Search Results (829)

Land subsidence in soft-soil urban transport hubs arises from the complex coupling of natural geology and intensive anthropogenic activities, yet its spatial differentiation mechanisms and seasonal drivers remain poorly understood in high-development core areas. This study develops a progressive analytical framework integrating Small Baseline Subset Interferometric Synthetic Aperture Radar (SBAS-InSAR), GeoDetector, Gaussian Mixture Model (GMM), and Singular Spectrum Analysis (SSA) to investigate spatiotemporal deformation patterns and driving mechanisms in the Shanghai Hongqiao Transport Hub Core Area from 2015 to 2024 using 209 Sentinel-1A images. Validation against official subsidence contours yields a Pearson correlation coefficient of 0.697 (p < 0.001) and an RMSE of 4.23 mm, confirming good spatial pattern agreement. Urban functional zones and construction stages are identified as the dominant influencing factors, with their interaction exhibiting notable bi-factor enhancement. Six distinct deformation response types are delineated via GMM, and two opposing seasonal signals are distinguished: near-instantaneous precipitation-driven surface loading on shallow soft soil and temperature-driven thermoelastic expansion of built structures. These findings may inform differentiated subsidence management and offer a transferable workflow for analogous soft-soil urban areas. Full article

Introduction: PKMYT1 is a WEE-family G2/M cell cycle checkpoint kinase commonly overexpressed in a broad spectrum of human malignancies. WEE1 exclusively phosphorylates CDK1 at Tyr15, whereas PKMYT1 targets both Thr14 and Tyr15. Unlike WEE1 inhibition, PKMYT1 suppression triggers synthetic lethality with CCNE1. Nearly all disclosed PKMYT1 inhibitors so far fall into structural analogs originating from RP-6306, making the discovery of PKMYT1 inhibitors with chemotypes distinct from RP-6306 crucial. Methods: The compounds were structurally optimized using CADD, synthesized, and characterized by ¹H NMR, ¹³C NMR, HRMS, and HPLC. They were then assessed for kinase binding affinity via the LanthaScreen^TM Eu kinase binding assay, for cellular activity using the CCK-8 assay, and for cell-cycle distribution by flow cytometry, along with investigations into related mechanisms. Results: This study yielded 24 compounds of 2-aminopyrimidine through substituent derivatization of the pyrimidine scaffold. Among these derivatives, MS13 exhibited potent kinase binding affinity against PKMYT1 (IC₅₀ = 0.86 nM) and demonstrated strong anti-proliferative activity against CCNE1 high-amplification OVCAR3 cells and HCC1569 cells (IC_50-OVCAR3 = 1.52 μM, IC_50-HCC1569 = 0.66 μM). Additionally, it showed some selectivity towards A549 and HEK293T cells, with SI values of 4.31 (A549/OVCAR3), 9.92 (A549/HCC1569), 2.04 (HEK293T/OVCAR3), and 4.70 (HEK293T/HCC1569). Compound MS13 dose-dependently suppressed clonogenicity and triggered S-phase cell cycle blockade. Pharmacokinetic studies showed moderate hepatic microsomal stability (t_1/2 = 32.2 min). Molecular dynamics simulations indicated a favorable binding mode between compound MS13 and PKMYT1 (docking score: −9.322 kcal/mol). Conclusions:MS13 is a promising highly potent tool compound that provides a clear direction for the future optimization of PKMYT1 inhibitors. Full article

Carbon dioxide water-alternating-gas (CO₂-WAG) flooding simultaneously enables carbon emission mitigation, improved oil displacement efficiency, and expanded gas sweep coverage. Nevertheless, the field performance of this technology remains significantly constrained by gravity override effects, especially in ultra-thick oil reservoirs. In this work, a synthetic heterogeneous dipping mechanistic reservoir model is constructed. Using a quantitative metric for gravity override index in WAG processes, the variation patterns of gravity override under various operational factors are systematically analyzed. Furthermore, the eXtreme Gradient Boosting (XGBoost) machine learning algorithm is employed to conduct feature importance analysis of the controlling factors, identifying parameters with the most substantial impacts. The results indicate that well spacing, oil production rate, WAG injection strategy, and WAG slug duration all exert pronounced effects on both gravity override index and oil recovery factor. Gravity override is confirmed as the dominant factor governing the production performance of WAG flooding in ultra-thick reservoirs. In addition, an optimal combination of operational parameters exists that counterbalances the adverse effects of gravitational and viscous forces, thereby maximizing gas sweep efficiency, delaying gas breakthrough, and enhancing oil recovery. This study provides valuable insights and technical guidance for gas channeling mitigation, vertical gas sweep improvement, and efficient development of analogous ultra-thick reservoirs. Full article

The progressive integration of Whole Slide Imaging (WSI) technology and Artificial Intelligence (AI) architectures is driving a structural transformation in pathology and precision oncology. This structured critical review analyzes and systematizes the impact of this technological transition along two fundamental operational dimensions of the modern biopharmaceutical industry: pre-registration Clinical Research and post-launch strategies governed by Medical Affairs. The first section explores how computational pathology is improving efficiency and reducing risk in drug development. Replacing analog visual assessment—intrinsically subject to inter-observer and intra-observer variability—with quantitative algorithms for cellular classification and segmentation enables optimization of patient recruitment in clinical trials, reducing screening failure rates. This review also examines the emerging role of Spatial Biology in extracting complex topological metrics from the Tumor Microenvironment (TME) and the use of AI for the objective and auditable quantification of critical surrogate endpoints, such as Pathological Complete Response (pCR), while acknowledging that algorithmic precision remains sensitive to pre-analytical variables and dataset biases. In the second section, the study investigates the strategic evolution of Medical Affairs, acting as a vital scientific communication and translational bridge between the complexity of Data Science and clinical hospital practice. Challenges related to AI adoption by clinicians are examined, emphasizing the importance of educational programs based on Explainable AI (XAI) to overcome the cognitive limitations of the black-box paradigm and the complex regulatory validation pathway for Software as a Medical Device (SaMD) under the stringent European IVDR framework—supported by an analysis of historical regulatory benchmarks such as the Paige Prostate case. The paper also explores the potential of AI in the large-scale generation of Real-World Evidence (RWE), applied to the creation of synthetic control arms in pharmacoeconomic settings. In conclusion, the study highlights that the diagnostic algorithm has ceased to be merely a laboratory support tool and has become a strategic asset and an integral adjunct to therapeutic decision-making. Overcoming current challenges related to data privacy through Federated Learning architectures, together with the imminent transition toward Foundation Models, foreshadows a fully data-driven healthcare ecosystem, making continuous skills development (digital upskilling) an essential requirement for professionals in the biopharmaceutical sector. Full article

Background/Objectives: Synthetic compounds, particularly thiadiazine derivatives with antibacterial properties, have emerged as promising candidates in addressing the growing challenge of bacterial multidrug resistance. Thiadiazine derivatives are six-membered heterocyclic compounds containing two nitrogen atoms and one sulfur atom, exhibiting diverse medical and pharmacological activities. This study aimed to evaluate the potentiating activity of thiadiazine derivatives against multidrug-resistant bacteria. Methods: ADMET (absorption, distribution, metabolism, excretion, and toxicity) assays were performed to assess similarity with more than 370,000 three-dimensional structures of bioactive compounds. The multidrug-resistant bacterial strains Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to investigate both the direct antibacterial activity and the antibiotic-modifying activity of thiadiazine derivatives. Results: The thiadiazine analogs did not exhibit direct antibacterial activity, presenting a minimum inhibitory concentration of 1024 μg/mL. However, they demonstrated a significant antibiotic-modifying effect, potentiating the activity of conventional antibiotics, particularly norfloxacin, against the tested strains. In silico analyses indicated that the analogs predominantly exhibited affinity for G protein-coupled receptors and possessed physicochemical characteristics compatible with potential drug candidates. Conclusions: Although the evaluated thiadiazine derivatives lacked direct antibacterial activity, they significantly enhanced the efficacy of antibiotics against multidrug-resistant bacteria. Combined with their favourable in silico pharmacokinetic and physicochemical profiles, these findings suggest that thiadiazine derivatives may represent promising antibiotic adjuvants for combating multidrug-resistant bacterial infections. Full article

Inflammasomes are central mediators of innate immune defense but can also drive pathological inflammation and pyroptotic cell death in numerous diseases. While several small-molecule inhibitors have been described, many selectively target individual inflammasomes or act through the adaptor protein ASC, leaving ASC-independent pathways unaffected. We previously identified thiomuscimol as a broad-spectrum inflammasome inhibitor that blocks both ASC-dependent and ASC-independent activation, although the structural basis for this activity remains unclear. Here, we examined the structure–activity relationship of thiomuscimol using related compounds and synthetic analogs. In primary macrophages, inflammasome activation and pyroptosis were assessed by live cell imaging of ASC speck formation, gasdermin D-mediated dye uptake, and cellular ATP levels. Structurally related sulfur-containing molecules, including taurine and isothiazole, failed to inhibit inflammasome activation, indicating that neither the sulfur in an electron-rich environment nor the heterocyclic scaffold confer activity. Replacement of the primary amine with a carbonyl group abolished activity, whereas substitution with a secondary amine preserved inhibitory potency comparable to thiomuscimol. Incorporation of the amine into an annulated piperidine ring reduced potency and revealed sensitivity to the precise positioning of the amine within the ring. Together, these findings identify key structural features required for thiomuscimol-mediated inflammasome inhibition and provide a framework for future studies to define its mechanism of action and guide the development of improved inhibitors. Full article

Natural products featuring a direct σ-bond between a cyclic monoterpene and an aromatic moiety provide a vast source of biological activities, such as antimicrobial, anticancer, antiviral, anticoagulant and cannabinoid regulatory, among others. Only few methods exist for synthetically accessing such hybrid structures and their analogs, all of which are prone to limitations, most notably the reliance on sensitive organometallic intermediates and the difficulty in furnishing certain stereoisomers. An efficient, three-stage synthetic methodology is described herein, that enables the production of hybrid structures featuring a C(sp³)-C(sp²) bond between six-membered cyclic monoterpenes and aromatic moieties. This process combines: enol triflate formation from a terpenoid ketone precursor, that introduces most of the stereochemical information; Suzuki–Miyaura C-C cross-coupling of the enol triflate with a pool of (hetero)arylboronic acids, to establish the terpene–aromatic link, initially in the form of a C(sp²)-C(sp²) bond; and a stereoselective hydrogenation of the resulting adducts to afford the target compounds, establishing the stereoconfiguration of the last chiral center. Enantiomeric terpenoid scaffolds derived from menthone and trans-tetrahydrocarvone have been combined with six (6) (hetero)arylboronic acids, including medicinally relevant moieties, such as methoxyphenyl, pyridine, quinoline and benzofuran. The power of this method, apart from circumventing the need for in situ-formed sensitive organometallic intermediates, resides in providing access, for the first time, to menthyl- and trans-tetrahydrocarvoneyl-type stereoisomers, that were unattainable by any previously described method. The resulting compound library members exhibit drug-like features, based on the computational assessment of 11 selected physicochemical parameters (molecular weight, polarity, aqueous solubility, degree of unsaturation, conformational flexibility, lipophilicity, BBB permeability, skin permeability, gastrointestinal absorption, P-glycoprotein substrate behavior and Lipinski compatibility), using the platforms SwissADME, ADMETLab 3.0 and pkCSM. A computational docking study employing AutoDock Vina further identified promising candidates for targeting the known binding sites of human cannabinoid receptors CB1 and CB2, with calculated binding affinities comparable to those of established ligands. Full article

Cadmium (Cd) contamination threatens wheat productivity by impairing growth, redox homeostasis, and metal partitioning. Beneficial fungi and phytohormones improve plant stress tolerance, but the combined role of Trichoderma harzianum and the synthetic strigolactone analog GR24 in wheat Cd tolerance remains unclear. This study evaluated whether co-application of T. harzianum and GR24 enhances Cd tolerance by improving growth, photosynthetic activity, and antioxidant defense, and by reducing Cd accumulation. A greenhouse pot experiment was conducted with two Cd levels (Cd₀ and Cd₁), two GR24 treatments (H₀, without GR24; H₁, 100 mg L⁻¹ GR24), and two T. harzianum treatments (TH₀ and TH₁; 2 g kg⁻¹ soil), using five biological replications. Cd stress markedly inhibited wheat growth, photosynthetic performance, and antioxidant defense while increasing oxidative injury and Cd accumulation in plant tissues. Under Cd stress, the combined GR24-T. harzianum treatment increased shoot growth and biomass by 53.04–80.43%, reduced EL, MDA, and H₂O₂ by 18.70–30.36%, enhanced SOD, POD, and CAT activities by 24.01–44.50%, and lowered Cd concentrations in roots, shoots, and leaves by 41.09–56.19%. These responses strengthen the treatment’s practical relevance. Collectively, these findings indicate that T. harzianum-GR24 co-application offers a promising biological approach to improve wheat resilience and reduce Cd accumulation in wheat tissues. Full article

Antisense oligonucleotides (ASOs) are short, synthetic DNA fragments able to modulate gene expression. In this work, the cytosolic isoform of glucose-6-phosphate dehydrogenase (Cyt-G6PDH) was selected as a target for ASOs to induce transient gene silencing in barley (Hordeum vulgare). G6PDH is the most important enzyme of the oxidative pentose phosphate pathway (OPPP), supplying NADPH and regulating the entire cycle. Different ASOs were tested at different concentrations on the leaf surface. Their effects were evaluated by measuring enzymatic activity, gene expression, and protein abundance. Treatment with 30 µM ASOs for 6 h represented the optimal condition, inducing a 40–60% reduction in G6PDH total activity in barley leaves, with a specific decrease in the cytosolic isoform, as determined by DTT-sensitive enzymatic assays. ASOs designed on the main regulator of cyt-G6PDH, the shaggy-like kinase (SK11), led to an analogous effect in terms of G6PDH activity, confirming the involvement of HvSK11 in the regulation of cyt-G6PDH in barley. Consistently, qRT-PCR analyses showed that ASO treatment simulates an abiotic stress condition obtained by the down-regulation of Cyt-G6PDH. These results support the use of ASOs as a rapid and efficient method for the functional analysis of key metabolic regulators in plants to overcome complications in recalcitrant organisms or lethal genes. Full article

This paper proposes a method of fault detection in analog circuits which involves various steps, including selection of benchmark circuits, dataset preparation, signal decomposition, model training, and performance analysis. The main aim of this work is to provide solid performance even in noisy environments. Monte Carlo analysis is used to generate a synthetic dataset with 200 runs per fault class by introducing component tolerances and realistic faults. A multi-stage pipeline is proposed; it begins with resampling the signals and normalizing them, and then noise is added at different levels: 5 dB, 10 dB and 20 dB. Feature fusion is performed by combining time-, frequency-, and statistical-domain features. Statistical-domain features are extracted by applying Variational Mode Decomposition (VMD) to split them into four IMF levels, followed by the application of Continuous Wavelet Transform (CWT) for time–frequency-domain analysis. Support Vector Machine (SVM), Random Forest, and Gradient Boosting are used as base-level classification models. A stacking ensemble model is developed which uses Random Forest, Gradient Boosting, and Extra Trees as base learners and Logistic Regression as the meta-learner. Full article

The paper gives an overview of new ideas related to the characterization of the structural features of minerals and their synthetic analogs with high ion mobility. The main conditions for fast ionic transport are related to the disorder in the positions occupied by the mobile ions and the presence of conduction channels running inside the structure. Special attention is paid to the principle distinction between solid electrolytes and cathode materials. It is noted that the growing industry of modern electronic devices implies an increase in lithium production. The main mineral sources of this technologically important element are described. Full article

A novel synthetic approach was developed to synthesize 6-methoxy substituted imidazo[1,2-a]pyridine derivatives, with the objective of obtaining analogs of previously identified antileishmanial hit compounds. The nitration of 8-bromo-2-(chloromethyl)-6-methoxyimidazo[1,2-a]pyridine under classical nitric acid/sulfuric acid conditions resulted in selective nitration at position 5 and the corresponding 3,5-dinitrated derivative. The structures of these compounds were established through a combination of experimental methods, including ¹H and ¹³C NMR, HRMS, HSQC, and HMBC experiments. These structural determinations were subsequently confirmed through single-crystal X-ray diffraction. These compounds represent the first examples of 5-nitrated and 3,5-dinitrated 6-methoxyimidazo[1,2-a]pyridines. Full article

To address the issues of high customization, long development cycles, and excessive power/volume in radio frequency (RF) transceiver modules for Synthetic Aperture Radar (SAR) and radar systems, this paper presents an ultra-compact universal RF transceiver module design based on a full application-specific integrated circuit (ASIC) architecture. Centered on a wideband RF System-on-chip (SoC) and a reconfigurable digital SoC, the module integrates the complete RF transceiver chain—including filtering, amplification, mixing, Analog-to-Digital/Digital-to-Analog Converter (ADC/DAC) conversion, digital preprocessing, and high-speed data transmission. Test results demonstrate that the 8-channel module achieves a 53.1% area reduction and 55.1% lower power consumption (only 40.9 W) compared with conventional architectures, while all key RF specifications meet system requirements. The proposed solution improves upon existing limitations in high integration, low power, and generality, offering a low-cost, rapid-development technical route for transceiver modules in radar and communication applications. Full article

Selective insertion of lipid probes from the external milieu into raft regions of the cell membrane would enable targeted studies of raft molecular organization and of raft-associated peptide and glycan components. In this work, we compared the insertion of several synthetic glycolipids into raft and non-raft membrane areas of Raji and EA.hy 926 endothelial cells. A glyco-cholesterol derivative in which the 3β oxygen atom is replaced by NH was selected as a candidate raft-selective probe. Although this glycolipid also inserted into other membrane areas, its raft-to-non-raft distribution ratio was higher than that of its O-analog (natural 3β-O-cholesterol). Full article