Bipolar affective disorder (manic-depressive illness)is a chronic, severe, debilitating illness affecting 1-2% of the population. The Food and Drug Administration-approved drugs lithium and valproate are not completely effective in the treatment of this disorder, and the mechanisms underlying their therapeutic effects have not been established. We are employing genetic and molecular approaches to identify common targets of lithium and valproate in the yeast Saccharomyces cerevisiae. We show that both drugs affect molecular targets in the inositol metabolic pathway. Lithium and valproate cause a decrease in intracellular myo-inositol mass and an increase in expression of both a structural (INO1) and a regulatory (INO2) gene required for inositol biosynthesis. The opi1 mutant, which exhibits constitutive expression of INO1, is more resistant to inhibition of growth by lithium but not by valproate, suggesting that valproate may inhibit the Ino1p-catalyzed synthesis of inositol 1-phosphate. Consistent with this possibility, growth in valproate leads to decreased synthesis of inositol monophosphate. Thus, both lithium and valproate perturb regulation of the inositol biosynthetic pathway, albeit via different mechanisms. This is the first demonstration of increased expression of genes in the inositol biosynthetic pathway by both lithium and valproate. Because inositol is a key regulator of many cellular processes, the effects of lithium and valproate on inositol synthesis have far-reaching implications for predicting genetic determinants of responsiveness and resistance to these agents.Bipolar disorder, or manic-depressive illness, is a common condition with a lifetime prevalence of 1-2% (1). It is characterized by recurring bouts of mania and depression, which have deleterious effects on career and interpersonal relationships. Approximately 15% of those afflicted commit suicide, and mortality rates because of physical disorders are also increased (2, 3). For decades, lithium has been the most effective agent for the treatment of bipolar illness (4). Despite the marked benefit that many patients obtain from lithium therapy, 20 -40% of patients fail to show a satisfactory antimanic response to lithium, and many patients suffer significant morbidity (5). More recently, the branched fatty acid valproate has been used for treatment of bipolar disorder (6). Like lithium, it is not completely effective, and the molecular mechanisms underlying its therapeutic effects have not been elucidated. Lithium and valproate exert a variety of biochemical effects, only some of which are likely to be related to their therapeutic mechanisms of action. Identifying common targets of lithium and valproate is an approach that may more directly address the therapeutic mechanisms underlying their efficacy (7-11).The inositol depletion hypothesis proposes that lithium acts by depletion of inositol from the brain. This is based on the observed uncompetitive inhibition of inositol monophosphatases by lithium, resulting in decreased inositol, an i...

U8 snoRNP is required for accumulation of mature 5.8S and 28S rRNA in vertebrates. We are identifying proteins that bind U8 RNA with high specificity to understand how U8 functions in ribosome biogenesis. Here, we characterize a Xenopus 29 kDa protein (X29), which we previously showed binds U8 RNA with high affinity. X29 and putative homologs in other vertebrates contain a NUDIX domain found in MutT and other nucleotide diphosphatases. Recombinant X29 protein has diphosphatase activity that removes m(7)G and m(227)G caps from U8 and other RNAs in vitro; the putative 29 kDa human homolog also displays this decapping activity. X29 is primarily nucleolar in Xenopus tissue culture cells. We propose that X29 is a member of a conserved family of nuclear decapping proteins that function in regulating the level of U8 snoRNA and other nuclear RNAs with methylated caps.

Aquaculture recently overtook capture fisheries as the largest producer of food fish, but to continue increasing fish production the industry is in search of better methods of improving fish health and growth. Pre- and probiotic supplementation has gained attention as a means of solving these issues, however, for such approaches to be successful, we must first gain a more holistic understanding of the factors influencing the microbial communities present in the intestines of fish. In this study, we characterize the bacterial communities associated with the digestive tract of a highly valuable U.S. aquaculture species, channel catfish Ictalurus punctatus, over the first 193 days of life to evaluate temporal changes that may occur throughout ontogenetic development of the host. Intestinal microbiota were surveyed with high-throughput DNA sequencing of 16S rRNA V4 gene amplicons derived from fish at 3, 65, 125, and 193 days post hatch (dph), while also characterizing the environmental microbes derived from the water supply and the administered diets. Microbial communities inhabiting the intestines of catfish early in life were dynamic, with significant shifts occurring up to 125 dph when the microbiota somewhat stabilized, as shifts were less apparent between 125 to 193 dph. Bacterial phyla present in the gut of catfish throughout ontogeny include Bacteroidetes, Firmicutes, Fusobacteria, and Proteobacteria; with the species Cetobacterium somerae and Plesiomonas shigelloides showing the highest abundance in the catfish microbiota after 3 dph. Comparisons of the gut microbiota to the environmental microbes reveals that the fish gut is maintained as a niche habitat, separate from the overall microbial communities present in diets and water-supply. Although, there is also evidence that the environmental microbiota serves as an inoculum to the fish gut. Our results have implications for future research related to channel catfish biology and culture, and increase our understanding of ontogenetic effects on the microbiota of teleost fish.

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