Novel Role of the JAK-STAT Pathway in Mediating the Effects of Atypical Antipsychotics on 5-HT2A Receptor Signaling

The therapeutic benefits of atypical antipsychotics are proposed to be mediated by antagonism and subsequent desensitization of 5-HT2A receptor signaling; however, the mechanisms underlying this desensitization response are not yet understood. We hypothesize that the desensitization of 5-HT2A receptors induced by atypical antipsychotics is dependent on activation of the JAK-STAT pathway. To test this hypothesis, we used a cell line, A1A1v cells, that natively expresses 5-HT2A receptor signaling system, and further confirmed the findings in rats. In A1A1v cells, we confirmed that treatment with both olanzapine and clozapine desensitizes 5-HT2A receptor signaling. Furthermore, olanzapine treatment also increased RGS7 mRNA and protein levels which were dependent on activation of JAK-STAT pathway. Similar results were found with MDL100907, a specific 5HT2A receptor antagonist; RGS7 protein and mRNA levels were increased along with activation of the JAK-STAT pathway, suggesting that antagonism of 5-HT2A receptors is sufficient to induce these changes. In addition, we also found an increase in STAT3 binding to the putative RGS7 promoter region with olanzapine treatment suggesting that the increase in RGS7 expression could be directly mediated by the JAK-STAT pathway. An increase in RGS protein could mediate desensitization of 5-HT2A receptor signaling by its GAP activity. Lastly, inhibition of the JAK-STAT pathway significantly attenuated olanzapine-induced desensitization of 5-HT2A receptor signaling in A1A1v cells. Similar findings were also observed in rats treated with olanzapine for 7 days. We found a decrease in 5-HT2A receptor-stimulated PLC activity in the frontal cortex which was dependent on activation of JAK-STAT pathway. Consistent with the cell culture data, the olanzapine-induced increase in RGS7 proteins and mRNA levels were dependent on activation of the JAK-STAT pathway. Olanzapine treatment significantly reduced plasma levels of oxytocin, adrenocorticotrophic hormone (ACTH), and corticosterone. Surprisingly, 5-HT2A receptor-stimulated oxytocin and corticosterone levels were also decreased in a dose-dependent manner by the JAK inhibitor whereas ACTH levels were not altered. Further studies are needed to investigate the role of the JAK-STAT pathway in the regulation of hormone levels. Taken together, these results from experiments in cells in culture and in rats suggest that increases in RGS7 expression via increased activation of the JAK-STAT pathway are necessary for antipsychotic-induced desensitization of 5-HT2A receptor signaling

Prediction of Damping in Three-phase Fibre-reinforced Composites

Fibre-reinforced composite materials are considered to comprise three components, i.e., fibre, matrix, and the interphase. The interphase is the part of the matrix placed in the vicinity of fibre surface all along its length and has distinct properties from that of the fibre and the matrix. In the present study, it is assumed that the interphase is homogeneous and isotropic. A 2-D and 3-D finite element modelling (micromechanical modelling) of the three-phase system is conducted to predict the four damping cocfficienrs- longitudinal; transverse, longitudinal shear, and transverse shear loss factors. Effect of interphase loss factor in the range 0.002 to 0.500 and the interphase volume fraction on the loss factors have been studied

Embolization of Cyanoacrylate glue in systemic circulation in a case of hepatocellular carcinoma: an autopsy report

We report a case of embolism of the sclerosant dye with subsequent formation of foreign-body giant cell reaction within the veins of pulmonary and portal circulation in an autopsy case of hepatocellular carcinoma developing over an underlying primary biliary cirrhosis

Prediction of morbidity and mortality in middle and old aged surgical patients-comparison of standard scoring system and addition of echocardiography with hemodynamic indices

Background: A prospective study was carried out in our hospital to predict morbidity and mortality in middle and old aged surgical patients by adding echocardiography to standard scoring system with hemodynamic studies.Methods: A total of 50 patients of either sex ranging from 40-70 years of ASA grade 1 & 2 scheduled for various types of noncardiac surgeries were enrolled for the study in our hospital. Patients were divided in two groups according to echocardiographic examinations. The patients with normal echocardiographic values were kept in control group and the patients with abnormal values were kept under study group. The patients in study group were further divided in three groups according to LVEF. Group1-LEVF≥60%, Group2-LVEF≥50-59%, Gr3≥40-49% Tab lorazepam was given to all the patients’ orally prior night of surgery. All the patients were induced with same type inducing agents according to body weight. All the patients were maintained on IPPV by anaesthesia machine with supplemental fentanyl, N2O, O2 and muscle relaxant. SPO2, electrocardiograph (ECG), Non-invasive/invasive blood pressure (BP), Spirometry, Capnography and temperature were monitored. At the end of the research project data’s were compiled systematically and were subjected to statistical analysis using odd’s ratio(OR),95% confidence interval (CI), z value and p value, two statistical software programme were used.Results: Significant difference in the results seen between the three study groups (Gr1, Gr2, Gr3) for perioperative ischemic changes, CHF and arrhythmias.Conclusions: In conclusion preoperative TTE before non-cardiac surgery can predict the risk of perioperative cardiac complications in known or suspected cases of cardiac disease patients.

Genome-wide analysis of Bkm sequences (GATA repeats): predominant association with sex chromosomes and potential role in higher order chromatin organization and function

Motivation: Bkm (Banded krait minor) satellite DNA sequences (GATA repeats) have been shown to be associated with the sex determining chromosomes of various eukaryotes and have been implicated in the evolution and differentiation of sex chromosomes in snakes. The objective of the study is to analyze the GATA repeats of human genome specifically, the Y-chromosome, and other model organisms to understand the possible function and potential role in higher order chromatin organization. Results: Our extensive analysis of GATA repeats in the prokaryotic and eukaryotic genomes, which have been completely sequenced so far, has revealed that GATA repeats are absent in prokaryotes and have been gradually accumulated in higher organisms during the course of evolution. In human, the Y-chromosome has the highest GATA repeat density, which predominantly exists in the Yq centromeric region. Generally, occurrence of repeats in the genomes decreases steadily as the length of the repeat increases. In contrast, we report, that the occurrence of GATA repeats increases as the length of the repeat increases from six tandem repeats onwards and peaks at (GATA)10-12. This has not been observed with any other simple repeat. Distribution of (GATA)10-12 along the chromosome and their close proximity to Matrix Associated Regions (GATA-MAR) suggests that it may be demarking chromatin domains for a coordinated expression of genes residing in these domains

Genome-wide analysis of microsatellite repeats in humans: their abundance and density in specific genomic regions

BACKGROUND: Simple sequence repeats (SSRs) are found in most organisms, and occupy about 3% of the human genome. Although it is becoming clear that such repeats are important in genomic organization and function and may be associated with disease conditions, their systematic analysis has not been reported. This is the first report examining the distribution and density of simple sequence repeats (1-6 base-pairs (bp)) in the entire human genome. RESULTS: The densities of SSRs across the human chromosomes were found to be relatively uniform. However, the overall density of SSR was found to be high in chromosome 19. Triplets and hexamers were more predominant in exonic regions compared to intronic and intergenic regions, except for chromosome Y. Comparison of densities of various SSRs revealed that whereas trimers and pentamers showed a similar pattern (500-1,000 bp/Mb) across the chromosomes, di- tetra- and hexa-nucleotide repeats showed patterns of higher (2,000-3,000 bp/Mb) density. Repeats of the same nucleotide were found to be higher than other repeat types. Repeats of A, AT, AC, AAT, AAC, AAG, AGC, AAAC, AAAT, AAAG, AAGG, AGAT predominate, whereas repeats of C, CG, ACT, ACG, AACC, AACG, AACT, AAGC, AAGT, ACCC, ACCG, ACCT, CCCG and CCGG are rare. CONCLUSIONS: The overall SSR density was comparable in all chromosomes. The density of different repeats, however, showed significant variation. Tri- and hexa-nucleotide repeats are more abundant in exons, whereas other repeats are more abundant in non-coding regions

Detection of substrate binding motifs for morphine biosynthetic pathway intermediates in novel wound inducible (R,S)-reticuline 7-O-methyltransferase of Papaver somniferum

The benzylisoquinoline alkaloids (BIA) comprise a large and diverse group of nitrogen-containing secondary metabolites with about 2500 compounds identified in plants. BIA biosynthesis begins with the condensation of the tyrosine derived precursors dopamine and p-hydroxyphenylacetaldehyde to (S)-norcoclaurine. Subsequent regiospecific O- and N-methylations and aromatic ring hydroxylation lead to (S)-reticuline, which is the central intermediate for almost all BIAs. For morphinan alkaloid biosynthesis, (S)-reticuline undergoes an inversion of stereochemistry to (R)-reticuline, followed by C-C phenol coupling catalyzed by a unique cytochrome P450-dependent monooxygenase to yield salutaridine. The cDNA sequence of enzymes leading to (S)-reticuline, as well as those involved in the conversion of (R)-reticuline to salutaridine-7-O-acetate are already characterized. The inversion of (S)-reticuline to (R)-reticuline represent the important steps in morphine biosynthesis. Wound induced transcript accumulation in Papaver reveals a novel wound inducible EST (NCBI DbEST: GO238757) showing homology with (R,S)-reticuline 7-O-methyltransferase (ID: Q6WUC2) isolated from Papaver somniferum. We compare the substrate binding homology of this novel wound inducible (R,S)-reticuline 7-O-methyltransferase (7-OMT) using template of P. somniferum (Q6WUC2; gb|AAQ01668) as experimental control. Homology modeling with 70% identity & 85% similarity with catalytic site of template protein i.e., (Q6WUC2) short chain dehydrogenase/reductase (SDR), showed docking energy -69.9 and -75.8 kcal/mol with (S)-Reticuline (CID:439653) and (R)-Reticuline (CID:440586) respectively, which are comparable with experimental control binding site interaction energies. Docking of S- & R-reticuline into the active site revealed eight (F(5), E(18), W(24), C(47), F(44), P(45), C(46) and I(47) amino acids presumably responsible for the high substrate specificity of (R,S)-reticuline 7-O-methyltransferase