Periodic catatonia: confirmation of linkage to chromosome 15 and further evidence for genetic heterogeneity

We earlier reported significant evidence for linkage on chromosome 15q15 in periodic catatonia, a sub-phenotype of schizophrenic psychoses. The disorder is characterized by qualitative hyperkinetic and akinetic psychomotor disturbances through acute psychotic episodes and debilitating symptoms in the long term, with psychomotor weakness, grimacing facial movements and apathy. Here, we confirm mapping of a major gene locus on chromosome 15q15 in a second genome scan in a new set of four multiplex families. Non-parametric multipoint linkage analyses identified a broad region with a maximum peak of Z(all) =3.91 ( P=0.006) and Z(lr) =3.04 at D15S1234 ( P=0.001), satisfying conventional criteria for confirmed linkage. Parametric affected-only analyses under an autosomal dominant model gave a maximum HLOD score of 1.65 (D15S1234) with an estimated 47% of families being linked. Analysis of individual families showed that one large family showed linkage, whereas two others could be clearly excluded, confirming genetic heterogeneity. No other locus reached suggestive levels of significance. Haplotype analysis on chromosome 15 in this and previously linked families placed the susceptibility region to a 11-cM interval between marker D15S1042 and D15S659. Periodic catatonia is the first sub-phenotype of schizophrenic psychoses with confirmed linkage despite the existence of considerable genetic heterogeneity.     

Examination of ethanol responsive liver and brain specific gene expression,in the mouse strains with variable ethanol preferences,using cDNA expression arrays

Strains of mice that differ in voluntary alcohol consumption (VAC) are valuable models for the identification of genes involved in the complex etiology of alcohol effects and alcoholism. These mice offer a novel approach to the identification of strain-specific ethanol responsive (SSER) genes in tissues directly involved in alcohol metabolism and preference. We assessed mRNA from the liver and brain from male mice representing C57BL/6J, BALB/c, A/J, and DBA/2J strains following ethanol treatment (chronic ethanol fed liquid diet for 14 days or acute i.p. injection at two doses; 4 g/kg or 8 g/kg), using an expression array containing 588 genes (Clontech #7741-1). The results have identified NADPH cytochrome P450 oxidoreductase, insulin-like growth factor binding protein-1, glutathione S-transferase Mu 1, and cathepsin L as ethanol responsive genes in the liver. Further, we have established that IkB-alpha and clusterin genes in the brain are ethanol responsive, but only at the lower dose of the ethanol challenge. Although a number of other genes showing subtle (<2X) differences across strains and treatment combinations were reproducible in repeated blots, they were not confirmed by still evolving independent technologies of gene specific mRNA quantitation. The results demonstrate that comparative expression studies are an efficient approach to discover interacting gene networks that underlie the etiology of complex phenotypes including response to alcohols.     

Isopestacin,an isobenzofuranone from Pestalotiopsis microspora,possessing antifungal and antioxidant activities

Isopestacin is an isobenzofuranone obtained from the endophytic fungus Pestalotiopsis microspora. While a few other isobenzofuranones are known from natural sources, isopestacin is the only one having a substituted benzene ring attached at the C-3 position of the furanone ring. The compound was isolated from culture broths of the fungus and crystallized and its structure was determined by X-ray crystallography. Both proton and carbon NMR spectral assignments are also reported for isopestacin. This compound possesses antifungal activity and, as measured by electron spin resonance specroscopy, it also behaves as an antioxidant scavenging both superoxide and hydroxy free radicals.     

Interaction of benzoquinone- and hydroquinone-derivatives of lower chlorinated biphenyls with DNA and nucleotides in vitro

Commercial polychlorinated biphenyls (PCBs) are complete carcinogens in rodents, however, their initiating (DNA damaging) activity has not been conclusively demonstrated. In the present study, we reacted synthetic 2-phenyl-1,4-benzoquinones (BQ) and 2-phenyl-1,4-hydroquinones (HQ) of 2-chloro-, 3-chloro-, 4-chloro-, 3,4-dichloro-, and 3,4,5-trichlorobiphenyls with calf thymus DNA and individual deoxynucleoside-3'-monophosphates for 4 h at 37 degrees C. Analysis of DNA adducts resulting from BQ and HQ derivatives of the test congeners by 32P-postlabeling showed essentially similar adduct patterns. However, the adduct pattern and reactivity differed with the congener used. Quantitatively, 2-chloro-BQ/HQ produced in the highest DNA adduct levels and 3,4,5-chloro-BQ/HQ was the least reactive. Chromatographic comparison of DNA and nucleotide adducts derived from 4-chloro-BQ revealed that cytosine, adenine, and thymidine in the DNA accounted for most of the DNA adducts. Interestingly, none of the adducts in DNA were guanine-derived, even though this mononucleotide was highly reactive. These results suggest that both BQ and HQ derivatives of PCBs are capable of covalently binding to DNA, and chromatographic similarity in adduct patterns resulting from these two metabolites suggest possible involvement of intermediary semiquinone radicals. Experiments are underway to determine their in vivo significance.     

Biscoumarin: new class of urease inhibitors; economical synthesis and activity

A variety of biscoumarins (1-21) with variable substituents at C-11 were synthesized with an improved method and evaluated as urease inhibitors. The synthesized compounds showed varying degree of urease inhibitory activity ranging from 15.06-91.35 microM. The size and electron donating or withdrawing effects of substituents influenced the activity, which lead to the urease inhibitors.     

Mechanisms of type-I interferon signal transduction

Interferons regulate a number of biological functions including control of cell proliferation, generation of antiviral activities and immumodulation in human cells. Studies by several investigators have identified a number of cellular signaling cascades that are activated during engagement of interferon receptors. The activation of multiple signaling cascades by the interferon receptors appears to be critical for the generation of interferon-mediated biological functions and immune surveillance. The present review summarizes the existing knowledge on the multiple signaling cascades activated by Type I interferons. Recent developments in this research area are emphasized and the implications of these new discoveries on our understanding of interferon actions are discussed.     

Small GTP binding protein Ras contributes to norepinephrine-induced mitogenesis of vascular smooth muscle cells(1)

Norepinephrine stimulates release of arachidonic acid from tissue lipids. Arachidonic acid metabolites generated through the lipoxygenase and cytochrome P-450 pathways but not cyclooxygenase stimulate mitogen activated protein (MAP) kinase activity and proliferation of vascular smooth muscle cells (VSMC). Moreover, norepinephrine has been shown to activate the Ras/MAP kinase pathway through generation of cytochrome P-450 metabolite of arachidonic acid, 20-hydroxyeicosatetraenoic acid (20-HETE). The purpose of this study was to investigate the contribution of Ras in norepinephrine-induced mitogenesis in aortic VSMC. Farnesylation of Ras by farnesyl transferase is required for its full activation. Norepinephrine-induced DNA synthesis, as measured by [(3)H]-thymidine incorporation, was attenuated by inhibitors of Ras farnesyl transferase FPT III and BMS-191563. These agents also inhibited 20-HETE-stimulated [(3)H]-thymidine incorporation. In cells transiently transfected with dominant negative Ras (RasN17), norepinephrine, and 20-HETE-induced proliferation of VSMC was attenuated. Both norepinephrine and 20-HETE increased localization of Ras to plasma membrane and MAP kinase activity; FPT III attenuated these effects. These data suggest that VSMC proliferation induced by norepinephrine and 20-HETE is mediated by Ras/MAP kinase pathway.     

Role of Melatonin in Inducing the Physiological and Biochemical Processes Associated with Heat Stress Tolerance in Tall Fescue (Festuca arundinaceous)

Journal of Plant Growth Regulation - Melatonin is a ubiquitous molecule having versatile physiological functions in an organism that has protective roles against biotic and abiotic stresses. Heat...     

Impact of Cigarette Smoke Condensate on Adhesion-Related Traits and Hemolysin Production of Oral Candida dubliniensis Isolates

Mycopathologia - Cigarette smoke is associated with higher oral Candida carriage and possible predisposition and increased susceptibility to oral candidal infection. Candida dubliniensis is...