STRUCTURAL AND FUNCTIONAL IMPACT OF G2032R MUTATION IN ROS1 – A THEORETICAL PERSPECTIVE

Objective: Drug resistance is an imperative issue in the treatment of patients with lung cancer. In this work, investigation of the drug resistance mechanism of G2032R mutation in ROS1 is carried out using computational simulation techniques.Methods: Molecular docking and molecular dynamics (MD) simulation approach have been utilized to uncover the mechanism behind crizotinib resistance in ROS1 at a molecular level. Normal mode analysis was carried out using ElNemo server which examines the movements and conformational changes in the protein structure. ArgusLab, PEARLS, and Autodock were employed for the docking analysis, whereas GROMACS package 4.5.3 was used for MD simulation approach.Results: The results from our analysis indicates that wild-type ROS1 (Protein Data Bank Code 3ZBF) could be more crucial for the crizotinib binding as it indicates largest binding affinity, minimum number of H-bonds, and higher flexibility than mutant-type ROS1. Moreover, the theoretical basis for the cause of drug insensitivity is the differences in the electrostatic properties of binding site residues between the wild and mutant ROS1 structures. Our analysis theoretically suggests that E-2027 is a key residue responsible for the ROS1 drug selectivity.Conclusion: Molecular docking and MD simulation results provide an explanation of the resistance caused by G2032R and may give a key clue for the drug design to encounter drug resistance.Â

Pneumonitis following diesel fuel siphonage

AbstractPetroleum diesel is a complex mixture of liquid hydrocarbons and mainly used as fuel in transport vehicles. The practice of manual siphoning of diesel from fuel tanks is common in developing countries but hydrocarbon pneumonitis due to diesel siphonage is rarely reported. We report pneumonitis following diesel fuel siphonage in a 30-year-old driver. Initially patient had severe nausea and vomiting followed by chest pain and breathlessness after three days. In our case, induced sputum was diagnostic as against majority of cases where bronchoscopy was used as diagnostic tool. Recovery was complete with medical treatment

The diagnostic utility of cell block as an adjunct to cytological smears

Objectives: Cytological examination of serous fluids is of paramount importance in detecting cancer cells. Distinguishing malignant cells from benign reactive mesothelial cells in fluid cytology is an everyday diagnostic problem. Cell blocks are valuable when the features in cytology are inconclusive. The motive of this study was to assess the utility of this method in increasing the diagnostic yield of serous fluids. Methods: 225 (25%) effusion fluids were analyzed carefully by both smear and cell block technique. Results: Among 225 fluids, 139 were pleural, 84 peritoneal and 2 pericardial. In case of pleural fluids and ascitic fluids, maximum numbers of cases were inflammatory. By the cell block technique, 5 additional cases of malignancy in pleural fluids and 7 additional cases of malignancy in ascitic fluids were diagnosed which could not be detected in the cytological smears. In pericardial fluids both cases were inflammatory. Male predominance was noted in case of pleural effusion and female predominance was noted in case of pericardial effusion and ascites. Maximum numbers of cases were seen in the age group of 40-60 years. Conclusion: We conclude that the cell block technique when used as an adjuvant to routine smear examination has increased the diagnostic yield because of better preservation of the architectural pattern

Targeted Deletion of Neuropeptide Y (NPY) Modulates Experimental Colitis

Neurogenic inflammation plays a major role in the pathogenesis of inflammatory bowel disease (IBD). We examined the role of neuropeptide Y (NPY) and neuronal nitric oxide synthase (nNOS) in modulating colitis.Colitis was induced by administration of dextran sodium sulphate (3% DSS) or streptomycin pre-treated Salmonella typhimurium (S.T.) in wild type (WT) and NPY (NPY(-/-)) knockout mice. Colitis was assessed by clinical score, histological score and myeloperoxidase activity. NPY and nNOS expression was assessed by immunostaining. Oxidative stress was assessed by measuring catalase activity, glutathione and nitrite levels. Colonic motility was assessed by isometric muscle recording in WT and DSS-treated mice.DSS/S.T. induced an increase in enteric neuronal NPY and nNOS expression in WT mice. WT mice were more susceptible to inflammation compared to NPY(-/-) as indicated by higher clinical & histological scores, and myeloperoxidase (MPO) activity (p<0.01). DSS-WT mice had increased nitrite, decreased glutathione (GSH) levels and increased catalase activity indicating more oxidative stress. The lower histological scores, MPO and chemokine KC in S.T.-treated nNOS(-/-) and NPY(-/-)/nNOS(-/-) mice supported the finding that loss of NPY-induced nNOS attenuated inflammation. The inflammation resulted in chronic impairment of colonic motility in DSS-WT mice. NPY -treated rat enteric neurons in vitro exhibited increased nitrite and TNF-alpha production.NPY mediated increase in nNOS is a determinant of oxidative stress and subsequent inflammation. Our study highlights the role of neuronal NPY and nNOS as mediators of inflammatory processes in IBD

Performance and Stability of Pearl Millet Varieties for Grain Yield and Micronutrients in Arid and Semi-Arid Regions of India

Pearl millet [Pennisetum glaucum (L.) R. Br.] is grown under both arid and semi-arid conditions in India, where other cereals are hard to grow. Pearl millet cultivars, hybrids, and OPVs (open pollinated varieties) are tested and released by the All India Coordinated Research Project on Pearl Millet (AICRP-PM) across three zones (A1, A, and B) that are classified based on rainfall pattern. Except in locations with extreme weather conditions, hybrids dominate pearl millet growing areas, which can be attributed to hybrid vigor and the active role of the private sector. The importance of OPVs cannot be ruled out, owing to wider adaptation, lower input cost, and timely seed availability to subsidiary farmers cultivating this crop. This study was conducted to scrutinize the presently used test locations for evaluation of pearl millet OPVs across India, identify the best OPVs across locations, and determine the variation in grain Fe and Zn contents across locations in these regions. Six varieties were evaluated across 20 locations in A1 and A (pooled as A) and B zones along with three common checks and additional three zonal adapted checks in the respective zones during the 2019 rainy season. Recorded data on yield and quality traits were analyzed using genotype main effects and genotype × environment interaction biplot method. The genotype × environment (G × E) interaction was found to be highly significant for all the grain yield and agronomic traits and for both micronutrients (iron and zinc). However, genotypic effect (G) was four (productive tillers) to 49 (grain Fe content) times that of G × E interaction effect for various traits across zones that show the flexibility of OPVs. Ananthapuramu is the ideal test site for selecting pearl millet cultivars effectively for adaptation across India, while Ananthapuramu, Perumallapalle, and Gurugram can also be used as initial testing locations. OPVs MP 599 and MP 600 are identified as ideal genotypes, because they showed higher grain and fodder yields and stability compared with other cultivars. Iron and zinc concentration showed highly significant positive correlation (across environment = 0.83; p < 0.01), indicating possibility of simultaneous effective selection for both traits. Three common checks were found to be significantly low yielders than the test entries or zonal checks in individual zones and across India, indicating the potential of genetic improvement through OPVs

Effect of Antihypertensive Therapy with Alpha Methyldopa on Levels of Angiogenic Factors in Pregnancies with Hypertensive Disorders

Antihypertensive drugs are believed to lower blood pressure in pre-eclampsia by direct or central vasodilatory mechanisms. However, they could also act by decreasing production of anti-angiogenic proteins involved in the pathophysiology of hypertension and proteinuria in pre-eclampsia (PE). The aim of our study was to evaluate the impact of antihypertensive therapy with alpha methyldopa on maternal circulating levels and placental production of soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin (sEng), vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in hypertensive disorders of pregnancy

Assessment of trace metal contamination in a historical freshwater canal (Buckingham Canal), Chennai, India

The present study was done to assess the sources and the major processes controlling the trace metal distribution in sediments of Buckingham Canal. Based on the observed geochemical variations, the sediments are grouped as South Buckingham Canal and North Buckingham Canal sediments (SBC and NBC, respectively). SBC sediments show enrichment in Fe, Ti, Mn, Cr, V, Mo, and As concentrations, while NBC sediments show enrichment in Sn, Cu, Pb, Zn, Ni, and Hg. The calculated Chemical Index of Alteration and Chemical Index of Weathering values for all the sediments are relatively higher than the North American Shale Composite and Upper Continental Crust but similar to Post-Archaean Average Shale, and suggest a source area with moderate weathering. Overall, SBC sediments are highly enriched in Mo, Zn, Cu, and Hg (geoaccumulation index (Igeo) class 4– 6), whereas NBC sediments are enriched in Sn, Cu,Zn, and Hg (Igeo class 4–6). Cu, Ni, and Cr show higher than Effects-Range Median values and hence the biological adverse effect of these metals is 20%; Zn, which accounts for 50%, in the NBC sediments, has a more biological adverse effect than other metalsfound in these sediments. The calculated Igeo, Enrichment Factor, and Contamination Factor values indicate that Mo, Hg, Sn, Cu, and Zn are highly enriched in the Buckingham Canal sediments, suggesting the rapid urban and industrial development of Chennai MetropolitanCity have negatively influenced on the surrounding aquatic ecosystem

Butyrate Transcriptionally Enhances Peptide Transporter PepT1 Expression and Activity

Background: PepT1, an intestinal epithelial apical di/tripeptide transporter, is normally expressed in the small intestine and induced in colon during chronic inflammation. This study aimed at investigating PepT1 regulation by butyrate, a short-chain fatty acid produced by commensal bacteria and accumulated inside inflamed colonocyte. Results: We found that butyrate treatment of human intestinal epithelial Caco2-BBE cells increased human PepT1 (hPepT1) promoter activity in a dose- and time-dependent manner, with maximal activity observed in cells treated with 5 mM butyrate for 24 h. Under this condition, hPepT1 promoter activity, mRNA and protein expression levels were increased as assessed by luciferase assay, real-time RT-PCR and Western blot, respectively. hPepT1 transport activity was accordingly increased by,2.5-fold. Butyrate did not alter hPepT1 mRNA half-life indicating that butyrate acts at the transcriptional level. Molecular analyses revealed that Cdx2 is the most important transcription factor for butyrate-induced increase of hPepT1 expression and activity in Caco2-BBE cells. Butyrate-activated Cdx2 binding to hPepT1 promoter was confirmed by gel shift and chromatin immunoprecipitation. Moreover, Caco2-BBE cells overexpressing Cdx2 exhibited greater hPepT1 expression level than wild-type cells. Finally, treatment of mice with 5 mM butyrate added to drinking water for 24 h increased colonic PepT1 mRNA and protein expression levels, as well as enhanced PepT1 transport activity in colonic apical membranes vesicles