<i>In silico</i> identification of potential drug compound against Peroxisome proliferator-activated receptor-gamma by virtual screening and toxicity studies for the treatment of Diabetic Nephropathy

<p>Diabetic Nephropathy is a serious complication of diabetes mellitus. Current therapeutic strategies of Diabetic Nephropathy are based on control of modifiable risks like hypertension, glucose levels, and dyslipidemia. Peroxisome proliferator activated receptor-gamma (PPAR-γ) is implicated in several metabolic syndromes including Diabetic Nephropathy, besides obesity, insulin insensitivity, dislipidemia, inflammation, and hypertension. In the present study, virtual screening of 617 compounds from two different public databases was done against PPAR-γ with an objective to find a possible lead compound. Two softwares, PyRx and iGEMDOCK, were used to achieve the docking accuracy in order to avoid loss of candidate compounds. Rosiglitazone (used to treat Diabetic Nephropathy) was taken as the standard compound. A total of 30 compounds with good binding affinity with PPAR-γ were selected for further filtering, on the basis of absorption, distribution, metabolism, excretion, and toxicity (ADMET). The interaction profiling of these 30 compounds, showed a minimum of one and maximum of three interactions with reference to rosiglitazone (SER-289, HIS-449, HIS-323, TYR-473). The fulfilling of ADMET analysis criteria of 30 compounds led to the selection of four compounds (ZINC ID 00181552, 00276456, 00298314, 00448009). Molecular dynamics simulation of these lead compounds in complex with PPAR-γ revealed that three of the four compounds formed a stable complex in the ligand-binding pocket of PPAR-γ during 20-ns simulation. Hence, these three (ZINC ID 00181552, 00276456, 00298314) of the four compounds are potential candidates for experimental validation of biological activity against PPAR-γ in future drug discovery studies.</p

Molecular modeling of viral nucleocapsid protein Zn fingers modulators

24-38The relationship between the biological activity and the physicochemical properties of agents is well documented. Using QSAR methodology, three different methods viz. multiple linear regression, partial least square and neural regression analysis were conducted on a series of 71 (sulfonyl) benzene analogs as viral nucleocapsid protein zinc finger modulators for HIV. Neural regression analysis was found to relate the two best. The best nonlinear regression model showed good correlative and predictive ability, r2 (training) =0.97 and r2 (test) =0.892 values. The results obtained from this study indicate the importance of Verloop, Ipso atom E-state index, electrostatic parameters such as dipole moment and electronic parameters such as VAMP polarization and Vamp dipole in determining the activity of viral nucleocapsid protein zinc finger inhibitors

Impact of Work Culture on Motivation and Performance Level of Employees in Private Sector Companies

Work culture has the potential to enhance managerial performance. The objective of the present study is to examine the dominant work culture prevalent in the two private sector manufacturing organizations X and Y and to study its impact on the contextual performance and motivation level of the employees at the middle management level. The statistical tools used to test the hypothesis were the mean, standard deviation, t-test, correlation, one-way ANOVA, and regression. The findings show that the technocratic culture has the strongest partial correlation or the purest relationship with role motivation. Through a regression analysis, the technocratic culture emerges as a strong predictor of motivation while the entrepreneurial culture as a strong predictor for performance. The findings imply that when individuals are satisfied with their roles and feel that their supervisor or leader provides them with support, their contextual performance is expected to increase.Work culture, technocratic culture, role motivation, entrepreneurial culture, dominant culture, contextual performance, bureaucratic culture, autocratic culture

In Silico Analysis of Ion Channels and Their Correlation with Epithelial to Mesenchymal Transition in Breast Cancer

Uncontrolled growth of breast cells due to altered gene expression is a key feature of breast cancer. Alterations in the expression of ion channels lead to variations in cellular activities, thus contributing to attributes of cancer hallmarks. Changes in the expression levels of ion channels were observed as a consequence of EMT. Additionally, ion channels were reported in the activation of EMT and maintenance of a mesenchymal phenotype. Here, to identify altered ion channels in breast cancer patients, differential gene expression and weighted gene co-expression network analyses were performed using transcriptomic data. Protein–protein interactions network analysis was carried out to determine the ion channels interacting with hub EMT-related genes in breast cancer. Thirty-two ion channels were found interacting with twenty-six hub EMT-related genes. The identified ion channels were further correlated with EMT scores, indicating mesenchymal phenotype. Further, the pathway map was generated to represent a snapshot of deregulated cellular processes by altered ion channels and EMT-related genes. Kaplan–Meier five-year survival analysis and Cox regressions indicated the expression of CACNA1B, ANO6, TRPV3, VDAC1 and VDAC2 to be potentially associated with poor survival. Deregulated ion channels correlate with EMT-related genes and have a crucial role in breast cancer-associated tumorigenesis. Most likely, they are potential candidates for the determination of prognosis in patients with breast cancer

Proteomic Signatures of Diffuse and Intestinal Subtypes of Gastric Cancer

Gastric cancer is a leading cause of death from cancer globally. Gastric cancer is classified into intestinal, diffuse and indeterminate subtypes based on histology according to the Laur&eacute;n classification. The intestinal and diffuse subtypes, although different in histology, demographics and outcomes, are still treated in the same fashion. This study was designed to discover proteomic signatures of diffuse and intestinal subtypes. Mass spectrometry-based proteomics using tandem mass tags (TMT)-based multiplexed analysis was used to identify proteins in tumor tissues from patients with diffuse or intestinal gastric cancer with adjacent normal tissue control. A total of 7448 or 4846 proteins were identified from intestinal or diffuse subtype, respectively. This quantitative mass spectrometric analysis defined a proteomic signature of differential expression across the two subtypes, which included gremlin1 (GREM1), bcl-2-associated athanogene 2 (BAG2), olfactomedin 4 (OLFM4), thyroid hormone receptor interacting protein 6 (TRIP6) and melanoma-associated antigen 9 (MAGE-A9) proteins. Although GREM1, BAG2, OLFM4, TRIP6 and MAGE-A9 have all been previously implicated in tumor progression and metastasis, they have not been linked to intestinal or diffuse subtypes of gastric cancer. Using immunohistochemical labelling of a tissue microarray comprising of 124 cases of gastric cancer, we validated the proteomic signature obtained by mass spectrometry in the discovery cohort. Our findings should help investigate the pathogenesis of these gastric cancer subtypes and potentially lead to strategies for early diagnosis and treatment

Factors associated with visual outcomes after cataract surgery: A cross-sectional or retrospective study in Liberia.

OBJECTIVE:To report the initial outcomes and associated risk factors for poor outcome of cataract surgery performed in Liberia. METHODS AND ANALYSIS:LV Prasad Eye Institute (LVPEI), Hyderabad, started providing eye care in Liberia since July 2017. Electronic Medical Records of 573 patients operated for age-related cataract from July 2017 to January 2019 were reviewed. One eye per patient was included for analysis. All patients underwent either phacoemulsification or manual small incision cataract surgery (MSICS). Pre and postoperative uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA) were recorded at one day, 1-3 weeks and 4-11 weeks. Main outcome measure was BCVA at 4-11 weeks; Intraoperative complications and preoperative ocular comorbidities (POC) were noted. BCVA less than 6/12 was classified as visual impairment (VI). Risk factor for VI was analysed using the logistic regression model. RESULTS:Of the 573 patients, 288 were males and 285 were females (49.7%). Mean age was 65.9±10.9 years; 14.3% had POC. The surgical technique was mainly MSICS (94.59%, n = 542). At 4-11 weeks, good outcome of 6/12 or better was noted in 38.55% (UCVA) and 82.54% (BCVA). Visual acuity (VA) of 6/18 or better as UCVA and BCVA was noted in 63.5% and 88% eyes respectively. Poor outcome of less than 6/60 was noted as UCVA (11.11%) and BCVA (5.22%). Multivariable analysis showed poor visual outcomes significantly higher in patients with POC (odds ratio 3.28; 95% CI: 1.70, 6.34). CONCLUSION:The cataract surgical outcomes in Liberia were good; with ocular comorbidities as the only risk factor