Virtual Screening, Molecular Dynamics Simulation, and Bioactivity Assessment Validate T13074 as a Dual-Target EGFR/c-Met Inhibitor.

OBJECTIVES: The objective of this study is to identify dual-target inhibitors against EGFR/c-Met through virtual screening, dynamic simulation, and biological activity evaluation. This endeavor is aimed at overcoming the challenge of drug resistance induced by L858R/T790M mutants. METHODS: Active structures were gathered to construct sets of drug molecules. Next, property filtering was applied to the drug structures within the compound library. Active compounds were then identified through virtual screening and cluster analysis. Subsequently, we conducted MTT antitumor activity evaluation and kinase inhibition assays for the active compounds to identify the most promising candidates. Furthermore, AO staining and JC-1 assays were performed on the selected compounds. Ultimately, the preferred compounds underwent molecular docking and molecular dynamics simulation with the EGFR and c-Met proteins, respectively. RESULT: The IC50 of T13074 was determined as 2.446 µM for EGFRL858R/T790M kinase and 7.401 nM for c-Met kinase, underscoring its potential in overcoming EGFRL858R/T790M resistance. Additionally, T13074 exhibited an IC50 of 1.93 µM on the H1975 cell. Results from AO staining and JC-1 assays indicated that T13074 induced tumor cell apoptosis in a concentration-dependent manner. Notably, the binding energy between T13074 and EGFR protein was found to be -90.329 ± 16.680 kJ/mol, while the binding energy with c-Met protein was -139.935 ± 17.414 kJ/mol. CONCLUSION: T13074 exhibited outstanding antitumor activity both in vivo and in vitro, indicating its potential utility as a dual-target EGFR/c-Met inhibitor. This suggests its promising role in overcoming EGFR resistance induced by the L858R/T790M mutation.

A holistic framework of biochar-augmented cementitious products and general applications: Technical, environmental, and economic evaluation.

In the context of the circular economy, the development of innovative and low-carbon concrete that incorporates different kinds of waste materials is gaining attention among the research community, regulatory agencies, and policymakers. These materials can be incorporated into concrete mixtures as aggregates or as fillers for improvement of product properties. This study aims to identify reliable designs for biochar-augmented cementitious products and general applications through technical, environmental, and economic assessments. The outcomes demonstrate that 5 wt% biochar addition could enhance the compressive strength of the final products. Using biochar, together with other recycled materials, can enormously reduce the environmental impacts, especially for global warming, enabling biochar-augmented cementitious products and general application as carbon-negative resources. The highest GWP reduction reached -720 kg CO2/tonne, equal to a 200% saving. A high quantity of biochar could be included in several specific applications (up to 60 wt%). The economic assessment highlights that the proposed designs are cost-effective and carbon tax can be significantly reduced. Carbon credits can also be earned for some carbon-negative designs. These findings can serve to mitigate GHG emissions and provide decision-makers with a reliable and holistic framework towards the goal of carbon neutrality.

Prediction of Catheter-Associated Urinary Tract Infections Among Neurosurgical Intensive Care Patients: A Decision Tree Analysis.

BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) are the most common device-associated infections in hospitals and can be prevented. To identify the risk factors and develop a risk prediction model for CAUTIs among neurosurgical intensive care unit (NICU) patients. METHODS: All patients admitted to the NICU of a tertiary hospital between January 2019 and January 2020 were enrolled. Two decision tree models were applied to analyze the risk factors associated with CAUTIs in NICU patients. The performance of the decision tree model was evaluated. RESULTS: A total of 537 patients admitted to the NICU with indwelling catheters were recruited for this study. The rate of CAUTIs was 4.44 per 1000 catheter days, and Escherichia coli was the predominant pathogen causing CAUTIs among indwelling catheter patients. The classification and regression tree model displayed good power of prediction (area under the curve : 0.920). Nine CAUTI risk factors (age ≥60 years (P = 0.004), Glasgow Coma Scale score ≤8 (P = 0.009), epilepsy at admission (P = 0.007), admission to the hospital during the summer (P < 0.001), ventilators use (P = 0.007), receiving less than 2 types of antibiotics (P < 0.001), albumin level <35 g/L (P = 0.002), female gender (P = 0.002), and having an indwelling catheter for 7-14 days (P = 0.001) were also identified. CONCLUSION: We developed a novel scoring model for predicting the risk of CAUTIs in patients with neuro-critical illness in daily clinical practice. This model identified several risk factors for CAUTI among NICU patients, novel factors including epilepsy and admission during the summer, can be used to help providers prevent and reduce the risk of CAUTI among vulnerable groups.

Association of childhood threat and deprivation with depressive symptoms and the moderating role of current economic status among middle-aged and older adults in China.

PURPOSE: To investigate the independent impact of threat-related and deprivation-related adverse childhood experiences (ACEs) on depressive symptoms among middle-aged and older adults, and to evaluate the moderating role of current economic status in these associations. METHODS: This cross-sectional study included 11,048 participants aged ≥ 45 years from the China Health and Retirement Longitudinal Study. We captured five threat-related ACEs and five deprivation-related ACEs by questionnaires. Depressive symptoms were assessed using the 10-item Centre for Epidemiological Studies Depression Scale. Current economic status was reflected by annual per capita household consumption expenditure. We performed logistic regression analyses to evaluate the independent association of childhood threat and deprivation with depressive symptoms, and conducted stratified analyses and tests for interaction to explore the moderation effect of current economic status in such associations. RESULTS: Compared with the nonexposed group, the experience of both childhood threat and deprivation were independently associated with greater risks of depressive symptoms later in life (odds ratio [OR] 1.75, 95% CI 1.49-2.05 for ≥ 2 threat-related ACEs; OR 2.02, 95% CI 1.67-2.43 for ≥ 2 deprivation-related ACEs). High current economic status significantly ameliorated the impact of childhood deprivation, but not threat, on depressive symptoms (P value for interaction 0.038). CONCLUSIONS: Both threat-related and deprivation-related ACEs were associated with the risk of depressive symptoms among middle-aged and older adults, while current economic status was a significant moderator in such risks only for childhood deprivation. The findings implied that prioritising targeted interventions for individuals with ACEs, especially for childhood deprivation victims who were economically disadvantaged in adulthood, may help mitigate depressive symptoms in later life.

Predictive Value of Preoperative Prostate Health Index and Serum Testosterone Testing for Biochemical Recurrence after Radical Prostatectomy for Non-Metastatic Prostate Cancer.

OBJECTIVE: To analyse the predictive value of prostate health index (PHI) combined with serum testosterone after radical prostatectomy (RP) for prostate cancer (PCa). METHODS: A total of 132 PCa patients who received RP treatment from January 2016 to December 2019 were selected, retrospectively. And then these patients were divided into biochemical recurrence (BCR) group (n = 51) and non-biochemical recurrence (non-BCR) group (n = 81) based on whether BCR was present after RP. Basic data of PCa patients were collected, and preoperative prostate health index (PHI) and serum testosterone levels were measured in both groups. Logistic regression analysis was used to analyse the influencing factors of BCR after RP. The predictive value of PHI and serum testosterone on BCR after RP was analysed using the receiver operating characteristic (ROC) curve. The Kaplan-Meier method was used to plot survival curves, and log rank test was used to analyse the differences between survival curves. RESULTS: The BCR rate of patients in this study was 38.64% (51/132). Single-factor analysis showed that BCR after RP in PCa patients was associated with prostate-specific antigen (PSA), Gleason score, pathological stage, postoperative adjuvant therapy, testosterone and PHI (p < 0.05). Logistics regression analysis showed that PSA >20 ng/mL, Gleason score (8 scores), pathological stage pT3, increased PHI and increased testosterone were independent risk factors for BCR after RP. ROC curve analysis showed that the area under curve (AUC) of PHI and serum testosterone predicting BCR after RP alone and in combination were 0.769, 0.725 and 0.906, respectively. Kaplan-Meier survival analysis showed that preoperative high PHI and low testosterone are negatively correlated with recurrence-free survival rate. CONCLUSIONS: Preoperative PHI and testosterone can serve as simple prognostic indicators for postoperative BCR in PCa patients undergoing RP. PCa patients with higher PHI levels and lower testosterone levels may be more prone to developing BCR. The combination of PHI and testosterone has a higher value in predicting BCR after RP.

Financial inclusion and its influence on economic-environmental performance: demand and supply perspectives.

In this study, we want to test the impact of financial inclusion on the economic growth and the environmental quality of OBOR economies. We have selected four different proxies of financial inclusion, two from the perspective of the supply side and two from the perspective of the demand side. For empirical analysis, we have applied 2SLS and GMM methods. In the economic growth model, among the variables of financial inclusion, only the variable of ATMS is positively significant in the 2SLS approach; however, when we apply the GMM approach, two variables, i.e., ATMS and branches, are positively significant implying that supply-side financial inclusion is vital for economic growth in OBOR countries. On the other side, the variables of financial inclusion, whether supply side or demand side, exerted a positive impact on the CO2 emissions irrespective of the estimation techniques, i.e., 2SLS and GMM. These findings imply that financial inclusion, in general, causes CO2 emissions to rise.

Big Five Personality, Academic Entrepreneurial Motivation, and Academic Entrepreneurial Intention: A Research Method Based on Fuzzy Set Qualitative Comparative Analysis.

Scholars are the main force behind academic entrepreneurship. The method of how to stimulate scholars' academic entrepreneurial intention and how to further promote social and economic development are important questions for the academic community. Research on the "net effect" of the factors affecting academic entrepreneurial intention has achieved some theoretical results. However, the results that affect academic entrepreneurial intention are complex and not influenced by a single factor, but rather by the interaction between various factors. Therefore, this study used a fuzzy set qualitative comparative analysis research method to explore how various factors can affect scholars' academic entrepreneurial intention from two dimensions: the Big Five personality traits and academic entrepreneurial motivation. Our findings showed two configurations that affect high academic entrepreneurial intention of university scholars: the openness to experience-ribbon-dominant path, and the ribbon-dominant path. Additionally, two configurations were revealed for the formation of not-high academic entrepreneurial intention: extraversion-conscientiousness-inhibition and extraversion-agreeableness-gold-hindrance paths. Moreover, this study revealed that a causal asymmetry exists between the high and the not-high academic entrepreneurial intention configurations. This study broadens the application of the fuzzy set qualitative comparative analysis method in the research of academic entrepreneurial intention and provides theoretical and practical insights for researchers and practitioners on how to effectively stimulate scholars' academic entrepreneurial intention.

CH4 and CO2 Adsorption Mechanism in Kaolinite Slit Nanopores as Studied by the Grand Canonical Monte Carlo Method.

To confirm the rules and transformation conditions of shale gas adsorption and establish a model for evaluating the adsorption capacity of shale gas quantitatively, it is necessary to reveal the shale gas adsorption mechanism. The adsorption mechanism of CH4 and CO2 in Kaolinite slit nanopores has been studied under the simulated conditions of 90 °C and 30 or 50 MPa by the grand canonical Monte Carlo (GCMC) method. The results indicate that CH4 is controlled only by the Van der Waals forces on the mineral surface because CH4 is nonpolar, while CO2 is controlled by both Van der Waals forces and Coulomb forces due to a certain electric quadrupole moment, which makes the adsorption capacity of CO2 on kaolinite greater than that of CH4. Due to the overlapping adsorption potential on the kaolinite surface of micropores (1 nm), the peak of the density profile is higher in the micropores than the peak in the mesopores (4 nm), resulting in the filling effect in the micropores. On the surface of the silicon-oxygen octahedron, the adsorption site for CH4 and CO2 is in the center of the silicone hexagon-ring, and CO2 with a quadrupole moment shifts near the polar oxygen atoms. In contrast, the adsorption sites of CH4 are relatively dispersed on the surface of the aluminum-oxygen octahedron with a hydroxyl group, while the adsorption sites of CO2 are concentrated in the location of the aggregated oxygen atoms. When CH4 and CO2 coexist, CO2 tends to be adsorbed prior to CH4. With the proportion of CO2 increasing, the competitive adsorption effect is gradually aggravated, which suggests the rationality of injecting CO2 to improve the recovery efficiency of shale gas. These findings can provide theoretical support for shale gas exploration and development.

Differentiating Westlake Longjing tea from the first- and second-grade producing regions using ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry-based untargeted metabolomics in combination with chemometrics.

There are numerous articles published for geographical discrimination of tea. However, few research works focused on the authentication and traceability of Westlake Longjing green tea from the first- and second-grade producing regions because the tea trees are planted in a limited growing zone with identical cultivate condition. In this work, a comprehensive analytical strategy was proposed by ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based untargeted metabolomics coupled with chemometrics. The automatic untargeted data analysis strategy was introduced to screen metabolites that expressed significantly among different regions. Chromatographic features of metabolites can be automatically and efficiently extracted and registered. Meanwhile, those that were valuable for geographical origin discrimination were screened based on statistical analysis and contents in samples. Metabolite identification was performed based on high-resolution mass values and tandem mass spectra of screened peaks. Twenty metabolites were identified, based on which the two-way encoding partial least squares discrimination analysis was built for geographical origin prediction. Monte Caro simulation results indicated that prediction accuracy was up to 99%. Our strategy can be applicable for practical applications in the quality control of Westlake Longjing green tea.

A web-based intervention to support increased physical activity among at-risk adults.

Physical inactivity is an important contributor to the development of numerous chronic conditions and alone is an independent risk factor for diabetes, cardiovascular disease, and depression and yet, most Americans consistently fail to achieve the recommended amount of physical activity. As part of Project HealthDesign, we designed and prototyped a personal health record application (PHA) that delivers and supports a highly individualized, behaviorally based lifestyle physical activity intervention for sedentary adults. Through a user centered design approach, we engaged consumers, health care providers, and personal trainers for multiple facilitated group discussions and structured interviews to determine their needs and wants related to an activity PHA. The PHA was developed to include elements of evidence-based approaches which help participants adopt cognitive and behavioral skills such as goal-setting, self-monitoring, accepting social support, cognitive restructuring, contingency management, decisional balance, and relapse prevention. This PHA demonstrated the potential for research-based behavioral interventions to be delivered via a web portal. This finding is important for both consumers and their providers who have the desire to implement physical activity recommendations, but lack the tools to facilitate or undertake such interventions.