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Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology is poorly understood. We hypothesized that the circadian clock within the cardiomyocyte influences diurnal variations in myocardial biology. We, therefore, generated a cardiomyocyte-specific circadian clock mutant (CCM) mouse to test this hypothesis. At 12 wk of age, CCM mice exhibit normal myocardial contractile function in vivo, as assessed by echocardiography. Radiotelemetry studies reveal attenuation of heart rate diurnal variations and hradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted in CCM hearts perfused ex vivo in the working mode, highlighting the intrinsic nature of this phenotype. Wild-type, but not CCM, hearts exhibited a marked diurnal variation in responsiveness to an elevation in workload (80 mmHg plus 1[micro]M epinephrine) ex vivo, with a greater increase in cardiac power and efficiency during the dark (active) phase vs. the light (inactive) phase. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, whereas cardiac efficiency was decreased, in CCM hearts. These observations were associated with no alterations in mitochondrial content or structure and modest mitochondrial dysfunction in CCM hearts. Gene expression microarray analysis identified 548 and 176 genes in atria and ventricles, respectively, whose normal diurnal expression patterns were altered in CCM mice. These studies suggest that the cardiomyocyte circadian clock influences myocardial contractile function, metabolism, and gene expression. bradycardia; carbohydrate; chronobiology; epinephrine; fatty acids

Multiple extracardiac stimuli, such as workload and circulating nutrients (e.g., fatty acids), known to influence myocardial metabolism and contractile function exhibit marked circadian rhythms. The aim of the present study was to investigate whether the rat heart exhibits circadian rhythms in its responsiveness to changes in workload and/or fatty acid (oleate) availability. Thus, hearts were isolated from male Wistar rats (housed during a 12:12-h light-dark cycle: lights on at 9 AM) at 9 AM, 3 PM, 9 PM, and 3 AM and perfused in the working mode ex vivo with 5 mM glucose plus either 0.4 or 0.8 mM oleate. Following 20-min perfusion at normal workload (i.e., 100 cm [H.sub.2]O afterload), hearts were challenged with increased workload (140 cm [H.sub.2]O afterload plus 1 [micro]M epinephrine). In the presence of 0.4 mM oleate, myocardial metabolism exhibited a marked circadian rhythm, with decreased rates of glucose oxidation, increased rates of lactate release, decreased glycogenolysis capacity, and increased channeling of oleate into nonoxidative pathways during the light phase. Rat hearts also exhibited a modest circadian rhythm in responsiveness to the workload challenge when perfused in the presence of 0.4 mM oleate, with increased myocardial oxygen consumption at the dark-to-light phase transition. However, rat hearts perfused in the presence of 0.8 mM oleate exhibited a markedly blunted contractile function response to the workload challenge during the light phase. In conclusion, these studies expose marked circadian rhythmicities in myocardial oxidative and nonoxidative metabolism as well as responsiveness of the rat heart to changes in workload and fatty acid availability. fatty acids; glucose; glycogen; triglyceride

The biological effect of curcumin in Schwann cells of Trembler-J (Tr-J) mice as well as its potential use for selected forms of inherited peripheral neuropathies is evaluated. It is concluded that curcumin treatment partially mitigates the clinical and neuropathologic phenotype of Tr-J mice by relieving the toxic effect of the mutant peripheral myelin protein 22 gene.

Background Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive dysfunction. Caused by an expanded polyglutamine tract in ataxin 1 (ATXN1), SCA1 [...]

The molecular assays of 35 subjects with dup(17)(p11.2p11.2) are reported. Phenotypic characterization of this microduplication syndrome shows mental retardation, autistic features and structural cardiovascular anomalies.

Circadian clocks are intracellular molecular mechanisms that allow the cell to anticipate the time of day. We have previously reported that the intact rat heart expresses the major components of the circadian clock, of which its rhythmic expression in vivo is consistent with the operation of a fully functional clock mechanism. The present study exposes oscillations of circadian clock genes [brain and arylhydrocarbon receptor nuclear translocator-like protein 1 (bmal1), reverse strand of the c-erba[alpha] gene (rev-erba[alpha]), period 2 (per2), albumin D-element binding protein (dbp)] for isolated adult rat cardiomyocytes in culture. Acute (2 h) and/or chronic (continuous) treatment of cardiomyocytes with FCS (50% and 2.5%, respectively) results in rhythmic expression of circadian clock genes with periodicities of 20-24 h. In contrast, cardiomyocytes cultured in the absence of serum exhibit dramatically dampened oscillations in bmal1 and dbp only. Zeitgebers (timekeepers) are factors that influence the timing of the circadian clock. Glucose, which has been previously shown to reactivate circadian clock gene oscillations in fibroblasts, has no effect on the expression of circadian clock genes in adult rat cardiomyocytes, either in the absence or presence of serum. Exposure of adult rat cardiomyocytes to the sympathetic neurotransmitter norephinephrine (10 [micro]M) for 2 h reinitiates rhythmic expression of circadian clock genes in a serum-independent manner. Oscillations in circadian clock genes were associated with 24-h oscillations in the metabolic genes pyruvate dehydrogenase kinase 4 (pdk4) and uncoupling protein 3 (ucp3). In conclusion, these data suggest that the circadian clock operates within the myocytes of the heart and that this molecular mechanism persists under standard cell culture conditions (i.e., 2.5% serum). Furthermore, our data suggest that norepinephrine, unlike glucose, influences the timing of the circadian clock within the heart and that the circadian clock may be a novel mechanism regulating myocardial metabolism. heart; metabolism; neurohumoral; rat; zeitgebers

Prior studies have demonstrated that glucocorticoid hormones elicit functional maturation of the small intestine as evidenced by their ability to induce increases in the expression of various digestive hydrolases, such as sucrase-isomaltase and trehalase. However, these increases have a lag time of ~24 h, suggesting that they are secondary effects of hormone action. To identify candidate primary response genes, we performed microarray analysis on pooled RNA from jejunums of untreated postnatal day 8 mouse pups and from littermates who earlier received dexamethasone 2 h. Fluorescent dye-labeled samples were hybridized in quadruplicate to glass-spotted eDNA microarrays containing 15,000 cDNA clones from the National Institute of Aging cDNA clone set. Analysis of the resulting signals using relatively stringent criteria identified 66 transcripts upregulated and 36 downregulated by 2 h of glucocorticoid treatment. Among the upregulated transcripts, the magnitude of the increase detected by microarray ranged from 1.4- to 16-fold. Selected mRNAs from throughout the range were subsequently analyzed by Northern blot analysis. Of 11 mRNAs chosen all were confirmed, and there was a strong correlation between the magnitude of the increase observed from the microarray analysis and from Northern blot analysis. Additional time points showed that these transcripts peaked between 2 and 6 h and had returned to baseline by 24 h. Gene ontology analysis showed pleiotropic effects of dexamethasone on the developing intestine and pointed to genes in the development category as being likely candidates for mediation of glucocorticoid-induced maturation of intestinal function. suckling mice; jejunum; sucrase-isomaltase; microarray; primary response genes

Cell adhesion molecules play an important physical role in shaping the structure of multicellular organisms. Recent studies show that they also playa role in intracellular and intercellular signaling. We describe a cell adhesion pathway that is mediated by the intercellular communication genes comC, lagC, and lagD during Dictyostelium development. Disruptions of these genes result in strains that are unable to generate spores when developed in a pure population but are capable of sporulation when developed in chimerae with wild-type cells. In contrast, any pair-wise chimera of the three mutants fails to form spores. We postulate that the wild-type cells supply the mutant cells with a signal that partially rescues their sporulation. We also propose that the three mutants are deficient in the production of that signal, suggesting that the three genes function in one signaling pathway. In support of that notion, the mutant cells share common non-cell-autonomous prespore and prestalk-specific defects and a common pattern of developmental progression and regression. We provide transcriptional and functional evidence for a network in which comC inhibits lagC and activates lagD expression, lagC and lagD are mutually inductive, and the cell adhesion gene lagC is the terminal node in this signaling network. Keywords: Cell-cell adhesion; Intercellular communication; Dictyostelium development

We performed a screen for signaling genes by selecting mutant strains of Dictyostelium that fail to develop spores in a pure population but sporulate well in chimerae with wild type cells. We found 9 strains whose sporulation was induced up to 10 million-fold in chimerae. Most strains were also able to sporulate in chimerae with each other, but 2 pairs failed to do so, suggesting that the genes in each pair participate in the production of 1 signal. One of the pairs, comD and comB, is described in detail. Sequence analysis revealed that both genes encode putative membrane proteins. ComD is predicted to have 15 transmembrane domains, and ComB has a region of high similarity to the Rab family of small GTPases and 1 transmembrane domain. Similarities between the developmental regulation and cell-type specificity of the genes' expression, the terminal developmental morphology, and the expression pattern of cell-type specific markers in the mutants suggest that comD and comB participate in 1 signal production pathway. This idea is also supported by a high similarity between the global transcriptional profiles of the mutant strains. Differences between the mutant phenotypes late in development suggest that comD and comB participate in separate processes as well. comD has a cell-autonomous role in the specialization of a novel prespore cell type, whereas comB has a cell-autonomous role in prestalk A cell differentiation.