QSAR analysis for some β-carboline derivatives as anti-tumor

Abstractβ-Carboline moieties are important structural subunits which occur as components of many biologically interesting molecules for antitumor activity. Quantitative structure–activity relationship (QSAR) studies have been performed on β-carboline derivatives to explore the structural necessities for antitumor activity. 3D QSAR studies were done using V-Life Sciences MDS 3.0 drug designing module to explain the structural requirements for the anti-tumor activity. The 3D-QSAR was performed using the Step Wise K Nearest Neighbour Molecular Field Analysis [(SW) kNN MFA] technique with the partial least-square (PLS) method on a database. Obtained best 3D-QSAR model having high predictive ability with q2=0.743, r2=0.721, pred_r2=0.708 and standard error=0.346, explaining the majority of the variance in the data with partial least square (PLS) components. The results of the present study may be useful on the designing of more potent compounds as antitumor drugs

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Comparison of Technological Options for Distributed Generation-Combined Heat and Power in Rajasthan State of India

Distributed generation (DG) of electricity is expected to become more important in the future electricity generation system. This paper reviews the different technological options available for DG. DG offers a number of potential benefits. The ability to use the waste heat from fuel-operated DG, known as combined heat and power (CHP), offers both reduced costs and significant reductions of CO2 emissions. The overall efficiency of DG-CHP system can approach 90 percent, a significant improvement over the 30 to 35 percent electric grid efficiency and 50 to 90 percent industrial boiler efficiency when separate production is used. The costs of generation of electricity from six key DG-CHP technologies; gas engines, diesel engines, biodiesel CI engines, microturbines, gas turbines, and fuel cells, are calculated. The cost of generation is dependent on the load factor and the discount rate. It is found that annualized life cycle cost (ALCC) of the DG-CHP technologies is approximately half that of the DG technologies without CHP. Considering the ALCC of different DG-CHP technologies, the gas I.C. engine CHP is the most effective for most of the cases but biodiesel CI engine CHP seems to be a promising DG-CHP technology in near future for Rajasthan state due to renewable nature of the fuel

Promising Anticancer Activity of β-Carboline Derivatives: Design, Synthesis, and Pharmacological Evaluation

β-carboline consists of a pyridine ring fused to an indole skeleton; it possesses numerous pharmacological activities, including anticancer. Previously, we reported a satisfactory 2D and 3D QSAR study on β-carboline derivatives. Based on QSAR studies, we designed, synthesized, characterized, and screened fourteen β-carboline derivatives for anticancer activity. Eleven of them demonstrated potent anticancer activity against both liver (HepG2) and adenocarcinoma (A549) cell lines. Compound 1-(N, N-dimethylbenzenamine)-3-(4-(p-tolylmethanimine)-5-thio-1, 2, 4-triazol-3-yl) β-carboline (9) was found to be most potent against both cancer cell lines and equipotent towards standard drug Adriamycin. Compounds 1-(p-tolyl)-3-(4-(p-(iminomethyl)-N, N-dimethylbenzenamine) -5-thio-1, 2, 4-triazol-3-yl) β-carboline (4) and 1-(N, N-dimethylbenzenamine)-3-(4-(m-tolylmethanimine)-5-thio-1, 2, 4-triazol-3-yl) β-carboline (10) were found to be 7 to 10 times less potent as compared to Adriamycin against the HepG2 cell line. Molecular docking was also performed with the Glide docking program to explore the binding mode between the synthesized β-carboline derivatives and the receptor CDK2 [1AQ1] protein

Promising Anticancer Activity of β-Carboline Derivatives: Design, Synthesis, and Pharmacological Evaluation

β-carboline consists of a pyridine ring fused to an indole skeleton; it possesses numerous pharmacological activities, including anticancer. Previously, we reported a satisfactory 2D and 3D QSAR study on β-carboline derivatives. Based on QSAR studies, we designed, synthesized, characterized, and screened fourteen β-carboline derivatives for anticancer activity. Eleven of them demonstrated potent anticancer activity against both liver (HepG2) and adenocarcinoma (A549) cell lines. Compound 1-(N, N-dimethylbenzenamine)-3-(4-(p-tolylmethanimine)-5-thio-1, 2, 4-triazol-3-yl) β-carboline (9) was found to be most potent against both cancer cell lines and equipotent towards standard drug Adriamycin. Compounds 1-(p-tolyl)-3-(4-(p-(iminomethyl)-N, N-dimethylbenzenamine) -5-thio-1, 2, 4-triazol-3-yl) β-carboline (4) and 1-(N, N-dimethylbenzenamine)-3-(4-(m-tolylmethanimine)-5-thio-1, 2, 4-triazol-3-yl) β-carboline (10) were found to be 7 to 10 times less potent as compared to Adriamycin against the HepG2 cell line. Molecular docking was also performed with the Glide docking program to explore the binding mode between the synthesized β-carboline derivatives and the receptor CDK2 [1AQ1] protein

Computational analysis of benzyl vinylogous derivatives as potent PDE3B inhibitors

Phosphodiesterases are a diverse family of enzymes that play a key role in regulating intracellular levels of the second messengers cAMP, cGMP and ultimate cell function. Selective PDE3B inhibitors were recognized to prevent oocyte maturation. In search of effective PDE3B inhibitors, the present study deals with 3D QSAR analysis on previously reported benzyl vinylogous derivative. The comparative molecular field analysis (CoMFA) studies resulted in reliable and remarkable computational models. The obtained CoMFA model showed high predictive ability with q2 = 0.556, r2 = 0.936 and standard error of estimation (SEE) = 0.231, explaining a majority of the variance in the data with four principal components. The result of the present study shows good correlation between descriptors and biological activity. On the basis of statistical significance of the generated model the results can be utilized in the design of new more potent benzyl vinylogous derivatives as PDE3B inhibitors

The effect of Mn on the structural and magnetic behaviour of Fe–6Si–8B alloy produced by high energy ball milling

The alloys of Fe–6Si–8B and Fe–6Si–8B–1Mn were prepared using high energy planetary ball mill. X-ray diffraction patterns of the milled samples confirmed the formation of the alloys by dissolution of Si in Fe after 30 and 24 h of milling for the Fe–6Si–8B and Fe–6Si–8B–1Mn samples respectively. The lattice parameter was found to increase continuously with milling time and the rise was steeper for the quaternary alloy. After 36 h of milling, the crystallite size for the two samples were reduced to 98 and 86 nm respectively. Mossbauer spectra suggested the formation of minor amount of α-Fe2O3. The value of saturation magnetization was 162 Am2/kg for Fe–6Si–8B alloy obtained after 18 h of milling. However, the value decreased with increased milling time as well as with Mn-addition. The remanance value showed similar tendency as that for saturation magnetization. In contrast, the coercivity value was found to be increasing with milling time and with Mn-addition

Diffusion Tensor and Dynamic Contrast-Enhanced Magnetic Resonance Imaging Correlate with Molecular Markers of Inflammation in the Synovium

Objectives: It is difficult to capture the severity of synovial inflammation on imaging. Herein we hypothesize that diffusion tensor imaging (DTI) derived metrics may delineate the aggregation of the inflammatory cells and expression of inflammatory cytokines and dynamic contrast-enhanced (DCE) imaging may provide information regarding vascularity in the inflamed synovium. Patients and methods: Patients with knee arthritis (>3-months duration) underwent conventional (T2-weighted fast spin echo and spin echo T1-weighted images) as well as DTI and DCE MRI and thereafter arthroscopic guided synovial biopsy. DCE and DTI metrics were extracted from the masks of the segments of the inflamed synovium which enhanced on post-contrast T1-weighted MRI. These metrics were correlated with immunohistochemistry (IHC) parameters of inflammation on synovium. Statistical analysis: Pearson’s correlation was performed to study the relationship between DTI- and DCE-derived metrics, IHC parameters, and post-contrast signal intensity. Linear regression model was used to predict the values of IHC parameters using various DTI and DCE derived metrics as predictors. Results: There were 80 patients (52 male) with mean age 39.78 years and mean disease duration 19.82 months. Nineteen patients had tuberculosis and the rest had chronic undifferentiated monoarthritis (n = 31), undifferentiated spondyloarthropathy (n = 14), rheumatoid arthritis (n = 6), osteoarthritis (n = 4), reactive arthritis (n = 3), ankylosing spondylitis (n = 2), and juvenile idiopathic arthritis (n = 1). Fractional anisotropy (FA), a metric of DTI, had significant correlation with number of immune cells (r = 0.87, p < 0.01) infiltrating into the synovium and cytokines (IL-1β, r = 0.55, p < 0.01; TNF-α, r = 0.42, p < 0.01) in all patients and also in each group of patients and adhesion molecule expressed on these cells in all patients (CD54, r = 0.51, p < 0.01). DCE parameters significantly correlated with CD34 (blood flow, r = 0.78, p < 0.01; blood volume, r = 0.76, p < 0.01) in each group of patients, a marker of neo-angiogenesis. FA was the best predictor of infiltrating inflammatory cells, adhesion molecule and proinflammatory cytokines. Amongst the DCE parameters, blood volume, was best predictor of CD34. Conclusion: DTI and DCE metrics capture cellular and molecular markers of synovial inflammation in patients with chronic inflammatory arthritis