine ligand from the platinum(IV) center, suggesting that sterically induced ligand lability plays an important role in modulating biological activity in this particular compound, giving new structural activity impetus for potential drug molecules. Full article

Background/Objectives: Police officers are exposed to chronic occupational stress and traumatic events, placing them at increased risk for mental health problems. Previous meta-analyses have been limited by heterogeneous samples and methodological variability. This study evaluated the effectiveness of psychological interventions on mental health and posttraumatic stress disorder (PTSD) symptoms among police officers using randomized controlled trials (RCTs). Methods: A systematic search of PubMed, Embase, Web of Science, PsycINFO, and MEDLINE was conducted for studies published between January 2000 and September 2025. The search strategy utilized key terms including “police officers,” “psychological interventions,” “mental health,” and “randomized controlled trials”. Only RCTs involving police officers were included. Psychological interventions were compared with waitlist, usual-care, or active control conditions. General mental health outcomes (depression, anxiety, and stress) were analyzed as the primary outcome, and PTSD symptoms as a secondary outcome. Effect sizes were calculated as Hedges’s g using random-effects models. Subgroup, meta-regression, sensitivity, and publication bias analyses were conducted when appropriate. Results: Ten RCTs comprising 637 police officers met the inclusion criteria. Psychological interventions demonstrated moderate improvements in overall mental health (Hedges’s g = 0.516, 95% CI = 0.296–0.735, p < 0.001), albeit with substantial heterogeneity. Comparable effects were observed across waitlist and usual-care/active control comparisons. For PTSD symptoms, significant improvements were found only in comparisons with waitlist controls, whereas the overall pooled effect was not statistically significant. Meta-regression showed no dose–response relationship between total intervention hours and treatment effects. Sensitivity analyses confirmed result robustness. The certainty of evidence was rated as moderate for general mental health and low for PTSD symptoms, primarily due to substantial inconsistency and imprecision. Conclusions: These findings suggest that structured psychological programs show potential to confer added benefits for general mental health beyond routine wellness activities, although the certainty of the evidence is moderate to low. In contrast, the evidence for PTSD symptoms remains inconclusive, with effects failing to reach robust statistical significance. This underscores that preliminary individual-level intervention may be insufficient for trauma-specific symptoms, necessitating further research into specialized, trauma-focused approaches and the role of organizational determinants in enhancing intervention efficacy. Full article

Background/Objectives: Lipid nanoparticles (LNPs) containing ionizable lipids represent the most advanced non-viral delivery vehicles and have become state-of-the-art carriers for RNA therapeutics. However, further improvements in endosomal escape efficiency and biodegradability are still needed, especially for nucleic acids with transient activity such as messenger RNA (mRNA) and transfer RNA (tRNA). Methods: In this study, a novel library of highly biodegradable ionizable lipids featuring thioester groups within the linker region was designed and synthesized, thereby expanding the chemical linker toolbox for future ionizable lipid development. Results: Comprehensive in vivo structure–activity relationship studies led to the identification of CP-LC-1272 as a lead candidate that markedly enhances endosomal escape and exhibits superior in vivo biodegradability, attributed to the high acid-lability of thioester bonds. LNPs containing CP-LC-1272 maintained in vivo activity after six months of storage in lyophilized form and demonstrated superior in vivo efficiency compared to SM-102 in mRNA expression studies, as well as similar protein restoration in a tRNA delivery model targeting premature stop-codon mutations. Conclusions: The rapid biodegradability of these thioester-activated ionizable lipids (TAILs) suggests a reduced risk of accumulation, with the potential to enable safe repeated dosing or high-dosage RNA therapies, positioning TAILs as a versatile and safe platform for next-generation RNA therapeutics. Full article

As the key enzyme catalyzing the final step in heme and chlorophyll biosynthesis, protoporphyrinogen oxidase (PPO) is a crucial target for herbicide development. To date, over 40 PPO inhibitors have been commercialized. They offer high efficacy, environmental safety, low application rates, and broad-spectrum weed control. Recently, significant progress has been made in PPO structural biology, with several crystal structures resolved. Despite decades of use, the emergence of resistant weeds necessitates the continuous innovation of novel PPO inhibitors. This review systematically summarizes PPO three-dimensional structures, enzyme-inhibitor interaction mechanisms, and quantitative structure–activity relationships (QSARs). Finally, we outline rational molecular design strategies for the next generation of PPO inhibitors. Full article

Bio-based, biodegradable, and renewable polymers offer a promising alternative to traditional synthetic polymers derived from petroleum or other non-renewable resources. However, their use is limited by suboptimal properties and high costs. Incorporating sustainable reinforcements into the polymer matrix significantly improves biopolymer performance while preserving key properties, sustainability, and cost-effectiveness. Bio-based polymeric composites have emerged as a crucial category of biopolymers, playing a key role in advancing a sustainable, circular economy. This review provides an updated overview of bio-based polymer composites and nanocomposites, focusing on reinforcement strategies using natural nanofillers and engineered nanoparticles. We summarize key synthesis and processing methods, discuss structure–property relationships, and highlight recent advances in applications such as food packaging, biomedical devices, energy systems, environmental remediation, 3D printing, and supercapacitors. Polymer nanocomposites are versatile, with their performance depending on the type, size, and interactions between the fillers and the polymer matrix. Progress in metallic, ceramic, carbon-based, natural, and hybrid fillers has improved their properties. Using bio-based polymers and renewable fillers supports sustainability. Natural nanofillers derived from renewable sources and industrial byproducts offer a sustainable approach to developing high-performance, biodegradable nanocomposites. Smart nanocomposites can react to external stimuli by integrating specialized fillers that enhance their mechanical and mobility properties. Shape memory nanocomposites can be remotely activated—using heat, electricity, magnets, or light—enabling advanced applications. Finally, we address major challenges and outline future directions for scalable, circular-material solutions, drawing on perspectives from the circular economy and life cycle assessment (LCA). Full article