Computational Studies of Drug Repurposing Targeting P-Glycoprotein-Mediated Multidrug Resistance Phenotypes in Priority Infectious Agents

ABCB1 P-glycoprotein (P-gp) is an ATP-dependent efflux pump with broad substrate specificity associated with cellular drug resistance. Homologous to role in mammalian biology, P-glycoproteins of bacterial and fungal pathogens mediate the emergence of multidrug resistance phenotypes, with widespread clinical/socioeconomic implications. This work aims to characterize P-gp homologues in certain WHO-prioritized infectious agents, namely (1) bacteria: Acinetobacter baumannii and Staphylococcus aureus and (2) fungi: Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. PSI-BLAST searches against the genome of each of these organisms confirmed the presence of P-gp homologues. Each homologue was aligned against five known P-gp structures, for structural modeling. FDA-approved antibiotics used in the current line of therapy were retrieved from PubChem, and potential antibiotics were identified based on similarity and repurposing of the existing drugs. The most tenable target-ligand conformations from docking studies of the respective modeled P-gp structures and the antibiotic ligands were assessed for interacting residues within 4.5 Å of the ligand, probable binding pockets and relative efficacies of the new drugs. Our studies could lay the foundation for the development of effective synergistic or new therapies against these pathogens

Computational Studies of Drug Repurposing Targeting P-Glycoprotein-Mediated Multidrug-Resistance Phenotypes in Agents of Neglected Tropical Diseases

Mammalian ABCB1 P-glycoprotein is an ATP- dependent efflux pump with broad substrate specificity associated with cellular drug resistance. Homologous to this role in mammalian biology, the P-glycoprotein of agents of neglected tropical diseases (NTDs) mediates the emergence of multidrug-resistance phenotypes. The clinical and socioeconomic implications of NTDs are exacerbated by the lack of research interest among Big Pharma for treating such conditions. This work aims to characterise P-gp homologues in certain agents of key NTDs, namely (1) Protozoa: Leishmania major, Trypanosoma cruzi; (2) Helminths: Onchocerca volvulus, Schistosoma mansoni. Based on structural modelling of the organismal P-gp homologues, potential antibiotics targeting these structures were identified based on similarity and repurposing of existing drugs. Docking studies of the Pgp receptor—antibiotic ligand complexes were carried out and the most tenable target-ligand conformations assessed. The interacting residues were identified, and binding pockets studied. The in silico studies yielded measurements of the relative efficacy of the new drugs, which need experimental validation. Our studies could lay the foundation for the development of effective synergistic or new therapies against key neglected tropical diseases. The potential mechanisms of multidrug resistance emergence in E. coli were examined

An NGO-Implemented Community-Clinic Health Worker Approach to Providing Long-Term Care for Hypertension in a Remote Region of Southern India.

Poor blood pressure control results in tremendous morbidity and mortality in India where the leading cause of death among adults is from coronary heart disease. Despite having little formal education, community health workers (CHWs) are integral to successful public health interventions in India and other low- and middle-income countries that have a shortage of trained health professionals. Training CHWs to screen for and manage chronic hypertension, with support from trained clinicians, offers an excellent opportunity for effecting systemwide change in hypertension-related burden of disease. In this article, we describe the development of a program that trained CHWs between 2014 and 2015 in the tribal region of the Sittilingi Valley in southern India, to identify hypertensive patients in the community, refer them for diagnosis and initial management in a physician-staffed clinic, and provide them with sustained lifestyle interventions and medications over multiple visits. We found that after 2 years, the CHWs had screened 7,176 people over age 18 for hypertension, 1,184 (16.5%) of whom were screened as hypertensive. Of the 1,184 patients screened as hypertensive, 898 (75.8%) had achieved blood pressure control, defined as a systolic blood pressure less than 140 and a diastolic blood pressure less than 90 sustained over 3 consecutive visits. While all of the 24 trained CHWs reported confidence in checking blood pressure with a manual blood pressure cuff, 4 of the 24 CHWs reported occasional difficulty documenting blood pressure values because they were unable to write numbers properly. They compensated by asking other CHWs or members of their community to help with documentation. Our experience and findings suggest that a CHW blood pressure screening system linked to a central clinic can be a promising avenue for improving hypertension control rates in low- and middle-income countries

Mechanism of photoinduced charge transfer at MEH-PPV and titanium dioxide nanoparticle interface

1278-1284In this study, we investigated mechanisms of photoinduced electron transfer from a conjugated polymer (poly(2-methoxy-5-(2-ethylhexyloxy) 1,4-phenylenevinylene (MEH-PPV) to titanium dioxide (TiO2) nanoparticles (acceptor) through steady-state photoluminescence (PL) spectroscopy. Since mixed phase TiO2 has better photocatalytic compared to single phase, it is an efficient charge separation process during photoexcitation of polymer nanocomposites by incorporating the mixed phase TiO2 nanoparticles into the MEH-PPV polymer matrix through in situ polymerization. Structural characterization revealed only physical interaction between the polymer matrix and dispersed nanoparticles. The absorbance spectra of nanocomposites also indicated the absence of ground state complex formation. Luminescence quenching of polymer nanocomposites compared to pristine MEH-PVV signifies the charge transfer taking place at the MEH-PPV/TiO2 interfaces. Thus, the MEH-PPV/ mixed phase TiO2 nanocomposite serves as an active layer for photovoltaic application

CESCProg: a compact prognostic model and nomogram for cervical cancer based on miRNA biomarkers

Cervical squamous cell carcinoma, more commonly cervical cancer, is the fourth common cancer among women worldwide with substantial burden of disease, and less-invasive, reliable and effective methods for its prognosis are necessary today. Micro-RNAs are increasingly recognized as viable alternative biomarkers for direct diagnosis and prognosis of disease conditions, including various cancers. In this work, we addressed the problem of systematically developing an miRNA-based nomogram for the reliable prognosis of cervical cancer. Towards this, we preprocessed public-domain miRNA -omics data from cervical cancer patients, and applied a cascade of filters in the following sequence: (i) differential expression criteria with respect to controls; (ii) significance with univariate survival analysis; (iii) passage through dimensionality reduction algorithms; and (iv) stepwise backward selection with multivariate Cox modeling. This workflow yielded a compact prognostic DEmiR signature of three miRNAs, namely hsa-miR-625-5p, hs-miR-95-3p, and hsa-miR-330-3p, which were used to construct a risk-score model for the classification of cervical cancer patients into high-risk and low-risk groups. The risk-score model was subjected to evaluation on an unseen test dataset, yielding a one-year AUROC of 0.84 and five-year AUROC of 0.71. The model was validated on an out-of-domain, external dataset yielding significantly worse prognosis for high-risk patients. The risk-score was combined with significant features of the clinical profile to establish a predictive prognostic nomogram. Both the miRNA-based risk score model and the integrated nomogram are freely available for academic and not-for-profit use at CESCProg, a web-app (https://apalania.shinyapps.io/cescprog)

<b>BC-Predict</b>: Mining of signal biomarkers and multilevel validation of cascade classifier for early-stage breast cancer subtyping and prognosis <i>-- Supplementary Information</i>

Supplementary material to: Muthamilselvan S, Palaniappan A. BC-Predict: Mining of signal biomarkers and multilevel validation of cascade classifier for early-stage breast cancer subtyping and prognosis (2024). Submitted Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, 613401, India.</p

A 4-compartment model based validation of air displacement plethysmography, dual energy X-ray absorptiometry, skinfold technique & bio-electrical impedance for measuring body fat in Indian adults

Background & objectives: Many methods are available for measuring body fat of an individual, each having its own advantages and limitations. The primary objective of the present study was to validate body fat estimates from individual methods using the 4-compartment (4C) model as reference. The second objective was to obtain estimates of hydration of fat free mass (FFM) using the 4C model. Methods: The body fat of 39 adults (19 men and 20 women) aged 20-40 yr was estimated using air displacement plethysmography (ADP), dual energy X-ray absorptiometry (DEXA), 4-skinfold technique and bio-electrical impedance (BIA). Total body water was estimated using isotope dilution method. Results: All the methods underestimated body fat when compared to 4C model, except for DEXA and the mean difference from the reference was lowest for DEXA and ADP. The precision of the fat mass estimated from 4C model using the propagation of error was 0.25 kg, while the mean hydration factor obtained by the 4C model was found to be 0.74 ± 0.02 in the whole group of men and women. Interpretations & conclusion: The results of the present study suggest that DEXA and ADP methods can provide reasonably accurate estimates of body fat, while skinfold and bio-electrical impedance methods require the use of population specific equations

Frustration Potential of Delinquent Adolescents

Aims: To identify the magnitude of different modes and global frustration, to find out the effect of domicile on level of frustration of delinquent adolescents and normal adolescents. Study Design: Present one was a comparative study to assess frustration potential of delinquent adolescents and normal adolescents. Place and Duration of Study: Sample: Delinquent adolescents (Observation Homes at Bangalore, Mysore, Shimoga and Dharwad cities of Karnataka State) and normal adolescents (Karnatak Public High School, Karnatak College, K E Board School and Basel Mission High School located in Dharwad City of Karnataka State), between August 2005 and September 2007. Methodology: After choosing the Observation Homes the delinquent subjects, those fall within the age group mentioned below, was selected on random method. Even in selecting the normal adolescents the same procedure was followed. The interview method of data collection was used to get more accurate responses by the subjects. Sample: We included 321 subjects comprising of delinquent adolescents and normal adolescents. Their age ranged between 14-18 years. Accordingly the scale suitable for this group was used to assess frustration level. In the delinquent adolescents group the male adolescents who had committed offense and conformed cases of offenses under Indian Penal Code (IPC) were selected. The comparison group of adolescents consisted of normal adolescents without having any delinquent background and studying in 8th grade to II pre-university course. The selected subjects were administered individually with frustration test. After calculating mean and SD for the groups‘t’ analyses were carried out. Results: Out of 321 adolescents, 150 were delinquent adolescents and 171 were normal adolescents. Significant high mean scores (157.17 on global frustration, 40.48 on regression, 39.99 on fixation, 38.53 on resignation, 38.17 on aggression modes of frustration) were found for delinquent adolescents and low mean scores (95.53 on global frustration, 28.36 on regression, 22.89 on fixation, 17.58 on resignation, 26.70 on aggression modes of frustration) for the normal adolescents. ‘t’ analysis revealed significant difference between both the groups and it was found that the delinquent adolescents have high frustration potential. Results related to domicile effect on global frustration revealed that there was no much difference between the rural and the urban delinquent adolescents, the mean scores difference between them were not larger (rural delinquent adolescents 158.52, and urban delinquent adolescents 156.92). ‘t’ analysis revealed non-significant difference between the rural and the urban delinquent adolescents. However, mean scores difference between the rural and the urban normal adolescents were found to be larger (rural normal adolescents 99.26 and urban normal adolescents 91.48). Further, ‘t’ analysis revealed significant higher frustration potential among the rural normal adolescents than the urban normal adolescents. Conclusion: The frustration potential is higher among the delinquent adolescents on global frustration and on different modes than the normal adolescents. Hence psychological counseling in the rehabilitation process should be essential for these adolescents. Irrespective of the domicile, the delinquent adolescents are prone for higher frustration, but among the normal adolescents only the rural adolescents are found to be prone for higher frustration potential