The circadian nature of mood and its dysfunction in affective disorders is well recognized, but the underlying molecular mechanisms are still unclear. Here, we show that the circadian nuclear receptor REV-ERBα, which is associated with bipolar disorder, impacts midbrain dopamine production and mood-related behavior in mice. Genetic deletion of the Rev-erbα gene or pharmacological inhibition of REV-ERBα activity in the ventral midbrain induced mania-like behavior in association with a central hyperdopaminergic state. Also, REV-ERBα repressed tyrosine hydroxylase (TH) gene transcription via competition with nuclear receptor-related 1 protein (NURR1), another nuclear receptor crucial for dopaminergic neuronal function, thereby driving circadian TH expression through a target-dependent antagonistic mechanism. In conclusion, we identified a molecular connection between the circadian timing system and mood regulation, suggesting that REV-ERBα could be targeting in the treatment of circadian rhythm-related affective disorders.

The objective of this study is to determine if distinct cognitive phenotypes could be identified in temporal lobe epilepsy. Epilepsy patients (n = 96) and healthy controls (n = 82) underwent comprehensive neuropsychological assessment. Adjusted (age, gender, and education) test scores for epilepsy subjects were grouped into cognitive domains (intelligence, language, visuoperception, immediate and delayed memory, executive function, and cognitive/psychomotor speed). Cluster analysis revealed three distinct cognitive profiles types: (1) minimally impaired (47% of subjects); (2) memory impaired (24%); and (3) memory, executive, and speed impaired (29%). The three cluster groups exhibited different patterns of results on demographic, clinical epilepsy, brain volumetrics, and cognitive course over a 4-year interval. The specific profile characteristics of the identified cognitive phenotypes are presented and their implications for the investigation of the neurobehavioral complications of epilepsy are discussed.

Background Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of upregulating compliant titins in a novel mouse model with a genetically altered titin splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure(P)-volume(V) analysis and Doppler echocardiography. Methods and Results Compliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20 (Rbm20ΔRRM mice). A genome-wide exon expression analysis and a candidate approach revealed that the phenotype is likely to be dominated by greatly increased lengths of titin’s spring-elements. At both cardiomyocyte and left ventricular (LV)chamber levels diastolic stiffness was reduced in heterozygous (+/−) Rbm20ΔRRM mice with a further reduction in homozygous (−/−) mice at only the intact myocyte level. Fibrosis was present in only −/− Rbm20ΔRRM hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20ΔRRM mice, at both the cardiomyocyte and LV chamber levels. Exercise tests revealed an increase in exercise capacity in +/− mice. Conclusions Titin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titins reduces diastolic chamber stiffness due to increased compliance of myocytes but depresses end-systolic elastance; under conditions of exercise the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system might be able to minimize effects on fibrosis and systolic function while improving diastolic function of heart failure patients.

For the synthesis of polylactic acid (PLA) and its copolymers by one-step fermentation process, heterologous pathways involving Clostridium propionicum propionate CoA transferase (Pct Cp ) and Pseudomonas sp. MBEL 6-19 polyhydroxyalkanoate (PHA) synthase 1 (PhaC1 Ps6-19 ) were introduced into Escherichia coli for the generation of lactyl-CoA endogenously and incorporation of lactyl-CoA into the polymer, respectively. Since the wild-type PhaC1 Ps6-19 did not efficiently accept lactyl-CoA as a substrate, site directed mutagenesis as well as saturation mutagenesis were performed to improve the enzyme. The wild-type Pct Cp was not able to efficiently convert lactate to lactyl-CoA and was found to exert inhibitory effect on cell growth, random mutagenesis by error-prone PCR was carried out. By employing engineered PhaC1 Ps6-19 and Pct Cp , poly(3-hydroxybutyrateco-lactate), P(3HB-co-LA), containing 20-49 mol% lactate could be produced up to 62 wt% from glucose and 3HB. By controlling the 3HB concentration in the medium, PLA homopolymer and P(3HB-co-LA) containing lactate as a major monomer unit could be synthesized. Also, P(3HB-co-LA) copolymers containing various lactate fractions could be produced from glucose alone by introducing the Cupriavidus necator b-ketothiolase and acetoacetyl-CoA reductase genes. Fed-batch cultures were performed to produce P(3HB-co-LA) copolymers having 9-64 mol% of lactate, and their molecular weights, thermal properties, and melt flow properties were determined.