Table1.XLSX

<p>Women with endometriosis (EMS) appear to be at a higher risk of developing other autoimmune diseases predominantly multiple sclerosis (MS). Though EMS and MS are evidently diverse in their phenotype, they are linked by a common autoimmune condition or immunodeficiency which could play a role in the expansion of endometriosis and possibly increase the risk of developing MS in women with EMS. However, the common molecular links connecting EMS with MS are still unclear. We conducted a meta-analysis of microarray experiments focused on EMS and MS with their respective controls. The GEO2R web application discovered a total of 711 and 1516 genes that are differentially expressed across the experimental conditions in EMS and MS, respectively with 129 shared DEGs between them. The functional enrichment analysis of DEGs predicts the shared gene expression signatures as well as the overlapping biological processes likely to infer the co-occurrence of EMS with MS. Network based meta-analysis unveiled six interaction networks/crosstalks through overlapping edges between commonly dysregulated pathways of EMS and MS. The PTPN1, ERBB3, and CDH1 were observed to be the highly ranked hub genes connected with disease-related genes of both EMS and MS. Androgen receptor (AR) and nuclear factor-kB p65 (RelA) were observed to be the most enriched transcription factor in the upstream of shared down-regulated and up-regulated genes, respectively. The two disease sample sets compared through crosstalk interactions between shared pathways revealed commonly up- and down-regulated expressions of 10 immunomodulatory proteins as probable linkers between EMS and MS. This study pinpoints the number of shared genes, pathways, protein kinases, and upstream regulators that may help in the development of biomarkers for diagnosis of MS and endometriosis at the same time through improved understanding of shared molecular signatures and crosstalk.</p

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<p>Women with endometriosis (EMS) appear to be at a higher risk of developing other autoimmune diseases predominantly multiple sclerosis (MS). Though EMS and MS are evidently diverse in their phenotype, they are linked by a common autoimmune condition or immunodeficiency which could play a role in the expansion of endometriosis and possibly increase the risk of developing MS in women with EMS. However, the common molecular links connecting EMS with MS are still unclear. We conducted a meta-analysis of microarray experiments focused on EMS and MS with their respective controls. The GEO2R web application discovered a total of 711 and 1516 genes that are differentially expressed across the experimental conditions in EMS and MS, respectively with 129 shared DEGs between them. The functional enrichment analysis of DEGs predicts the shared gene expression signatures as well as the overlapping biological processes likely to infer the co-occurrence of EMS with MS. Network based meta-analysis unveiled six interaction networks/crosstalks through overlapping edges between commonly dysregulated pathways of EMS and MS. The PTPN1, ERBB3, and CDH1 were observed to be the highly ranked hub genes connected with disease-related genes of both EMS and MS. Androgen receptor (AR) and nuclear factor-kB p65 (RelA) were observed to be the most enriched transcription factor in the upstream of shared down-regulated and up-regulated genes, respectively. The two disease sample sets compared through crosstalk interactions between shared pathways revealed commonly up- and down-regulated expressions of 10 immunomodulatory proteins as probable linkers between EMS and MS. This study pinpoints the number of shared genes, pathways, protein kinases, and upstream regulators that may help in the development of biomarkers for diagnosis of MS and endometriosis at the same time through improved understanding of shared molecular signatures and crosstalk.</p

Structure Based <i>In Silico</i> Analysis of Quinolone Resistance in Clinical Isolates of <i>Salmonella</i> Typhi from India

<div><p>Enteric fever is a major cause of morbidity in several parts of the Indian subcontinent. The treatment for typhoid fever majorly includes the fluoroquinolone group of antibiotics. Excessive and indiscriminate use of these antibiotics has led to development of acquired resistance in the causative organism <i>Salmonella</i> Typhi. The resistance towards fluoroquinolones is associated with mutations in the target gene of DNA Gyrase. We have estimated the Minimum Inhibitory Concentration (MIC) of commonly used fluoroquinolone representatives from three generations, ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin, for 100 clinical isolates of <i>Salmonella</i> Typhi from patients in the Indian subcontinent. The MICs have been found to be in the range of 0.032 to 8 μg/ml. The gene encoding DNA Gyrase was subsequently sequenced and point mutations were observed in DNA Gyrase in the quinolone resistance determining region comprising Ser83Phe/Tyr and Asp87Tyr/Gly. The binding ability of these four fluoroquinolones in the quinolone binding pocket of wild type as well as mutant DNA Gyrase was computationally analyzed by molecular docking to assess their differential binding behaviour. This study has revealed that mutations in DNA Gyrase alter the characteristics of the binding pocket resulting in the loss of crucial molecular interactions and consequently decrease the binding affinity of fluoroquinolones with the target protein. The present study assists in understanding the underlying molecular and structural mechanism for decreased fluoroquinolone susceptibility in clinical isolates as a consequence of mutations in DNA Gyrase.</p></div

Wild type and mutant <i>st</i>GyrA.

<p>Model structure of wild type <i>st</i>GyrA (cartoon, green) superimposed on mutants showing side chains in ball and stick to indicate the differences in the wild type and mutant structures at the site of substitution (a) Ser83Phe (cyan), Ser83Tyr (yellow), Asp87Tyr (brick) and (b) Asp87Gly (orange).</p

<i>st</i>DNA-Gyrase Structure.

<p>The homology modeled core complex of <i>st</i>DNA-Gyrase (cartoon, green) superimposed on crystal structure of <i>Staphylococcus aureus</i> (carton, yellow) with the DNA fragment (orange) and fluoroquinolones (sphere, blue). The structure clearly reveals the two-fold symmetry present in the heterodimer and shows the identical binding of the drug molecule in their respective quinolone binding pocket located in each dimer.</p

Surface diagram of wild type and mutant (Arg98Gln) Troponin complex.

<p>(a) model structure of wild type troponin complex, TnI (green) and TnC (wheat) and (b) model structure of mutant (Arg98Gln) TnI (cyan) in troponin complex indicating the side chain of Arg98/Gln98 and interacting residues (ball and stick). Surface potentials are different in wild type and mutant due to the difference of side chain as well as due to flipping of amide group in Gln94.</p

<i>st</i>DNA-Gyrase—ciprofloxacin.

<p>Docked position of ciprofloxacin (ball and stick, grey) in the QBP of <i>st</i>DNA-Gyrase (cartoon) where DNA is drawn in orange, GyrB in yellow (a) wild type GyrA in green and (b) Asp87Gly GyrA mutant in cyan. Ser83 and Asp87/Gly87 are represented in ball and stick in respective colour. Hydrogen bonds are indicated as black dotted lines.</p

Sensogram for the binding of (A) LPS and (C) SA.

<p>(B) and (D) regions corresponding to injection stage.</p

Arg141Gln mutation.

<p>Model structure of troponin complex (cartoon) of (a) wild type, TnI (green), TnT (yellow) and TnC (wheat) and (b) mutant (Arg141Gln) TnI (cyan). The side chain of Arg141/Gln141 and interacting residues (ball and stick) are in respective color. The hydrogen bond interactions are shown as black dotted lines.</p

Potential energy of wild type and mutant troponin I.

<p>Potential energy of wild type and mutant troponin I.</p