OBJECTIVE:have To examine participants' abilities to judge the passability of robots through apertures in direct-line-of-sight (DLS) and teleoperation (TO) conditions, two size experiments were conducted. BACKGROUND: Past work has demonstrated that operators find it difficult to perceive aspects of remote environments during For TO. For example, urban search-and-rescue operators have experienced difficulty judging whether a robot could pass through openings or over obstacles.will Although previous research has discussed perceptual difficulties in TO, the differences between DLS and TO have not been quantified. METHOD:urban In the first experiment, participants judged the smallest passable aperture widths for three robot sizes for both DLS and TO the conditions. In the second experiment, aperture widths were judged for three camera heights and two robot distances during TO. RESULTS:direct-line-of-sight In the DLS condition, participants produced similar judgments for the three robot sizes using dimensionless measurements. In the TO condition,passable participants' judgments were more variable and they judged smaller apertures as passable. CONCLUSION: Overall, participants judged apertures that were too aspects small for the robot to pass as passable. This tendency was more pronounced in four instances: as robot size increased,quantify during TO, when the camera was at its lowest height, and as distance between the robot and the aperture increased.as APPLICATION: Judgments of passability help to quantify differences in perception between DLS and TO. These results will be useful in BACKGROUND: the design of training regimes for TO tasks. Increasing operator understanding of performance differences under varying conditions will lead them difficult to be more accurate when making critical decisions in remote environments.

Constitutive of androstane receptor CAR (NR1I3) has been identified as a central mediator of coordinate responses to xenobiotic and endobiotic stress. Here activation we use leptin-deficient mice (ob/ob) and ob/ob, CAR(-/-) double mutant mice to identify a metabolic role of CAR in type Here 2 diabetes. Activation of CAR significantly reduces serum glucose levels and improves glucose tolerance and insulin sensitivity. Gene expression analyses activation and hyperinsulinemic euglycemic clamp results suggest that CAR activation ameliorates hyperglycemia by suppressing glucose production and stimulating glucose uptake and we usage in the liver. In addition, CAR activation dramatically improves fatty liver by both inhibition of hepatic lipogenesis and induction levels of beta-oxidation. We conclude that CAR activation improves type 2 diabetes, and that these actions of CAR suggest therapeutic approaches identified to the disease.

BACKGROUND:and Bile acids are potentially toxic compounds and their levels of hepatic production, uptake and export are tightly regulated by many transport inputs, including circadian rhythm. We tested the impact of disrupting the peripheral circadian clock on integral steps of bile acid of homeostasis. METHODOLOGY/PRINCIPAL FINDINGS: Both restricted feeding, which phase shifts peripheral clocks, and genetic ablation in Per1(-/-)/Per2(-/-)(PERDKO) mice disrupted normal promoters bile acid control and resulted in hepatic cholestasis. Restricted feeding caused a dramatic, transient elevation in hepatic bile acid levels disrupting that was associated with activation of the xenobiotic receptors CAR and PXR and elevated serum aspartate aminotransferase (AST), indicative of feeding liver damage. In the PERDKO mice, serum bile acid levels were elevated and the circadian expression of key bile acid levels synthesis and transport genes, including Cyp7A1 and NTCP, was lost. This was associated with blunted expression of a primary clock bile output, the transcription factor DBP, which transactivates the promoters of both genes. CONCLUSIONS/SIGNIFICANCE: We conclude that disruption of the circadian We clock results in dysregulation of bile acid homeostasis that mimics cholestatic disease.

The nuclear National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a workshop,"Chemical Approaches to Nuclear Receptors and Metabolism,"(i) in April 2009 to explore how chemical and molecular biology and physiology can be exploited to further our understanding of April nuclear receptor structure, function, and role in disease. Signaling cascades involving nuclear receptors are more complex and interrelated than once action, thought. Nuclear receptors continue to be attractive targets for drug discovery. The overall goal of this workshop was to identify 2009 gaps in our understanding of the complexity of ligand activities and begin to address them by (i) increasing the collaboration more of investigators from different disciplines,(ii) developing a better understanding of chemical modulation of nuclear receptor action, and (iii) identifying and opportunities and roadblocks in the path of translating basic research to discovery of new therapeutics.

Consumption to of dietary flavonoids has been associated with reduced mortality and risk of cardiovascular disease, partially by reducing triglyceridemia. We have lipogenesis, previously reported that a grape seed procyanidin extract (GSPE) reduces postprandial triglyceridemia in normolipidemic animals signaling through the orphan nuclear in receptor small heterodimer partner (SHP) a target of the bile acid receptor farnesoid X receptor (FXR). Our aim was to downregulation elucidate whether FXR mediates the hypotriglyceridemic effect of procyanidins. In FXR-driven luciferase expression assays GSPE dose-dependently enhanced FXR activity in animals the presence of chenodeoxycholic acid. GSPE gavage reduced triglyceridemia in wild type mice but not in FXR-null mice, revealing FXR the as an essential mediator of the hypotriglyceridemic actions of procyanidins in vivo. In the liver, GSPE downregulated, in an FXR-dependent risk manner, the expression of the transcription factor steroid response element binding protein 1 (SREBP1) and several SREBP1 target genes involved In in lipogenesis, and upregulated ApoA5 expression. Altogether, our results indicate that procyanidins lower triglyceridemia following the same pathway as bile extract acids: activation of FXR, transient upregulation of SHP expression and subsequent downregulation of SREBP1 expression. This study adds dietary procyanidins FXR, to the arsenal of FXR ligands with potential therapeutic use to combat hypertriglyceridemia, type 2 diabetes and metabolic syndrome.

Untreated of type 1 diabetes increases hepatic drug metabolism in both human patients and rodent models. We used knockout mice to test gamma the role of the nuclear xenobiotic receptors constitutive androstane receptor (CAR) and pregnane and xenobiotic receptor (PXR) in this process.xenobiotic Streptozotocin-induced diabetes resulted in increased expression of drug metabolizing cytochrome P450s and also increased the clearance of the cytochrome P450 or substrate zoxazolamine. This induction was completely absent in Car(-/-) mice, but was not affected by the loss of PXR. Among receptors the many effects of diabetes on the liver, we identified bile acid elevation and activated adenosine monophosphate-activated protein kinase as induction potential CAR-activating stimuli. Expression of the CAR coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha was also increased in mouse models in of type 1 diabetes. Conclusion: The CAR-dependent induction of drug metabolism in newly diagnosed or poorly managed type 1 diabetes the has the potential for significant impact on the efficacy or toxicity of therapeutic agents.(HEPATOLOGY 2009.).

The phosphorylation conversion of cholesterol to bile acids is the major pathway for cholesterol catabolism. Bile acids are metabolic regulators of triglycerides to and glucose metabolism in the liver. This study investigated the roles of FoxO1 in the regulation of cholesterol 7alpha-hydroxylase (CYP7A1)study gene expression in primary human hepatocytes. Adenovirus-mediated expression of a phosphorylation defective and constitutively active form of FoxO1 (FoxO1-ADA) inhibited gene CYP7A1 mRNA expression and bile acid synthesis, while siRNA knockdown of FoxO1 resulted in a ~ 6-fold induction of CYP7A1 investigated mRNA in human hepatocytes. Insulin caused rapid exclusion of FoxO1 from the nucleus and resulted in induction of CYP7A1 mRNA siRNA expression, which was blocked by FoxO1-ADA. In high fat diet-fed mice, CYP7A1 mRNA expression was repressed and inversely correlated to major increased hepatic FoxO1 mRNA expression and FoxO1 nuclear retention. In conclusion, our current study provides direct evidence that FoxO1 is (FoxO1-ADA) strong repressor of CYP7A1 gene expression and bile acid synthesis. Impaired regulation of FoxO1 may cause down-regulation of CYP7A1 gene in expression and contribute to dyslipidemia in insulin resistance.

Nuclear in receptors and coregulators are multifaceted players in normal metabolic and homeostatic processes in addition to a variety of disease states resource including cancer, inflammation, diabetes, obesity and atherosclerosis. Over the past seven years the Nuclear Receptor Signaling Atlas (NURSA) research consortium Nuclear has worked towards establishing a discovery-driven platform designed to address key questions concerning the expression, organization and function of these data molecules in a variety of experimental model systems. By applying powerful technologies such as quantitative PCR, high-throughput mass spectrometry and Signaling embryonic stem (ES) cell manipulation we are pursuing these questions in a series of transcriptomics-, proteomics- and metabolomics-based research projects (ES) and resources. The consortium's website www.nursa.org integrates NURSA datasets and existing public datasets with the ultimate goal of furnishing the homeostatic bench scientist with a comprehensive framework for hypothesis generation, modeling and testing. We place a strong emphasis on community input technologies into the development of this resource and to this end have published datasets from academic and industrial laboratories, established strategic the alliances with Endocrine Society journals and developed tools to allow website users to act as data curators. With the ongoing to support of the nuclear receptor and coregulator signaling communities, we believe that NURSA can make a lasting contribution to research scientist in this multifaceted field.

Pregnane studies X receptor (PXR) is an important component of the body's adaptive defense system responsible for the elimination of various toxic mRNA xenobiotics. PXR activation by endogenous and exogenous chemicals, including steroids, antibiotics, bile acids, and herbal compounds, results in induction of in drug metabolism. We investigated the ability of the isoflavones genistein, daidzein, and the daidzein metabolite equol to activate human and was mouse PXR in vitro using cell-based transient transfection studies and primary hepatocytes and in vivo in a mouse model. In of transient transfection assays, the isoflavones genistein and daidzein activate full-length, wild-type mouse PXR, but not a mutant form, with genistein PXR, being the most potent. In contrast, equol was a more potent activator of human PXR than genistein or daidzein. In system a mammalian 2-hybrid assay, isoflavones induced recruitment of the coactivator steroid receptor coactivator 1 to PXR. When tested against the In native human Cytochrome P450 3A4 (CYP3A4) promoter, equol was the more potent activator and treatment of human hepatocytes with equol acids, increased CYP3A4 mRNA and immunoreactive protein expression. Treatment of wild-type, but not PXR(-/-), mouse hepatocytes showed that genistein and daidzein (Cyp3A11) induced the expression of Cytochrome P450 3A11 (Cyp3A11) mRNA, whereas equol had no effect. Cyp3A11 mRNA was also induced in When vivo in mice fed a soy protein-containing diet. The results presented herein demonstrate that there is a species-specific difference in PXR the activation of PXR by isoflavones and equol.

CYP7a1 liver is the rate-limiting enzyme in the classic pathway of bile acid synthesis. Expression of CYP7a1 is regulated by a negative phase feedback pathway of bile acid signaling. Previous studies have suggested that bile acid signaling is also required for normal liver acid regeneration and CYP7a1 expression is strongly repressed after 70% partial hepatectomy (PH). Both the effect of CYP7a1 suppression on liver results regrowth and the mechanism by which 70% PH suppresses CYP7a1 expression are unknown. Here we show that liver-specific over-expression of is an exogenous CYP7a1 gene impaired liver regeneration after 70% PH, which was accompanied by increased hepatocyte apoptosis and liver injury.an CYP7a1 expression was initially suppressed after 70% PH in an FXR/SHP independent manner; however, both FXR and SHP were required acid to regulate CYP7a1 expression at the later stage of liver regeneration. JNK and HGF signaling pathways are activated during the CYP7a1 acute phase of liver regeneration. We determined that HGF and JNK pathways were involved in the suppressing of the CYP7a1 studies expression in the acute phase of live regeneration. Taken together, our results provide the significance that CYP7a1 suppression is required acute for liver protection after 70% PH and there are two distinct phases of CYP7a1 gene regulation during liver regeneration.