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Sample records for enhancing glut-2 glucokinase

  1. Rosiglitazone stimulates the release and synthesis of insulin by enhancing GLUT-2, glucokinase and BETA2/NeuroD expression

    SciTech Connect

    Kim, Hyo-Sup; Noh, Jung-Hyun; Hong, Seung-Hyun; Hwang, You-Cheol; Yang, Tae-Young; Lee, Myung-Shik; Kim, Kwang-Won; Lee, Moon-Kyu

    2008-03-14

    Peroxisome proliferator-activated receptor (PPAR)-{gamma} is a member of the nuclear receptor superfamily, and its ligands, the thiazolidinediones, might directly stimulate insulin release and insulin synthesis in pancreatic {beta}-cells. In the present study, we examined the effects of rosiglitazone (RGZ) on insulin release and synthesis in pancreatic {beta}-cell (INS-1). Insulin release and synthesis were stimulated by treatment with RGZ for 24 h. RGZ upregulated the expressions of GLUT-2 and glucokinase (GCK). Moreover, it was found that RGZ increased the expression of BETA2/NeuroD gene which could regulate insulin gene expression. These results suggest that RGZ could stimulate the release and synthesis of insulin through the upregulation of GLUT-2, GCK, and BETA2/NeuroD gene expression.

  2. Myrtenal ameliorates hyperglycemia by enhancing GLUT2 through Akt in the skeletal muscle and liver of diabetic rats.

    PubMed

    Rathinam, Ayyasamy; Pari, Leelavinothan

    2016-08-25

    Insulin signaling pathway is an important role in glucose utilization in tissues. Our Previous study has established that myrtenal has antihyperglycemic effect against diabetic rats. The aim of this study was to explore the molecular mechanism of myrtenal in Streptozotocin-induced diabetic rats. Experimental diabetes was induced by single intraperitoneal injection of Streptozotocin (STZ) (40 mg/kg bw) in Wistar albino rats. Diabetic rats were administered myrtenal (80 mg/kg bw) for a period of 28 days. Diabetic rats showed an increased the levels of plasma glucose, decreased the levels of plasma insulin, down-regulation of insulin receptor substrate 2 (IRS2), Akt and glucose transporter 2 (GLUT2) in liver and insulin receptor substrate 2 (IRS2), Akt and glucose transporter 4 (GLUT4) protein expression in skeletal muscle. However, myrtenal treated diabetic rats revealed decreased the levels of plasma glucose, improved the plasma insulin levels, up-regulation of IRS2, Akt and GLUT2 in liver and IRS2, Akt and GLUT4 protein expression in skeletal muscle. The up-regulation of glucose transporters enhances the glucose uptake in liver and skeletal muscle. The histopathology and immunohistochemical analysis of the pancreas also corroborates with the above findings. Our findings suggest that myrtenal could be a potent phytochemical in the management of diabetes. PMID:27417257

  3. Exendin-4 enhances expression of Neurod1 and Glut2 in insulin-producing cells derived from mouse embryonic stem cells

    PubMed Central

    Zhao, Qiaoshi; Yang, Yuzhi; Hu, Jing; Shan, Zhiyan; Wu, Yanshuang

    2016-01-01

    Introduction Stem cells involved cell replacement therapies for type 1 diabetes mellitus is promising, yet time-consuming and inefficient. Exendin-4 is a glucagon-like peptide-1 (GLP-1) receptor agonist which has been reported to possess anti-apoptotic effects, thereby increasing β-cell mass and improving β-cell function. The present study aimed to investigate whether exendin-4 would enhance the differentiation of embryonic stem cells into insulin-secreting cells and improve the pancreatic differentiation strategy. Material and methods R1 embryonic stem cells were treated with different concentrations of exendin-4 and divided into three groups. In the high dosage group (group H), exendin-4 was added at the dosage of 10 nmol/l. In the low dosage group (group L), exendin-4 was added at the dosage of 0.1 nmol/l. Group C was a control. Expression of genes related to the β-cell phenotype and immunofluorescence staining of insulin and C-peptide were detected. Results Compared with groups L and C, group H had the highest mRNA expression levels of Isl1, Pdx1, Ngn3, and Insulin1 (p < 0.05). Neurod1 and Glut2 only emerged at the final stage of differentiation in group H. Immunofluorescence analysis revealed that exendin-4 upregulated the protein expression of insulin and C-peptide. Conclusions Exendin-4 remarkably facilitated Neurod1 and Glut2 gene transcription, and was able to induce differentiation of embryonic stem cells into endocrine and insulin-producing cells. PMID:26925137

  4. Effects of isoleucine on glucose uptake through the enhancement of muscular membrane concentrations of GLUT1 and GLUT4 and intestinal membrane concentrations of Na+/glucose co-transporter 1 (SGLT-1) and GLUT2.

    PubMed

    Zhang, Shihai; Yang, Qing; Ren, Man; Qiao, Shiyan; He, Pingli; Li, Defa; Zeng, Xiangfang

    2016-08-01

    Knowledge of regulation of glucose transport contributes to our understanding of whole-body glucose homoeostasis and human metabolic diseases. Isoleucine has been reported to participate in regulation of glucose levels in many studies; therefore, this study was designed to examine the effect of isoleucine on intestinal and muscular GLUT expressions. In an animal experiment, muscular GLUT and intestinal GLUT were determined in weaning pigs fed control or isoleucine-supplemented diets. Supplementation of isoleucine in the diet significantly increased piglet average daily gain, enhanced GLUT1 expression in red muscle and GLUT4 expression in red muscle, white muscle and intermediate muscle (P<0·05). In additional, expressions of Na+/glucose co-transporter 1 and GLUT2 were up-regulated in the small intestine when pigs were fed isoleucine-supplemented diets (P<0·05). C2C12 cells were used to examine the expressions of muscular GLUT and glucose uptake in vitro. In C2C12 cells supplemented with isoleucine in the medium, cellular 2-deoxyglucose uptake was increased (P<0·05) through enhancement of the expressions of GLUT4 and GLUT1 (P<0·05). The effect of isoleucine was greater than that of leucine on glucose uptake (P<0·05). Compared with newborn piglets, 35-d-old piglets have comparatively higher GLUT4, GLUT2 and GLUT5 expressions. The results of this study demonstrated that isoleucine supplementation enhanced the intestinal and muscular GLUT expressions, which have important implications that suggest that isoleucine could potentially increase muscle growth and intestinal development by enhancing local glucose uptake in animals and human beings. PMID:27464458

  5. GLUT2 Accumulation in Enterocyte Apical and Intracellular Membranes

    PubMed Central

    Ait-Omar, Amal; Monteiro-Sepulveda, Milena; Poitou, Christine; Le Gall, Maude; Cotillard, Aurélie; Gilet, Jules; Garbin, Kevin; Houllier, Anne; Château, Danièle; Lacombe, Amélie; Veyrie, Nicolas; Hugol, Danielle; Tordjman, Joan; Magnan, Christophe; Serradas, Patricia; Clément, Karine; Leturque, Armelle; Brot-Laroche, Edith

    2011-01-01

    OBJECTIVE In healthy rodents, intestinal sugar absorption in response to sugar-rich meals and insulin is regulated by GLUT2 in enterocyte plasma membranes. Loss of insulin action maintains apical GLUT2 location. In human enterocytes, apical GLUT2 location has not been reported but may be revealed under conditions of insulin resistance. RESEARCH DESIGN AND METHODS Subcellular location of GLUT2 in jejunal enterocytes was analyzed by confocal and electron microscopy imaging and Western blot in 62 well-phenotyped morbidly obese subjects and 7 lean human subjects. GLUT2 locations were assayed in ob/ob and ob/+ mice receiving oral metformin or in high-fat low-carbohydrate diet–fed C57Bl/6 mice. Glucose absorption and secretion were respectively estimated by oral glucose tolerance test and secretion of [U-14C]-3-O-methyl glucose into lumen. RESULTS In human enterocytes, GLUT2 was consistently located in basolateral membranes. Apical GLUT2 location was absent in lean subjects but was observed in 76% of obese subjects and correlated with insulin resistance and glycemia. In addition, intracellular accumulation of GLUT2 with early endosome antigen 1 (EEA1) was associated with reduced MGAT4a activity (glycosylation) in 39% of obese subjects on a low-carbohydrate/high-fat diet. Mice on a low-carbohydrate/high-fat diet for 12 months also exhibited endosomal GLUT2 accumulation and reduced glucose absorption. In ob/ob mice, metformin promoted apical GLUT2 and improved glucose homeostasis. Apical GLUT2 in fasting hyperglycemic ob/ob mice tripled glucose release into intestinal lumen. CONCLUSIONS In morbidly obese insulin-resistant subjects, GLUT2 was accumulated in apical and/or endosomal membranes of enterocytes. Functionally, apical GLUT2 favored and endosomal GLUT2 reduced glucose transepithelial exchanges. Thus, altered GLUT2 locations in enterocytes are a sign of intestinal adaptations to human metabolic pathology. PMID:21852673

  6. Does apical membrane GLUT2 have a role in intestinal glucose uptake?

    PubMed Central

    Naftalin, Richard J

    2014-01-01

    It has been proposed that the non-saturable component of intestinal glucose absorption, apparent following prolonged exposure to high intraluminal glucose concentrations, is mediated via the low affinity glucose and fructose transporter, GLUT2, upregulated within the small intestinal apical border. The evidence that the non-saturable transport component is mediated via an apical membrane sugar transporter is that it is inhibited by phloretin, after exposure to phloridzin. Since the other apical membrane sugar transporter, GLUT5, is insensitive to inhibition by either cytochalasin B, or phloretin, GLUT2 was deduced to be the low affinity sugar transport route. As in its uninhibited state, polarized intestinal glucose absorption depends both on coupled entry of glucose and sodium across the brush border membrane and on the enterocyte cytosolic glucose concentration exceeding that in both luminal and submucosal interstitial fluids, upregulation of GLUT2 within the intestinal brush border will usually stimulate downhill glucose reflux to the intestinal lumen from the enterocytes; thereby reducing, rather than enhancing net glucose absorption across the luminal surface. These states are simulated with a computer model generating solutions to the differential equations for glucose, Na and water flows between luminal, cell, interstitial and capillary compartments. The model demonstrates that uphill glucose transport via SGLT1 into enterocytes, when short-circuited by any passive glucose carrier in the apical membrane, such as GLUT2, will reduce transcellular glucose absorption and thereby lead to increased paracellular flow. The model also illustrates that apical GLUT2 may usefully act as an osmoregulator to prevent excessive enterocyte volume change with altered luminal glucose concentrations. PMID:25671087

  7. The ergogenic supplement β-hydroxy-β-methylbutyrate (HMB) attenuates insulin resistance through suppressing GLUT-2 in rat liver.

    PubMed

    Sharawy, Maha H; El-Awady, Mohammed S; Megahed, Nirmeen; Gameil, Nariman M

    2016-05-01

    This study investigates the effect of the ergogenic supplement β-hydroxy-β-methylbutyrate (HMB) on insulin resistance induced by high-fructose diet (HFD) in rats. Male Sprague Dawley rats were fed 60% HFD for 12 weeks and HMB (320 mg·kg(-1)·day(-1), orally) for 4 weeks. HFD significantly increased fasting insulin, fasting glucose, glycosylated hemoglobin (HBA1C), liver glycogen content, and homeostasis model assessment of insulin resistance (HOMA-IR) index, while it decreased glucose and insulin tolerance. Furthermore, HFD significantly increased serum triglycerides (TG), low density lipoprotein cholesterol (LDL-C), and very low density lipoprotein cholesterol (VLDL-C) levels, while it significantly decreased high density lipoprotein cholesterol (HDL-C). Moreover, HFD significantly increased mRNA expression of glucose transporter type-2 (GLUT-2), the mammalian target of rapamycin (mTOR), and sterol regulatory element-binding protein-1c (SREBP-1c) but decreased peroxisome proliferator-activated receptor-alpha (PPAR-α) in liver. Aortic relaxation to acetylcholine (ACh) was impaired and histopathology showed severe hepatic steatosis. HMB significantly increased insulin tolerance and decreased fasting insulin, HOMA-IR, HBA1C, hepatic glycogen content, serum TG, LDL-C, and VLDL-C. Additionally, HMB enhanced ACh-induced relaxation, ameliorated hepatic steatosis, and decreased mRNA expression of GLUT-2. In conclusion, HMB may attenuate insulin resistance and hepatic steatosis through inhibiting GLUT-2 in liver. PMID:26871756

  8. Hormonal and Metabolite Regulation of Hepatic Glucokinase.

    PubMed

    Agius, Loranne

    2016-07-17

    Liver glucose metabolism is dependent on glucokinase activity. Glucokinase expression is transcriptionally regulated by hormones and metabolites of glucose, and glucokinase activity is dependent on reversible binding of glucokinase to a specific inhibitor protein, glucokinase regulatory protein (GKRP), and to other binding proteins such as 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFK2/FBP2), which functions as an activator. Glucokinase is inhibited in the postabsorptive state by sequestration in the nucleus bound to GKRP, and it is activated postprandially by portal hyperglycemia and fructose through dissociation from GKRP, translocation to the cytoplasm, and binding to PFK2/FBP2. Glucagon dissociates this interaction, promoting translocation back to the nucleus. In humans, changes in glucokinase expression and activity are associated with poorly controlled type 2 diabetes and with nonalcoholic fatty liver disease, and a common variant of GKRP with altered binding affinity for glucokinase is associated with increased blood and liver lipids and other metabolic traits that implicate a role for GKRP in maintaining intrahepatic metabolite homeostasis. PMID:27146014

  9. Comparative Structural and Functional Analysis of Staphylococcus aureus Glucokinase with other Bacterial Glucokinases

    PubMed Central

    Kumar, P. S.; Kumar, Y. N.; Prasad, U. V.; Yeswanth, S.; Swarupa, V.; Vasu, D.; Venkatesh, K.; Srikanth, L.; Rao, V. K.; Sarma, P. V. G. K.

    2014-01-01

    Glucokinase is classified in bacteria based upon having ATP binding site and ‘repressor/open reading frames of unknown function/sugar kinases’ motif, the sequence of glucokinase gene (JN645812) of Staphylococcus aureus ATCC12600 showed presence of ATP binding site and ‘repressor/open reading frames of unknown function/sugar kinases’ motif. We have earlier observed glucokinase of S. aureus has higher affinity towards the substrate compared to other bacterial glucokinase and under anaerobic condition with increased glucose concentration S. aureus exhibited higher rate of biofilm formation. To establish this, 3D structure of glucokinase was built using homology modeling method, the PROCHECK and ProSA-Web analysis indicated this built glucokinase structure was close to the crystal structure. This structure was superimposed with different bacterial glucokinase structures and from the root-mean-square deviation values, it is concluded that S. aureus glucokinase exhibited very close homology with Enterococcus faecalis and Clostridium difficle while with other bacteria it showed high degree of variations both in domain and nondomain regions. Glucose docking results indicated -12.3697 kcal/mol for S. aureus glucokinase compared with other bacterial glucokinase suggesting higher affinity of glucose which correlates with enzyme kinetics and higher rate of biofilm formation. PMID:25425757

  10. Fructose transporters GLUT5 and GLUT2 expression in adult patients with fructose intolerance

    PubMed Central

    Li, Xinhua; Ho, Sherry SY; Leong, Sai Mun; Wong, Reuben K; Koay, Evelyn SC; Ferraris, Ronaldo P

    2014-01-01

    Background Gastrointestinal symptoms and malabsorption following fructose ingestion (fructose intolerance) are common in functional gastrointestinal disorders (FGID). The underlying mechanism is unclear, but is hypothesized to be related an abnormality of intestinal fructose transporter proteins. Objective To assess the expression of the main intestinal fructose transporter proteins, glucose transport protein 5 (GLUT5) and 2 (GLUT2), in FGID. Methods The expression of GLUT5 and GLUT2 protein and mRNA in small intestinal biopsy tissue was investigated using real-time reverse-transcription PCR and Western immunoblotting in 11 adults with FGID and fructose intolerance ascertained by breath testing and in 15 controls. Results Median expression levels of GLUT5 mRNA normalized to beta-actin were 0.18 (interquartile range, IQR, 0.13–0.21) in patients and 0.17 (IQR 0.12–0.19) in controls (p > 0.05). Respective levels of GLUT2 mRNA were 0.26 (IQR 0.20–0.31) and 0.26 (IQR 0.19–0.31) (p > 0.05). Median expression levels of GLUT5 protein normalized to alpha-tubulin were 0.95 (IQR 0.52–1.68) in patients and 0.95 (IQR 0.59–1.15) in controls (p > 0.05). Respective protein expression levels for GLUT2 were 1.56 (IQR 1.06–2.14) and 1.35 (IQR 0.96–1.79) (p > 0.05). Conclusions Human fructose intolerance may not be associated with marked changes in GLUT5 and GLUT2 expression. Replication of these results in a larger subject group, including measures of transporter activation and membrane and subcellular localization, is warranted. PMID:24918004

  11. Insights into the role of neuronal glucokinase

    PubMed Central

    De Backer, Ivan; Hussain, Sufyan S.; Gardiner, James V.

    2016-01-01

    Glucokinase is a key component of the neuronal glucose-sensing mechanism and is expressed in brain regions that control a range of homeostatic processes. In this review, we detail recently identified roles for neuronal glucokinase in glucose homeostasis and counterregulatory responses to hypoglycemia and in regulating appetite. We describe clinical implications from these advances in our knowledge, especially for developing novel treatments for diabetes and obesity. Further research required to extend our knowledge and help our efforts to tackle the diabetes and obesity epidemics is suggested. PMID:27189932

  12. Insights into the role of neuronal glucokinase.

    PubMed

    De Backer, Ivan; Hussain, Sufyan S; Bloom, Stephen R; Gardiner, James V

    2016-07-01

    Glucokinase is a key component of the neuronal glucose-sensing mechanism and is expressed in brain regions that control a range of homeostatic processes. In this review, we detail recently identified roles for neuronal glucokinase in glucose homeostasis and counterregulatory responses to hypoglycemia and in regulating appetite. We describe clinical implications from these advances in our knowledge, especially for developing novel treatments for diabetes and obesity. Further research required to extend our knowledge and help our efforts to tackle the diabetes and obesity epidemics is suggested. PMID:27189932

  13. Attenuation of insulin resistance in rats by agmatine: role of SREBP-1c, mTOR and GLUT-2.

    PubMed

    Sharawy, Maha H; El-Awady, Mohammed S; Megahed, Nirmeen; Gameil, Nariman M

    2016-01-01

    Insulin resistance is a serious health condition worldwide; however, its exact mechanisms are still unclear. This study investigates agmatine (AGM; an endogenous metabolite of L-arginine) effects on insulin resistance induced by high fructose diet (HFD) in rats and the possible involved mechanisms. Sprague Dawley rats were fed 60% HFD for 12 weeks, and AGM (10 mg/kg/day, orally) was given from week 9 to 12. AGM significantly reduced HFD-induced elevation in fasting insulin level, homeostasis model assessment of insulin resistance (HOMA-IR) index and liver glycogen content from 3.44-, 3.62- and 2.07- to 2.59-, 2.78- and 1.3-fold, respectively, compared to the control group, while it increased HFD-induced reduction in glucose tolerance. Additionally, AGM significantly decreased HFD-induced elevation in serum triglycerides, low density lipoprotein cholesterol and very low density lipoprotein cholesterol levels from 3.18-, 2.97- and 4.75- to 1.25-, 1.25- and 1.07-fold, respectively, compared to control group. Conversely, AGM had no significant effect on HFD-induced changes in fasting glucose, glycosylated hemoglobin, insulin tolerance and high density lipoprotein cholesterol. Furthermore, AGM significantly reduced HFD-induced elevation in mRNA expression of glucose transporter type-2 (GLUT-2), mammalian target of rapamycin (mTOR) and sterol regulatory element-binding protein-1c (SREBP-1c) without affecting that of peroxisome proliferator-activated receptor-alpha (PPAR-α) in the liver. Additionally, AGM enhanced ACh-induced aortic relaxation and attenuated liver steatosis induced by HFD. In conclusion, AGM may have a therapeutic potential in insulin resistance through suppressing SREBP-1c, mTOR and GLUT-2 in liver. PMID:26449613

  14. Autoantibodies to the GLUT-2 glucose transporter of beta cells in insulin-dependent diabetes mellitus of recent onset.

    PubMed Central

    Inman, L R; McAllister, C T; Chen, L; Hughes, S; Newgard, C B; Kettman, J R; Unger, R H; Johnson, J H

    1993-01-01

    Purified immunoglobulin G (IgG) from the serum of patients with insulin-dependent diabetes mellitus (IDDM) of recent onset inhibits high-Km uptake of 3-O-methyl-beta-D-glucose by rat pancreatic islets. To determine if the inhibition is the result of antibodies against GLUT-2, the high-Km glucose transporter of beta cells, we incubated IDDM sera with rat islet cells and with AtT-20ins cells transfected to express GLUT-2. IDDM sera inhibited glucose uptake in islet cells and in GLUT-2-expressing AtT-20ins cells but not in AtT-20ins cells transfected to express the low-Km isoform, GLUT-1. In 24 of 30 (77%) patients with newly diagnosed IDDM, IgG binding as measured by immunofluorescence and flow cytometry of the cells transfected to express GLUT-2 was > 2 standard deviations from the mean of the nondiabetic population; 29 of 31 (96%) of nondiabetic children were negative (P < 0.0001). Increased IgG binding could be removed by absorption with GLUT-2-expressing cells but not with GLUT-1-expressing cells. We conclude that most patients with IDDM of recent onset have autoantibodies to GLUT-2. PMID:8433987

  15. Structure-Activity Relationship of Azaindole-Based Glucokinase Activators.

    PubMed

    Paczal, Attila; Bálint, Balázs; Wéber, Csaba; Szabó, Zoltán B; Ondi, Levente; Theret, Isabelle; De Ceuninck, Frédéric; Bernard, Catherine; Ktorza, Alain; Perron-Sierra, Francoise; Kotschy, András

    2016-01-28

    7-Azaindole has been identified as a novel bidentate anchor point for allosteric glucokinase activators. A systematic investigation around three principal parts of the new small molecule glucokinase activators led to a robust SAR in agreement with structural data that also helped to assess the conformational flexibility of the allosteric activation site. The increase in glucose uptake resulting from glucokinase activation in hepatocytes in vitro translated into the efficient lowering of glucose levels in vivo with the best compounds. PMID:26685731

  16. GLUT2 proteins and PPARγ transcripts levels are increased in liver of ovariectomized rats: reversal effects of resistance training

    PubMed Central

    Tomaz, Luciane M.; Barbosa, Marina R.; Farahnak, Zahra; Lagoeiro, Cristiani G.; Magosso, Natalia S.S; Lavoie, Jean-Marc; Perez, Sérgio E. A.

    2016-01-01

    [Purpose] This study investigated the effects of ovariectomy (Ovx) and 12 weeks of resistance training (RT) on gene expression of GLUT2, the main glucose transporter in the liver, and on PPARγ, a transcription factor known to target GLUT2 expression. [Methods] Forty Holtzman rats were divided into 5 groups: Sham-sedentary (Sed), Sham- RT, Ovx-Sed, Ovx-RT, and Ovx-Sed with hormone replacement (E2). The RT protocol consisted of sessions held every 72 h for 12 weeks, during which the animals performed 4 to 9 vertical climbs (1.1 m) at 2 min intervals with progressively heavier weights (30 g after the fourth climb) tied to the tail. The E2 silastic capsule was inserted into the rats’ backs 48 hours before the first RT session. [Results] In addition to liver fat, GLUT2 protein levels and PPARγ transcripts were increased (P < 0.05) in Ovx compared to Sham-Sed animals, suggesting increased hepatic glucose uptake under estrogen deficient conditions. RT and E2 in Ovx rats decreased liver fat accumulation as well as GLUT2 and PPARγ gene expression to the level of Sham- Sed animals. [Conclusion] The results of this study suggest that liver GLUT2 as well as PPARγ expression in Ovx rats are accompanied by increased fat accumulation and glucose uptake, thus providing a substrate for increased de novo lipogenesis. RT appears to be an appropriate exercise model to circumvent these effects. PMID:27508154

  17. Expression of the Human Glucokinase Gene: Important Roles of the 5′ Flanking and Intron 1 Sequences

    PubMed Central

    Li, Zhixin; Mao, Yiqing; Li, Hui; Wang, Xi; Wang, Rong; Xu, Wei; Song, Rongjing; Jin, Ling; Li, Xiuli; Irwin, David M.; Niu, Gang; Tan, Huanran

    2012-01-01

    Background Glucokinase plays important tissue-specific roles in human physiology, where it acts as a sensor of blood glucose levels in the pancreas, and a few other cells of the gut and brain, and as the rate-limiting step in glucose metabolism in the liver. Liver-specific expression is driven by one of the two tissue-specific promoters, and has an absolute requirement for insulin. The sequences that mediate regulation by insulin are incompletely understood. Methodology/Principal Findings To better understand the liver-specific expression of the human glucokinase gene we compared the structures of this gene from diverse mammals. Much of the sequence located between the 5′ pancreatic beta-cell-specific and downstream liver-specific promoters of the glucokinase genes is composed of repetitive DNA elements that were inserted in parallel on different mammalian lineages. The transcriptional activity of the liver-specific promoter 5′ flanking sequences were tested with and without downstream intronic sequences in two human liver cells lines, HepG2 and L-02. While glucokinase liver-specific 5′ flanking sequences support expression in liver cell lines, a sequence located about 2000 bases 3′ to the liver-specific mRNA start site represses gene expression. Enhanced reporter gene expression was observed in both cell lines when cells were treated with fetal calf serum, but only in the L-02 cells was expression enhanced by insulin. Conclusions/Significance Our results suggest that the normal liver L-02 cell line may be a better model to understand the regulation of the liver-specific expression of the human glucokinase gene. Our results also suggest that sequences downstream of the liver-specific mRNA start site have important roles in the regulation of liver-specific glucokinase gene expression. PMID:23029263

  18. Dual allosteric activation mechanisms in monomeric human glucokinase

    PubMed Central

    Whittington, A. Carl; Larion, Mioara; Bowler, Joseph M.; Ramsey, Kristen M.; Brüschweiler, Rafael; Miller, Brian G.

    2015-01-01

    Cooperativity in human glucokinase (GCK), the body’s primary glucose sensor and a major determinant of glucose homeostatic diseases, is fundamentally different from textbook models of allostery because GCK is monomeric and contains only one glucose-binding site. Prior work has demonstrated that millisecond timescale order-disorder transitions within the enzyme’s small domain govern cooperativity. Here, using limited proteolysis, we map the site of disorder in unliganded GCK to a 30-residue active-site loop that closes upon glucose binding. Positional randomization of the loop, coupled with genetic selection in a glucokinase-deficient bacterium, uncovers a hyperactive GCK variant with substantially reduced cooperativity. Biochemical and structural analysis of this loop variant and GCK variants associated with hyperinsulinemic hypoglycemia reveal two distinct mechanisms of enzyme activation. In α-type activation, glucose affinity is increased, the proteolytic susceptibility of the active site loop is suppressed and the 1H-13C heteronuclear multiple quantum coherence (HMQC) spectrum of 13C-Ile–labeled enzyme resembles the glucose-bound state. In β-type activation, glucose affinity is largely unchanged, proteolytic susceptibility of the loop is enhanced, and the 1H-13C HMQC spectrum reveals no perturbation in ensemble structure. Leveraging both activation mechanisms, we engineer a fully noncooperative GCK variant, whose functional properties are indistinguishable from other hexokinase isozymes, and which displays a 100-fold increase in catalytic efficiency over wild-type GCK. This work elucidates specific structural features responsible for generating allostery in a monomeric enzyme and suggests a general strategy for engineering cooperativity into proteins that lack the structural framework typical of traditional allosteric systems. PMID:26283387

  19. Present status of clinical deployment of glucokinase activators.

    PubMed

    Nakamura, Akinobu; Terauchi, Yasuo

    2015-03-01

    Glucokinase is one of four members of the hexokinase family of enzymes. Its expression is limited to the major organs (such as the pancreas, liver, brain and the gastrointestinal tract) that are thought to have an integrated role in glucose sensing. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the β-cells, it results in insulin release. Studies of glucokinase-linked genetically-modified mice and mutations in humans have illustrated the important roles played by glucokinase in whole-body glucose homeostasis, and suggest that the use of pharmacological agents that augment glucokinase activity could represent a viable treatment strategy in patients with type 2 diabetes. Since 2003, many glucokinase activators (GKAs) have been developed, and their ability to lower the blood glucose has been shown in several animal models of type 2 diabetes. Also, we and others have shown in mouse models that GKAs also have the effect of stimulating the proliferation of β-cells. However, the results of recent phase II trials have shown that GKAs lose their efficacy within several months of use, and that their use is associated with a high incidence of hypoglycemia; furthermore, patients treated with GKAs frequently developed dyslipidemia. A better understanding of the role of glucokinase in metabolic effects is required to resolve several issues identified in clinical trials. PMID:25802718

  20. Mutations in SLC2A2 Gene Reveal hGLUT2 Function in Pancreatic β Cell Development*

    PubMed Central

    Michau, Aurélien; Guillemain, Ghislaine; Grosfeld, Alexandra; Vuillaumier-Barrot, Sandrine; Grand, Teddy; Keck, Mathilde; L'Hoste, Sébastien; Chateau, Danielle; Serradas, Patricia; Teulon, Jacques; De Lonlay, Pascale; Scharfmann, Raphaël; Brot-Laroche, Edith; Leturque, Armelle; Le Gall, Maude

    2013-01-01

    The structure-function relationships of sugar transporter-receptor hGLUT2 coded by SLC2A2 and their impact on insulin secretion and β cell differentiation were investigated through the detailed characterization of a panel of mutations along the protein. We studied naturally occurring SLC2A2 variants or mutants: two single-nucleotide polymorphisms and four proposed inactivating mutations associated to Fanconi-Bickel syndrome. We also engineered mutations based on sequence alignment and conserved amino acids in selected domains. The single-nucleotide polymorphisms P68L and T110I did not impact on sugar transport as assayed in Xenopus oocytes. All the Fanconi-Bickel syndrome-associated mutations invalidated glucose transport by hGLUT2 either through absence of protein at the plasma membrane (G20D and S242R) or through loss of transport capacity despite membrane targeting (P417L and W444R), pointing out crucial amino acids for hGLUT2 transport function. In contrast, engineered mutants were located at the plasma membrane and able to transport sugar, albeit with modified kinetic parameters. Notably, these mutations resulted in gain of function. G20S and L368P mutations increased insulin secretion in the absence of glucose. In addition, these mutants increased insulin-positive cell differentiation when expressed in cultured rat embryonic pancreas. F295Y mutation induced β cell differentiation even in the absence of glucose, suggesting that mutated GLUT2, as a sugar receptor, triggers a signaling pathway independently of glucose transport and metabolism. Our results describe the first gain of function mutations for hGLUT2, revealing the importance of its receptor versus transporter function in pancreatic β cell development and insulin secretion. PMID:23986439

  1. Positive Regulatory Control Loop between Gut Leptin and Intestinal GLUT2/GLUT5 Transporters Links to Hepatic Metabolic Functions in Rodents

    PubMed Central

    Sakar, Yassine; Nazaret, Corinne; Lettéron, Philippe; Ait Omar, Amal; Avenati, Mathilde; Viollet, Benoît; Ducroc, Robert; Bado, André

    2009-01-01

    Background and Aims The small intestine is the major site of absorption of dietary sugars. The rate at which they enter and exit the intestine has a major effect on blood glucose homeostasis. In this study, we determine the effects of luminal leptin on activity/expression of GLUT2 and GLUT5 transporters in response to sugars intake and analyse their physiological consequences. Methodology Wistar rats, wild type and AMPKα2−/− mice were used. In vitro and in vivo isolated jejunal loops were used to quantify transport of fructose and galactose in the absence and the presence of leptin. The effects of fructose and galactose on gastric leptin release were determined. The effects of leptin given orally without or with fructose were determined on the expression of GLUT2/5, on some gluconeogenesis and lipogenic enzymes in the intestine and the liver. Principal Findings First, in vitro luminal leptin activating its receptors coupled to PKCβII and AMPKα, increased insertion of GLUT2/5 into the brush-border membrane leading to enhanced galactose and fructose transport. Second in vivo, oral fructose but not galactose induced in mice a rapid and potent release of gastric leptin in gastric juice without significant changes in plasma leptin levels. Moreover, leptin given orally at a dose reproducing comparable levels to those induced by fructose, stimulated GLUT5-fructose transport, and potentiated fructose-induced: i) increase in blood glucose and mRNA levels of key gluconeogenesis enzymes; ii) increase in blood triglycerides and reduction of mRNA levels of intestinal and hepatic Fasting-induced adipocyte factor (Fiaf) and iii) increase in SREBP-1c, ACC-1, FAS mRNA levels and dephosphorylation/activation of ACC-1 in liver. Conclusion/Significance These data identify for the first time a positive regulatory control loop between gut leptin and fructose in which fructose triggers release of gastric leptin which, in turn, up-regulates GLUT5 and concurrently modulates

  2. Partial structure of the mouse glucokinase gene

    SciTech Connect

    Ishimura-Oka, Kazumi; Chu, Mei-Jin; Sullivan, M.; Oka, Kazuhiro

    1995-10-10

    A complementary DNA for glucokinase (GK) was cloned from mouse liver total RNA by a combination of the polymerase chain reaction (PCR) and mouse liver cDNA library screening. Liver- and {beta}-cell-specific exons 1 were isolated by PCR using mouse and rat genomic DNAs. These clones were then used to screen a mouse genomic library; three genomic clones were isolated and characterized. The mouse GK gene spans over 20 kb, containing 11 exons including a liver- or {beta}-cell-specific exon 1, which encodes a tissue-specific 15-aa peptide at the N-terminus of the protein. Both types of GK contain 465 amino acid residues. The predicted amino acid sequence of mouse {beta}-cell-specific GK showed 98 and 96% identity to the rat and human enzymes, respectively; the corresponding values are 98 and 95% respectively, for the liver-specific GK. Several transcription factor-binding consensus sequences are identified in the 5{prime} flanking region of the mouse GK gene. 21 refs., 1 fig.

  3. Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity

    PubMed Central

    Park, Joo-Man; Kim, Tae-Hyun; Jo, Seong-Ho; Kim, Mi-Young; Ahn, Yong-Ho

    2015-01-01

    Glucokinase (GK), mainly expressed in the liver and pancreatic β-cells, is critical for maintaining glucose homeostasis. GK expression and kinase activity, respectively, are both modulated at the transcriptional and post-translational levels. Post-translationally, GK is regulated by binding the glucokinase regulatory protein (GKRP), resulting in GK retention in the nucleus and its inability to participate in cytosolic glycolysis. Although hepatic GKRP is known to be regulated by allosteric mechanisms, the precise details of modulation of GKRP activity, by post-translational modification, are not well known. Here, we demonstrate that GKRP is acetylated at Lys5 by the acetyltransferase p300. Acetylated GKRP is resistant to degradation by the ubiquitin-dependent proteasome pathway, suggesting that acetylation increases GKRP stability and binding to GK, further inhibiting GK nuclear export. Deacetylation of GKRP is effected by the NAD+-dependent, class III histone deacetylase SIRT2, which is inhibited by nicotinamide. Moreover, the livers of db/db obese, diabetic mice also show elevated GKRP acetylation, suggesting a broader, critical role in regulating blood glucose. Given that acetylated GKRP may affiliate with type-2 diabetes mellitus (T2DM), understanding the mechanism of GKRP acetylation in the liver could reveal novel targets within the GK-GKRP pathway, for treating T2DM and other metabolic pathologies. PMID:26620281

  4. Radiometric oil well assay for glucokinase in microscopic structures

    SciTech Connect

    Bedoya, F.J.; Meglasson, M.D.; Wilson, J.M.; Matschinsky, F.M.

    1985-02-01

    Glucokinase plays a pivotal role in hepatic glucose metabolism and serves as the glucose sensor in pancreatic islet beta-cells. Biochemical studies of this enzyme are complicated by the cellular heterogeneity of the liver and the pancreas and because the presence of hexokinases seriously interferes with currently available analytical procedures. A radiometric assay was designed to deal with these problems. It is based on the liberation of /sup 3/H/sub 2/O from D-(2-/sup 3/H(N))glucose 6-phosphate, the product of the glucokinase reaction, using exogenous phosphoglucose isomerase. Interference by hexokinases was largely eliminated by using glucose 6-phosphate as inhibitor and the sensitivity of the assay was greatly increased by using small volumes with the oil well procedure. The assay was sufficiently sensitive to detect about 1 pg of glucokinase. It thus allowed the application of quantitative histochemical procedures to the study of intralobular hepatic glucokinase profiles and the pancreatic beta-cell glucose sensor. The quantitative histochemical procedures were sufficiently sensitive and reliable for measuring important kinetic constants of glucokinase in microscopic samples of tissue.

  5. Roles of hepatic glucokinase in intertissue metabolic communication: Examination of novel liver-specific glucokinase knockout mice.

    PubMed

    Hayashi, Hirofumi; Sato, Yoshifumi; Li, Zhenghua; Yamamura, Ken-ichi; Yoshizawa, Tatsuya; Yamagata, Kazuya

    2015-05-01

    Glucokinase is expressed principally in pancreatic β-cells and hepatocytes, and catalyzes the phosphorylation of glucose to glucose-6-phosphate, a rate-limiting step of glycolysis. To better understand the roles of hepatic glucokinase, we generated Gck knockout mice by ablating liver-specific exon 1b. The knockout mice exhibited impaired glucose tolerance, decreased hepatic glycogen content, and reduced Pklr and Fas gene expression in the liver, indicating that hepatic glucokinase plays important roles in glucose metabolism. It has also been reported that hepatic glucokinase regulates the expression of thermogenesis-related genes in brown adipose tissue (BAT) and insulin secretion in response to glucose. However, the liver-specific Gck knockout mice displayed neither altered expression of thermogenesis-related genes in BAT nor impaired insulin secretion by β-cells under a normal chow diet. These results suggest that chronic suppression of hepatic glucokinase has a small influence on intertissue (liver-to-BAT as well as liver-to-β-cell) metabolic communication. PMID:25817793

  6. Determination of endopolyphosphatase using polyphosphate glucokinase.

    PubMed

    Kowalczyk, T H; Phillips, N F

    1993-07-01

    A method has been developed for determining endopolyphosphatase (polyphosphate depolymerase, EC 3.6.1.10) activity. The enzyme catalyzes the hydrolysis of inorganic polyphosphates [poly(Ps)] by cleaving internal phosphoanhydride bonds without removal of terminal phosphate residues. During the reaction, shorter poly(P) chains are formed and the molar concentration of poly(P) increases. This enzymatic activity is difficult to quantitate, because the substrates and products of the reaction are chemically identical. The commonly used viscometric method lacks sensitivity and cannot be used with shorter poly(P) substrates. The method described here overcomes these problems, and in addition is rapid, simple, and can be used for distinguishing between the endopolyphosphatase and exopolyphosphatase (EC 3.6.1.11) activities. It is based on monitoring the increase in the number of poly(P) chains generated by endopolyphosphatase. For this purpose, the method takes advantage of the specific property of poly(P) glucokinase (EC 2.7.1.63) which utilizes poly(Ps) of different sizes present in the endopolyphosphatase reaction mixture and reduces them to fairly uniform very short-chain product, poly(P)m. The concentration of poly(P)m is expressed in terms of acid-labile phosphorus and is proportional to the duration of the endopolyphosphatase reaction (i.e., the number of original poly(P) chains) and to protein concentration. The increase in the poly(P)m concentration is a relative measure of the endopolyphosphatase activity. Under certain conditions, m equals 3.5 and the activity can be expressed in standard units, since the exact number of poly(P) chains formed by endopolyphosphatase can be calculated from the increase in molar concentration of poly(P)3.5. Accuracy and advantages of the assay are discussed. PMID:8396361

  7. Cloning of genes that complement yeast hexokinase and glucokinase mutants.

    PubMed Central

    Walsh, R B; Kawasaki, G; Fraenkel, D G

    1983-01-01

    Genes complementing the glucose-negative fructose-negative Saccharomyces cerevisiae triple mutant strain (hxkl hxk2 glk1), which lacks hexokinase PI, hexokinase PII, and glucokinase, were obtained from a pool of yeast DNA in the multicopy plasmid YEp13. Images PMID:6341351

  8. Multiple Comparisons of Glucokinase Activation Mechanisms of Five Mulberry Bioactive Ingredients in Hepatocyte.

    PubMed

    He, Hao; Yu, Wan-Guo; Yang, Jun-Peng; Ge, Sheng; Lu, Yan-Hua

    2016-03-30

    Glucokinase (GK) activity, which is rapidly regulated by glucokinase regulatory protein (GKRP) in the liver, is crucial for blood glucose homeostasis. In this paper, the GK activation mechanisms of 1-deoxynojrimycin (DNJ), resveratrol (RES), oxyresveratrol (OXY), cyanidin-3-glucoside (C3G), and cyanidin-3-rutinoside (C3R) were compared. The results revealed that DNJ, RES, C3G, and C3R could differently improve glucose consumption and enhance intracellular GK activities. DNJ and RES significantly promoted GK translocation at 12.5 μM, whereas other ingredients showed moderate effects. DNJ, C3G, and C3R could rupture intramolecular hydrogen bonds of GK to accelerate its allosteric activation at early stage. RES and OXY could bind to a "hydrophobic pocket" on GK to stabilize the active GK at the final stage. Otherwise, RES, OXY, C3G, and C3R could interact with GKRP at the F1P binding site to promote GK dissociation and translocation. Enzymatic assay showed that RES (15-50 μM) and OXY (25-50 μM) could significantly enhance GK activities, which was caused by their binding properties with GK. Moreover, the most dramatic up-regulation effects on GK expression were observed in C3G and C3R groups. This work expounded the differences between GK activation mechanisms, and the new findings would help to develop new GK activators. PMID:26292150

  9. Non-contact measurement technique for enzymatic reaction of glucokinase

    NASA Astrophysics Data System (ADS)

    Staforelli, Juan P.; Gallardo, María. J.; Meza, Pablo; Torres, Sergio; Mella, Héctor; Reyes, Claudio

    2014-03-01

    A non-contact infrared imaging-based measurement technique is applied to quantify the enzymatic reaction of glucokinase. The method is implemented by a long-wave (8-12 [μm]) infrared microbolometer imaging array and a germanium-based infrared optical vision system adjusted to the size of a small biological sample. The enzymatic reaction is carried out by the glucokinase enzyme, which is representative of the internal dynamics of the cell. Such reactions produce a spontaneous exothermal release of energy detected by the infrared imaging system as a non-contact measurement technique. It is shown by stoichiometry computations and infrared thermal resolution metrics that the infrared imaging system can detect the energy release at the [mK] range. This allows to quantify the spontaneity of the enzymatic reaction in a three dimensional (surface and time) single and noncontact real- time measurement. The camera is characterized for disclosing its sensibility, and the fixed pattern noise is compensated by a two point calibration method. On the other hand, the glucokinase enzyme is isolated from Pyrococcus furiosus. Therefore, the experiment is carried out by manual injection with graduated micropipettes using 40 [μl] of glucokinase at the surface of the substrate contained in an eppendorf tube. For recording, the infrared camera is adjusted in-focus at 25.4 [mm] from the superficial level of the substrate. The obtained values of energy release are 139 +/- 22 [mK] at room temperature and 274 +/- 22 [mK] for a bath temperature of 334 [K].

  10. Oat β-glucan depresses SGLT1- and GLUT2-mediated glucose transport in intestinal epithelial cells (IEC-6).

    PubMed

    Abbasi, Nazanin N; Purslow, Peter P; Tosh, Susan M; Bakovic, Marica

    2016-06-01

    Oat β-glucan consumption is linked to reduced risk factors associated with diabetes and obesity by lowering glycemic response and serum level of low-density lipoproteins. The purpose of this study was to identify the mechanism of action of oat β-glucan at the interface between the gut wall and the lumen responsible for attenuating glucose levels. We proposed that viscous oat β-glucan acts as a physical barrier to glucose uptake in normally absorptive gut epithelial cells IEC-6 by affecting the expression of intestinal glucose transporters. Concentration and time-dependent changes in glucose uptake were established by using a nonmetabolizable glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose. The effectiveness of nutrient transport in IEC-6 cells was shown by significant differences in glucose uptake and corresponding transporter expression. The expressions of glucose transporters sodium-glucose-linked transport protein 1 (SGLT1) and glucose transporter 2 (GLUT2) increased with time (0-60 minutes) and glucose levels (5-25 mmol/L). The suppression of glucose uptake and SGLT1 and GLUT2 expression by increasing concentrations (4-8 mg/mL) of oat β-glucan demonstrated a direct effect of the physical properties of oat β-glucan on glucose transport. These results affirmed oat β-glucan as a dietary agent for minimizing postprandial glucose and showed that modulating the activity of the key intestinal glucose transporters with oat β-glucan could be an effective way of lowering blood glucose levels in patients with diabetes. PMID:27188900

  11. Effect of CCK-8 on pentose phosphate shunt activity, pyridine nucleotides, and glucokinase of rat islets

    SciTech Connect

    Verspohl, E.J.; Breuning, I.; Ammon, H.P.

    1989-01-01

    In rat pancreatic islets the effects of cholecystokinin octapeptide (CCK-8) on pentose phosphate shunt (PPS) activity, glucokinase and hexokinase activity, and NADPH, NADP+, NADH, and NAD+ were studied. By elevating the glucose concentration from 3.0 to 8.3 and 16.7 mM the oxidation of (1-14C)- and (6-14C)glucose and the calculated PPS activity were increased in a concentration-dependent manner; 10 nM CCK-8 enhanced selectively the effect on (1-14C)glucose oxidation thereby increasing the PPS activity but only at an intermediate glucose concentration (8.3 mM). CCK-8 had no effect on glucokinase or hexokinase activity and CCK-8 did not influence glucose utilization. By elevating the glucose concentration, total NADPH and NADH were increased and total NADP+ and NAD+ were decreased. CCK-8 (10 nM) increased selectively NADPH and decreased NADP+ but did not change NADH or NAD+; the effect of CCK-8 on NADPH and NADH was only observed in the presence of an intermediate stimulatory glucose concentration (8.3 mM) but not at either a substimulatory glucose concentration or a maximally stimulatory glucose concentration for insulin release (3.0 or 16.7 mM). The data indicate first that CCK-8 does not act on glucose phosphorylation or glucose utilization and second that CCK-8 increases PPS activity and NADPH levels in rat pancreatic islets. Since the concentrations of glucose necessary for these CCK-8 effects are in the range of 8.3 mM and parallel with those necessary for insulin release as shown in earlier observations, glucose oxidation via pentose phosphate shunt and NADPH are suggested to be related to the CCK-8-modulated insulin release.

  12. Insulin-positive, Glut2-low cells present within mouse pancreas exhibit lineage plasticity and are enriched within extra-islet endocrine cell clusters.

    PubMed

    Beamish, Christine A; Strutt, Brenda J; Arany, Edith J; Hill, David J

    2016-04-18

    Regeneration of insulin-producing β-cells from resident pancreas progenitors requires an understanding of both progenitor identity and lineage plasticity. One model suggested that a rare β-cell sub-population within islets demonstrated multi-lineage plasticity. We hypothesized that β-cells from young mice (postnatal day 7, P7) exhibit such plasticity and used a model of islet dedifferentiation toward a ductal epithelial-cell phenotype to test this theory. RIPCre;Z/AP(+/+) mice were used to lineage trace the fate of β-cells during dedifferentiation culture by a human placental alkaline phosphatase (HPAP) reporter. There was a significant loss of HPAP-expressing β-cells in culture, but remaining HPAP(+) cells lost insulin expression while gaining expression of the epithelial duct cell marker cytokeratin-19 (Ck19). Flow cytometry and recovery of β-cell subpopulations from whole pancreas vs. islets suggest that the HPAP(+)Ck19(+) cells had derived from insulin-positive, glucose-transporter-2-low (Ins(+)Glut2(LO)) cells, representing 3.5% of all insulin-expressing cells. The majority of these cells were found outside of islets within clusters of <5 β-cells. These insulin(+)Glut2(LO) cells demonstrated a greater proliferation rate in vivo and in vitro as compared to insulin(+)Glut2(+) cells at P7, were retained into adulthood, and a subset differentiated into endocrine, ductal, and neural lineages, illustrating substantial plasticity. Results were confirmed using RIPCre;ROSA- eYFP mice. Quantitative PCR data indicated these cells possess an immature β-cell phenotype. These Ins(+)Glut2(LO) cells may represent a resident population of cells capable of forming new, functional β-cells, and which may be potentially exploited for regenerative therapies in the future. PMID:27010375

  13. Insulin secretion impairment in Sirt6 knockout pancreatic β cells is mediated by suppression of the FoxO1-Pdx1-Glut2 pathway.

    PubMed

    Song, Mi-Young; Wang, Jie; Ka, Sun-O; Bae, Eun Ju; Park, Byung-Hyun

    2016-01-01

    Sirtuin 6 (Sirt6), a chromatin associated class III deacetylase, controls whole-body energy homeostasis and has a critical role in glucose-stimulated insulin secretion (GSIS) in pancreatic β cells. However, its underlying molecular mechanism remains poorly understood. To gain further insights, we studied the pathway by which Sirt6 regulates GSIS utilizing mice lacking Sirt6 in their β cells (βS6KO). Further, we overexpressed wild type or deacetylase-inactive mutant Sirt6 in isolated islets as well as in MIN6 cells. We confirmed that βS6KO mice developed glucose intolerance with severely impaired GSIS. Gene expression analysis of knockout islets and overexpression studies demonstrated that Sirt6 deacetylates forkhead box protein O1 (FoxO1) to trigger its nuclear export and releases its transcriptional repression of key glucose sensing genes such as Pdx1 and Glut2. Ectopic overexpression of Sirt6 in knockout islets resulted in rescue of the defective insulin secretion and restoration of the expression of Pdx1 and Glut2. These results show that Sirt6 in pancreatic β cells deacetylates FoxO1 and subsequently increases the expression of Pdx1 and Glut2 to maintain the glucose-sensing ability of pancreatic β cells and systemic glucose tolerance. PMID:27457971

  14. Psychological stress impairs Na+-dependent glucose absorption and increases GLUT2 expression in the rat jejunal brush-border membrane.

    PubMed

    Boudry, Gaëlle; Cheeseman, Christopher I; Perdue, Mary H

    2007-02-01

    Chronic psychological stress impacts many functions of the gastrointestinal tract. However, the effect of stress on nutrient absorption is poorly documented. This study was designed to investigate glucose transporters in rats submitted to different periods of water-avoidance stress (WAS). Rats were subjected to WAS (1 h/day) for 1, 5, or 10 consecutive days. Four hours after the last WAS session, rats were killed and segments of jejunum were mounted in Ussing chambers to study electrophysiological properties of the jejunum and Na+-dependent glucose absorption kinetics. Mucosa was obtained to prepare brush-border membrane vesicles (BBMV) used to measure [14C]fructose uptake as well as sodium-glucose transporter 1 (SGLT-1) and GLUT2 expression by Western blot analysis. Exposure of animals to WAS induced a decrease in Na+-dependent glucose absorption Vmax after 1, 5, and 10 days without any change in SGLT-1 expression. Potential difference across the jejunum was decreased for all stressed groups. Furthermore, we observed an increase in phloretin-sensitive uptake of [14C]fructose by BBMV after 1, 5, or 10 days of WAS, which was not present in control animals. This suggested the abnormal appearance of GLUT2 in the brush border, which was confirmed by Western blot analysis. We concluded that psychological stress induces major changes in glucose transport with a decrease in Na+-dependent glucose absorption and an increase in GLUT2 expression at the brush-border membrane level. PMID:17053095

  15. Insulin secretion impairment in Sirt6 knockout pancreatic β cells is mediated by suppression of the FoxO1-Pdx1-Glut2 pathway

    PubMed Central

    Song, Mi-Young; Wang, Jie; Ka, Sun-O; Bae, Eun Ju; Park, Byung-Hyun

    2016-01-01

    Sirtuin 6 (Sirt6), a chromatin associated class III deacetylase, controls whole-body energy homeostasis and has a critical role in glucose-stimulated insulin secretion (GSIS) in pancreatic β cells. However, its underlying molecular mechanism remains poorly understood. To gain further insights, we studied the pathway by which Sirt6 regulates GSIS utilizing mice lacking Sirt6 in their β cells (βS6KO). Further, we overexpressed wild type or deacetylase-inactive mutant Sirt6 in isolated islets as well as in MIN6 cells. We confirmed that βS6KO mice developed glucose intolerance with severely impaired GSIS. Gene expression analysis of knockout islets and overexpression studies demonstrated that Sirt6 deacetylates forkhead box protein O1 (FoxO1) to trigger its nuclear export and releases its transcriptional repression of key glucose sensing genes such as Pdx1 and Glut2. Ectopic overexpression of Sirt6 in knockout islets resulted in rescue of the defective insulin secretion and restoration of the expression of Pdx1 and Glut2. These results show that Sirt6 in pancreatic β cells deacetylates FoxO1 and subsequently increases the expression of Pdx1 and Glut2 to maintain the glucose-sensing ability of pancreatic β cells and systemic glucose tolerance. PMID:27457971

  16. The Hepatoselective Glucokinase Activator PF-04991532 Ameliorates Hyperglycemia without Causing Hepatic Steatosis in Diabetic Rats

    PubMed Central

    Erion, Derek M.; Lapworth, Amanda; Amor, Paul A.; Bai, Guoyun; Vera, Nicholas B.; Clark, Ronald W.; Yan, Qingyun; Zhu, Yimin; Ross, Trenton T.; Purkal, Julie; Gorgoglione, Matthew; Zhang, Guodong; Bonato, Vinicius; Baker, Levenia; Barucci, Nicole; D’Aquila, Theresa; Robertson, Alan; Aiello, Robert J.; Yan, Jiangli; Trimmer, Jeff; Rolph, Timothy P.; Pfefferkorn, Jeffrey A.

    2014-01-01

    Hyperglycemia resulting from type 2 diabetes mellitus (T2DM) is the main cause of diabetic complications such as retinopathy and neuropathy. A reduction in hyperglycemia has been shown to prevent these associated complications supporting the importance of glucose control. Glucokinase converts glucose to glucose-6-phosphate and determines glucose flux into the β-cells and hepatocytes. Since activation of glucokinase in β-cells is associated with increased risk of hypoglycemia, we hypothesized that selectively activating hepatic glucokinase would reduce fasting and postprandial glucose with minimal risk of hypoglycemia. Previous studies have shown that hepatic glucokinase overexpression is able to restore glucose homeostasis in diabetic models; however, these overexpression experiments have also revealed that excessive increases in hepatic glucokinase activity may also cause hepatosteatosis. Herein we sought to evaluate whether liver specific pharmacological activation of hepatic glucokinase is an effective strategy to reduce hyperglycemia without causing adverse hepatic lipids changes. To test this hypothesis, we evaluated a hepatoselective glucokinase activator, PF-04991532, in Goto-Kakizaki rats. In these studies, PF-04991532 reduced plasma glucose concentrations independent of changes in insulin concentrations in a dose-dependent manner both acutely and after 28 days of sub-chronic treatment. During a hyperglycemic clamp in Goto-Kakizaki rats, the glucose infusion rate was increased approximately 5-fold with PF-04991532. This increase in glucose infusion can be partially attributed to the 60% reduction in endogenous glucose production. While PF-04991532 induced dose-dependent increases in plasma triglyceride concentrations it had no effect on hepatic triglyceride concentrations in Goto-Kakizaki rats. Interestingly, PF-04991532 decreased intracellular AMP concentrations and increased hepatic futile cycling. These data suggest that hepatoselective glucokinase

  17. GLUT2 (SLC2A2) is not the principal glucose transporter in human pancreatic beta cells: implications for understanding genetic association signals at this locus.

    PubMed

    McCulloch, Laura J; van de Bunt, Martijn; Braun, Matthias; Frayn, Keith N; Clark, Anne; Gloyn, Anna L

    2011-12-01

    SLC2A2 encoding glucose transporter -2 (GLUT2) acts as the primary glucose transporter and sensor in rodent pancreatic islets and is widely assumed to play a similar role in humans. In healthy adults SLC2A2 variants are associated with elevated fasting plasma glucose (fpg) concentrations but physiological characterisation does not support a defect in pancreatic beta-cell function. Interspecies differences can create barriers for the follow up of disease association signals. We hypothesised that GLUT2 is not the principal glucose transporter in human beta-cells and that SLC2A2 variants exert their effect on fpg levels through defects in other tissues. SLC2A1-4 (GLUT 1-4) mRNA expression levels were determined in human and mouse islets, beta-cells, liver, muscle and adipose tissue by qRT-PCR whilst GLUT1-3 protein levels were examined by immunohistochemistry. The presence of all three glucose transporters was demonstrated in human and mouse islets and purified beta-cells. Quantitative expression profiling demonstrated that Slc2a2 is the predominant glucose transporter (expression >10 fold higher that Slc2a1) in mouse islets whilst SLC2A1 and SLC2A3 predominate in both human islets and beta-cells (expression 2.8 and 2.7 fold higher than SLC2A2 respectively). Our data therefore suggest that GLUT2 is unlikely to be the principal glucose transporter in human beta-cells and that SLC2A2 defects in other metabolic tissues drive the observed differences in glucose levels between carriers of SLC2A2 variants. Direct extrapolation from rodent to human islet glucose transporter activity is unlikely to be appropriate. PMID:21920790

  18. Effect of GLP-1 treatment on GLUT2 and GLUT4 expression in type 1 and type 2 rat diabetic models.

    PubMed

    Villanueva-Peñacarrillo, M L; Puente, J; Redondo, A; Clemente, F; Valverde, I

    2001-07-01

    Glucagon-like peptide-1 (G LP-1) is an incretin with glucose-dependent insulinotropic and insulin-independent antidiabetic properties that exerts insulin-like effects on glucose metabolism in rat liver, skeletal muscle, and fat. This study aimed to search for the effect of a prolonged treatment, 3 ds, with GLP-1 on glucotransporter GLUT2 expression in liver, and on that of GLUT4 in skeletal muscle and fat, in rats. Normal rats and streptozotocin-induced type 1 and type 2 diabetic models were used; diabetic rats were also treated with insulin for comparison. In normal rats, GLP-1 treatment reduced in the three tissues the corresponding glucotransporter protein level, without modifying their mRNA. In the type 2 diabetic model, GLP-1, like insulin, stimulated in liver and fat only the glucotransporter translational process, while in the muscle an effect at the GLUT4 transcriptional level was also observed. In the type 1 diabetic model, GLP-1 apparently exerted in the liver only a posttranslational effect on GLUT2 expression; in muscle and fat, while insulin was shown to have an action on GLUT4 at both transcriptional and translational levels, the effect of GLP-1 was restricted to glucotransporter translation. In normal and diabetic rats, exogenous GLP-1 controlled the glucotransporter expression in extrapancreatic tissues participating in the overall glucose homeostasis-liver, muscle, and fat-where the effect of the peptide seems to be exerted only at the translational and/or posttranslational level; in muscle and fat, the presence of insulin seems to be required for GLP-1 to activate the transcriptional process. The stimulating action of GLP-1 on GLUT2 and GLUT4 expression, mRNA or protein, could be a mechanism by which, at least in part, the peptide exerts its lowering effect on blood glucose. PMID:11720253

  19. Sequence variations of the pancreatic islet/liver glucose transporter (GLUT2) gene in Japanese subjects with noninsulin dependent diabetes mellitus

    SciTech Connect

    Matsubara, Atsushi; Tanizawa, Yukio; Matsutani, Akira

    1995-10-01

    To assess the genetic susceptibility to noninsulin-dependent diabetes mellitus (NIDDM) in Japanese subjects, we investigated the role of GLUT2 gene defects in patients with NIDDM. When the allelic frequency of a simple tandem repeat polymorphism in the GLUT2 gene was compared, the allele with 155 base pairs was more common in NIDDM patients (n = 99) than in controls (n = 89; 5.1% v. 0.6%; P = 0.0118, by Fisher`s exact test), whereas this was not significant after the correction for multiple comparisons. To directly identify mutations, we then analyzed each of 11 exons by the polymerase chain reaction-single strand conformation polymorphism analysis in 60 NIDDM patients. We found 2 missense mutations in exon 3: CCC{r_arrow}CTC (Pro{sup 68}{r_arrow}Leu) in 1 patient and ACT{r_arrow}ATT (Thr{sup 110}{r_arrow}Ile) in 3 patients, all in the heterozygous state. These mutations were found in 60 control subjects. To evaluate the significance of the Pro{sup 68}{r_arrow}Leu mutation, the family members of the proband were studied. The mutation did not appear to be associated with the disease or other clinical parameters including change in immunoreactive insulin/change in plasma glucose or oral glucose load. The other mutation (Thr{sup 110}{r_arrow}Ile) is known to be functionally insignificant. We identified 4 additional nucleotide changes, all of which appeared to be silent. We concluded that the mutations in the GLUT2 gene were not major determinants of genetic susceptibility to NIDDM in Japanese. 34 refs., 2 figs., 3 tabs.

  20. Chronic ethanol consumption inhibits glucokinase transcriptional activity by Atf3 and triggers metabolic syndrome in vivo.

    PubMed

    Kim, Ji Yeon; Hwang, Joo-Yeon; Lee, Dae Yeon; Song, Eun Hyun; Park, Keon Jae; Kim, Gyu Hee; Jeong, Eun Ae; Lee, Yoo Jeong; Go, Min Jin; Kim, Dae Jin; Lee, Seong Su; Kim, Bong-Jo; Song, Jihyun; Roh, Gu Seob; Gao, Bin; Kim, Won-Ho

    2014-09-26

    Chronic ethanol consumption induces pancreatic β-cell dysfunction through glucokinase (Gck) nitration and down-regulation, leading to impaired glucose tolerance and insulin resistance, but the underlying mechanism remains largely unknown. Here, we demonstrate that Gck gene expression and promoter activity in pancreatic β-cells were suppressed by chronic ethanol exposure in vivo and in vitro, whereas expression of activating transcription factor 3 (Atf3) and its binding to the putative Atf/Creb site (from -287 to -158 bp) on the Gck promoter were up-regulated. Furthermore, in vitro ethanol-induced Atf3 inhibited the positive effect of Pdx-1 on Gck transcriptional regulation, enhanced recruitment of Hdac1/2 and histone H3 deacetylation, and subsequently augmented the interaction of Hdac1/Pdx-1 on the Gck promoter, which were diminished by Atf3 siRNA. In vivo Atf3-silencing reversed ethanol-mediated Gck down-regulation and β-cell dysfunction, followed by the amelioration of impaired glucose tolerance and insulin resistance. Together, we identified that ethanol-induced Atf3 fosters β-cell dysfunction via Gck down-regulation and that its loss ameliorates metabolic syndrome and could be a potential therapeutic target in treating type 2 diabetes. The Atf3 gene is associated with the induction of type 2 diabetes and alcohol consumption-induced metabolic impairment and thus may be the major negative regulator for glucose homeostasis. PMID:25074928

  1. Nutritional regulation of glucokinase: a cross-species story.

    PubMed

    Panserat, Stéphane; Rideau, Nicole; Polakof, Sergio

    2014-06-01

    The glucokinase (GK) enzyme (EC 2.7.1.1.) is essential for the use of dietary glucose because it is the first enzyme to phosphorylate glucose in excess in different key tissues such as the pancreas and liver. The objective of the present review is not to fully describe the biochemical characteristics and the genetics of this enzyme but to detail its nutritional regulation in different vertebrates from fish to human. Indeed, the present review will describe the existence of the GK enzyme in different animal species that have naturally different levels of carbohydrate in their diets. Thus, some studies have been performed to analyse the nutritional regulation of the GK enzyme in humans and rodents (having high levels of dietary carbohydrates in their diets), in the chicken (moderate level of carbohydrates in its diet) and rainbow trout (no carbohydrate intake in its diet). All these data illustrate the nutritional importance of the GK enzyme irrespective of feeding habits, even in animals known to poorly use dietary carbohydrates (carnivorous species). PMID:24896238

  2. All1371 is a polyphosphate-dependent glucokinase in Anabaena sp. PCC 7120

    PubMed Central

    Klemke, Friederike; Beyer, Gabriele; Sawade, Linda; Saitov, Ali; Korte, Thomas; Maldener, Iris; Lockau, Wolfgang; Nürnberg, Dennis J.

    2014-01-01

    The polyphosphate glucokinases can phosphorylate glucose to glucose 6-phosphate using polyphosphate as the substrate. ORF all1371 encodes a putative polyphosphate glucokinase in the filamentous heterocyst-forming cyanobacterium Anabaena sp. PCC 7120. Here, ORF all1371 was heterologously expressed in Escherichia coli, and its purified product was characterized. Enzyme activity assays revealed that All1371 is an active polyphosphate glucokinase that can phosphorylate both glucose and mannose in the presence of divalent cations in vitro. Unlike many other polyphosphate glucokinases, for which nucleoside triphosphates (e.g. ATP or GTP) act as phosphoryl group donors, All1371 required polyphosphate to confer its enzymic activity. The enzymic reaction catalysed by All1371 followed classical Michaelis–Menten kinetics, with kcat = 48.2 s−1 at pH 7.5 and 28 °C and KM = 1.76 µM and 0.118 mM for polyphosphate and glucose, respectively. Its reaction mechanism was identified as a particular multi-substrate mechanism called the ‘bi-bi ping-pong mechanism’. Bioinformatic analyses revealed numerous polyphosphate-dependent glucokinases in heterocyst-forming cyanobacteria. Viability of an Anabaena sp. PCC 7120 mutant strain lacking all1371 was impaired under nitrogen-fixing conditions. GFP promoter studies indicate expression of all1371 under combined nitrogen deprivation. All1371 might play a substantial role in Anabaena sp. PCC 7120 under these conditions. PMID:25320362

  3. Mutations in the glucokinase gene of the fetus result in reduced birth weight.

    PubMed

    Hattersley, A T; Beards, F; Ballantyne, E; Appleton, M; Harvey, R; Ellard, S

    1998-07-01

    Low birth weight and fetal thinness have been associated with non-insulin dependent diabetes mellitus (NIDDM) and insulin resistance in childhood and adulthood. It has been proposed that this association results from fetal programming in response to the intrauterine environment. An alternative explanation is that the same genetic influences alter both intrauterine growth and adult glucose tolerance. Fetal insulin secretion in response to maternal glycaemia plays a key role in fetal growth, and adult insulin secretion is a primary determinant of glucose tolerance. We hypothesized that a defect in the sensing of glucose by the pancreas, caused by a heterozygous mutation in the glucokinase gene, could reduce fetal growth and birth weight in addition to causing hyperglycaemia after birth. In 58 offspring, where one parent has a glucokinase mutation, the inheritance of a glucokinase mutation by the fetus resulted in a mean reduction of birth weight of 533 g (P=0.002). In 19 of 21 sibpairs discordant for the presence of a glucokinase mutation, the child with the mutation had a lower birth weight, with a mean difference of 521 g (P=0.0002). Maternal hyperglycaemia due to a glucokinase mutation resulted in a mean increase in birth weight of 601 g (P=0.001). The effects of maternal and fetal glucokinase mutations on birth weight were additive. We propose that these changes in birth weight reflect changes in fetal insulin secretion which are influenced directly by the fetal genotype and indirectly, through maternal hyperglycaemia, by the maternal genotype. This observation suggests that variation in fetal growth could be used in the assessment of the role of genes which modify either insulin secretion or insulin action. PMID:9662401

  4. Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors

    NASA Astrophysics Data System (ADS)

    Lloyd, David J.; St Jean, David J.; Kurzeja, Robert J. M.; Wahl, Robert C.; Michelsen, Klaus; Cupples, Rod; Chen, Michelle; Wu, John; Sivits, Glenn; Helmering, Joan; Komorowski, Renée; Ashton, Kate S.; Pennington, Lewis D.; Fotsch, Christopher; Vazir, Mukta; Chen, Kui; Chmait, Samer; Zhang, Jiandong; Liu, Longbin; Norman, Mark H.; Andrews, Kristin L.; Bartberger, Michael D.; van, Gwyneth; Galbreath, Elizabeth J.; Vonderfecht, Steven L.; Wang, Minghan; Jordan, Steven R.; Véniant, Murielle M.; Hale, Clarence

    2013-12-01

    Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate in pancreatic β-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production, and is subject to the endogenous inhibitor GK regulatory protein (GKRP). During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK-GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.

  5. 5-Alkyl-2-urea-Substituted Pyridines: Identification of Efficacious Glucokinase Activators with Improved Properties.

    PubMed

    Kohn, Todd J; Du, Xiaohui; Lai, SuJen; Xiong, YuMei; Komorowski, Renee; Veniant, Murielle; Fu, Zice; Jiao, Xianyun; Pattaropong, Vatee; Chow, David; Cardozo, Mario; Jin, Lixia; Conn, Marion; DeWolf, Walter E; Kraser, Christopher F; Hinklin, Ronald J; Boys, Mark L; Medina, Julio C; Houze, Jonathan; Dransfield, Paul; Coward, Peter

    2016-07-14

    Two 1-(4-aryl-5-alkyl-pyridin-2-yl)-3-methylurea glucokinase activators were identified with robust in vivo efficacy. These two compounds possessed higher solubilities than the previously identified triaryl compounds (i.e., AM-2394). Structure-activity relationship studies are presented along with relevant pharmacokinetic and in vivo data. PMID:27437074

  6. Glucokinase expression is regulated by glucose through O-GlcNAc glycosylation.

    PubMed

    Baldini, Steffi F; Steenackers, Agata; Olivier-Van Stichelen, Stéphanie; Mir, Anne-Marie; Mortuaire, Marlène; Lefebvre, Tony; Guinez, Céline

    2016-09-16

    Blood glucose fluctuates with the fasting-feeding cycle. One of the liver's functions is to maintain blood glucose concentrations within a physiological range. Glucokinase (GCK) or hexokinase IV, is the main enzyme that regulates the flux and the use of glucose in the liver leading to a compensation of hyperglycemia. In hepatocytes, GCK catalyzes the phosphorylation of glucose into glucose-6-phosphate. This critical enzymatic reaction is determinant for the metabolism of glucose in the liver which includes glycogen synthesis, glycolysis, lipogenesis and gluconeogenesis. In liver, simultaneous increase of glucose and insulin enhances GCK activity and gene expression, changes its subcellular location and interaction with regulatory proteins. The post-translational O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) acts as a glucose-sensitive modification and is believed to take part in hepatic glucose sensing by modifying key regulatory proteins. Therefore, we aimed to determine whether GCK is modified by O-GlcNAcylation in the liver of mice and investigated the role that this modification plays in regulating GCK protein expression. We demonstrated that endogenous GCK expression correlated with O-GlcNAc levels in the pathophysiological model ob/ob mice. More specifically, in response to the pharmacological inhibition of O-GlcNAcase (OGA) contents of GCK increased. Using the GlcNAc specific lectin succinylated-WGA and click chemistry labeling approaches, we demonstrated that GCK is modified by O-GlcNAcylation. Further, we demonstrated that siRNA-mediated Ogt knock-down not only decreases O-GlcNAc content but also GCK protein level. Altogether, our in vivo and in vitro results demonstrate that GCK expression is regulated by nutrient-sensing O-GlcNAc cycling in liver. PMID:27520373

  7. Phosphorylation of D-glucose in Escherichia coli mutants defective in glucosephosphotransferase, mannosephosphotransferase, and glucokinase.

    PubMed Central

    Curtis, S J; Epstein, W

    1975-01-01

    Genetic studies show that Escherichia coli has three enzymes capable of phosphorylating glucose: soluble adenosine 5'-triphosphate-dependent glucokinase, which plays only a minor role in glucose metabolism; an enzyme II, called glucosephosphotransferase, with high specificity for the D-glucose configuration; and another enzyme II, called mannosephosphotransferase, with broader specificity. The former enzyme II is active on glucose and methyl-alpha-glucopyranoside, whereas the latter is active on D-glucose, D-mannose, 2-deoxy-D-glucose, D-glucosamine, and D-mannosamine. Mutations leading to loss of glucosephosphotransferase activity and designated by the symbol gpt are between the purB and pyrC markers in a locus previously called cat. The locus of mutations to loss of mannosephosphotransferase, mpt, is between the eda and fadD genes. Mutations to loss of glucokinase, glk, are between the ptsI and dsd genes. PMID:1097393

  8. A novel functional glucose transporter in the white shrimp Litopenaeus vannamei -LvGLUT2- is up-regulated during hypoxia in hepatopancreas.

    PubMed

    Martínez-Quintana, José A; Kikuta, Shingo; Felix-Portillo, Monserrath; Peregrino-Uriarte, Alma B; Yepiz-Plascencia, Gloria

    2015-12-01

    In hypoxia conditions, the white shrimp Litopenaeus vannamei shifts its energetic metabolism from aerobic to anaerobic, requiring more glucose uptake into the cells by GLUT proteins. We here report a novel glucose transporter in shrimp. The Lvglut2 cDNA is 2473 bp-long containing an ORF of 1458 bp encoding 486 amino acid residues. The deduced protein has the features of a facilitative sugar transporter. The Lvglut2 gene product tagged with GFP was expressed in the cell membrane of Xenopus oocytes. In the same expression system, untagged LvGLUT2 resulted to be a bidirectional glucose transporter that functions moving glucose down its concentration gradient in and out of the cell. Lvglut2 mRNA is expressed in hepatopancreas while in muscle and gills it was not detected. Hypoxia up-regulates the expression of Lvglut2 transcripts in hepatopancreas. These results provide a better understanding of facilitative glucose transporters and gene regulation during hypoxia in crustaceans. PMID:26415036

  9. Evolution of Hepatic Glucose Metabolism: Liver-Specific Glucokinase Deficiency Explained by Parallel Loss of the Gene for Glucokinase Regulatory Protein (GCKR)

    PubMed Central

    Wang, Zhao Yang; Jin, Ling; Tan, Huanran; Irwin, David M.

    2013-01-01

    Background Glucokinase (GCK) plays an important role in the regulation of carbohydrate metabolism. In the liver, phosphorylation of glucose to glucose-6-phosphate by GCK is the first step for both glycolysis and glycogen synthesis. However, some vertebrate species are deficient in GCK activity in the liver, despite containing GCK genes that appear to be compatible with function in their genomes. Glucokinase regulatory protein (GCKR) is the most important post-transcriptional regulator of GCK in the liver; it participates in the modulation of GCK activity and location depending upon changes in glucose levels. In experimental models, loss of GCKR has been shown to associate with reduced hepatic GCK protein levels and activity. Methodology/Principal Findings GCKR genes and GCKR-like sequences were identified in the genomes of all vertebrate species with available genome sequences. The coding sequences of GCKR and GCKR-like genes were identified and aligned; base changes likely to disrupt coding potential or splicing were also identified. Conclusions/Significance GCKR genes could not be found in the genomes of 9 vertebrate species, including all birds. In addition, in multiple mammalian genomes, whereas GCKR-like gene sequences could be identified, these genes could not predict a functional protein. Vertebrate species that were previously reported to be deficient in hepatic GCK activity were found to have deleted (birds and lizard) or mutated (mammals) GCKR genes. Our results suggest that mutation of the GCKR gene leads to hepatic GCK deficiency due to the loss of the stabilizing effect of GCKR. PMID:23573289

  10. Phosphotransferase system-independent glucose utilization in corynebacterium glutamicum by inositol permeases and glucokinases.

    PubMed

    Lindner, Steffen N; Seibold, Gerd M; Henrich, Alexander; Krämer, Reinhard; Wendisch, Volker F

    2011-06-01

    Phosphoenolpyruvate-dependent glucose phosphorylation via the phosphotransferase system (PTS) is the major path of glucose uptake in Corynebacterium glutamicum, but some growth from glucose is retained in the absence of the PTS. The growth defect of a deletion mutant lacking the general PTS component HPr in glucose medium could be overcome by suppressor mutations leading to the high expression of inositol utilization genes or by the addition of inositol to the growth medium if a glucokinase is overproduced simultaneously. PTS-independent glucose uptake was shown to require at least one of the inositol transporters IolT1 and IolT2 as a mutant lacking IolT1, IolT2, and the PTS component HPr could not grow with glucose as the sole carbon source. Efficient glucose utilization in the absence of the PTS necessitated the overexpression of a glucokinase gene in addition to either iolT1 or iolT2. IolT1 and IolT2 are low-affinity glucose permeases with K(s) values of 2.8 and 1.9 mM, respectively. As glucose uptake and phosphorylation via the PTS differs from glucose uptake via IolT1 or IolT2 and phosphorylation via glucokinase by the requirement for phosphoenolpyruvate, the roles of the two pathways for l-lysine production were tested. The l-lysine yield by C. glutamicum DM1729, a rationally engineered l-lysine-producing strain, was lower than that by its PTS-deficient derivate DM1729Δhpr, which, however, showed low production rates. The combined overexpression of iolT1 or iolT2 with ppgK, the gene for PolyP/ATP-dependent glucokinase, in DM1729Δhpr enabled l-lysine production as fast as that by the parent strain DM1729 but with 10 to 20% higher l-lysine yield. PMID:21478323

  11. Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394.

    PubMed

    Dransfield, Paul J; Pattaropong, Vatee; Lai, Sujen; Fu, Zice; Kohn, Todd J; Du, Xiaohui; Cheng, Alan; Xiong, Yumei; Komorowski, Renee; Jin, Lixia; Conn, Marion; Tien, Eric; DeWolf, Walter E; Hinklin, Ronald J; Aicher, Thomas D; Kraser, Christopher F; Boyd, Steven A; Voegtli, Walter C; Condroski, Kevin R; Veniant-Ellison, Murielle; Medina, Julio C; Houze, Jonathan; Coward, Peter

    2016-07-14

    Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes. PMID:27437083

  12. Theoretical investigations on the interactions of glucokinase regulatory protein with fructose phosphates.

    PubMed

    Ling, Baoping; Yan, Xueyuan; Sun, Min; Bi, Siwei

    2016-02-01

    Glucokinase (GK) plays a critical role in maintaining glucose homeostasis in the human liver and pancreas. In the liver, the activity of GK is modulated by the glucokinase regulatory protein (GKRP) which functions as a competitive inhibitor of glucose to bind to GK. Moreover, the inhibitory intensity of GKRP-GK is suppressed by fructose 1-phosphate (F1P), and reinforced by fructose 6-phosphate (F6P). Here, we employed a series of computational techniques to explore the interactions of fructose phosphates with GKRP. Calculation results reveal that F1P and F6P can bind to the same active site of GKRP with different binding modes, and electrostatic interaction provides a major driving force for the ligand binding. The presence of fructose phosphate severely influences the motions of protein and the conformational space, and the structural change of sugar phosphate influences its interactions with GKRP, leading to a large conformational rearrangement of loop2 in the SIS2 domain. In particular, the binding of F6P to GKRP facilitates the protruding loop2 contacting with GK to form the stable GK-GKRP complex. The conserved residues 179-184 of GKRP play a major role in the binding of phosphate group and maintaining the stability of GKRP. These results may provide deep insight into the regulatory mechanism of GKRP to the activity of GK. PMID:26629747

  13. Glucokinase regulatory proten genetic variant interacts with omega-3 PUFA to influence insulin resistance and inflammation in metabolic syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glucokinase Regulatory Protein (GCKR) plays a central role regulating both hepatic triglyceride and glucose metabolism. Fatty acids are key metabolic regulators, which interact with genetic factors and influence glucose metabolism and other metabolic traits. Omega-3 polyunsaturated fatty acids (n-3...

  14. Relevant associations of the glucokinase regulatory protein/glucokinase gene variation with TAG concentrations in a high-cardiovascular risk population: modulation by the Mediterranean diet.

    PubMed

    Sotos-Prieto, Mercedes; Guillén, Marisa; Vicente Sorli, Jose; Portolés, Olga; Guillem-Saiz, Patricia; Ignacio Gonzalez, Jose; Qi, Lu; Corella, Dolores

    2013-01-28

    The SNP rs1260326 (P446L) and rs1799884 (-30G>A) for the glucokinase regulatory protein (GCKR) and glucokinase (GCK) genes, respectively, have been associated with opposing effects on TAG and glucose concentrations. However, their genetic modulation by diet (dietary patterns or foods) remains to be investigated. We studied 945 high-cardiovascular risk subjects aged 67 (sd 6) years who participated in the PREvención con DIeta MEDiterránea-Valencia Study. Demographic, clinical, biochemical and genetic data were obtained. Adherence to the Mediterranean diet (MD) and food intake were measured by validated questionnaires. Carriers of the L allele of GKCR had significantly higher TAG concentrations (PP: 1.34 (SD 0.05) mmol/l v. PL+LL: 1.54 (SD 0.03) mmol/l; P= 0.014) and LL carriers had lower glucose concentrations (PL+PP: 6.85 (SD 0.08) mmol/l v. LL: 6.40 (SD 0.16) mmol/l; P= 0.032) after multivariate adjustment. Conversely, homozygous subjects for the variant allele (A) in the GCK gene had significantly lower TAG (GG+GA: 1.48 (SD 0.03) mmol/l v. AA: 1.17 (SD 0.18) mmol/l; P= 0.033) and a higher risk of diabetes (OR 3.3, 95 % CI 1.2, 9.2). Combined effects for both SNP increased TAG concentrations by 37 % (P= 0.033). Adherence to the MD modulated the effects of GCKR polymorphism on TAG: subjects with genetic risk had lower TAG (L-allele carriers; PP: 1.48 (SD 0.14) mmol/l v. PL+LL: 1.51 (SD 0.08) mmol/l; P= 0.917) compared with those with a higher adherence. Analysis of the joint effects of the GCKR and individual food items identified significant associations (olive oil (P= 0.035), vegetables (P= 0.012), red meat (P= 0.017), butter (P= 0.039), sweetened carbonated beverages (P= 0.036) and nuts (P= 0.038)). In conclusion, we found that rs1260326 (GCKR) is significantly associated with higher TAG concentrations, but is modulated by adherence to the MD. PMID:22716779

  15. A Fresh View of Glycolysis and Glucokinase Regulation: History and Current Status*

    PubMed Central

    Lenzen, Sigurd

    2014-01-01

    This minireview looks back at a century of glycolysis research with a focus on the mechanisms of flux regulation. Traditionally, glycolysis is regarded as a feeder pathway that prepares glucose for further catabolism and energy production. However, glycolysis is much more than that, in particular in those tissues that express the low affinity glucose-phosphorylating enzyme glucokinase. This enzyme equips the glycolytic pathway with a special steering function for the regulation of intermediary metabolism. In beta cells, glycolysis acts as a transducer for triggering and amplifying physiological glucose-induced insulin secretion. On the basis of these considerations, I have defined a glycolytic flux regulatory unit composed of the two fructose ester steps of this pathway with various enzymes and metabolites that regulate glycolysis. PMID:24637025

  16. Substrate-induced Nuclear Export and Peripheral Compartmentalization of Hepatic Glucokinase Correlates with Glycogen Deposition

    PubMed Central

    Shiota, Masa; Knobel, Susan M.; Piston, David W.; Cherrington, Alan D.; Magnuson, Mark A.

    2001-01-01

    Hepatic glucokinase (GK) is acutely regulated by binding to its nuclear-anchored regulatory protein (GKRP). Although GK release by GKRP is tightly coupled to the rate of glycogen synthesis, the nature of this association is obscure. To gain insight into this coupling mechanism under physiological stimulating conditions in primary rat hepatocytes, we analyzed the subcellular distribution of GK and GKRP with immunofluorescence, and glycogen deposition with glycogen cytochemical fluorescence, using confocal microscopyand quantitative image analysis. Following stimulation, a fraction of the GK signal translocated from the nucleus to the cytoplasm. The reduction in the nuclear to cytoplasmic ratio of GK, an index of nuclear export, correlated with a >50% increase in glycogen cytochemical fluorescence over a 60min stimulation period. Furthermore, glycogen accumulation was initially deposited in a peripheral pattern in hepatocytes similar to that of GK. These data suggest that a compartmentalization exists of both active GK and the initial sites of glycogen deposition at the hepatocyte surface. PMID:12369705

  17. Features for instantaneous emissions of low-level infrared signals of glucokinase enzyme from Pyrococcus furiosus.

    PubMed

    Torres, Sergio; Mella, Héctor; Reyes, Claudio; Meza, Pablo; Gallardo, Maria J; Staforelli, Juan P

    2015-03-10

    A noncontact infrared (IR) imaging-based methodology and signal recovery tools are applied on an enzyme reaction as a test target. The method is implemented by a long-wave (8-12 μm) IR microbolometer imaging array and a germanium-based IR optical vision. The reaction is carried out by the glucokinase, which produces a rapid exothermal release of energy that is weak, and, even worse, the IR video captured by the uncooled microbolometer detector is affected by spatial and temporal noise with specific complexities. Hitherto, IR-based signal recovery tools have worked with a standard acquisition frequency, which is clearly beyond the time scale of a real scenario. The implications of this (and similar) rapid reactions motivate the designs of a signal recovery method using prior information of the processes to extract and quantify the spontaneity of the enzymatic reaction in a three-dimensional (space and time) single and noncontact online measurement. PMID:25968383

  18. Structure of the human glucokinase gene and identification of a missense mutation in a Japanese patient with early-onset non-insulin-dependent diabetes mellitus

    SciTech Connect

    Sakura, Hiroshi; Eto, Kazuhiro; Ueno, Hirohisa; Yazaki, Yoshio; Kadowaki, Takashi ); Kadowaki, Hiroko; Simokawa, Kotaro; Akanuma, Yasuo ); Koda, Naoya; Fukushima, Yoshimitsu )

    1992-12-01

    Glucokinase is thought to play a glucose-sensor role in the pancreas, and abnormalities in its structure, function, and regulation can induce diabetes. The authors isolated the human glucokinase gene, and determined its genomic structure including exon-intron boundaries. Structure of the glucokinase gene in human was very similar to that in rat. Then, by screening Japanese diabetic patients using polymerase chain reaction - single strand conformation polymorphism (PCR-SSCP) and direct-sequencing strategies, they identified a missense mutation substituting ariginine (AGG) for glycine (GGG) at position 261 in exon 7 of the glucokinase gene in a patient with early-onset non-insulin-dependent diabetes (NIDDM). 12 refs., 3 figs., 2 tabs.

  19. Ischemic preconditioning maintains the immunoreactivities of glucokinase and glucokinase regulatory protein in neurons of the gerbil hippocampal CA1 region following transient cerebral ischemia

    PubMed Central

    CHO, YOUNG SHIN; CHO, JUN HWI; SHIN, BICH-NA; CHO, GEUM-SIL; KIM, IN HYE; PARK, JOON HA; AHN, JI HYEON; OHK, TAEK GEUN; CHO, BYUNG-RYUL; KIM, YOUNG-MYEONG; HONG, SEONGKWEON; WON, MOO-HO; LEE, JAE-CHUL

    2015-01-01

    Glucokinase (GK) is involved in the control of blood glucose homeostasis. In the present study, the effect of ischemic preconditioning (IPC) on the immunoreactivities of GK and its regulatory protein (GKRP) following 5 min of transient cerebral ischemia was investigated in gerbils. The gerbils were randomly assigned to four groups (sham-operated group, ischemia-operated group, IPC + sham-operated group and IPC + ischemia-operated group). IPC was induced by subjecting the gerbils to 2 min of ischemia, followed by 1 day of recovery. In the ischemia-operated group, a significant loss of neurons was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) at 5 days post-ischemia; however, in the IPC+ischemia-operated group, the neurons in the SP were well protected. Following immunohistochemical investigation, the immunoreactivities of GK and GKRP in the neurons of the SP were markedly decreased in the CA1, but not the CA2/3, from 2 days post-ischemia, and were almost undetectable in the SP 5 days post-ischemia. In the IPC + ischemia-operated group, the immunoreactivities of GK and GKRP in the SP of the CA1 were similar to those in the sham-group. In brief, the findings of the present study demonstrated that IPC notably maintained the immunoreactivities of GK and GKRP in the neurons of the SP of CA1 following ischemia-reperfusion. This indicated that GK and GKRP may be necessary for neuron survival against transient cerebral ischemia. PMID:26134272

  20. Ischemic preconditioning maintains the immunoreactivities of glucokinase and glucokinase regulatory protein in neurons of the gerbil hippocampal CA1 region following transient cerebral ischemia.

    PubMed

    Cho, Young Shin; Cho, Jun Hwi; Shin, Bich-Na; Cho, Geum-Sil; Kim, In Hye; Park, Joon Ha; Ahn, Ji Hyeon; Ohk, Taek Geun; Cho, Byung-Ryul; Kim, Young-Myeong; Hong, Seongkweon; Won, Moo-Ho; Lee, Jae-Chul

    2015-10-01

    Glucokinase (GK) is involved in the control of blood glucose homeostasis. In the present study, the effect of ischemic preconditioning (IPC) on the immunoreactivities of GK and its regulatory protein (GKRP) following 5 min of transient cerebral ischemia was investigated in gerbils. The gerbils were randomly assigned to four groups (sham‑operated group, ischemia‑operated group, IPC + sham‑operated group and IPC + ischemia‑operated group). IPC was induced by subjecting the gerbils to 2 min of ischemia, followed by 1 day of recovery. In the ischemia‑operated group, a significant loss of neurons was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) at 5 days post‑ischemia; however, in the IPC+ischemia‑operated group, the neurons in the SP were well protected. Following immunohistochemical investigation, the immunoreactivities of GK and GKRP in the neurons of the SP were markedly decreased in the CA1, but not the CA2/3, from 2 days post‑ischemia, and were almost undetectable in the SP 5 days post‑ischemia. In the IPC + ischemia‑operated group, the immunoreactivities of GK and GKRP in the SP of the CA1 were similar to those in the sham‑group. In brief, the findings of the present study demonstrated that IPC notably maintained the immunoreactivities of GK and GKRP in the neurons of the SP of CA1 following ischemia‑reperfusion. This indicated that GK and GKRP may be necessary for neuron survival against transient cerebral ischemia. PMID:26134272

  1. Substrate Recognition Mechanism and Substrate-Dependent Conformational Changes of an ROK Family Glucokinase from Streptomyces griseus

    PubMed Central

    Miyazono, Ken-ichi; Tabei, Nobumitsu; Morita, Sho; Ohnishi, Yasuo; Horinouchi, Sueharu

    2012-01-01

    Carbon catabolite repression (CCR) is a widespread phenomenon in many bacteria that is defined as the repression of catabolic enzyme activities for an unfavorable carbon source by the presence of a preferable carbon source. In Streptomyces, secondary metabolite production often is negatively affected by the carbon source, indicating the involvement of CCR in secondary metabolism. Although the CCR mechanism in Streptomyces still is unclear, glucokinase is presumably a central player in CCR. SgGlkA, a glucokinase from S. griseus, belongs to the ROK family glucokinases, which have two consensus sequence motifs (1 and 2). Here, we report the crystal structures of apo-SgGlkA, SgGlkA in complex with glucose, and SgGlkA in complex with glucose and adenylyl imidodiphosphate (AMPPNP), which are the first structures of an ROK family glucokinase. SgGlkA is divided into a small α/β domain and a large α+β domain, and it forms a dimer-of-dimer tetrameric configuration. SgGlkA binds a β-anomer of glucose between the two domains, and His157 in consensus sequence 1 plays an important role in the glucose-binding mechanism and anomer specificity of SgGlkA. In the structures of SgGlkA, His157 forms an HC3-type zinc finger motif with three cysteine residues in consensus sequence 2 to bind a zinc ion, and it forms two hydrogen bonds with the C1 and C2 hydroxyls of glucose. When the three structures are compared, the structure of SgGlkA is found to be modified by the binding of substrates. The substrate-dependent conformational changes of SgGlkA may be related to the CCR mechanism in Streptomyces. PMID:22101842

  2. Onset of carbon catabolite repression in Aspergillus nidulans. Parallel involvement of hexokinase and glucokinase in sugar signaling.

    PubMed

    Flipphi, Michel; van de Vondervoort, Peter J I; Ruijter, George J G; Visser, Jaap; Arst, Herbert N; Felenbok, Béatrice

    2003-04-01

    The role of hexose phosphorylating enzymes in the signaling of carbon catabolite repression was investigated in the filamentous fungus Aspergillus nidulans. A d-fructose non-utilizing, hexokinase-deficient (hxkA1, formerly designated frA1) strain was utilized to obtain new mutants lacking either glucokinase (glkA4) or both hexose kinases (hxkA1/glkA4). d-Glucose and d-fructose phosphorylation is completely abolished in the double mutant, which consequently cannot grow on either sugar. The glucokinase single mutant exhibits no nutritional deficiencies. Three repressible diagnostic systems, ethanol utilization (alcA and alcR genes), xylan degradation (xlnA), and acetate catabolism (facA), were analyzed in these hexose kinase mutants at the transcript level. Transcriptional repression by d-glucose is fully retained in the two single kinase mutants, whereas the hexokinase mutant is partially derepressed for d-fructose. Thus, hexokinase A and glucokinase A compensate each other for carbon catabolite repression by d-glucose in the single mutants. In contrast, both d-glucose and d-fructose repression are severely impaired for all three diagnostic systems in the double mutant. Unlike the situation in Saccharomyces cerevisiae, the hexose phosphorylating enzymes play parallel roles in glucose repression in A. nidulans. PMID:12519784

  3. Cloning, expression and characterization of glucokinase gene involved in the glucose-6- phosphate formation in Staphylococcus aureus

    PubMed Central

    Lakshmi, Hanumanthu Prasanna; Yeswanth, Sthanikam; Prasad, Uppu Venkateswara; Vasu, Dudipeta; Swarupa, Vimjam; Kumar, Pasupuleti Santhosh; Narasu, Mangamoori Lakshmi; Krishna Sarma, Potukuchi Venkata Gurunadha

    2013-01-01

    Glucose-6-phosphate (G-6-P) formation in Staphylococcus aureus is catalysed by glucokinase (glkA) gene under high glucose concentration leading to upregulation of various pathogenic factors; therefore the present study is aimed in the cloning and characterization of glk A gene from S. aureus ATCC12600. The glk A gene was cloned in the Sma I site of pQE 30, sequenced (Accession number: JN645812) and expressed in E. coli DH5α. The recombinant glk A expressed from the resultant glk A 1 clone was purified using nickel metal chelate chromatography, the pure enzyme gave single band in SDS-PAGE with molecular weight of 33kDa. The rglk A showed very high affinity to glucose Km 5.1±0.06mM with Hill coefficient of 1.66±0.032mM. Analysis of glucokinase sequence of S. aureus showed presence of typical ATP binding site and ROK motif CNCGRSGCIE. Sequentially and phylogenetically S. aureus glk A exhibited low identity with other bacterial glk A and 21% homology with human glucokinase (GCK). Functionally, S. aureus glk A showed higher rate of G-6-P formation compared to human GCK which may have profound role in the pathogenesis. PMID:23519063

  4. Overexpression of a glucokinase point mutant in the treatment of diabetes mellitus

    PubMed Central

    Lu, G; Teng, X; Zheng, Z; Zhang, R; Peng, L; Zheng, F; Liu, J; Huang, H; Xiong, H

    2016-01-01

    Glucokinase (GCK) is an important enzyme critical for glucose metabolism, and has been targeted as such in the pursuit of a cure for diabetes mellitus. We show that streptozotocin (STZ)-induced diabetic murine model exhibits low GCK expression with high blood glucose levels; moreover, aggravated glomerulonephritis is observed in the model when there is IL10 deficiency. Although T cells infiltrate into the liver and pancreas in STZ-induced diabetes mice, T helper 1 (Th1) and T helper 17 (Th17) cells decrease significantly with STZ addition in in vitro polarization. Using a mutant GCK gene (GCK 262) with a knocked out cytosine at position 2643 results in lower protein expression and more ubiquitination-led protein degradation compared with wild-type GCK (GCK 261). We further observed that hsa-mir-1302 can bind to 3′-untranslated region of mutant GCK, which can decrease GCK mRNA translation. Finally, delivery of mutant GCK by subcutaneous injection is more effective at decreasing blood glucose in the STZ-treated (STZ) murine diabetes model than insulin treatment alone. Similarly, mutant GCK consistently and moderately decreases blood glucose levels in GK rats over a period of 12 and 70 days without inducing hypoglycemia, whereas insulin is only effective over 12 h. These results suggest that mutant GCK may be a future cure for diabetes. PMID:26752353

  5. Dynamic Localization of Glucokinase and Its Regulatory Protein in Hypothalamic Tanycytes

    PubMed Central

    Ordenes, Patricio; Millán, Carola; Yañez, María José; Llanos, Paula; Villagra, Marcos; Elizondo-Vega, Roberto; Martínez, Fernando; Nualart, Francisco; Uribe, Elena; de los Angeles García-Robles, María

    2014-01-01

    Glucokinase (GK), the hexokinase involved in glucose sensing in pancreatic β cells, is also expressed in hypothalamic tanycytes, which cover the ventricular walls of the basal hypothalamus and are implicated in an indirect control of neuronal activity by glucose. Previously, we demonstrated that GK was preferentially localized in tanycyte nuclei in euglycemic rats, which has been reported in hepatocytes and is suggestive of the presence of the GK regulatory protein, GKRP. In the present study, GK intracellular localization in hypothalamic and hepatic tissues of the same rats under several glycemic conditions was compared using confocal microscopy and Western blot analysis. In the hypothalamus, increased GK nuclear localization was observed in hyperglycemic conditions; however, it was primarily localized in the cytoplasm in hepatic tissue under the same conditions. Both GK and GKRP were next cloned from primary cultures of tanycytes. Expression of GK by Escherichia coli revealed a functional cooperative protein with a S0.5 of 10 mM. GKRP, expressed in Saccharomyces cerevisiae, inhibited GK activity in vitro with a Ki 0.2 µM. We also demonstrated increased nuclear reactivity of both GK and GKRP in response to high glucose concentrations in tanycyte cultures. These data were confirmed using Western blot analysis of nuclear extracts. Results indicate that GK undergoes short-term regulation by nuclear compartmentalization. Thus, in tanycytes, GK can act as a molecular switch to arrest cellular responses to increased glucose. PMID:24739934

  6. Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus.

    PubMed Central

    Stoffel, M; Froguel, P; Takeda, J; Zouali, H; Vionnet, N; Nishi, S; Weber, I T; Harrison, R W; Pilkis, S J; Lesage, S

    1992-01-01

    DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in approximately 80% of French families with this form of diabetes. We previously identified a nonsense mutation in exon 7 in one of these families and showed that it was the likely cause of glucose intolerance in this dominantly inherited disorder. Here we report the isolation and partial sequence of the human glucokinase gene and the identification of two missense mutations in exon 7, Thr-228----Met and Gly-261----Arg, that cosegregate with early-onset non-insulin-dependent diabetes mellitus. To assess the molecular mechanism by which mutations at these two sites may affect glucokinase activity, the crystal structure of the related yeast hexokinase B was used as a simple model for human beta-cell glucokinase. Computer-assisted modeling suggests that mutation of Thr-228 affects affinity for ATP and mutation of Gly-261 may alter glucose binding. The identification of mutations in glucokinase, a protein that plays an important role in hepatic and beta-cell glucose metabolism, indicates that early-onset non-insulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism. Images PMID:1502186

  7. Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase.

    PubMed

    D'Antonio, Edward L; Deinema, Mason S; Kearns, Sean P; Frey, Tyler A; Tanghe, Scott; Perry, Kay; Roy, Timothy A; Gracz, Hanna S; Rodriguez, Ana; D'Antonio, Jennifer

    2015-12-01

    Glucokinase and hexokinase from pathogenic protozoa Trypanosoma cruzi are potential drug targets for antiparasitic chemotherapy of Chagas' disease. These glucose kinases phosphorylate d-glucose with co-substrate ATP and yield glucose 6-phosphate and are involved in essential metabolic pathways, such as glycolysis and the pentose phosphate pathway. An inhibitor class was conceived that is selective for T. cruzi glucokinase (TcGlcK) using structure-based drug design involving glucosamine having a linker from the C2 amino that terminates with a hydrophobic group either being phenyl, p-hydroxyphenyl, or dioxobenzo[b]thiophenyl groups. The synthesis and characterization for two of the four compounds are presented while the other two compounds were commercially available. Four high-resolution X-ray crystal structures of TcGlcK inhibitor complexes are reported along with enzyme inhibition constants (Ki) for TcGlcK and Homo sapiens hexokinase IV (HsHxKIV). These glucosamine analogue inhibitors include three strongly selective TcGlcK inhibitors and a fourth inhibitor, benzoyl glucosamine (BENZ-GlcN), which is a similar variant exhibiting a shorter linker. Carboxybenzyl glucosamine (CBZ-GlcN) was found to be the strongest glucokinase inhibitor known to date, having a Ki of 0.71±0.05μM. Also reported are two biologically active inhibitors against in vitro T. cruzi culture that were BENZ-GlcN and CBZ-GlcN, with intracellular amastigote growth inhibition IC50 values of 16.08±0.16μM and 48.73±0.69μM, respectively. These compounds revealed little to no toxicity against mammalian NIH-3T3 fibroblasts and provide a key starting point for further drug development with this class of compound. PMID:26778112

  8. Role of connecting loop I in catalysis and allosteric regulation of human glucokinase

    PubMed Central

    Martinez, Juliana A; Larion, Mioara; Conejo, Maria S; Porter, Carol M; Miller, Brian G

    2014-01-01

    Glucokinase (GCK, hexokinase IV) is a monomeric enzyme with a single glucose binding site that displays steady-state kinetic cooperativity, a functional characteristic that affords allosteric regulation of GCK activity. Structural evidence suggests that connecting loop I, comprised of residues 47–71, facilitates cooperativity by dictating the rate and scope of motions between the large and small domains of GCK. Here we investigate the impact of varying the length and amino acid sequence of connecting loop I upon GCK cooperativity. We find that sequential, single amino acid deletions from the C-terminus of connecting loop I cause systematic decreases in cooperativity. Deleting up to two loop residues leaves the kcat value unchanged; however, removing three or more residues reduces kcat by 1000-fold. In contrast, the glucose K0.5 and KD values are unaffected by shortening the connecting loop by up to six residues. Substituting alanine or glycine for proline-66, which adopts a cis conformation in some GCK crystal structures, does not alter cooperativity, indicating that cis/trans isomerization of this loop residue does not govern slow conformational reorganizations linked to hysteresis. Replacing connecting loop I with the corresponding loop sequence from the catalytic domain of the noncooperative isozyme human hexokinase I (HK-I) eliminates cooperativity without impacting the kcat and glucose K0.5 values. Our results indicate that catalytic turnover requires a minimal length of connecting loop I, whereas the loop has little impact upon the binding affinity of GCK for glucose. We propose a model in which the primary structure of connecting loop I affects cooperativity by influencing conformational dynamics, without altering the equilibrium distribution of GCK conformations. PMID:24723372

  9. Role of connecting loop I in catalysis and allosteric regulation of human glucokinase.

    PubMed

    Martinez, Juliana A; Larion, Mioara; Conejo, Maria S; Porter, Carol M; Miller, Brian G

    2014-07-01

    Glucokinase (GCK, hexokinase IV) is a monomeric enzyme with a single glucose binding site that displays steady-state kinetic cooperativity, a functional characteristic that affords allosteric regulation of GCK activity. Structural evidence suggests that connecting loop I, comprised of residues 47-71, facilitates cooperativity by dictating the rate and scope of motions between the large and small domains of GCK. Here we investigate the impact of varying the length and amino acid sequence of connecting loop I upon GCK cooperativity. We find that sequential, single amino acid deletions from the C-terminus of connecting loop I cause systematic decreases in cooperativity. Deleting up to two loop residues leaves the kcat value unchanged; however, removing three or more residues reduces kcat by 1000-fold. In contrast, the glucose K0.5 and KD values are unaffected by shortening the connecting loop by up to six residues. Substituting alanine or glycine for proline-66, which adopts a cis conformation in some GCK crystal structures, does not alter cooperativity, indicating that cis/trans isomerization of this loop residue does not govern slow conformational reorganizations linked to hysteresis. Replacing connecting loop I with the corresponding loop sequence from the catalytic domain of the noncooperative isozyme human hexokinase I (HK-I) eliminates cooperativity without impacting the kcat and glucose K0.5 values. Our results indicate that catalytic turnover requires a minimal length of connecting loop I, whereas the loop has little impact upon the binding affinity of GCK for glucose. We propose a model in which the primary structure of connecting loop I affects cooperativity by influencing conformational dynamics, without altering the equilibrium distribution of GCK conformations. PMID:24723372

  10. Glucose- and glucokinase-controlled mal gene expression in Escherichia coli.

    PubMed

    Lengsfeld, Christina; Schönert, Stefan; Dippel, Renate; Boos, Winfried

    2009-02-01

    MalT is the central transcriptional activator of all mal genes in Escherichia coli. Its activity is controlled by the inducer maltotriose. It can be inhibited by the interaction with certain proteins, and its expression can be controlled. We report here a novel aspect of mal gene regulation: the effect of cytoplasmic glucose and glucokinase (Glk) on the activity and the expression of MalT. Amylomaltase (MalQ) is essential for the metabolism of maltose. It forms maltodextrins and glucose from maltose or maltodextrins. We found that glucose above a concentration of 0.1 mM blocked the activity of the enzyme. malQ mutants when grown in the absence of maltodextrins are endogenously induced by maltotriose that is derived from the degradation of glycogen. Therefore, the fact that glk malQ(+) mutants showed elevated mal gene expression finds its explanation in the reduced ability to remove glucose from MalQ-catalyzed maltodextrin formation and is caused by a metabolically induced MalQ(-) phenotype. However, even in mutants lacking glycogen, Glk controls endogenous induction. We found that overexpressed Glk due to its structural similarity with Mlc, the repressor of malT, binds to the glucose transporter (PtsG), releasing Mlc and thus increasing malT repression. In addition, even in mutants lacking Mlc (and glycogen), the overexpression of glk leads to a reduction in mal gene expression. We interpret this repression by a direct interaction of Glk with MalT concomitant with MalT inhibition. This repression was dependent on the presence of either maltodextrin phosphorylase or amylomaltase and led to the inactivation of MalT. PMID:19028900

  11. Regulation of glucokinase activity in liver of hibernating ground squirrel Spermophilus undulatus.

    PubMed

    Khu, L Ya; Storey, K B; Rubtsov, A M; Goncharova, N Yu

    2014-07-01

    The kinetic properties of glucokinase (GLK) from the liver of active and hibernating ground squirrels Spermophilus undulatus have been studied. Entrance of ground squirrels into hibernation from their active state is accompanied by a sharp decrease in blood glucose (Glc) level (from 14 to 2.9 mM) and with a significant (7-fold) decrease of GLK activity in the liver cytoplasm. Preparations of native GLK practically devoid of other molecular forms of hexokinase were obtained from the liver of active and hibernating ground squirrels. The dependence of GLK activity upon Glc concentration for the enzyme from active ground squirrel liver showed a pronounced sigmoid character (Hill coefficient, h=1.70 and S0.5=6.23 mM; the experiments were conducted at 25°C in the presence of enzyme stabilizers, K+ and DTT). The same dependence of enzyme activity on Glc concentration was found for GLK from rat liver. However, on decreasing the temperature to 2°C (simulation of hibernation conditions), this dependency became almost hyperbolic (h=1.16) and GLK affinity for substrate was reduced (S0.5=23 mM). These parameters for hibernating ground squirrels (body temperature 5°C) at 25°C were found to be practically equal to the corresponding values obtained for GLK from the liver of active animals (h=1.60, S0.5=9.0 mM, respectively); at 2°C sigmoid character was less expressed and affinity for Glc was drastically decreased (h=1.20, S0.5=45 mM). The calculations of GLK activity in the liver of hibernating ground squirrels based on enzyme kinetic characteristics and seasonal changes in blood Glc concentrations have shown that GLK activity in the liver of hibernating ground squirrels is decreased about 5500-fold. PMID:25108335

  12. MiR-206 is expressed in pancreatic islets and regulates glucokinase activity

    PubMed Central

    Sachdev, Vinay; Frank, Saša; Graier, Wolfgang F.; Kratky, Dagmar; Kostner, Gerhard M.

    2016-01-01

    Glucose homeostasis is a complex indispensable process, and its dysregulation causes hyperglycemia and type 2 diabetes mellitus. Glucokinase (GK) takes a central role in these pathways and is thus rate limiting for glucose-stimulated insulin secretion (GSIS) from pancreatic islets. Several reports have described the transcriptional regulation of Gck mRNA, whereas its posttranscriptional mechanisms of regulation, especially those involving microRNAs (miR), are poorly understood. In this study, we investigated the role of miR-206 as a posttranscriptional regulator of Gck. In addition, we examined the effects of miR-206 on glucose tolerance, GSIS, and gene expression in control and germ line miR-206 knockout (KO) mice fed either with chow or high-fat diet (HFD). MiR-206 was found in Gck-expressing tissues and was differentially altered in response to HFD feeding. Pancreatic islets showed the most profound induction in the expression of miR-206 in response to HFD. Chow- and HFD-fed miR-206KO mice have improved glucose tolerance and GSIS but unaltered insulin sensitivity. In silico analysis of Gck mRNA revealed a conserved 8-mer miR-206 binding site. Hence, the predicted regulation of Gck by miR-206 was confirmed in reporter and GK activity assays. Concomitant with increased GK activity, miR-206KO mice had elevated liver glycogen content and plasma lactate concentrations. Our findings revealed a novel mechanism of posttranscriptional regulation of Gck by miR-206 and underline the crucial role of pancreatic islet miR-206 in the regulation of whole body glucose homeostasis in a murine model that mimics the metabolic syndrome. PMID:27221121

  13. Lactose metabolism in Streptococcus lactis: studies with a mutant lacking glucokinase and mannose-phosphotransferase activities

    SciTech Connect

    Thompson, J.; Chassy, B.M.; Egan, W.

    1985-04-01

    A mutant of Streptococcus lactis 133 has been isolated that lacks both glucokinase and phosphoenolpyruvate-dependent mannose- phosphotransferase (mannose-PTS) activities. The double mutant S. lactis 133 mannose-PTSd GK- is unable to utilize either exogenously supplied or intracellularly generated glucose for growth. Fluorographic analyses of metabolites formed during the metabolism of (/sup 14/C)lactose labeled specifically in the glucose or galactosyl moiety established that the cells were unable to phosphorylate intracellular glucose. However, cells of S. lactis 133 mannose-PTSd GK- readily metabolized intracellular glucose 6-phosphate, and the growth rates and cell yield of the mutant and parental strains on sucrose were the same. During growth on lactose, S. lactis 133 mannose-PTSd GK- fermented only the galactose moiety of the disaccharide, and 1 mol of glucose was generated per mol of lactose consumed. For an equivalent concentration of lactose, the cell yield of the mutant was 50% that of the wild type. The specific rate of lactose utilization by growing cells of S. lactis 133 mannose-PTSd GK- was ca. 50% greater than that of the wild type, but the cell doubling times were 70 and 47 min, respectively. High-resolution /sup 31/P nuclear magnetic resonance studies of lactose transport by starved cells of S. lactis 133 and S. lactis 133 mannose-PTSd GK- showed that the latter cells contained elevated lactose-PTS activity. Throughout exponential growth on lactose, the mutant maintained an intracellular steady-state glucose concentration of 100 mM.

  14. Design and Synthesis of Acetylenyl Benzamide Derivatives as Novel Glucokinase Activators for the Treatment of T2DM

    PubMed Central

    2015-01-01

    Novel acetylenyl-containing benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucokinase activity stimulated by 10 mM glucose concentration and glucose uptake in rat hepatocytes. Lead optimization of an acetylenyl benzamide series led to the discovery of several active compounds via in vitro enzyme assays (EC50 < 40 nM) and in vivo OGTT assays (AUC reduction > 40% at 50 mg/kg). Of the active compounds tested, 3-(3-amino-phenylethynyl)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-benzamide (19) was identified as a potent glucokinase activator exhibiting an EC50 of 27 nM and eliciting a 2.16-fold increase in glucose uptake. Compound 19 caused a glucose AUC reduction of 47.4% (30 mg/kg) in an OGTT study in C57BL/6J mice compared to 22.6% for sitagliptin (30 mg/kg). Single treatment of the compound 19 in C57BL/6J mice elicited basal glucose lowering activity without any significant evidence for hypoglycemia risk. Compound 19 was therefore selected as a candidate for further preclinical development for the treatment of type 2 diabetes. PMID:25815149

  15. Association between glucokinase regulatory protein (GCKR) and apolipoprotein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Hypertriglyceridemia is a risk factor for cardiovascular disease. Variation in the apolipoprotein A5 (APOA5) and glucokinase regulatory protein (GCKR) genes has been associated with fasting plasma triacylglycerol. Objective: We investigated the combined effects of the GCKR rs780094C-->T,...

  16. A Common Missense Variant in the Glucokinase Regulatory Protein Gene (GCKR) Is Associated with Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    OBJECTIVE-Using the genome-wide-association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metaboli...

  17. Cloning and characterization of glucokinase from a methylotrophic yeast Hansenula polymorpha: different effects on glucose repression in H. polymorpha and Saccharomyces cerevisiae.

    PubMed

    Laht, Silja; Karp, Helen; Kotka, Pille; Järviste, Aiki; Alamäe, Tiina

    2002-08-21

    Glucokinase gene (HPGLK1) was cloned from a methylotrophic yeast Hansenula polymorpha by complementation of glucose-phosphorylation deficiency in a H. polymorpha double kinase-negative mutant A31-10 by a genomic library. An open reading frame of 1416 nt encoding a 471-amino-acid protein with calculated molecular weight 51.6 kDa was characterized in the genomic insert of the plasmid pH3. The protein sequence deduced from HPGLK1 exhibited 55 and 46% identity with glucokinases from Saccharomyces cerevisiae and Aspergillus niger, respectively. The enzyme phosphorylated glucose, mannose and 2-deoxyglucose, but not fructose. Transformation of HPGLK1 into A31-10 restored glucose repression of alcohol oxidase and catalase in the mutant. Transformation of HPGLK1 into S. cerevisiae triple kinase-negative mutant DFY632 showed that H. polymorpha glucokinase cannot transmit the glucose repression signal in S. CEREVSIAE: synthesis of invertase and maltase in respective transformants was insensitive to glucose repression similarly to S. cerevisiae DFY568 possessing only glucokinase. PMID:12383517

  18. Low glucokinase activity and high rates of gluconeogenesis contribute to hyperglycemia in barn owls (Tyto alba) after a glucose challenge.

    PubMed

    Myers, M R; Klasing, K C

    1999-10-01

    Barn owls (Tyto alba) and leghorn chickens were fed a low protein high glucose (33.44% protein, 23.67% glucose) or a high protein low glucose (55.35% protein, 1.5% glucose) diet. After an intravenous glucose infusion, the peak in plasma glucose was not affected by diet in either species and was 22.6 and 39.4 mmol/L in chickens and barn owls, respectively. Glucose levels returned to normal within 30 min in chickens, but remained elevated for 3.5 h in barn owls. An oral glucose challenge also resulted in greater and longer hyperglycemia in barn owls than in chickens. The activities of hepatic glucokinase, malic enzyme and phosphoenolpyruvate carboxykinase of barn owls were 16, 35, and 333% of the levels in chickens. Malic enzyme (P = 0.024) was less affected by dietary glucose level in barn owls than in chickens. Cultured hepatocytes from chickens produced 43% more glucose from lactate than hepatocytes from barn owls and, conversely, barn owl hepatocytes produced 87% more glucose from threonine than chickens (P = 0.001). Gluconeogenesis from lactate was greatly suppressed by high media glucose in chicken hepatocytes but not in those of barn owls (P = 0.0001 for species by glucose level interaction). When threonine was the substrate, gluconeogenesis was suppressed by increased glucose in both species but to a greater relative extent in chickens (P = 0.007 for species by glucose level interaction). Owls were glucose intolerant at least in part because of low hepatic glucokinase activity and an inadequate suppression of gluconeogenesis in the presence of exogenous glucose, apparently because they evolved with large excesses of amino acids and limited glucose in their normal diet. PMID:10498765

  19. Characterization of the heterozygous glucokinase knockout mouse as a translational disease model for glucose control in type 2 diabetes

    PubMed Central

    Baker, D J; Atkinson, A M; Wilkinson, G P; Coope, G J; Charles, A D; Leighton, B

    2014-01-01

    Background and Purpose The global heterozygous glucokinase (GK) knockout (gkwt/del) male mouse, fed on a high-fat (60% by energy) diet, has provided a robust and reproducible model of hyperglycaemia. This model could be highly relevant to some facets of human type 2 diabetes (T2D). We aimed to investigate the ability of standard therapeutic agents to lower blood glucose at translational doses, and to explore the glucose-lowering potential of novel glucokinase activators (GKAs) in this model. Experimental Approach We measured the ability of insulin, metformin, glipizide, exendin-4 and sitagliptin, after acute or repeat dose administration, to lower free-feeding glucose levels in gkwt/del mice. Further, we measured the ability of novel GKAs, GKA23, GKA71 and AZD6370 to control glucose either alone or in combination with some standard agents. Key Results A single dose of insulin (1 unit·kg−1), metformin (150, 300 mg·kg−1), glipizide (0.1, 0.3 mg·kg−1), exendin-4 (2, 20 μg·kg−1) and GKAs reduced free-feeding glucose levels. Sitagliptin (10 mg·kg−1), metformin (300 mg·kg−1) and AZD6370 (30, 400 mg·kg−1) reduced glucose excursions on repeat dosing. At a supra-therapeutic dose (400 mg·kg−1), AZD6370 also lowered basal levels of glucose without inducing hypoglycaemia. Conclusion and Implications Standard glucose-lowering therapeutic agents demonstrated significant acute glucose lowering in male gkwt/del mice at doses corresponding to therapeutic free drug levels in man, suggesting the potential of these mice as a translatable model of human T2D. Novel GKAs also lowered glucose in this mouse model. PMID:24772483

  20. Effects of a glucokinase activator on hepatic intermediary metabolism: study with 13C-isotopomer-based metabolomics

    PubMed Central

    Nissim, Itzhak; Horyn, Oksana; Nissim, Ilana; Daikhin, Yevgeny; Wehrli, Suzanne L.; Yudkoff, Marc; Matschinsky, Franz M.

    2013-01-01

    GKAs (glucokinase activators) are promising agents for the therapy of Type 2 diabetes, but little is known about their effects on hepatic intermediary metabolism. We monitored the fate of 13C-labelled glucose in both a liver perfusion system and isolated hepatocytes. MS and NMR spectroscopy were deployed to measure isotopic enrichment. The results demonstrate that the stimulation of glycolysis by GKA led to numerous changes in hepatic metabolism: (i) augmented flux through the TCA (tricarboxylic acid) cycle, as evidenced by greater incorporation of 13C into the cycle (anaplerosis) and increased generation of 13C isotopomers of citrate, glutamate and aspartate (cataplerosis); (ii) lowering of hepatic [Pi] and elevated [ATP], denoting greater phosphorylation potential and energy state; (iii) stimulation of glycogen synthesis from glucose, but inhibition of glycogen synthesis from 3-carbon precursors; (iv) increased synthesis of N-acetylglutamate and consequently augmented ureagenesis; (v) increased synthesis of glutamine, alanine, serine and glycine; and (vi) increased production and outflow of lactate. The present study provides a deeper insight into the hepatic actions of GKAs and uncovers the potential benefits and risks of GKA for treatment of diabetes. GKA improved hepatic bioenergetics, ureagenesis and glycogenesis, but decreased gluconeogenesis with a potential risk of lactic acidosis and fatty liver. PMID:22448977

  1. Cloning and characterization of the mouse glucokinase gene locus and identification of distal liver-specific DNase I hypersensitive sites

    SciTech Connect

    Postic, C.; Niswender, K.D.; Shelton, K.D.; Pettepher, C.C.; Granner, D.K.; Magnuson, M.A.

    1995-10-10

    We cloned and characterized an 83-kb fragment of mouse genomic DNA containing the entire glucokinase (GK) gene. The 11 exons of the gene span a total distance of 49 kb, with exons 1{beta} and 1L being separated by 35 kb. A total of 25,266 bp of DNA sequence information was determined: from {approximately}-9.2 to {approximately}+15 kb (24,195 bp), relative to the hepatocyte transcription start site, and from -335 to -736 bp (1071 bp), relative to the transcription start site in {beta} cells. These sequences revealed that mouse GK is >94% identical to rat and human GK. Mouse hepatic GK mRNA is regulated by fasting and refeeding, as also occurs in the rat. Alignment of the upstream and downstream promoter regions of the mouse, rat, and human genes revealed several evolutionarily conserved regions that may contribute to transcriptional regulation. However, fusion gene studies in transgenic mice indicate that the conserved regions near the transcription start site in hepatocytes are themselves not sufficient for position-independent expression in liver. Analysis of the chromatin structure of a 48-kb region of the mouse gene using DNase I revealed eight liver-specific hypersensitive sites whose locations ranged from 0.1 to 36 kb upstream of the liver transcription start site. The availability of a single, contiguous DNA fragment containing the entire mouse GK gene should allow further studies of cell-specific expression of GK to be performed. 46 refs., 8 figs.

  2. Evidence for the Presence of Glucosensor Mechanisms Not Dependent on Glucokinase in Hypothalamus and Hindbrain of Rainbow Trout (Oncorhynchus mykiss).

    PubMed

    Otero-Rodiño, Cristina; Librán-Pérez, Marta; Velasco, Cristina; López-Patiño, Marcos A; Míguez, Jesús M; Soengas, José L

    2015-01-01

    We hypothesize that glucosensor mechanisms other than that mediated by glucokinase (GK) operate in hypothalamus and hindbrain of the carnivorous fish species rainbow trout and stress affected them. Therefore, we evaluated in these areas changes in parameters which could be related to putative glucosensor mechanisms based on liver X receptor (LXR), mitochondrial activity, sweet taste receptor, and sodium/glucose co-transporter 1 (SGLT-1) 6 h after intraperitoneal injection of 5 mL x Kg(-1) of saline solution alone (normoglycaemic treatment) or containing insulin (hypoglycaemic treatment, 4 mg bovine insulin x Kg(-1) body mass), or D-glucose (hyperglycaemic treatment, 500 mg x Kg(-1) body mass). Half of tanks were kept at a 10 Kg fish mass x m(-3) and denoted as fish under normal stocking density (NSD) whereas the remaining tanks were kept at a stressful high stocking density (70 kg fish mass x m(-3)) denoted as HSD. The results obtained in non-stressed rainbow trout provide evidence, for the first time in fish, that manipulation of glucose levels induce changes in parameters which could be related to putative glucosensor systems based on LXR, mitochondrial activity and sweet taste receptor in hypothalamus, and a system based on SGLT-1 in hindbrain. Stress altered the response of parameters related to these systems to changes in glycaemia. PMID:25996158

  3. Studies on recombinant glucokinase (r-glk) protein of Brucella abortus as a candidate vaccine molecule for brucellosis.

    PubMed

    Vrushabhendrappa; Singh, Amit Kumar; Balakrishna, Konduru; Sripathy, Murali Harishchandra; Batra, Harsh Vardhan

    2014-09-29

    Brucellosis is one of the most prevalent zoonotic diseases of worldwide distribution caused by the infection of genus Brucella. Live attenuated vaccines such as B. abortus S19, B. abortus RB51 and B. melitensis Rev1 are found most effective against brucellosis infection in animals, contriving a number of serious side effects and having chances to revert back into their active pathogenic form. In order to engineer a safe and effective vaccine candidate to be used in both animals and human, a recombinant subunit vaccine molecule comprising the truncated region of glucokinase (r-glk) gene from B. abortus S19 was cloned and expressed in Escherichia coli BL21DE3 host. Female BALB/c mice immunized with purified recombinant protein developed specific antibody titer of 1:64,000. The predominant IgG2a and IgG2b isotypes signified development of Th1 directed immune responses. In vitro cell cytotoxicity assay using anti-r-glk antibodies incubated with HeLa cells showed 81.20% and 78.5% cell viability against lethal challenge of B. abortus 544 and B. melitensis 16M, respectively. The lymphocyte proliferative assay indicated a higher splenic lymphocyte responses at 25μg/ml concentration of protein which implies the elevated development of memory immune responses. In contrast to control, the immunized group of mice intra-peritoneal (I.P.) challenged with B. abortus 544 were significantly protected with no signs of necrosis and vacuolization in their liver and spleen tissue. The elevated B-cell response associated with Th1 adopted immunity, significant in vitro cell viability as well as protection afforded in experimental animals after challenge, supplemented with histopathological analysis are suggestive of r-glk protein as a prospective candidate vaccine molecule against brucellosis. PMID:25131740

  4. Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY).

    PubMed

    Thomson, K L; Gloyn, A L; Colclough, K; Batten, M; Allen, L I S; Beards, F; Hattersley, A T; Ellard, S

    2003-11-01

    Maturity-onset diabetes of the young (MODY) resulting from mutations in the glucokinase (GCK) gene accounts for approximately 20% of MODY in the UK. We have performed fluorescent single stranded conformation polymorphism (F-SSCP) analysis or direct sequencing of the GCK gene in 212 patients referred as part of a research cohort or for diagnostic molecular genetic testing. Mutation screening has identified 43 different mutations in 61 individuals, of which 21 are novel. This report details the mutations identified and their associated clinical features. PMID:14517956

  5. Post-prandial regulation of hepatic glucokinase and lipogenesis requires the activation of TORC1 signalling in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Dai, Weiwei; Panserat, Stéphane; Mennigen, Jan A; Terrier, Frédéric; Dias, Karine; Seiliez, Iban; Skiba-Cassy, Sandrine

    2013-12-01

    To assess the potential involvement of TORC1 (target of rapamycin complex 1) signalling in the regulation of post-prandial hepatic lipid and glucose metabolism-related gene expression in trout, we employed intraperitoneal administration of rapamycin to achieve an acute inhibition of the TOR pathway. Our results reveal that rapamycin inhibits the phosphorylation of TORC1 and its downstream effectors (S6K1, S6 and 4E-BP1), without affecting Akt and the Akt substrates Forkhead-box Class O1 (FoxO1) and glycogen synthase kinase 3α/β (GSK 3α/β). These results indicate that acute administration of rapamycin in trout leads to the inhibition of TORC1 activation. No effect is observed on the expression of genes involved in gluconeogenesis, glycolysis and fatty acid oxidation, but hepatic TORC1 inhibition results in decreased sterol regulatory element binding protein 1c (SREBP1c) gene expression and suppressed fatty acid synthase (FAS) and glucokinase (GK) at gene expression and activity levels, indicating that FAS and GK activity is controlled at a transcriptional level in a TORC1-dependent manner. This study demonstrates for the first time in fish that post-prandial regulation of hepatic lipogenesis and glucokinase in rainbow trout requires the activation of TORC1 signalling. PMID:24031053

  6. Toward a unified model of passive drug permeation II: the physiochemical determinants of unbound tissue distribution with applications to the design of hepatoselective glucokinase activators.

    PubMed

    Ghosh, Avijit; Maurer, Tristan S; Litchfield, John; Varma, Manthema V; Rotter, Charles; Scialis, Renato; Feng, Bo; Tu, Meihua; Guimaraes, Cris R W; Scott, Dennis O

    2014-10-01

    In this work, we leverage a mathematical model of the underlying physiochemical properties of tissues and physicochemical properties of molecules to support the development of hepatoselective glucokinase activators. Passive distribution is modeled via a Fick-Nernst-Planck approach, using in vitro experimental data to estimate the permeability of both ionized and neutral species. The model accounts for pH and electrochemical potential across cellular membranes, ionization according to Henderson-Hasselbalch, passive permeation of the neutral species using Fick's law, and passive permeation of the ionized species using the Nernst-Planck equation. The mathematical model of the physiochemical system allows derivation of a single set of parameters governing the distribution of drug molecules across multiple conditions both in vitro and in vivo. A case study using this approach in the development of hepatoselective glucokinase activators via organic anion-transporting polypeptide-mediated hepatic uptake and impaired passive distribution to the pancreas is described. The results for these molecules indicate the permeability penalty of the ionized form is offset by its relative abundance, leading to passive pancreatic exclusion according to the Nernst-Planck extension of Fickian passive permeation. Generally, this model serves as a useful construct for drug discovery scientists to understand subcellular exposure of acids or bases using specific physiochemical properties. PMID:25024402

  7. Use of alpha-toxin from Staphylococcus aureus to test for channelling of intermediates of glycolysis between glucokinase and aldolase in hepatocytes.

    PubMed

    Cascante, M; Centelles, J J; Agius, L

    2000-12-15

    We investigated whether hepatocytes permeabilized with alpha-toxin from Staphylococcus aureus are a valid model for studying the channelling of intermediates of glycolysis between glucokinase and triosephosphate isomerase. These cells are permeable to 2-aminoisobutyrate, ATP, glucose 6-phosphate (Glc6P) and fructose 2, 6-bisphosphate [Fru(2,6)P(2)], but maintain cell integrity in the presence of ATP as judged by the retention of cytoplasmic enzymes. During incubation with 25 mM glucose, an ATP-generating system and saturating concentrations of Fru(2,6)P(2), rates of detritiation of [2-(3)H]glucose and [3-(3)H]glucose were similar. Exogenous Glc6P (1 mM) and to a lesser extent fructose 6-phosphate, but not Fru(1, 6)P(2), decreased the rate of detritiation of [3-(3)H]glucose. During incubation with 25 mM glucose and Glc6P (0.2-1 mM), with either [3-(3)H]glucose or [3-(3)H]Glc6P as labelled substrate, there was dilution of metabolism of [3-(3)H]glucose with increasing Glc6P but no overall increase in glycolytic flux from glucose and Glc6P, indicating that glycolysis is apparently saturated with Glc6P despite the permeability of the cells to this metabolite. These findings could be explained by partial channelling of Glc6P between glucokinase and glycolysis in the presence of saturating concentrations of Fru(2,6)P(2). They provide an alternative explanation for the concept that there is more than one Glc6P pool. PMID:11104701

  8. Functional Characterization of MODY2 Mutations Highlights the Importance of the Fine-Tuning of Glucokinase and Its Role in Glucose Sensing

    PubMed Central

    García-Herrero, Carmen-María; Rubio-Cabezas, Oscar; Azriel, Sharona; Gutierrez-Nogués, Angel; Aragonés, Angel; Vincent, Olivier; Campos-Barros, Angel; Argente, Jesús; Navas, María-Angeles

    2012-01-01

    Glucokinase (GK) acts as a glucose sensor in the pancreatic beta-cell and regulates insulin secretion. Heterozygous mutations in the human GK-encoding GCK gene that reduce the activity index increase the glucose-stimulated insulin secretion threshold and cause familial, mild fasting hyperglycaemia, also known as Maturity Onset Diabetes of the Young type 2 (MODY2). Here we describe the biochemical characterization of five missense GK mutations: p.Ile130Thr, p.Asp205His, p.Gly223Ser, p.His416Arg and p.Ala449Thr. The enzymatic analysis of the corresponding bacterially expressed GST-GK mutant proteins show that all of them impair the kinetic characteristics of the enzyme. In keeping with their position within the protein, mutations p.Ile130Thr, p.Asp205His, p.Gly223Ser, and p.His416Arg strongly decrease the activity index of GK, affecting to one or more kinetic parameters. In contrast, the p.Ala449Thr mutation, which is located in the allosteric activator site, does not affect significantly the activity index of GK, but dramatically modifies the main kinetic parameters responsible for the function of this enzyme as a glucose sensor. The reduced Kcat of the mutant (3.21±0.28 s−1 vs 47.86±2.78 s−1) is balanced by an increased glucose affinity (S0.5 = 1.33±0.08 mM vs 7.86±0.09 mM) and loss of cooperativity for this substrate. We further studied the mechanism by which this mutation impaired GK kinetics by measuring the differential effects of several competitive inhibitors and one allosteric activator on the mutant protein. Our results suggest that this mutation alters the equilibrium between the conformational states of glucokinase and highlights the importance of the fine-tuning of GK and its role in glucose sensing. PMID:22291974

  9. Importance of glucokinase −258G/A polymorphism in Asian Indians with post-transplant and type 2 diabetes mellitus

    PubMed Central

    Khan, Imran Ali; Vattam, Kiran Kumar; Jahan, Parveen; Hasan, Qurratulain; Rao, Pragna

    2016-01-01

    Summary Type 2 diabetes mellitus (T2DM) and post-transplant diabetes mellitus (PTDM) are non-synonymous forms of diabetes. Glucokinase (GCK) plays a key role in glucose metabolism. The relationship between the GCK promoter and specific types of diabetes, such as PTDM and T2DM, in the Asian Indian population is unknown. We examined the occurrence of a specific GCK promoter variant (−258G/A) in patients with T2DM and PTDM. The case-control study enrolled 640 Asian Indian subjects, including controls (n = 250) and T2DM (n = 250), PTDM (n = 42), and non-post-transplant diabetes mellitus (non-PTDM) (n = 98) patients. Purified Deoxyribonucleic acid (DNA) was genotyped with the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. The digested PCR products were analyzed on 12% polyacrylamide gels. The anthropometric, biochemical, and clinical details of each group were documented. GCK −258G/A alleles and genotypes were not associated with T2DM. However, among PTDM subjects, we detected a higher frequency of heterozygotes (52.4%) and a positive association with alleles/genotypes. The results suggest that the promoter region (−258G/A) of GCK plays an important role in PTDM in Asian Indians. PMID:26989645

  10. Doubling the referral rate of monogenic diabetes through a nationwide information campaign--update on glucokinase gene mutations in a Polish cohort.

    PubMed

    Borowiec, M; Fendler, W; Antosik, K; Baranowska, A; Gnys, P; Zmyslowska, A; Malecki, M; Mlynarski, W

    2012-12-01

    In order to improve recruitment efficiency of patients with monogenic diabetes in Poland, in September 2010 a nationwide advertising campaign was launched to inform multiple target groups interested or participating in pediatric diabetologic care. Promotional actions aimed at informing physicians, patients, parents and educators were carried out through nationwide newspapers, medical and patient-developed websites and educational conference presentations. Recruitment efficiency was compared between September 2010 (publication of the first report on project's results) and the following 12 months. The number of families and patients referred to genetic screening was increased by 92% and 96% respectively nearly reaching the numbers recruited throughout the initial 4 years of the project. Participation of non-academic centers was also significantly increased from 2.3% to 7.5% (p = 0.0005). DNA sequencing and Multiplex Ligation-dependant Probe Amplification of the glucokinase gene resulted in finding 50 different mutations. Among those mutations, 19 were novel variants, which included: 17 missense mutations (predicted to be pathogenic according to bioinformatic analysis), 1 nonsense mutation and 1 mutation affecting a consensus intronic splice site. Advertising actions directed at increasing recruitment efficiency are a powerful and possibly neglected tool in screening for rare genetic disorders with a clinically defined phenotype. PMID:22035297

  11. Production of a mouse strain with impaired glucose tolerance by systemic heterozygous knockout of the glucokinase gene and its feasibility as a prediabetes model

    PubMed Central

    SAITO, Mikako; KANEDA, Asako; SUGIYAMA, Tae; IIDA, Ryousuke; OTOKUNI, Keiko; KABURAGI, Misako; MATSUOKA, Hideaki

    2015-01-01

    Exon II of glucokinase (Gk) was deleted to produce a systemic heterozygous Gk knockout (Gk+/−) mouse. The relative expression levels of Gk in the heart, lung, liver, stomach, and pancreas in Gk+/− mice ranged from 0.41–0.68 versus that in wild (Gk+/+) mice. On the other hand, its expression levels in the brain, adipose tissue, and muscle ranged from 0.95–1.03, and its expression levels in the spleen and kidney were nearly zero. Gk knockout caused no remarkable off-target effect on the expression of 7 diabetes causing genes (Shp, Hnf1a, Hnf1b, Irs1, Irs2, Kir6.2, and Pdx1) in 10 organs. The glucose tolerance test was conducted to determine the blood glucose concentrations just after fasting for 24 h (FBG) and at 2 h after high-glucose application (GTT2h). The FBG-GTT2h plots obtained with the wild strain fed the control diet (CD), Gk+/− strain fed the CD, and Gk+/− strain fed the HFD were distributed in separate areas in the FBG-GTT2h diagram. The respective areas could be defined as the normal state, prediabetes state, and diabetes state, respectively. Based on the results, the criteria for prediabetes could be defined for the Gk+/− strain developed in this study. PMID:25765873

  12. Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations

    PubMed Central

    Orho-Melander, Marju; Melander, Olle; Guiducci, Candace; Perez-Martinez, Pablo; Corella, Dolores; Roos, Charlotta; Tewhey, Ryan; Rieder, Mark J.; Hall, Jennifer; Abecasis, Goncalo; Tai, E. Shyong; Welch, Cullan; Arnett, Donna K.; Lyssenko, Valeriya; Lindholm, Eero; Saxena, Richa; de Bakker, Paul I.W.; Burtt, Noel; Voight, Benjamin F.; Hirschhorn, Joel N.; Tucker, Katherine L.; Hedner, Thomas; Tuomi, Tiinamaija; Isomaa, Bo; Eriksson, Karl-Fredrik; Taskinen, Marja-Riitta; Wahlstrand, Björn; Hughes, Thomas E.; Parnell, Laurence D.; Lai, Chao-Qiang; Berglund, Göran; Peltonen, Leena; Vartiainen, Erkki; Jousilahti, Pekka; Havulinna, Aki S.; Salomaa, Veikko; Nilsson, Peter; Groop, Leif; Altshuler, David; Ordovas, Jose M.; Kathiresan, Sekar

    2008-01-01

    OBJECTIVE—Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval. RESEARCH DESIGN AND METHODS—We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the ∼417-kb region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval. RESULTS—We provide comprehensive evidence that GCKR rs780094 is associated with opposite effects on fasting plasma triglyceride (Pmeta = 3 × 10−56) and glucose (Pmeta = 1 × 10−13) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 × 10−5). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r2 = 0.93 with rs780094) as the strongest association signal in the region. CONCLUSIONS—These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism. PMID:18678614

  13. Genetic Polymorphism of Glucokinase on the Risk of Type 2 Diabetes and Impaired Glucose Regulation: Evidence Based on 298, 468 Subjects

    PubMed Central

    Ma, Yushui; Cai, Haidong; Cai, Mingxiang; Li, Dan; Lv, Mingli; Yuan, Xueyu; Huang, Yinghui; Lv, Zhongwei

    2013-01-01

    Background Glucokinase (GCK) is the key glucose phosphorylation enzyme which has attracted considerable attention as a candidate gene for type 2 diabetes (T2D) based on its enzyme function as the first rate-limiting step in the glycolysis pathway and regulates glucose-stimulated insulin secretion. In the past decade, the relationship between GCK and T2D has been reported in various ethnic groups. To derive a more precise estimation of the relationship and the effect of factors that might modify the risk, we performed this meta-analysis. Methods Databases including Pubmed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Results A total of 24 articles involving 88, 229 cases and 210, 239 controls were included. An overall random-effects per-allele OR of 1.06 (95% CI: 1.03–1.09; P<10−4) was found for the GCK −30G>A polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians; whereas no significant associations were found among Asians. In addition, we found that the −30G>A polymorphism is a risk factor associated with increased impaired glucose regulation susceptibility. Besides, −30G>A homozygous was found to be significantly associated with increased fasting plasma glucose level with weighted mean difference (WMD) of 0.15 (95%: 0.05–0.24, P = 0.001) compared with G/G genotype. Conclusions This meta-analysis demonstrated that the −30G>A polymorphism of GCK is a risk factor associated with increased T2D susceptibility, but these associations vary in different ethnic populations. PMID:23441155

  14. The glucokinase locus is an important contributor to glucose variation in the Chinese population at high risk for type II diabetes

    SciTech Connect

    Wu, D.A. |; Warden, C.H.; Lusis, A.J.

    1994-09-01

    Recently, major advances have been achieved in the genetics of maturity onset diabetes of the young (MODY) with two loci identified: the glucokinase (GCK) gene on chromosome (chr.) 7p and a locus near the adenosine deaminase (ADA) gene on chr. 20q. However, it is not known whether either of these MODY loci contribute to variation in glucose metabolism in populations other than MODY families. To examine this question, we have studied 94 Chinese nuclear families; 54 have both parents affected with type II diabetes, 22 have only one parent affected, and 18 have both normal parents. None of the affected diabetic probands were diagnosed prior to adulthood. Nondiabetic offspring were phenotyped by measuring plasma glucose and insulin responses to an oral glucose challenge. Parents and nondiabetic offspring were genotyped for dinucleotide repeat markers. two near the GCK locus and one near the ADA locus. Prior to linkage analysis, both glucose and insulin response variables were adjusted for the effects of age, sex, and body mass index. By non-parametric quantitative sib-pair linkage analysis, we found no evidence for linkage of glucose response variables with the ADA locus on chr. 20q (p=0.64-0.92, 146 sibpairs). However, significant evidence for linkage of log-transformed integrated glucose response area was observed with the GCK locus (haplotypes based on two tightly linked GCK markers) on chr. 7p (p=0.001, N=127). Linkage with the GCK locus was also demonstrated. In contrast, insulin variables, including integrated response area and responses at different time points, showed no evidence of linkage with either the ADA or GCK loci, despite the positive correlation between glucose and insulin responses in these families. These data raise the possibility that the GCK gene may be involved as one of the contributing genes in the etiology of type II diabetes in the Chinese population.

  15. Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study

    PubMed Central

    Xu, Hongrong; Sheng, Lei; Chen, Weili; Yuan, Fei; Yang, Mengjie; Li, Hui; Li, Xuening; Choi, John; Zhao, Guiyu; Hu, Tianxin; Li, Yongguo; Zhang, Yi; Chen, Li

    2016-01-01

    Background HMS5552, a novel fourth-generation glucokinase (GK) activator, has demonstrated promising effects on glycemic control in preclinical models of type 2 diabetes. This single ascending dose study was conducted to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of HMS5552 during its first-in-human exposure. Methods Sixty healthy subjects were enrolled. In each of six dose-cohorts (5, 10, 15, 25, 35, and 50 mg), ten subjects were randomized with eight subjects receiving the same cohort-dose of HMS5552 and two receiving placebo. Plasma HMS5552 exposure, glucose, and insulin were measured repeatedly during fasting and after a standardized meal. Assessment included safety, PK, and PD endpoints. Results HMS5552 showed dose-proportional increases in area under the curve 0 to the last quantifiable concentration (AUC0–t) and maximum plasma concentration (Cmax). Slopes estimated by linear regression for AUC0–t and Cmax were ~1.0 (0.932 and 0.933, respectively). Geometric mean elimination half-life ranged from 4.48 to 7.51 hours and apparent clearance ranged from 11.5 to 13.1 L/h across all doses. No significant sex effect was observed in PK parameters. HMS5552 also demonstrated dose-related PD responses in terms of maximum glucose change from baseline (%) and mean glucose area under effect curve 0–4 hours change from baseline (%) (P<0.001). Fifteen adverse events were reported by nine subjects (ten with HMS5552 and five with the placebo). All adverse events were mild in intensity and resolved without any treatment. Conclusion This first-in-human single ascending dose study provided predicted PK of HMS5552 with dose-proportional increases in AUC0–t and Cmax, as well as dose-related glucose-lowering effects over the range of 5–50 mg in healthy subjects. HMS5552 at doses up to 50 mg in healthy subjects was safe and well-tolerated. PMID:27274195

  16. Vanadate treatment restores the expression of genes for key enzymes in the glucose and ketone bodies metabolism in the liver of diabetic rats.

    PubMed Central

    Valera, A; Rodriguez-Gil, J E; Bosch, F

    1993-01-01

    Oral administration of vanadate to diabetic streptozotocin-treated rats decreased the high blood glucose and D-3-hydroxybutyrate levels related to diabetes. The increase in the expression of the P-enolpyruvate carboxykinase (PEPCK) gene, the main regulatory enzyme of gluconeogenesis, was counteracted in the liver and the kidney after vanadate administration to diabetic rats. Vanadate also counteracted the induction in tyrosine aminotransferase gene expression due to diabetes and was able to increase the expression of the glucokinase gene to levels even higher than those found in healthy animals. Similarly, an induction in pyruvate kinase mRNA transcripts was observed in diabetic vanadate-treated rats. These effects were correlated with changes on glucokinase and pyruvate kinase activities. Vanadate treatment caused a decrease in the expression of the liver-specific glucose transporter, GLUT-2. Thus, vanadate was able to restore liver glucose utilization and block glucose production in diabetic rats. The increase in the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCoAS) gene, the key regulatory enzyme in the ketone bodies production pathway, observed in diabetic rats was also blocked by vanadate. Furthermore, a similar pattern in the expression of PEPCK, GLUT-2, HMGCoAS, and the transcription factor CCAAT/enhancer-binding protein alpha genes has been observed. All of these results suggest that the regulation of the expression of genes involved in the glucose and ketone bodies metabolism could be a key step in the normalization process induced by vanadate administration to diabetic rats. Images PMID:8100835

  17. Collagen esterification enhances the function and survival of pancreatic β cells in 2D and 3D culture systems

    SciTech Connect

    Ko, Jae Hyung; Kim, Yang Hee; Jeong, Seong Hee; Lee, Song; Park, Si-Nae; Shim, In Kyong; Kim, Song Cheol

    2015-08-07

    Collagen, one of the most important components of the extracellular matrix (ECM), may play a role in the survival of pancreatic islet cells. In addition, chemical modifications that change the collagen charge profile to a net positive charge by esterification have been shown to increase the adhesion and proliferation of various cell types. The purpose of this study was to characterize and compare the effects of native collagen (NC) and esterified collagen (EC) on β cell function and survival. After isolation by the collagenase digestion technique, rat islets were cultured with NC and EC in 2 dimensional (2D) and 3 dimensional (3D) environments for a long-term duration in vitro. The cells were assessed for islet adhesion, morphology, viability, glucose-induced insulin secretion, and mRNA expression of glucose metabolism-related genes, and visualized by scanning electron microscopy (SEM). Islet cells attached tightly in the NC group, but islet cell viability was similar in both the NC and EC groups. Glucose-stimulated insulin secretion was higher in the EC group than in the NC group in both 2D and 3D culture. Furthermore, the mRNA expression levels of glucokinase in the EC group were higher than those in the NC group and were associated with glucose metabolism and insulin secretion. Finally, SEM observation confirmed that islets had more intact component cells on EC sponges than on NC sponges. These results indicate that modification of collagen may offer opportunities to improve function and viability of islet cells. - Highlights: • We changed the collagen charge profile to a net positive charge by esterification. • Islets cultured on esterified collagen improved survival in both 2D and 3D culture. • Islets cultured on esterified collagen enhanced glucose-stimulated insulin release. • High levels of glucokinase mRNA may be associated with increased insulin release.

  18. Interindividual variations in metabolism and pharmacokinetics of 3-(6-methylpyridine-3-yl-sulfanyl)-6-(4H-[1,2,4]triazole-3-yl-sulfanyl)-N-(1,3-thiazole-2-yl)-2-pyridine carboxamide, a glucokinase activator, in rats caused by the genetic polymorphism of CYP2D1.

    PubMed

    Hasegawa, Takuro; Eiki, Jun-ichi; Chiba, Masato

    2014-09-01

    3-(6-Methylpyridine-3-yl-sulfanyl)-6-(4H-[1,2,4]triazole-3-yl-sulfanyl)-N-(1,3-thiazole-2-yl)-2-pyridine carboxamide (Cpd-D) is a novel glucokinase activator that is being developed for the treatment of type 2 diabetes. Large interindividual variations were observed in the pharmacokinetics of Cpd-D in male Sprague-Dawley (SD) rats, which were subsequently divided into two phenotypes; >6-fold longer terminal-phase half-life and ∼10-fold larger AUC0-∞ values were observed in slow metabolizers (SM) than in fast metabolizers (FM) after the oral administration of Cpd-D. The thiohydantoic acid analog (M2) was the predominant metabolite detected in the urine, bile, and plasma after the oral administration of [(14)C]Cpd-D to the FM phenotypes of bile-duct cannulated SD rats. The liver microsomes prepared from FM phenotyped rats extensively formed M2 with the highest affinity (Km = 0.09 μM) and largest Vmax/Km value in primary metabolism, whereas those from SM phenotypes had little capacity to form M2. Of the rat cytochrome P450 isoforms tested, the formation of M2 was only catalyzed by recombinant CYP2D1. Sequence substitutions (418A/421C and 418G/421T) were detected in the CYP2D1 gene and were designated F and S alleles, respectively. The genotype-phenotype correlation analysis indicated that two S alleles were homozygous (S/S) in the SM phenotypes, whereas the FM phenotypes were either homozygous for the F-alleles (F/F) or heterozygous (F/S). These results indicated that the CYP2D1 polymorphism caused by nucleotide substitutions (418A/421C versus 418G/421T) was responsible for interindividual variations leading to the polymorphism in the major metabolism and pharmacokinetics of Cpd-D in male SD rats. PMID:24924387

  19. Moral Enhancement

    PubMed Central

    Douglas, Thomas

    2008-01-01

    Opponents of biomedical enhancement often claim that, even if such enhancement would benefit the enhanced, it would harm others. But this objection looks unpersuasive when the enhancement in question is a moral enhancement — an enhancement that will expectably leave the enhanced person with morally better motives than she had previously. In this article I (1) describe one type of psychological alteration that would plausibly qualify as a moral enhancement, (2) argue that we will, in the medium-term future, probably be able to induce such alterations via biomedical intervention, and (3) defend future engagement in such moral enhancements against possible objections. My aim is to present this kind of moral enhancement as a counter-example to the view that biomedical enhancement is always morally impermissible. PMID:19132138

  20. Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

    SciTech Connect

    Kandasamy, Neelamegam; Ashokkumar, Natarajan

    2014-09-01

    Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)–cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ–Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ–Cd induced diabetic nephrotoxic rats. - Highlights: • Diabetic rats are more susceptible to cadmium nephrotoxicity. • Cadmium plays as a cumulative

  1. Soy Leaf Extract Containing Kaempferol Glycosides and Pheophorbides Improves Glucose Homeostasis by Enhancing Pancreatic β-Cell Function and Suppressing Hepatic Lipid Accumulation in db/db Mice.

    PubMed

    Li, Hua; Ji, Hyeon-Seon; Kang, Ji-Hyun; Shin, Dong-Ha; Park, Ho-Yong; Choi, Myung-Sook; Lee, Chul-Ho; Lee, In-Kyung; Yun, Bong-Sik; Jeong, Tae-Sook

    2015-08-19

    This study investigated the molecular mechanisms underlying the antidiabetic effect of an ethanol extract of soy leaves (ESL) in db/db mice. Control groups (db/+ and db/db) were fed a normal diet (ND), whereas the db/db-ESL group was fed ND with 1% ESL for 8 weeks. Dietary ESL improved glucose tolerance and lowered plasma glucose, glycated hemoglobin, HOMA-IR, and triglyceride levels. The pancreatic insulin content of the db/db-ESL group was significantly greater than that of the db/db group. ESL supplementation altered pancreatic IRS1, IRS2, Pdx1, Ngn3, Pax4, Ins1, Ins2, and FoxO1 expression. Furthermore, ESL suppressed lipid accumulation and increased glucokinase activity in the liver. ESL primarily contained kaempferol glycosides and pheophorbides. Kaempferol, an aglycone of kaempferol glycosides, improved β-cell proliferation through IRS2-related FoxO1 signaling, whereas pheophorbide a, a product of chlorophyll breakdown, improved insulin secretion and β-cell proliferation through IRS1-related signaling with protein kinase A in MIN6 cells. ESL effectively regulates glucose homeostasis by enhancing IRS-mediated β-cell insulin signaling and suppressing SREBP-1-mediated hepatic lipid accumulation in db/db mice. PMID:26211813

  2. Mafa expression enhances glucose-responsive insulin secretion in neonatal rat beta cells

    PubMed Central

    Aguayo-Mazzucato, C.; Koh, A.; El Khattabi, I.; Li, W.-C.; Toschi, E.; Jermendy, A.; Juhl, K.; Mao, K.; Weir, G. C.

    2011-01-01

    Aim/hypothesis Neonatal beta cells lack glucose-stimulated insulin secretion and are thus functionally immature. We hypothesised that this lack of glucose responsiveness results from a generalised low expression of genes characteristic of mature functional beta cells. Important glucose-responsive transcription factors, Mafa and Pdx1, regulate genes involved in insulin synthesis and secretion, and have been implicated in late beta cell development. The aim of this study was to assess whether Mafa and/or Pdx1 regulates the postnatal functional maturation of beta cells. Methods By quantitative PCR we evaluated expression of these and other beta cell genes over the first month compared with adult. After infection with adenovirus expressing MAFA, Pdx1 or green fluorescent protein (Gfp), P2 rat islets were evaluated by RT-PCR and insulin secretion with static incubation and reverse haemolytic plaque assay (RHPA). Results At P2 most beta cell genes were expressed at about 10% of adult, but by P7 Pdx1 and Neurod1 no longer differ from adult; by contrast, Mafa expression remained significantly lower than adult through P21. Overexpression of Pdx1 increased Mafa, Neurod1, glucokinase (Gck) mRNA and insulin content but failed to enhance glucose responsiveness. Similar overexpression of MAFA resulted in increased Neurod1, Nkx6-1, Gck and Glp1r mRNAs and no change in insulin content but, importantly, acquisition of glucose-responsive insulin secretion. Both the percentage of secreting beta cells and the amount of insulin secreted per beta cell increased, approaching that of adult beta cells. Conclusions/interpretation In the process of functional maturation acquiring glucose-responsive insulin secretion, neonatal beta cells undergo a coordinated gene expression programme in which Mafa plays a crucial role. PMID:21190012

  3. Biocatalyst Enhancement

    EPA Science Inventory

    The increasing availability of enzyme collections has assisted attempts by pharmaceutical producers to adopt green chemistry approaches to manufacturing. A joint effort between an enzyme producer and a pharmaceutical manufacturer has been enhanced over the past three years by ena...

  4. Enhancer Analysis

    NASA Astrophysics Data System (ADS)

    Uchikawa, Masanori; Takemoto, Tatsuya

    During embryonic development, genes are expressed under a strict spatial and temporal order in cells and tissues. This regulation is governed by regulatory regions in the genome, usually identified as enhancers (Kondoh, 2008). The identification and mapping of a set of enhancers allow clarification of essential regulatory elements involved in the enhancer action and their interacting protein factors. Enhancer analysis also determines upstream signaling cascades that regulate interacting protein factors. If the regulatory regions do not function properly, spatio-temporal order of the gene expression will be disrupted, and this may cause abnormal development and dis eases (Kleinjan & van Heyningen, 2005; Sabherwal et al., 2007). Thus, identifica tion of the regulatory regions provides an important entry point to clarify regulatory mechanisms underlying embryonic development.

  5. LASIK enhancements.

    PubMed

    Durrie, D S; Vande Garde, T L

    2000-01-01

    As the field of refractive surgery continues to evolve, an increasing number of surgical options are available for LASIK enhancements. Nonetheless, older methods such as AK continue to play an important role in enhancement procedures. Improvements in instruments and techniques allow for previously made LASIK flaps to be safely lifted for additional myopic or hyperopic ablations. Newer methods such as Intacs placement provide an effective option for patients who are not good candidates for further ablative procedures. These advancements allow refractive surgeons to treat a wider range of myopia, hyperopia, and astigmatism effectively in eyes with a history of LASIK surgery. PMID:10941651

  6. Curcumin enhances recovery of pancreatic islets from cellular stress induced inflammation and apoptosis in diabetic rats

    SciTech Connect

    Rashid, Kahkashan; Sil, Parames C.

    2015-02-01

    The phytochemical, curcumin, has been reported to play many beneficial roles. However, under diabetic conditions, the detail mechanism of its beneficial action in the glucose homeostasis regulatory organ, pancreas, is poorly understood. The present study has been designed and carried out to explore the role of curcumin in the pancreatic tissue of STZ induced and cellular stress mediated diabetes in eight weeks old male Wistar rats. Diabetes was induced with a single intraperitoneal dose of STZ (65 mg/kg body weight). Post to diabetes induction, animals were treated with curcumin at a dose of 100 mg/kg body weight for eight weeks. Underlying molecular and cellular mechanism was determined using various biochemical assays, DNA fragmentation, FACS, histology, immunoblotting and ELISA. Treatment with curcumin reduced blood glucose level, increased plasma insulin and mitigated oxidative stress related markers. In vivo and in vitro experimental results revealed increased levels of proinflammatory cytokines (TNF-α, IL1-β and IFN-γ), reduced level of cellular defense proteins (Nrf-2 and HO-1) and glucose transporter (GLUT-2) along with enhanced levels of signaling molecules of ER stress dependent and independent apoptosis (cleaved Caspase-12/9/8/3) in STZ administered group. Treatment with curcumin ameliorated all the adverse changes and helps the organ back to its normal physiology. Results suggest that curcumin protects pancreatic beta-cells by attenuating inflammatory responses, and inhibiting ER/mitochondrial dependent and independent pathways of apoptosis and crosstalk between them. This uniqueness and absence of any detectable adverse effect proposes the possibility of using this molecule as an effective protector in the cellular stress mediated diabetes mellitus. - Highlights: • STZ induced cellular stress plays a vital role in pancreatic dysfunction. • Cellular stress causes inflammation, pancreatic islet cell death and diabetes. • Deregulation of Nrf-2

  7. Enhancing bioremediation

    SciTech Connect

    Koenigsberg, S.

    1997-02-01

    Oxygen is often the limiting factor in aerobic bioremediation. Without adequate oxygen, contaminant degradation will either cease or proceed by highly inefficient anaerobic processes. Researchers at Regenesis Bioremediation Products recently develope a technology to combat this problem, Oxygen Release Compound (ORC) a unique formulation of magnesium peroxide release oxygen slowly when hydrated. ORC is idea for supporting bioremediation of underground storage tank releases. ORC treatment represents a low intensity approach to remediation - simple, passive, low-cost, long term enhancement of a natural attenuation. 1 fig.

  8. EDITORIAL: Enhancing nanolithography Enhancing nanolithography

    NASA Astrophysics Data System (ADS)

    Demming, Anna

    2012-01-01

    Lithography was invented in late 18th century Bavaria by an ambitious young playwright named Alois Senefelder. Senefelder experimented with stone, wax, water and ink in the hope of finding a way of reproducing text so that he might financially gain from a wider distribution of his already successful scripts. His discovery not only facilitated the profitability of his plays, but also provided the world with an affordable printing press that would ultimately democratize the dissemination of art, knowledge and literature. Since Senefelder, experiments in lithography have continued with a range of innovations including the use of electron beams and UV that allow increasingly higher-resolution features [1, 2]. Applications for this have now breached the limits of paper printing into the realms of semiconductor and microelectronic mechanical systems technology. In this issue, researchers demonstrate a technique for fabricating periodic features in poly(3,4-ethylene dioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) [3]. Their method combines field enhancements from silica nanospheres with laser-interference lithography to provide a means of patterning a polymer that has the potential to open the market of low-end, high-volume microelectronics. Laser-interference lithography has already been used successfully in patterning. Researchers in Korea used laser-interference lithography to generate stamps for imprinting a two-dimensional photonic crystal structure into green light emitting diodes (LEDs) [4]. The imprinted patterns comprised depressions 100 nm deep and 180 nm wide with a periodicity of 295 nm. In comparison with unpatterned LEDs, the intensity of photoluminescence was enhanced by a factor of seven in the LEDs that had the photonic crystal structures imprinted in them. The potential of exploiting field enhancements around nanostructures for new technologies has also attracted a great deal of attention. Researchers in the USA and Australia have used the field

  9. Dietary supplementation of a mixture of Lactobacillus strains enhances performance of broiler chickens raised under heat stress conditions

    NASA Astrophysics Data System (ADS)

    Faseleh Jahromi, Mohammad; Wesam Altaher, Yassir; Shokryazdan, Parisa; Ebrahimi, Roohollah; Ebrahimi, Mahdi; Idrus, Zulkifli; Tufarelli, Vincenzo; Liang, Juan Boo

    2016-07-01

    High ambient temperature is a major problem in commercial broiler production in the humid tropics because high producing broiler birds consume more feed, have higher metabolic activity, and thus higher body heat production. To evaluate the effects of two previously isolated potential probiotic strains ( Lactobacillus pentosus ITA23 and Lactobacillus acidophilus ITA44) on broilers growing under heat stress condition, a total of 192 chicks were randomly allocated into four treatment groups of 48 chickens each as follows: CL, birds fed with basal diet raised in 24 °C; PL, birds fed with basal diet plus 0.1 % probiotic mixture raised in 24 °C; CH, birds fed with basal diet raised in 35 °C; and PH, birds fed with basal diet plus 0.1 % probiotic mixture raised in 35 °C. The effects of probiotic mixture on the performance, expression of nutrient absorption genes of the small intestine, volatile fatty acids (VFA) and microbial population of cecal contents, antioxidant capacity of liver, and fatty acid composition of breast muscle were investigated. Results showed that probiotic positively affected the final body weight under both temperature conditions (PL and PH groups) compared to their respective control groups (CL and CH). Probiotic supplementation numerically improved the average daily gain (ADG) under lower temperature, but significantly improved ADG under the higher temperature ( P < 0.05) by sustaining high feed intake. Under the lower temperature environment, supplementation of the two Lactobacillus strains significantly increased the expression of the four sugar transporter genes tested (GLUT2, GLUT5, SGLT1, and SGLT4) indicating probiotic enhances the absorption of this nutrient. Similar but less pronounced effect was also observed under higher temperature (35 °C) condition. In addition, the probiotic mixture improved bacterial population of the cecal contents, by increasing beneficial bacteria and decreasing Escherichia coli population, which could be

  10. Dietary supplementation of a mixture of Lactobacillus strains enhances performance of broiler chickens raised under heat stress conditions

    NASA Astrophysics Data System (ADS)

    Faseleh Jahromi, Mohammad; Wesam Altaher, Yassir; Shokryazdan, Parisa; Ebrahimi, Roohollah; Ebrahimi, Mahdi; Idrus, Zulkifli; Tufarelli, Vincenzo; Liang, Juan Boo

    2015-11-01

    High ambient temperature is a major problem in commercial broiler production in the humid tropics because high producing broiler birds consume more feed, have higher metabolic activity, and thus higher body heat production. To evaluate the effects of two previously isolated potential probiotic strains (Lactobacillus pentosus ITA23 and Lactobacillus acidophilus ITA44) on broilers growing under heat stress condition, a total of 192 chicks were randomly allocated into four treatment groups of 48 chickens each as follows: CL, birds fed with basal diet raised in 24 °C; PL, birds fed with basal diet plus 0.1 % probiotic mixture raised in 24 °C; CH, birds fed with basal diet raised in 35 °C; and PH, birds fed with basal diet plus 0.1 % probiotic mixture raised in 35 °C. The effects of probiotic mixture on the performance, expression of nutrient absorption genes of the small intestine, volatile fatty acids (VFA) and microbial population of cecal contents, antioxidant capacity of liver, and fatty acid composition of breast muscle were investigated. Results showed that probiotic positively affected the final body weight under both temperature conditions (PL and PH groups) compared to their respective control groups (CL and CH). Probiotic supplementation numerically improved the average daily gain (ADG) under lower temperature, but significantly improved ADG under the higher temperature (P < 0.05) by sustaining high feed intake. Under the lower temperature environment, supplementation of the two Lactobacillus strains significantly increased the expression of the four sugar transporter genes tested (GLUT2, GLUT5, SGLT1, and SGLT4) indicating probiotic enhances the absorption of this nutrient. Similar but less pronounced effect was also observed under higher temperature (35 °C) condition. In addition, the probiotic mixture improved bacterial population of the cecal contents, by increasing beneficial bacteria and decreasing Escherichia coli population, which could be

  11. Dietary supplementation of a mixture of Lactobacillus strains enhances performance of broiler chickens raised under heat stress conditions.

    PubMed

    Faseleh Jahromi, Mohammad; Wesam Altaher, Yassir; Shokryazdan, Parisa; Ebrahimi, Roohollah; Ebrahimi, Mahdi; Idrus, Zulkifli; Tufarelli, Vincenzo; Liang, Juan Boo

    2016-07-01

    High ambient temperature is a major problem in commercial broiler production in the humid tropics because high producing broiler birds consume more feed, have higher metabolic activity, and thus higher body heat production. To evaluate the effects of two previously isolated potential probiotic strains (Lactobacillus pentosus ITA23 and Lactobacillus acidophilus ITA44) on broilers growing under heat stress condition, a total of 192 chicks were randomly allocated into four treatment groups of 48 chickens each as follows: CL, birds fed with basal diet raised in 24 °C; PL, birds fed with basal diet plus 0.1 % probiotic mixture raised in 24 °C; CH, birds fed with basal diet raised in 35 °C; and PH, birds fed with basal diet plus 0.1 % probiotic mixture raised in 35 °C. The effects of probiotic mixture on the performance, expression of nutrient absorption genes of the small intestine, volatile fatty acids (VFA) and microbial population of cecal contents, antioxidant capacity of liver, and fatty acid composition of breast muscle were investigated. Results showed that probiotic positively affected the final body weight under both temperature conditions (PL and PH groups) compared to their respective control groups (CL and CH). Probiotic supplementation numerically improved the average daily gain (ADG) under lower temperature, but significantly improved ADG under the higher temperature (P < 0.05) by sustaining high feed intake. Under the lower temperature environment, supplementation of the two Lactobacillus strains significantly increased the expression of the four sugar transporter genes tested (GLUT2, GLUT5, SGLT1, and SGLT4) indicating probiotic enhances the absorption of this nutrient. Similar but less pronounced effect was also observed under higher temperature (35 °C) condition. In addition, the probiotic mixture improved bacterial population of the cecal contents, by increasing beneficial bacteria and decreasing Escherichia coli population, which could

  12. GLUCAGON-LIKE PEPTIDE-2 INCREASES GLUCOSE UPTAKE BY INCREASING SGLT-1 AND GLUT2 ABUNDANCE IN TPN-FED NEONATAL PIGS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Children with intestinal dysfunction, often require total parenteral nutrition (TPN) to meet their nutritional needs. Although TPN provides the necessary nutrition, it may limit intestinal adaptation, growth, and restoration of normal function. The trophic gut peptide, glucagon-like peptide-2 (GLP-2...

  13. Autonomy and Enhancement.

    PubMed

    Schaefer, G Owen; Kahane, Guy; Savulescu, Julian

    2014-01-01

    Some have objected to human enhancement on the grounds that it violates the autonomy of the enhanced. These objections, however, overlook the interesting possibility that autonomy itself could be enhanced. How, exactly, to enhance autonomy is a difficult problem due to the numerous and diverse accounts of autonomy in the literature. Existing accounts of autonomy enhancement rely on narrow and controversial conceptions of autonomy. However, we identify one feature of autonomy common to many mainstream accounts: reasoning ability. Autonomy can then be enhanced by improving people's reasoning ability, in particular through cognitive enhancement; given how valuable autonomy is usually taken to be, this gives us extra reason to pursue such cognitive enhancements. Moreover, autonomy-based objections will be especially weak against such enhancements. As we will argue, those who are worried that enhancements will inhibit people's autonomy should actually embrace those enhancements that will improve autonomy. PMID:25045410

  14. Cognitive Enhancement and Education

    ERIC Educational Resources Information Center

    Buchanan, Allen

    2011-01-01

    Cognitive enhancement--augmenting normal cognitive capacities--is not new. Literacy, numeracy, computers, and the practices of science are all cognitive enhancements. Science is now making new cognitive enhancements possible. Biomedical cognitive enhancements (BCEs) include the administration of drugs, implants of genetically engineered or…

  15. Enhancement and Civic Virtue

    PubMed Central

    Jefferson, Will; Douglas, Thomas; Kahane, Guy; Savulescu, Julian

    2014-01-01

    Opponents of biomedical enhancement frequently adopt what Allen Buchanan has called the Personal Goods Assumption. On this assumption, the benefits of biomedical enhancement will accrue primarily to those individuals who undergo enhancements, not to wider society. Buchanan has argued that biomedical enhancements might in fact have substantial social benefits by increasing productivity. We outline another way in which enhancements might benefit wider society: by augmenting civic virtue and thus improving the functioning of our political communities. We thus directly confront critics of biomedical enhancement who argue that it will lead to a loss of social cohesion and a breakdown in political life. PMID:24882886

  16. Current enhancement update

    SciTech Connect

    Chambers, F.W.; Clark, J.C.; Struve, K.W.; Yu, S.S.

    1984-06-14

    Net current enhancement to levels in excess of the beam current has been observed in gases at pressures excess of 50 torr. We delineate the regimes where enhancement is observed. The experimental results fall into two very distinct classes; current enhancement at injection where the beam is only slightly displaced and current enhancement clearly associated with the high amplitude hose instability. A careful theoretical and experimental study of the diagnostics revealed no fundamental flaws although there are several complex and unlikely scenarios which could introduce fictitious current enhancement. Theoretical efforts indicate several mechanisms for generating enhancement but none of the theories can account for the detailed observations. 4 references, 4 figures.

  17. Enhancement and Civic Virtue.

    PubMed

    Jefferson, Will; Douglas, Thomas; Kahane, Guy; Savulescu, Julian

    2014-07-01

    Opponents of biomedical enhancement frequently adopt what Allen Buchanan has called the Personal Goods Assumption. On this assumption, the benefits of biomedical enhancement will accrue primarily to those individuals who undergo enhancements, not to wider society. Buchanan has argued that biomedical enhancements might in fact have substantial social benefits by increasing productivity. We outline another way in which enhancements might benefit wider society: by augmenting civic virtue and thus improving the functioning of our political communities. We thus directly confront critics of biomedical enhancement who argue that it will lead to a loss of social cohesion and a breakdown in political life. PMID:24882886

  18. Smart Image Enhancement Process

    NASA Technical Reports Server (NTRS)

    Jobson, Daniel J. (Inventor); Rahman, Zia-ur (Inventor); Woodell, Glenn A. (Inventor)

    2012-01-01

    Contrast and lightness measures are used to first classify the image as being one of non-turbid and turbid. If turbid, the original image is enhanced to generate a first enhanced image. If non-turbid, the original image is classified in terms of a merged contrast/lightness score based on the contrast and lightness measures. The non-turbid image is enhanced to generate a second enhanced image when a poor contrast/lightness score is associated therewith. When the second enhanced image has a poor contrast/lightness score associated therewith, this image is enhanced to generate a third enhanced image. A sharpness measure is computed for one image that is selected from (i) the non-turbid image, (ii) the first enhanced image, (iii) the second enhanced image when a good contrast/lightness score is associated therewith, and (iv) the third enhanced image. If the selected image is not-sharp, it is sharpened to generate a sharpened image. The final image is selected from the selected image and the sharpened image.

  19. Suboptimization of developmental enhancers.

    PubMed

    Farley, Emma K; Olson, Katrina M; Zhang, Wei; Brandt, Alexander J; Rokhsar, Daniel S; Levine, Michael S

    2015-10-16

    Transcriptional enhancers direct precise on-off patterns of gene expression during development. To explore the basis for this precision, we conducted a high-throughput analysis of the Otx-a enhancer, which mediates expression in the neural plate of Ciona embryos in response to fibroblast growth factor (FGF) signaling and a localized GATA determinant. We provide evidence that enhancer specificity depends on submaximal recognition motifs having reduced binding affinities ("suboptimization"). Native GATA and ETS (FGF) binding sites contain imperfect matches to consensus motifs. Perfect matches mediate robust but ectopic patterns of gene expression. The native sites are not arranged at optimal intervals, and subtle changes in their spacing alter enhancer activity. Multiple tiers of enhancer suboptimization produce specific, but weak, patterns of expression, and we suggest that clusters of weak enhancers, including certain "superenhancers," circumvent this trade-off in specificity and activity. PMID:26472909

  20. Credit Enhancement Overview Guide

    SciTech Connect

    Financing Solutions Working Group

    2014-01-01

    Provides considerations for state and local policymakers and energy efficiency program administrators designing and implementing successful credit enhancement strategies for residential and commercial buildings.

  1. [Medical image enhancement: Sharpening].

    PubMed

    Kats, L; Vered, M

    2015-04-01

    Most digital imaging systems provide opportunities for image enhancement operations. These are applied to improve the original image and to make the image more appealing visually. One possible means of enhancing digital radiographic image is sharpening. The purpose of sharpening filters is to improve image quality by removing noise or edge enhancement. Sharpening filters may make the radiographic images subjectively more appealing. But during this process, important radiographic features may disappear while artifacts that simulate pathological process might be generated. Therefore, it is of utmost importance for dentists to be familiar with and aware of the use of image enhancement operations, provided by medical digital imaging programs. PMID:26255429

  2. Enhancement of video images.

    PubMed

    Baily, N A; Nachazel, R J

    1980-04-01

    The enhancement of radiographic and fluoroscopic images using simple video analog techniques is described. In each instance, both the degree of enhancement and the features of the image to be enhanced are under the direct control of the radiologist. Noise is suppressed with a sharp cut-off, low-pass filter. Three types of analog circuits are discussed. One provides edge sharpening and contrast enhancement; one allows either black or white suppression, with expansion of the remaining shades of gray; and one provides an exponential response to selectable portions of the input signal. PMID:7360962

  3. Heat exchange enhancement structure

    SciTech Connect

    Cornelison, R.C.; Kreith, F.

    1980-12-02

    A passive heat exchange enhancement structure which operates by free convection includes a flat mounting portion having a plurality of integral fins bent outwardly from one side edge thereof. The mounting portion is securable around a stovepipe, to a flat surface or the like for transferring heat from the pipe through the fins to the surrounding air by rotation-enhanced free convection.

  4. Enhancing Drug Court Success

    ERIC Educational Resources Information Center

    Deschenes, Elizabeth Piper; Ireland, Connie; Kleinpeter, Christine B.

    2009-01-01

    This study evaluates the impact of enhanced drug court services in a large county in Southern California. These enhanced services, including specialty counseling groups, educational/employment resources, and increased Residential Treatment (RT) beds, were designed to increase program retention and successful completion (graduation) of drug court.…

  5. Enhanced oil recovery update

    SciTech Connect

    Smith, R.V

    1989-03-01

    Technology continues to grow in the realm of enhanced oil recovery. Since 1950 several processes have proven economic for oil recovery. Others are still in their infancy and must be custom designed for each reservoir. This paper gives a general overview of these processes. The author focuses on the latest technology and the outlook for enhanced oil recovery operations.

  6. Enhancing Individual Readiness.

    ERIC Educational Resources Information Center

    1997

    This document contains three papers from a symposium on enhancing individual readiness through human resource development (HRD). "Secondary School Administrator's Perception of Enhancing Self-Worth through Service" (Thomas Li-Ping Tang, Emily James Weatherford) presents results of a study to examine secondary school administrators' endorsement of…

  7. Should we enhance animals?

    PubMed Central

    Chan, Sarah

    2012-01-01

    Much bioethical discussion has been devoted to the subject of human enhancement through various technological means such as genetic modification. Although many of the same technologies could be, indeed in many cases already have been, applied to non-human animals, there has been very little consideration of the concept of “animal enhancement”, at least not in those specific terms. This paper addresses the notion of animal enhancement and the ethical issues surrounding it. A definition of animal enhancement is proposed that provides a framework within which to consider these issues; and it is argued that if human enhancement can be considered to be a moral obligation, so too can animal enhancement. PMID:19880704

  8. EDITORIAL: Nano-enhanced! Nano-enhanced!

    NASA Astrophysics Data System (ADS)

    Demming, Anna

    2010-08-01

    In the early 19th century, a series of engineering and scientific breakthroughs by Nicolas Léonard Sadi Carnot, James Watt and many others led to the foundations of thermodynamics and a new pedigree of mechanical designs that reset the standards of engineering efficiency. The result was the industrial revolution. In optical- and electronics- based nanotechnology research, a similarly subtle bargain is being made; we cannot alter the fact that systems have a finite response to external excitations, but what we can do is enhance that response. The promising attributes of ZnO have long been recognised; its large band gap and high exciton binding energy lend it to a number of applications from laser diodes, LEDs, optical waveguides and switches, and acousto-optic applications to sun cream. When this material is grown into nanowires and nanorods, the material gains a whole new dimension, as quantum confinement effects come into play. Discovery of the enhanced radiative recombination, which has potential for exploitation in many optical and opto-electronic applications, drove intensive research into investigating these structures and into finding methods to synthesise them with optimised properties. This research revealed further subtleties in the properties of these materials. One example is the work by researchers in the US reporting synthesis procedures that produced a yield—defined as the weight ratio of ZnO nanowires to the original graphite flakes—of 200%, and which also demonstrated, through photoluminescence analysis of nanowires grown on graphite flakes and substrates, that graphite induces oxygen vacancies during annealing, which enhances the deep-level to near-band-edge emission ratio [1]. Other one-dimensional materials that provide field emission enhancements include carbon nanotubes, and work has been performed to find ways of optimising the emission efficiency from these structures, such as through control of the emitter density [2]. One of the

  9. Long-Term Administration of Dehydroepiandrosterone Accelerates Glucose Catabolism via Activation of PI3K/Akt-PFK-2 Signaling Pathway in Rats Fed a High-Fat Diet.

    PubMed

    Kang, Jian; Ge, Chongyang; Yu, Lei; Li, Longlong; Ma, Haitian

    2016-01-01

    Dehydroepiandrosterone (DHEA) has a fat-reducing effect, while little information is available on whether DHEA regulates glucose metabolism, which would in turn affect fat deposition. To investigate the effects of DHEA on glucose metabolism, rats were administered a high-fat diet containing either 0 (HCG), 25 (HLG), 50 (HMG), or 100 (HHG) mg·kg-1 DHEA per day via gavage for 8 weeks. Results showed that long-term administration of DHEA inhibited body weight gain in rats on a high-fat diet. No statistical differences in serum glucose levels were observed, whereas hepatic glycogen content in HMG and HHG groups and muscle glycogen content in HLG and HMG groups were higher than those in HCG group. Glucokinase, malate dehydrogenase and phosphofructokinase-2 activities in HMG and HHG groups, pyruvate kinase and succinate dehydrogenase activities in HMG group, and pyruvate dehydrogenase activity in all DHEA treatment groups were increased compared with those in HCG group. Phosphoenolpyruvate carboxykinase and glycogen phosphorylase mRNA levels were decreased in HMG and HHG groups, whereas glycogen synthase-2 mRNA level was increased in HMG group compared with those in HCG. The abundance of Glut2 mRNA in HMG and HHG groups and Glut4 mRNA in HMG group was higher than that in HCG group. DHEA treatment increased serum leptin content in HMG and HHG groups compared with that in HCG group. Serum insulin content and insulin receptor mRNA level in HMG group and insulin receptor substrate-2 mRNA level in HMG and HHG group were increased compared with those in HCG group. Furthermore, Pi3k mRNA level in HMG and Akt mRNA level in HMG and HHG groups were significantly increased than those in HCG group. These data showed that DHEA treatment could enhance glycogen storage and accelerate glucose catabolism in rats fed a high-fat diet, and this effect may be associated with the activation of PI3K/Akt-PFK-2 signaling pathway. PMID:27410429

  10. Long-Term Administration of Dehydroepiandrosterone Accelerates Glucose Catabolism via Activation of PI3K/Akt-PFK-2 Signaling Pathway in Rats Fed a High-Fat Diet

    PubMed Central

    Kang, Jian; Ge, Chongyang; Yu, Lei; Li, Longlong; Ma, Haitian

    2016-01-01

    Dehydroepiandrosterone (DHEA) has a fat-reducing effect, while little information is available on whether DHEA regulates glucose metabolism, which would in turn affect fat deposition. To investigate the effects of DHEA on glucose metabolism, rats were administered a high-fat diet containing either 0 (HCG), 25 (HLG), 50 (HMG), or 100 (HHG) mg·kg-1 DHEA per day via gavage for 8 weeks. Results showed that long-term administration of DHEA inhibited body weight gain in rats on a high-fat diet. No statistical differences in serum glucose levels were observed, whereas hepatic glycogen content in HMG and HHG groups and muscle glycogen content in HLG and HMG groups were higher than those in HCG group. Glucokinase, malate dehydrogenase and phosphofructokinase-2 activities in HMG and HHG groups, pyruvate kinase and succinate dehydrogenase activities in HMG group, and pyruvate dehydrogenase activity in all DHEA treatment groups were increased compared with those in HCG group. Phosphoenolpyruvate carboxykinase and glycogen phosphorylase mRNA levels were decreased in HMG and HHG groups, whereas glycogen synthase-2 mRNA level was increased in HMG group compared with those in HCG. The abundance of Glut2 mRNA in HMG and HHG groups and Glut4 mRNA in HMG group was higher than that in HCG group. DHEA treatment increased serum leptin content in HMG and HHG groups compared with that in HCG group. Serum insulin content and insulin receptor mRNA level in HMG group and insulin receptor substrate-2 mRNA level in HMG and HHG group were increased compared with those in HCG group. Furthermore, Pi3k mRNA level in HMG and Akt mRNA level in HMG and HHG groups were significantly increased than those in HCG group. These data showed that DHEA treatment could enhance glycogen storage and accelerate glucose catabolism in rats fed a high-fat diet, and this effect may be associated with the activation of PI3K/Akt-PFK-2 signaling pathway. PMID:27410429

  11. Antidiabetic activity of zinc oxide and silver nanoparticles on streptozotocin-induced diabetic rats.

    PubMed

    Alkaladi, Ali; Abdelazim, Aaser Mohamed; Afifi, Mohamed

    2014-01-01

    The use of nanoparticles in medicine is an attractive proposition. In the present study, zinc oxide and silver nanoparticles were evaluated for their antidiabetic activity. Fifty male albino rats with weight 120 ± 20 and age 6 months were used. Animals were grouped as follows: control; did not receive any type of treatment, diabetic; received a single intraperitoneal dose of streptozotocin (100 mg/kg), diabetic + zinc oxide nanoparticles (ZnONPs), received single daily oral dose of 10 mg/kg ZnONPs in suspension, diabetic + silver nanoparticles (SNPs); received a single daily oral dose of SNP of 10 mg/kg in suspension and diabetic + insulin; received a single subcutaneous dose of 0.6 units/50 g body weight. Zinc oxide and silver nanoparticles induce a significant reduced blood glucose, higher serum insulin, higher glucokinase activity higher expression level of insulin, insulin receptor, GLUT-2 and glucokinase genes in diabetic rats treated with zinc oxide, silver nanoparticles and insulin. In conclusion, zinc oxide and sliver nanoparticles act as potent antidiabetic agents. PMID:24477262

  12. Enhancer Malfunction in Cancer

    PubMed Central

    Herz, Hans-Martin; Hu, Deqing; Shilatifard, Ali

    2014-01-01

    Why certain point mutations in a general transcription factor are associated with specific forms of cancer has been a major question in cancer biology. Enhancers are DNA regulatory elements that are major regulators of tissue-specific gene expression. Recent studies suggest that enhancer malfunction through point mutations in either regulatory elements or factors modulating enhancer-promoter communication could be the cause of tissue-specific cancer development. In this Perspective, we will discuss recent findings in the identification of cancer-related enhancer mutations and the role of Drosophila Trr and its human homologs, the MLL3 and MLL4/COMPASS-like complexes, as enhancer histone H3 lysine 4 (H3K4) monomethyltransferases functioning in enhancer-promoter communication. Recent genome-wide studies in the cataloging of somatic mutations in cancer have identified mutations in intergenic sequences encoding regulatory elements, and in MLL3 and MLL4 in both hematological malignancies and solid tumors. We propose that cancer-associated mutations in MLL3 and MLL4 exert their properties through the malfunction of Trr/MLL3/MLL4-dependent enhancers. PMID:24656127

  13. On latent fingerprint enhancement

    NASA Astrophysics Data System (ADS)

    Yoon, Soweon; Feng, Jianjiang; Jain, Anil K.

    2010-04-01

    Automatic feature extraction in latent fingerprints is a challenging problem due to poor quality of most latents, such as unclear ridge structures, overlapped lines and letters, and overlapped fingerprints. We proposed a latent fingerprint enhancement algorithm which requires manually marked region of interest (ROI) and singular points. The core of the proposed enhancement algorithm is a novel orientation field estimation algorithm, which fits orientation field model to coarse orientation field estimated from skeleton outputted by a commercial fingerprint SDK. Experimental results on NIST SD27 latent fingerprint database indicate that by incorporating the proposed enhancement algorithm, the matching accuracy of the commercial matcher was significantly improved.

  14. Hierarchical image enhancement

    NASA Astrophysics Data System (ADS)

    Qi, Wei; Han, Jing; Zhang, Yi; Bai, Lian-fa

    2016-05-01

    Image enhancement is an important technique in computer vision. In this paper, we propose a hierarchical image enhancement approach based on the structure layer and texture layer. In the structure layer, we propose a structure-based method based on GMM, which better exploits structure details with fewer noise. In the texture layer, we present a structure-filtering method to filter unwanted texture with keeping completeness of detected salient structure. Next, we introduce a structure constraint prior to integrate them, leading to an improved enhancement result. Extensive experiments demonstrate that the proposed approach achieves higher quality results than previous approaches.

  15. Enhanced Chemical Cleaning

    SciTech Connect

    Spires, Renee H.

    2010-11-01

    Renee Spires, Project Manager at Savannah River Remediation, opens Session 3 (Accelerated Waste Retrieval and Closure: Key Technologies) at the 2010 EM Waste Processing Technical Exchange with a talk on enhanced chemical cleaning.

  16. LIGNITE FUEL ENHANCEMENT

    SciTech Connect

    Charles Bullinger

    2005-06-07

    This 3rd quarterly Technical Progress Report for the Lignite Fuel Enhancement Project summarizes activities from January 1st through March 31st of 2005. It also summarizes the subsequent purchasing activity and final dryer/process design.

  17. Plasmon-Enhanced Upconversion.

    PubMed

    Wu, Di M; García-Etxarri, Aitzol; Salleo, Alberto; Dionne, Jennifer A

    2014-11-20

    Upconversion, the conversion of photons from lower to higher energies, is a process that promises applications ranging from high-efficiency photovoltaic and photocatalytic cells to background-free bioimaging and therapeutic probes. Existing upconverting materials, however, remain too inefficient for viable implementation. In this Perspective, we describe the significant improvements in upconversion efficiency that can be achieved using plasmon resonances. As collective oscillations of free electrons, plasmon resonances can be used to enhance both the incident electromagnetic field intensity and the radiative emission rates. To date, this approach has shown upconversion enhancements up to 450×. We discuss both theoretical underpinnings and experimental demonstrations of plasmon-enhanced upconversion, examining the roles of upconverter quantum yield, plasmonic geometry, and plasmon spectral overlap. We also discuss nonoptical consequences of including metal nanostructures near upconverting emitters. The rapidly expanding field of plasmon-enhanced upconversion provides novel fundamental insight into nanoscale light-matter interactions while improving prospects for technological relevance. PMID:26276488

  18. LIGNITE FUEL ENHANCEMENT

    SciTech Connect

    Charles Bullinger

    2005-07-07

    This 4th quarterly Technical Progress Report for the Lignite Fuel Enhancement Project summarizes activities from April 1st through June 30th of 2005. It also summarizes the subsequent purchasing activity and dryer/process construction.

  19. Enhanced metabolite generation

    DOEpatents

    Chidambaram, Devicharan

    2012-03-27

    The present invention relates to the enhanced production of metabolites by a process whereby a carbon source is oxidized with a fermentative microbe in a compartment having a portal. An electron acceptor is added to the compartment to assist the microbe in the removal of excess electrons. The electron acceptor accepts electrons from the microbe after oxidation of the carbon source. Other transfers of electrons can take place to enhance the production of the metabolite, such as acids, biofuels or brewed beverages.

  20. Enhancing Displays by Blurring

    NASA Technical Reports Server (NTRS)

    Tiana, C.; Pavel, M.; Ahumada, Albert J., Jr.; Statler, Irving C. (Technical Monitor)

    1994-01-01

    Some Enhanced Vision cockpit displays consist of synthetic imagery superimposed on a real image. The high spatial frequency components of the synthetic imagery can mislead an operator by masking features of the real image. We demonstrate that blurring the synthetic image prior to superposition reduces its masking effect in high- contrast regions of the real image, while maintaining its enhancing properties in regions of the real image where visibility is low.

  1. MORAL ENHANCEMENT AND FREEDOM

    PubMed Central

    Harris, John

    2011-01-01

    This paper identifies human enhancement as one of the most significant areas of bioethical interest in the last twenty years. It discusses in more detail one area, namely moral enhancement, which is generating significant contemporary interest. The author argues that so far from being susceptible to new forms of high tech manipulation, either genetic, chemical, surgical or neurological, the only reliable methods of moral enhancement, either now or for the foreseeable future, are either those that have been in human and animal use for millennia, namely socialization, education and parental supervision or those high tech methods that are general in their application. By that is meant those forms of cognitive enhancement that operate across a wide range of cognitive abilities and do not target specifically ‘ethical’ capacities. The paper analyses the work of some of the leading contemporary advocates of moral enhancement and finds that in so far as they identify moral qualities or moral emotions for enhancement they have little prospect of success. PMID:21133978

  2. Normality, therapy, and enhancement.

    PubMed

    Giubilini, Alberto

    2015-07-01

    According to human enhancement advocates, it is morally permissible (and sometimes obligatory) to use biomedical means to modulate or select certain biological traits in order to increase people's welfare, even when there is no pathology to be treated or prevented. Some authors have recently proposed to extend the use of biomedical means to modulate lust, attraction, and attachment. I focus on some conceptual implications of this proposal, particularly with regard to bioconservatives' understanding of the notions of therapy and enhancement I first explain what makes the proposal of medicalizing love interesting and unique, compared to the other forms of bioenhancement usually advocated. I then discuss how the medicalization of love bears on the more general debate on human enhancement, particularly with regard to the key notion of "normality" that is commonly used to define the therapy-enhancement distinction. This analysis suggests that the medicalization of love, in virtue of its peculiarity, requires bioconservatives to reconsider their way of understanding and applying the notions of "therapy" and "enhancement." More in particular, I show that, because a non-arbitrary and value-free notion of "therapy" cannot be applied to the case of love, bioconservatives have the burden of either providing some new criterion that could be used for drawing a line between permissible and impermissible medicalization, or demonstrating that under no circumstances-including the cases in which love is already acknowledged to require medical intervention-can love fall within the domain of medicine. PMID:26059959

  3. Enhanced condensation heat transfer

    NASA Astrophysics Data System (ADS)

    Michel, J. W.; Murphy, R. W.

    1980-07-01

    Work has centered on optimizing the design variables associated with fluted surfaces on vertical tubes and comparing the tube performance with available enhanced tubes either for vertical or horizontal operation. Data with seven fluids including a hydrocarbon, fluorocarbons, and ammonia condensing on up to 30 different tubes were obtained. Data for tubes of different effective lengths (1/2 to 4 ft) and inclination were also obtained. The primary conclusion is that the best fluted tubes can provide an enhancement in condensation coefficient by a factor of approximately 6 over smooth vertical tube performance and a factor of approximately 2 over the best enhanced commercial tubes either operating vertically or horizontally. These data, together with field test data, have formed the basis for designing two prototype condensers, one for the 60 kWe Raft River, Idaho, pilot plant and one for the 500 kWe East Mesa, California, direct contact demonstration plant.

  4. Degraded document image enhancement

    NASA Astrophysics Data System (ADS)

    Agam, G.; Bal, G.; Frieder, G.; Frieder, O.

    2007-01-01

    Poor quality documents are obtained in various situations such as historical document collections, legal archives, security investigations, and documents found in clandestine locations. Such documents are often scanned for automated analysis, further processing, and archiving. Due to the nature of such documents, degraded document images are often hard to read, have low contrast, and are corrupted by various artifacts. We describe a novel approach for the enhancement of such documents based on probabilistic models which increases the contrast, and thus, readability of such documents under various degradations. The enhancement produced by the proposed approach can be viewed under different viewing conditions if desired. The proposed approach was evaluated qualitatively and compared to standard enhancement techniques on a subset of historical documents obtained from the Yad Vashem Holocaust museum. In addition, quantitative performance was evaluated based on synthetically generated data corrupted under various degradation models. Preliminary results demonstrate the effectiveness of the proposed approach.

  5. Rituals enhance consumption.

    PubMed

    Vohs, Kathleen D; Wang, Yajin; Gino, Francesca; Norton, Michael I

    2013-09-01

    Four experiments tested the novel hypothesis that ritualistic behavior potentiates and enhances ensuing consumption--an effect found for chocolates, lemonade, and even carrots. Experiment 1 showed that participants who engaged in ritualized behavior, compared with those who did not, evaluated chocolate as more flavorful, valuable, and deserving of behavioral savoring. Experiment 2 demonstrated that random gestures do not boost consumption as much as ritualistic gestures do. It further showed that a delay between a ritual and the opportunity to consume heightens enjoyment, which attests to the idea that ritual behavior stimulates goal-directed action (to consume). Experiment 3 found that performing a ritual oneself enhances consumption more than watching someone else perform the same ritual, suggesting that personal involvement is crucial for the benefits of rituals to emerge. Finally, Experiment 4 provided direct evidence of the underlying process: Rituals enhance the enjoyment of consumption because of the greater involvement in the experience that they prompt. PMID:23863754

  6. Human freedom and enhancement.

    PubMed

    Heilinger, Jan-Christoph; Crone, Katja

    2014-02-01

    Ideas about freedom and related concepts like autonomy and self-determination play a prominent role in the moral debate about human enhancement interventions. However, there is not a single understanding of freedom available, and arguments referring to freedom are simultaneously used to argue both for and against enhancement interventions. This gives rise to misunderstandings and polemical arguments. The paper attempts to disentangle the different distinguishable concepts, classifies them and shows how they relate to one another in order to allow for a more structured and clearer debate. It concludes in identifying the individual underpinnings and the social conditions of choice and decision-making as particularly salient dimensions of freedom in the ethical debate about human enhancement. PMID:23519909

  7. Surface Enhanced Quantum Control

    NASA Astrophysics Data System (ADS)

    Rangan, Chitra

    2013-05-01

    Miniaturization of quantum technologies have led to physics that require the marriage of atomic physics and nanomaterials science. Some of the resulting areas of research are hybrid quantum devices, single-molecule spectroscopies, table-top intense field generators, etc. I will present an area of research that I dub ``Surface-enhanced quantum control'' that is an exciting way of controlling light and nanomatter. By combining the electromagnetic enhancement properties of plasmonic nanomaterials with the modification of the atomic properties, we can achieve an unprecedented level of control over quantum dynamics. I will present examples of surface-enhanced state purification, in which quantum states near metal nanostructures can be rapidly purified by the application of a weak near-resonant control field. We gratefully acknowledge support from the NSERC Discovery Grant Program and the NSERC Strategic Network for Bioplasmonic Systems.

  8. Fiber enhanced Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Frosch, T.; Yan, D.; Hanf, S.; Popp, J.

    2014-05-01

    Fiber enhanced Raman sensing is presented for versatile and extremely sensitive analysis of pharmaceutical drugs and biogenic gases. Elaborated micro-structured optical fibers guide the light with very low losses within their hollow core and provide at the same time a miniaturized sample container for the analytes. Thus, fiber enhanced Raman spectroscopy (FERS) allows for chemically selective detection of minimal sample amounts with high sensitivity. Two examples are presented in this contribution: (i) the detection of picomolar concentrations of pharmaceutical drugs; and (ii) the analysis of biogenic gases within a complex mixture of gases with analytical sensitivities in the ppm range.

  9. Low Vision Enhancement System

    NASA Technical Reports Server (NTRS)

    1995-01-01

    NASA's Technology Transfer Office at Stennis Space Center worked with the Johns Hopkins Wilmer Eye Institute in Baltimore, Md., to incorporate NASA software originally developed by NASA to process satellite images into the Low Vision Enhancement System (LVES). The LVES, referred to as 'ELVIS' by its users, is a portable image processing system that could make it possible to improve a person's vision by enhancing and altering images to compensate for impaired eyesight. The system consists of two orientation cameras, a zoom camera, and a video projection system. The headset and hand-held control weigh about two pounds each. Pictured is Jacob Webb, the first Mississippian to use the LVES.

  10. Biomedical enhancements as justice.

    PubMed

    Nam, Jeesoo

    2015-02-01

    Biomedical enhancements, the applications of medical technology to make better those who are neither ill nor deficient, have made great strides in the past few decades. Using Amartya Sen's capability approach as my framework, I argue in this article that far from being simply permissible, we have a prima facie moral obligation to use these new developments for the end goal of promoting social justice. In terms of both range and magnitude, the use of biomedical enhancements will mark a radical advance in how we compensate the most disadvantaged members of society. PMID:24117708

  11. Enhancing Learning in Science.

    ERIC Educational Resources Information Center

    Boylan, Colin

    1988-01-01

    Reviews the theoretical framework of instructional programs and the emphasis on enhancing formal reasoning ability. Investigates the effect of an instructional program using inquiry-based learning in pre-service science teacher education students. Reports that the promotion of formal reasoning abilities may be achieved through the five-phase…

  12. Potato germplasm enhancement

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Madison USDA-ARS Germplasm Enhancement Program focuses on the development of parents for breeding programs by putting novel valuable traits into adapted, fertile germplasm. The first germplasm release from this program is five clones with resistance to cold sweetening. These clones are named M1-...

  13. Investigations into Character Enhancement.

    ERIC Educational Resources Information Center

    Hartoonian, H. Michael

    2001-01-01

    Presents six different investigations of character enhancement that attempts to answer three questions: (1) who are you; (2) what is your destination; and (3) who is your captain? Intends to build relationships among ideas such as perspective taking, seeing and making connections with the other, and understanding more about ethical development.…

  14. Enhancing Employee Skills.

    ERIC Educational Resources Information Center

    1999

    This document contains four symposium papers on enhancing employee skills. "The Effect of Study Skills Training Intervention on United States Air Force Aeromedical Apprentices" (John C. Griffith) demonstrates how study skills intervention resulted in a significant increase in the end-of-course scores of a sample of 90 randomly selected Air Force…

  15. Payload Documentation Enhancement Project

    NASA Technical Reports Server (NTRS)

    Brown, Betty G.

    1999-01-01

    In late 1998, the Space Shuttle Program recognized a need to revitalize its payload accommodations documentation. As a result a payload documentation enhancement project was initiated to review and update payload documentation and improve the accessibility to that documentation by the Space Shuttle user community.

  16. Teaching to Enhance Research

    ERIC Educational Resources Information Center

    Harland, Tony

    2016-01-01

    In this paper, I present a conceptual argument for "teaching-led research" in which university lecturers construct courses that directly and positively influence their research, while at the same time, safeguard and enhance the student experience. A research-pedagogy for higher education considers the link between teaching and research,…

  17. Electrostatically Enhanced Vortex Separator

    NASA Technical Reports Server (NTRS)

    Collins, Earl R.

    1993-01-01

    Proposed device removes fine particles from high-pressure exhaust gas of chemical reactor. Negatively charged sectors on rotating disks in vortex generator attracts positively charged particles from main stream of exhaust gas. Electrostatic charge enhances particle-separating action of vortex. Gas without particles released to atmosphere.

  18. Music Enhances Learning.

    ERIC Educational Resources Information Center

    Campabello, Nicolette; De Carlo, Mary Jane; O'Neil, Jean; Vacek, Mary Jill

    An action research project implemented musical strategies to affect and enhance student recall and memory. The target population was three suburban elementary schools near a major midwestern city: (1) a kindergarten classroom contained 32-38 students; (2) a second grade classroom contained 23 students and five Individualized Education Program…

  19. Enhancing Learning and Thinking.

    ERIC Educational Resources Information Center

    Mulcahy, Robert F., Ed.; And Others

    This book presents 16 papers on programs and approaches that have been developed around the world to enhance learning and thinking skills for children and adults. Papers are divided among three main sections focussing respectively on issues and applications, specific applications to school content, and assessment and evaluation. Papers have the…

  20. Enhanced oil recovery

    SciTech Connect

    Brigand, G.; Kragen, H.

    1982-10-12

    Application of an agent for the enhanced oil recovery by means of an aqueous solution capable of increasing the viscosity of the solution is disclosed. Said agent consists of a mixture of a xanthan salt of a trivalent metal, iron or aluminum, with a complexant for the ion of the trivalent metal.

  1. Measuring and Enhancing Creativity

    ERIC Educational Resources Information Center

    Mahboub, Kamyar C.; Portillo, Margaret B.; Liu, Yinhui; Chandraratna, Susantha

    2004-01-01

    The purpose of this study was to assess ways by which creativity may be enhanced in a design-oriented course. In order to demonstrate the validity of the approach, a statistically based study was employed. Additionally, the experiment was replicated in two design-oriented fields at the University of Kentucky. These fields were civil engineering…

  2. Cognition-Enhancing Drugs

    PubMed Central

    Mehlman, Maxwell J

    2004-01-01

    New drugs that enhance cognition in cognitively healthy individuals present difficult public policy challenges. While their use is not inherently unethical, steps must be taken to ensure that they are safe, that they are widely available to promote equality of opportunity, and that individuals are free to decide whether or not to use them. PMID:15330974

  3. Does Powerpoint enhance learning?

    PubMed

    Penciner, Rick

    2013-03-01

    The ubiquitous nature of PowerPoint begs the question, does PowerPoint enhance learning? This narrative explores the evidence for the effectiveness of PowerPoint and multimedia presentations in learning and information processing. Practical recommendations are provided for presentations. PMID:23458142

  4. Oral Skills Enhance Learning.

    ERIC Educational Resources Information Center

    Jensen, J. Vernon

    1980-01-01

    Twelve methods to enhance the learning of college students and at the same time increase their oral communication skills and classroom participation are presented. They include: facilitators of class discussions, triadic critiques of students' essays, panel discussions, forum periods, debates, and manuscript reading. (JMD)

  5. Piezoelectrically Enhanced Photocathodes

    NASA Technical Reports Server (NTRS)

    Beach, Robert A.; Nikzad, Shouleh; Bell, Lloyd Douglas; Strittmatter, Robert

    2011-01-01

    Doping of photocathodes with materials that have large piezoelectric coefficients has been proposed as an alternative means of increasing the desired photoemission of electrons. Treating cathode materials to increase emission of electrons is called "activation" in the art. It has been common practice to activate photocathodes by depositing thin layers of suitable metals (usually, cesium). Because cesium is unstable in air, fabrication of cesiated photocathodes and devices that contain them must be performed in sealed tubes under vacuum. It is difficult and costly to perform fabrication processes in enclosed, evacuated spaces. The proposed piezoelectrically enhanced photocathodes would have electron-emission properties similar to those of cesiated photocathodes but would be stable in air, and therefore could be fabricated more easily and at lower cost. Candidate photocathodes include nitrides of elements in column III of the periodic table . especially compounds of the general formula Al(x)Ga(1.x)N (where 0< or = x < or =.1). These compounds have high piezoelectric coefficients and are suitable for obtaining response to ultraviolet light. Fabrication of a photocathode according to the proposal would include inducement of strain in cathode layers during growth of the layers on a substrate. The strain would be induced by exploiting structural mismatches among the various constituent materials of the cathode. Because of the piezoelectric effect in this material, the strain would give rise to strong electric fields that, in turn, would give rise to a high concentration of charge near the surface. Examples of devices in which piezoelectrically enhanced photocathodes could be used include microchannel plates, electron- bombarded charge-coupled devices, image tubes, and night-vision goggles. Piezoelectrically enhanced photocathode materials could also be used in making highly efficient monolithic photodetectors. Highly efficient and stable piezoelectrically enhanced

  6. Hypothalamic POMC Deficiency Improves Glucose Tolerance Despite Insulin Resistance by Increasing Glycosuria.

    PubMed

    Chhabra, Kavaljit H; Adams, Jessica M; Fagel, Brian; Lam, Daniel D; Qi, Nathan; Rubinstein, Marcelo; Low, Malcolm J

    2016-03-01

    Hypothalamic proopiomelanocortin (POMC) is essential for the physiological regulation of energy balance; however, its role in glucose homeostasis remains less clear. We show that hypothalamic arcuate nucleus (Arc)POMC-deficient mice, which develop severe obesity and insulin resistance, unexpectedly exhibit improved glucose tolerance and remain protected from hyperglycemia. To explain these paradoxical phenotypes, we hypothesized that an insulin-independent pathway is responsible for the enhanced glucose tolerance. Indeed, the mutant mice demonstrated increased glucose effectiveness and exaggerated glycosuria relative to wild-type littermate controls at comparable blood glucose concentrations. Central administration of the melanocortin receptor agonist melanotan II in mutant mice reversed alterations in glucose tolerance and glycosuria, whereas, conversely, administration of the antagonist Agouti-related peptide (Agrp) to wild-type mice enhanced glucose tolerance. The glycosuria of ArcPOMC-deficient mice was due to decreased levels of renal GLUT 2 (rGLUT2) but not sodium-glucose cotransporter 2 and was associated with reduced renal catecholamine content. Epinephrine treatment abolished the genotype differences in glucose tolerance and rGLUT2 levels, suggesting that reduced renal sympathetic nervous system (SNS) activity is the underlying mechanism for the observed glycosuria and improved glucose tolerance in ArcPOMC-deficient mice. Therefore, the ArcPOMC-SNS-rGLUT2 axis is potentially an insulin-independent therapeutic target to control diabetes. PMID:26467632

  7. Enhanced magnetocaloric effect material

    DOEpatents

    Lewis, Laura J. H.

    2006-07-18

    A magnetocaloric effect heterostructure having a core layer of a magnetostructural material with a giant magnetocaloric effect having a magnetic transition temperature equal to or greater than 150 K, and a constricting material layer coated on at least one surface of the magnetocaloric material core layer. The constricting material layer may enhance the magnetocaloric effect by restriction of volume changes of the core layer during application of a magnetic field to the heterostructure. A magnetocaloric effect heterostructure powder comprising a plurality of core particles of a magnetostructural material with a giant magnetocaloric effect having a magnetic transition temperature equal to or greater than 150 K, wherein each of the core particles is encapsulated within a coating of a constricting material is also disclosed. A method for enhancing the magnetocaloric effect within a giant magnetocaloric material including the step of coating a surface of the magnetocaloric material with a constricting material is disclosed.

  8. Superposition Enhanced Nested Sampling

    NASA Astrophysics Data System (ADS)

    Martiniani, Stefano; Stevenson, Jacob D.; Wales, David J.; Frenkel, Daan

    2014-07-01

    The theoretical analysis of many problems in physics, astronomy, and applied mathematics requires an efficient numerical exploration of multimodal parameter spaces that exhibit broken ergodicity. Monte Carlo methods are widely used to deal with these classes of problems, but such simulations suffer from a ubiquitous sampling problem: The probability of sampling a particular state is proportional to its entropic weight. Devising an algorithm capable of sampling efficiently the full phase space is a long-standing problem. Here, we report a new hybrid method for the exploration of multimodal parameter spaces exhibiting broken ergodicity. Superposition enhanced nested sampling combines the strengths of global optimization with the unbiased or athermal sampling of nested sampling, greatly enhancing its efficiency with no additional parameters. We report extensive tests of this new approach for atomic clusters that are known to have energy landscapes for which conventional sampling schemes suffer from broken ergodicity. We also introduce a novel parallelization algorithm for nested sampling.

  9. Orographic enhancement of snowfall.

    PubMed

    Dore, A J; Choularton, T W; Fowler, D; Crossley, A

    1992-01-01

    Field studies have been conducted at a hill site in Scotland to measure the variation with altitude of wet deposition by snowfall. The results showed that, due to wind drift effects, snowflakes were captured very inefficiently by snow collectors. It was therefore not possible to measure an increase in precipitation with altitude. The average concentrations of principal ions dissolved in the snow water were calculated over a two-month period. The results showed that the concentrations increased by factors of between 1.4 and 1.9 with an altitude rise of 400 m. A model of the orographic enhancement of snowfall by the seeder-feeder effect showed that the orographic enhancements of precipitation and pollutant deposition were significantly greater for snowfall than for rainfall. The wind drift of snow crystals and the evaporation of precipitation in dry valley air were important in determining the patterns of deposition. PMID:15092031

  10. Academic Enhancement site.

    PubMed

    DeJong, Judith A; Holder, Stanley R

    2006-01-01

    This off-reservation boarding school serves over 600 students in grades 4-12; approximately 85% of the students reside in campus dormitories. After having documented significant improvement on a number of outcomes during a previous High Risk Youth Prevention demonstration grant, the site submitted a Therapeutic Residential Model proposal, requesting funding to continue successful elements developed under the demonstration grant and to expand mental health services. The site received Therapeutic Residential Model funding for school year 2001-2002. Once funds were received, the site chose to shift Therapeutic Residential Model funds to an intensive academic enhancement effort. While not in compliance with the Therapeutic Residential Model initiative and therefore not funded in subsequent years, this site created the opportunity to enhance the research design by providing a naturally occurring placebo condition at a site with extensive cross-sectional data baselines that addressed issues related to current federal educational policies. PMID:17602403

  11. Image enhancement by holography.

    NASA Technical Reports Server (NTRS)

    Stroke, G. W.

    1973-01-01

    The speed of the holographic image deblurring method has recently been further enhanced by a new speed in the realization of the powerful holographic image-deblurring filter. The filter makes it possible to carry out the deblurring, in the optical computer used, in times of the order of one second. The experimental achievements using the holographic image-enhancement method are illustrated with examples ranging from out-of-focus or motion-blurred photographs, including 'amateur' photos recorded on Polaroid film, to the sharpening of the best available electron micrographs of viruses. Images recorded with X-rays, notably from rocket-borne photos of the sun, and out-of-focus photographs from cameras in NASA satellites have been similarly deblurred.

  12. Enhanced Microfluidic Electromagnetic Measurements

    NASA Technical Reports Server (NTRS)

    Giovangrandi, Laurent (Inventor); Ricco, Antonio J. (Inventor); Kovacs, Gregory (Inventor)

    2015-01-01

    Techniques for enhanced microfluidic impedance spectroscopy include causing a core fluid to flow into a channel between two sheath flows of one or more sheath fluids different from the core fluid. Flow in the channel is laminar. A dielectric constant of a fluid constituting either sheath flow is much less than a dielectric constant of the core fluid. Electrical impedance is measured in the channel between at least a first pair of electrodes. In some embodiments, enhanced optical measurements include causing a core fluid to flow into a channel between two sheath flows of one or more sheath fluids different from the core fluid. An optical index of refraction of a fluid constituting either sheath flow is much less than an optical index of refraction of the core fluid. An optical property is measured in the channel.

  13. Microbial enhanced oil recovery

    SciTech Connect

    Finnerty, W.R.; Singer, M.E.

    1983-06-01

    Microbial enhanced oil recovery (MEOR) attempts to exploit the metabolic processes of microorganisms to increase oil production from reservoirs of marginal oil productivity. MEOR can be achieved by direct stimulation of existing microflora within the reservoir, introduction of specialized microroganisms, or above ground use of bioproducts as chemically enhanced oil recovery agents. Reservoir microbiology, the biotransformation of crude oil, and bioproducts applicable to EOR all need further study. Xanthan and polyacrylamine have been applied to EOR, but with some problems. Other selected polysaccharides for which reasonable data bases exist are listed. Some tests on injection of microorganisms, CEOR use, and use of biosurfactants (bacteria that reduces the viscosity of crude oil) are reviewed. The status of MEOR currently resides at a basic level of research and developement.

  14. Lignite Fuel Enhancement

    SciTech Connect

    Charles Bullinger

    2006-02-03

    This 6th quarterly Technical Progress Report for the Lignite Fuel Enhancement Project summarizes activities from October 1st through December 31st of 2005. It also summarizes the subsequent purchasing activity and dryer/process construction. Hypothesis remains the same. We will be able to dry lignite an increment to benefit the performance of and reduce emissions from a coal burning electric power generating station.

  15. LIGNITE FUEL ENHANCEMENT

    SciTech Connect

    Charles Bullinger

    2004-10-29

    This 1st quarterly Technical Progress Report for the Lignite Fuel Enhancement Project explains what has transpired since Great River Energy was selected to negotiate the Cooperative agreement in February of 2003. The report will summarize Pre-award activities and any other activity since signature of the contract on July 9th of this year. It also summarizes the subsequent purchasing activity and final dryer/process design up to September 30th of 2004.

  16. Enhanced Rescue Lift Capability

    NASA Technical Reports Server (NTRS)

    Young, Larry A.

    2007-01-01

    The evolving and ever-increasing demands of emergency response and disaster relief support provided by rotorcraft dictate, among other things, the development of enhanced rescue lift capability for these platforms. This preliminary analysis is first-order in nature but provides considerable insight into some of the challenges inherent in trying to effect rescue using a unique form of robotic rescue device deployed and operated from rotary-wing aerial platforms.

  17. Digital Enhancement Of Pneumothoraces

    NASA Astrophysics Data System (ADS)

    Cocklin, M.; Kaye, G.; Kerr, I.; Lams, P.

    1982-11-01

    If a patient presents with symptoms indicative of a pneumothorax it is improbable that it would not be detected in a chest radiograph. However, detection on the radiograph can be difficult and a small pneumothorax may be missed when there is no clinical suspicion of its presence. This report presents some methods by which the characteristic pneumothorax edge may be enhanced by digital image processing. Various examples are given.

  18. Skin penetration enhancers.

    PubMed

    Lane, Majella E

    2013-04-15

    The skin has evolved to prevent excessive water loss from the internal organs and to limit the ability of xenobiotics and hazardous substances to enter the body. Notwithstanding this barrier function, a number of strategies have been developed by scientists to deliver drugs to and through the skin. The aim of this review is to consider the various types of chemical penetration enhancers (CPEs) which have been investigated in the scientific literature. Potential pathways for CPEs to exert their action are examined with reference to the physical chemistry of passive skin transport. The emphasis is on those studies which have focussed on human and porcine skin because of the limitations associated with skin permeation data collated from other species. Where known, the mechanisms of action of these compounds are also discussed. Examples of enhancers used in commercial topical and transdermal formulations are provided. It is proposed that overall the effects of CPEs on the skin barrier may best be explained by a Diffusion-Partition-Solubility theory. Finally, some of the limitations of studies in the literature are considered and the importance of monitoring the fate of the penetration enhancer as well as the active is highlighted. PMID:23462366

  19. Sleep for cognitive enhancement

    PubMed Central

    Diekelmann, Susanne

    2014-01-01

    Sleep is essential for effective cognitive functioning. Loosing even a few hours of sleep can have detrimental effects on a wide variety of cognitive processes such as attention, language, reasoning, decision making, learning and memory. While sleep is necessary to ensure normal healthy cognitive functioning, it can also enhance performance beyond the boundaries of the normal condition. This article discusses the enhancing potential of sleep, mainly focusing on the domain of learning and memory. Sleep is known to facilitate the consolidation of memories learned before sleep as well as the acquisition of new memories to be learned after sleep. According to a widely held model this beneficial effect of sleep relies on the neuronal reactivation of memories during sleep that is associated with sleep-specific brain oscillations (slow oscillations, spindles, ripples) as well as a characteristic neurotransmitter milieu. Recent research indicates that memory processing during sleep can be boosted by (i) cueing memory reactivation during sleep; (ii) stimulating sleep-specific brain oscillations; and (iii) targeting specific neurotransmitter systems pharmacologically. Olfactory and auditory cues can be used, for example, to increase reactivation of associated memories during post-learning sleep. Intensifying neocortical slow oscillations (the hallmark of slow wave sleep (SWS)) by electrical or auditory stimulation and modulating specific neurotransmitters such as noradrenaline and glutamate likewise facilitates memory processing during sleep. With this evidence in mind, this article concludes by discussing different methodological caveats and ethical issues that should be considered when thinking about using sleep for cognitive enhancement in everyday applications. PMID:24765066

  20. Chemically enhanced oil recovery

    SciTech Connect

    Nelson, R.C.

    1989-03-01

    Yet when conducted according to present state of the art, chemical flooding (i.e., micellar/polymer flooding, surfactant/polymer flooding, surfactant flooding) can mobilize more residual crude oil than any other method of enhanced oil recovery. It also is one of the most expensive methods of enhanced oil recovery. This contribution will describe some of the technology that comprises the state of the art technology that must be adhered to if a chemical flood is to be successful. Although some of the efforts to reduce cost and other points are discussed, the principle focus is on technical considerations in designing a good chemical flooding system. The term chemical flooding is restricted here to methods of enhanced oil recovery that employs a surfactant, either injected into the oil reservoir or generated in situ, primarily to reduce oil-water interfacial tension. Hence, polymer-water floods for mobility or profile control, steam foams, and carbon dioxide foams are excluded. Some polymer considerations are mentioned because they apply to providing mobility control for chemical flooding systems.

  1. Enhancing transgender health care.

    PubMed Central

    Lombardi, E

    2001-01-01

    As awareness of transgender men and women grows among health care educators, researchers, policymakers, and clinicians of all types, the need to create more inclusive settings also grows. Greater sensitivity and relevant information and services are required in dealing with transgender men and women. These individuals need their identities to be recognized as authentic, they need better access to health care resources, and they need education and prevention material appropriate to their experience. In addition, a need exists for activities designed to enhance understanding of transgender health issues and to spur innovation. PMID:11392924

  2. Enhance separations with electricity

    SciTech Connect

    Muralidhara, H.S.

    1994-05-01

    To satisfy growing environmental regulations, control energy costs, or just to stay competitive, one must improve existing separation technologies and make them more efficient. New challenges in food processing and requirements for novel purification technologies in the biotech industry also will require more efficient separation techniques. This paper discusses some enhanced separation processes based on the application of an electric field in the combined-fields approach. In a combined-fields approach, the emphasis is on the generation of additional driving forces to work simultaneously with the conventional driving force of the process. Here the authors concentrate on the application of an electric field to generate the additional driving force.

  3. Enhanced recovery of petroleum

    SciTech Connect

    Buinicky, E.P.; Estes, J.H.

    1980-09-16

    An enhanced oil recovery method comprising injecting an aqueous ammonium bisulfite (NH/sub 4/HSO/sub 3/) solution into a petroleum-bearing earth formation, heating said injected aqueous solution to a temperature in the range of about 120*-300* F., or higher in the presence of said petroleum-bearing earth formation, flowing said aqueous solution through said petroleum bearing earth formation to drive petroleum to a recovery well, and producing increased amounts of petroleum from said earth formation through said recovery well.

  4. Cell Growth Enhancement

    NASA Technical Reports Server (NTRS)

    1992-01-01

    Exogene Corporation uses advanced technologies to enhance production of bio-processed substances like proteins, antibiotics and amino acids. Among them are genetic modification and a genetic switch. They originated in research for Jet Propulsion Laboratory. Extensive experiments in cell growth through production of hemoglobin to improve oxygen supply to cells were performed. By improving efficiency of oxygen use by cells, major operational expenses can be reduced. Greater product yields result in decreased raw material costs and more efficient use of equipment. A broad range of applications is cited.

  5. Enhanced by Frost

    NASA Technical Reports Server (NTRS)

    2005-01-01

    30 September 2005 This Mars Global Surveyor (MGS) Mars Orbiter Camera (MOC) image shows outcrops of south polar layered terrain. Their appearance in this July 2005 springtime image is enhanced by bright patches of carbon dioxide frost. The frost is left over from the previous southern winter season; by summer, the frost would be gone.

    Location near: 84.6oS, 203.5oW Image width: width: 3 km (1.9 mi) Illumination from: upper left Season: Southern Spring

  6. Computer enhancement of radiographs

    NASA Technical Reports Server (NTRS)

    Dekaney, A.; Keane, J.; Desautels, J.

    1973-01-01

    Examination of three relevant noise processes and the image degradation associated with Marshall Space Flight Center's (MSFC) X-ray/scanning system was conducted for application to computer enhancement of radiographs using MSFC's digital filtering techniques. Graininess of type M, R single coat and R double coat X-ray films was quantified as a function of density level using root-mean-square (RMS) granularity. Quantum mottle (including film grain) was quantified as a function of the above film types, exposure level, specimen material and thickness, and film density using RMS granularity and power spectral density (PSD). For various neutral-density levels the scanning device used in digital conversion of radiographs was examined for noise characteristics which were quantified by RMS granularity and PSD. Image degradation of the entire pre-enhancement system (MG-150 X-ray device; film; and optronics scanner) was measured using edge targets to generate modulation transfer functions (MTF). The four parameters were examined as a function of scanning aperture sizes of approximately 12.5 25 and 50 microns.

  7. Graphene-enhanced nanorefrigerants.

    PubMed

    Ozturk, Serdar; Hassan, Yassin A; Ugaz, Victor M

    2013-01-21

    Recent reports that a host liquid's thermal properties can be augmented by dispersal of small quantities of nanoparticles have stimulated intense interest as an intriguing avenue to produce advanced heat transfer fluids. But effects are challenging to exploit in practical settings because it is difficult to prepare refrigerant-based dispersions displaying sufficient long-term stability. Moreover, the most dramatic enhancements in thermal conductivity obtained using anisotropic nanomaterials (e.g., carbon nanotubes) are achieved at the expense of a severe viscosity increase. Here we overcome these limitations by introducing a robust surfactant-mediated dispersal method that enables stable suspensions containing a range of nanomaterials to be straightforwardly prepared as additives to ordinary commercial refrigerants. We apply this approach to formulate a new class of nanorefrigerants containing graphene nanosheets that uniquely match the superior thermal conductivity enhancements attained in carbon nanotube suspensions without their accompanying viscosity penalty. These suspensions can be directly substituted for conventional refrigerants to inexpensively achieve increased efficiency in many thermal management applications. PMID:23229852

  8. Computer enhanced digital angiography.

    PubMed

    Vas, R; Diamond, G A; Levisman, J A; Nakano, F H; Neidorf, B S; Rose, R M; Whiting, J S; Forrester, J S

    1982-05-01

    A new computer image enhancement technique was employed on cardiac images of 10 dogs and 7 patients to demonstrate the feasibility of an on-line automatic delineation of the left ventricular endocardial silhouette with a peripheral venous injection of contrast material while simultaneously reducing the x-ray dosage. This technique employs a very fast analog-to-digital conversion system capable of digitizing on-line video frames. By storing and continuously updating the first 30 video frames and then subtracting each incoming frame from this memory, most of the background is eliminated leaving only the contrast filled ventricle. Using calibrated densitometric measurements, we found that iodine concentrations in the human left ventricle following venous injection of 40 ml Renografin-76 (25 ml/s), peaked at 4.3 +/- 0.3 mg/ml (mean +/- SD) compared to 14.8 +/- 0.8 mg/ml following direct injection of 40 ml at 13 ml/s (p less than 0.001). The computer enhanced venous-injected images had an optical contrast 14 times greater than that of the unenhanced direct left ventriculogram. This increase in optical contrast provided unambiguous subjective definition of the endocardial borders. This technique is applicable to both central and peripheral contrast injection whereby high quality images can be obtained at approximately 98% reduction in radiation (5 mA, 65-85 kV), allowing performance of serial studies. PMID:7094444

  9. Acoustically enhanced heat transport.

    PubMed

    Ang, Kar M; Yeo, Leslie Y; Friend, James R; Hung, Yew Mun; Tan, Ming K

    2016-01-01

    We investigate the enhancement of heat transfer in the nucleate boiling regime by inducing high frequency acoustic waves (f ∼ 10(6) Hz) on the heated surface. In the experiments, liquid droplets (deionized water) are dispensed directly onto a heated, vibrating substrate. At lower vibration amplitudes (ξs ∼ 10(-9) m), the improved heat transfer is mainly due to the detachment of vapor bubbles from the heated surface and the induced thermal mixing. Upon increasing the vibration amplitude (ξs ∼ 10(-8) m), the heat transfer becomes more substantial due to the rapid bursting of vapor bubbles happening at the liquid-air interface as a consequence of capillary waves travelling in the thin liquid film between the vapor bubble and the air. Further increases then lead to rapid atomization that continues to enhance the heat transfer. An acoustic wave displacement amplitude on the order of 10(-8) m with 10(6) Hz order frequencies is observed to produce an improvement of up to 50% reduction in the surface temperature over the case without acoustic excitation. PMID:26827343

  10. Acoustically enhanced heat transport

    NASA Astrophysics Data System (ADS)

    Ang, Kar M.; Yeo, Leslie Y.; Friend, James R.; Hung, Yew Mun; Tan, Ming K.

    2016-01-01

    We investigate the enhancement of heat transfer in the nucleate boiling regime by inducing high frequency acoustic waves (f ˜ 106 Hz) on the heated surface. In the experiments, liquid droplets (deionized water) are dispensed directly onto a heated, vibrating substrate. At lower vibration amplitudes (ξs ˜ 10-9 m), the improved heat transfer is mainly due to the detachment of vapor bubbles from the heated surface and the induced thermal mixing. Upon increasing the vibration amplitude (ξs ˜ 10-8 m), the heat transfer becomes more substantial due to the rapid bursting of vapor bubbles happening at the liquid-air interface as a consequence of capillary waves travelling in the thin liquid film between the vapor bubble and the air. Further increases then lead to rapid atomization that continues to enhance the heat transfer. An acoustic wave displacement amplitude on the order of 10-8 m with 106 Hz order frequencies is observed to produce an improvement of up to 50% reduction in the surface temperature over the case without acoustic excitation.

  11. Surfactant-enhanced bioremediation

    SciTech Connect

    Churchill, P.F.; Dudley, R.J.; Churchill, S.A.

    1995-12-31

    This study was undertaken to examine the effect of three structurally related, non-ionic surfactants, Triton X-45, Triton X-100 and Triton X-165, as well as the oleophilic fertilizer, Inipol EAP 22, on the rate of biodegradation of phenanthrene by pure bacterial cultures. Each surfactant dramatically increased the apparent aqueous solubility of phenanthrene. Model studies were conducted to investigate the ability of these surfactants to enhance the rate of transport and uptake of polycyclic aromatic hydrocarbons into bacterial cells, and to assess the impact that increasing the aqueous solubility of hydrocarbons has on their rate of biodegradation. The results indicate that increasing the apparent aqueous solubility of hydrocarbons can lead to enhanced biodegradation rates by two Pseudomonas saccharophila strains. However, the experiments also suggest that some surfactants can inhibit aromatic hydrocarbon biodegradation by certain bacteria. The data also support the hypothesis that surface-active components present in the oleophilic fertilizer formulation, Inipol EAP 22, may have significantly contributed to the positive results reported in tests of remedial agent impact on bioremediation, which was used as a supplemental clean-up technology on Exxon Valdez crude oil-contaminated Alaskan beaches.

  12. Telemetry-Enhancing Scripts

    NASA Technical Reports Server (NTRS)

    Maimone, Mark W.

    2009-01-01

    Scripts Providing a Cool Kit of Telemetry Enhancing Tools (SPACKLE) is a set of software tools that fill gaps in capabilities of other software used in processing downlinked data in the Mars Exploration Rovers (MER) flight and test-bed operations. SPACKLE tools have helped to accelerate the automatic processing and interpretation of MER mission data, enabling non-experts to understand and/or use MER query and data product command simulation software tools more effectively. SPACKLE has greatly accelerated some operations and provides new capabilities. The tools of SPACKLE are written, variously, in Perl or the C or C++ language. They perform a variety of search and shortcut functions that include the following: Generating text-only, Event Report-annotated, and Web-enhanced views of command sequences; Labeling integer enumerations with their symbolic meanings in text messages and engineering channels; Systematic detecting of corruption within data products; Generating text-only displays of data-product catalogs including downlink status; Validating and labeling of commands related to data products; Performing of convenient searches of detailed engineering data spanning multiple Martian solar days; Generating tables of initial conditions pertaining to engineering, health, and accountability data; Simplified construction and simulation of command sequences; and Fast time format conversions and sorting.

  13. Direct vs. Indirect Moral Enhancement.

    PubMed

    Schaefer, G Owen

    2015-09-01

    Moral enhancement is an ostensibly laudable project. Who wouldn't want people to become more moral? Still, the project's approach is crucial. We can distinguish between two approaches for moral enhancement: direct and indirect. Direct moral enhancements aim at bringing about particular ideas, motives or behaviors. Indirect moral enhancements, by contrast, aim at making people more reliably produce the morally correct ideas, motives or behaviors without committing to the content of those ideas, motives and/or actions. I will argue, on Millian grounds, that the value of disagreement puts serious pressure on proposals for relatively widespread direct moral enhancement. A more acceptable path would be to focus instead on indirect moral enhancements while staying neutral, for the most part, on a wide range of substantive moral claims. I will outline what such indirect moral enhancement might look like, and why we should expect it to lead to general moral improvement. PMID:26412738

  14. Cavity enhanced atomic magnetometry.

    PubMed

    Crepaz, Herbert; Ley, Li Yuan; Dumke, Rainer

    2015-01-01

    Atom sensing based on Faraday rotation is an indispensable method for precision measurements, universally suitable for both hot and cold atomic systems. Here we demonstrate an all-optical magnetometer where the optical cell for Faraday rotation spectroscopy is augmented with a low finesse cavity. Unlike in previous experiments, where specifically designed multipass cells had been employed, our scheme allows to use conventional, spherical vapour cells. Spherical shaped cells have the advantage that they can be effectively coated inside with a spin relaxation suppressing layer providing long spin coherence times without addition of a buffer gas. Cavity enhancement shows in an increase in optical polarization rotation and sensitivity compared to single-pass configurations. PMID:26481853

  15. Cavity enhanced atomic magnetometry

    NASA Astrophysics Data System (ADS)

    Crepaz, Herbert; Ley, Li Yuan; Dumke, Rainer

    2015-10-01

    Atom sensing based on Faraday rotation is an indispensable method for precision measurements, universally suitable for both hot and cold atomic systems. Here we demonstrate an all-optical magnetometer where the optical cell for Faraday rotation spectroscopy is augmented with a low finesse cavity. Unlike in previous experiments, where specifically designed multipass cells had been employed, our scheme allows to use conventional, spherical vapour cells. Spherical shaped cells have the advantage that they can be effectively coated inside with a spin relaxation suppressing layer providing long spin coherence times without addition of a buffer gas. Cavity enhancement shows in an increase in optical polarization rotation and sensitivity compared to single-pass configurations.

  16. Memnonia Fossae (Enhanced Color)

    NASA Technical Reports Server (NTRS)

    1995-01-01

    Tharsis-centered volcanic and tectonic activity resulted in the formation of radial grabens of Memnonia Fossae, which cut materials of the ancient cratered highlands and the relatively young, highland-embaying lava flows from the Tharsis volcanoes. Center of picture is at latitude 16 degrees S., longitude 142 degrees W. The enhanced color version (following decorrelation stretch) reveals a diversity of subtle color variations; many of the color variations may be due to different lava flow units and variable amounts of weathering, possible alteration by water, and eolian redistributions. Viking Orbiter Picture Numbers 41B52 (green) 41B54 (red), and 41B56 (blue) at 198 m/pixel resolution. Picture width is 206 km. North is 119 degrees counter-clockwise from top.

  17. Digitally Enhanced Heterodyne Interferometry

    NASA Technical Reports Server (NTRS)

    Shaddock, Daniel; Ware, Brent; Lay, Oliver; Dubovitsky, Serge

    2010-01-01

    Spurious interference limits the performance of many interferometric measurements. Digitally enhanced interferometry (DEI) improves measurement sensitivity by augmenting conventional heterodyne interferometry with pseudo-random noise (PRN) code phase modulation. DEI effectively changes the measurement problem from one of hardware (optics, electronics), which may deteriorate over time, to one of software (modulation, digital signal processing), which does not. DEI isolates interferometric signals based on their delay. Interferometric signals are effectively time-tagged by phase-modulating the laser source with a PRN code. DEI improves measurement sensitivity by exploiting the autocorrelation properties of the PRN to isolate only the signal of interest and reject spurious interference. The properties of the PRN code determine the degree of isolation.

  18. Cavity enhanced atomic magnetometry

    PubMed Central

    Crepaz, Herbert; Ley, Li Yuan; Dumke, Rainer

    2015-01-01

    Atom sensing based on Faraday rotation is an indispensable method for precision measurements, universally suitable for both hot and cold atomic systems. Here we demonstrate an all-optical magnetometer where the optical cell for Faraday rotation spectroscopy is augmented with a low finesse cavity. Unlike in previous experiments, where specifically designed multipass cells had been employed, our scheme allows to use conventional, spherical vapour cells. Spherical shaped cells have the advantage that they can be effectively coated inside with a spin relaxation suppressing layer providing long spin coherence times without addition of a buffer gas. Cavity enhancement shows in an increase in optical polarization rotation and sensitivity compared to single-pass configurations. PMID:26481853

  19. Enhanced oil recovery process

    SciTech Connect

    Martin, A. B.; Jackson, E. J.

    1985-10-15

    An improved portable, versatile, modular, above-ground system and process for generating combustion gases, principally nitrogen and carbon dioxide, and steam, for removing particulate matter and corrosive components from the combustion gases, and for injecting the purified nitrogen and CO/sub 2/, and steam, individually or in selected mixtures, at controlled temperatures and pressures into a subterranean formation bearing hydrocarbons to enhance the recovery thereof. The system includes a high-pressure combustion reactor for efficient generation of combustion gases at the required rates and at pressures up to about 8000 psi and temperatures up to about 4500/sup 0/ F. The reactor is water-jacketed but lined with refractory material to minimize soot formation. Combustion chamber temperature is reduced to a safe level by water injection with the fuel.

  20. Enhanced Geothermal Systems

    SciTech Connect

    Jeanloz, R.; Stone, H.

    2013-12-31

    DOE, through the Geothermal Technologies Office (GTO) within the Office of Energy Efficiency and Renewable Energy, requested this study, identifying a focus on: i) assessment of technologies and approaches for subsurface imaging and characterization so as to be able to validate EGS opportunities, and ii) assessment of approaches toward creating sites for EGS, including science and engineering to enhance permeability and increase the recovery factor. Two days of briefings provided in-depth discussion of a wide range of themes and challenges in EGS, and represented perspectives from industry, government laboratories and university researchers. JASON also contacted colleagues from universities, government labs and industry in further conversations to learn the state of the field and potential technologies relevant to EGS.

  1. Enhanced oil recovery system

    DOEpatents

    Goldsberry, Fred L.

    1989-01-01

    All energy resources available from a geopressured geothermal reservoir are used for the production of pipeline quality gas using a high pressure separator/heat exchanger and a membrane separator, and recovering waste gas from both the membrane separator and a low pressure separator in tandem with the high pressure separator for use in enhanced oil recovery, or in powering a gas engine and turbine set. Liquid hydrocarbons are skimmed off the top of geothermal brine in the low pressure separator. High pressure brine from the geothermal well is used to drive a turbine/generator set before recovering waste gas in the first separator. Another turbine/generator set is provided in a supercritical binary power plant that uses propane as a working fluid in a closed cycle, and uses exhaust heat from the combustion engine and geothermal energy of the brine in the separator/heat exchanger to heat the propane.

  2. Teacher Enhancement Institute

    NASA Technical Reports Server (NTRS)

    Marshall-Bradley, Tina

    1994-01-01

    During the 1980's, a period of intense concern over educational quality in the United States, few indicators of U.S. student achievement garnered the interest of policy makers and pundits as successfully as the results of international testing in mathematics and science. This concern was so great that as a part of the Goals 2000 initiative, President George Bush indicated that 'By the year 2000, U.S. students should be first in the world in mathematics and science.' The Clinton Administration is placing a major emphasis, not only on rigorous academic standards and creating a new system for assessing students' progress, but also including professional development as a major focus. The argument being that teachers need more sustained, intensive training to prepare them to teach to higher standards. Executive order 12821 mandates that national laboratories 'assist in the mathematics and science education of our Nation's students, teachers, parents and the public by establishing programs at their agency to provide for training elementary and secondary school teachers to improve their knowledge of mathematics and science'. These and other issues led to the development of ideas for a project that addresses the need for excellence in mathematics, science and technology instruction. In response to these initiatives the NASA/LaRC Teacher Enhancement Institute was proposed. The TEI incorporated systemic reform perspectives, enhanced content knowledge for teachers, and teacher preparation. Emphasis was also placed on recruiting those educators who teach in impoverished urban school districts with at-risk student populations who have been traditionally under represented in science, mathematics, technology and engineering. Participants in the Teacher Enhancement Institute were 37 teachers from grades K-8, teaching in Region 2 in the state of Virginia, as well as 2 preservice teachers from Norfolk State University and one teacher from Dublin, Virginia, where a Science

  3. Attention enhances feature integration.

    PubMed

    Paul, Liza; Schyns, Philippe G

    2003-08-01

    Perceptual processing delays between attribute dimensions (e.g. color, form and motion) [Proceedings of the Royal Society of London Series B 264 (1997) 1407] have been attributed to temporal processing asynchronies resulting from functional segregation of visual information [Science 240 (1988) 740]. In addition, several lines of evidence converge to suggest that attention plays an important role in the integration of functionally processed information. However, exactly how attention modulates the temporal integration of information remains unclear. Here, we examined how attention modulates the integration of color and form into a unitary perception. Results suggest that attending to the location of an object enhances the integration of its defining attributes by speeding up the perceptual processing of each attribute dimension. Moreover, the perceptual asynchrony between attributes remains constant across attended and unattended conditions because attention seems to offer each processing dimension an equal processing advantage. PMID:12826102

  4. Structure Size Enhanced Histogram

    NASA Astrophysics Data System (ADS)

    Wesarg, Stefan; Kirschner, Matthias

    Direct volume visualization requires the definition of transfer functions (TFs) for the assignment of opacity and color. Multi-dimensional TFs are based on at least two image properties, and are specified by means of 2D histograms. In this work we propose a new type of a 2D histogram which combines gray value with information about the size of the structures. This structure size enhanced (SSE) histogram is an intuitive approach for representing anatomical features. Clinicians — the users we are focusing on — are much more familiar with selecting features by their size than by their gradient magnitude value. As a proof of concept, we employ the SSE histogram for the definition of two-dimensional TFs for the visualization of 3D MRI and CT image data.

  5. Enhanced optical tracking

    NASA Astrophysics Data System (ADS)

    McSheery, Tracy

    2008-04-01

    Enhanced tracking is accomplished by increasing the resolution, frame rate and processing capabilities in tracking dynamic regions of interest for vision applications. In many proven algorithms, the ability to distinguish an object and track it is dependent on the system performance in more than one attribute. We have conducted studies on proven techniques such as Active Appearance Models, Principle Component Analysis and Eigen tracking. All perform better as the camera resolution increases, and camera frame rate increases. Additional opportunities have been observed by combining these techniques, taking advantage of Multicore CPUs, and GPU graphic card processing. Results from an 8 Megapixel commercial sensor combined with a Field Programmable Gate array are presented, and algorithm performance compared with down scaled images of the same scenes, and simulated typical 30 hertz frame rates verses the 120 hertz to 300 hertz typical of this smart camera.

  6. Photon enhanced thermionic emission

    SciTech Connect

    Schwede, Jared; Melosh, Nicholas; Shen, Zhixun

    2014-10-07

    Photon Enhanced Thermionic Emission (PETE) is exploited to provide improved efficiency for radiant energy conversion. A hot (greater than 200.degree. C.) semiconductor cathode is illuminated such that it emits electrons. Because the cathode is hot, significantly more electrons are emitted than would be emitted from a room temperature (or colder) cathode under the same illumination conditions. As a result of this increased electron emission, the energy conversion efficiency can be significantly increased relative to a conventional photovoltaic device. In PETE, the cathode electrons can be (and typically are) thermalized with respect to the cathode. As a result, PETE does not rely on emission of non-thermalized electrons, and is significantly easier to implement than hot-carrier emission approaches.

  7. Plasmonic enhanced ultrafast switch.

    SciTech Connect

    Subramania,Ganapathi Subramanian; Reno, John Louis; Passmore, Brandon Scott; Harris, Tom.; Shaner, Eric Arthur; Barrick, Todd A.

    2009-09-01

    Ultrafast electronic switches fabricated from defective material have been used for several decades in order to produce picosecond electrical transients and TeraHertz radiation. Due to the ultrashort recombination time in the photoconductor materials used, these switches are inefficient and are ultimately limited by the amount of optical power that can be applied to the switch before self-destruction. The goal of this work is to create ultrafast (sub-picosecond response) photoconductive switches on GaAs that are enhanced through plasmonic coupling structures. Here, the plasmonic coupler primarily plays the role of being a radiation condenser which will cause carriers to be generated adjacent to metallic electrodes where they can more efficiently be collected.

  8. Enhanced Identification of Transcriptional Enhancers Provides Mechanistic Insights into Diseases.

    PubMed

    Murakawa, Yasuhiro; Yoshihara, Masahito; Kawaji, Hideya; Nishikawa, Miki; Zayed, Hatem; Suzuki, Harukazu; Fantom Consortium; Hayashizaki, Yoshihide

    2016-02-01

    Enhancers are distal cis-regulatory DNA elements that increase the expression of target genes. Various experimental and computational approaches including chromatin signature profiling have been developed to predict enhancers on a genome-wide scale, although each method has its advantages and disadvantages. Here we overview an emerging method to identify transcribed enhancers at exceedingly high nucleotide resolution based on enhancer RNA transcripts captured by Cap Analysis of Gene Expression (CAGE) technology. We further argue that disease-causative regulatory mutations at enhancers are increasingly recognized, emphasizing the importance of enhancer identification in functional and clinical genomics including, but not limited to, genome-wide association studies (GWASs) and cancer genomics studies. PMID:26780995

  9. Lignite Fuel Enhancement

    SciTech Connect

    Charles Bullinger; Nenad Sarunac

    2010-03-31

    Pulverized coal power plants which fire lignites and other low-rank high-moisture coals generally operate with reduced efficiencies and increased stack emissions due to the impacts of high fuel moisture on stack heat loss and pulverizer and fan power. A process that uses plant waste heat sources to evaporate a portion of the fuel moisture from the lignite feedstock in a moving bed fluidized bed dryer (FBD) was developed in the U.S. by a team led by Great River Energy (GRE). The demonstration was conducted with Department of Energy (DOE) funding under DOE Award Number DE-FC26-04NT41763. The objectives of GRE's Lignite Fuel Enhancement project were to demonstrate reduction in lignite moisture content by using heat rejected from the power plant, apply technology at full scale at Coal Creek Station (CCS), and commercialize it. The Coal Creek Project has involved several stages, beginning with lignite drying tests in a laboratory-scale FBD at the Energy Research Center (ERC) and development of theoretical models for predicting dryer performance. Using results from these early stage research efforts, GRE built a 2 ton/hour pilot-scale dryer, and a 75 ton/hour prototype drying system at Coal Creek Station. Operated over a range of drying conditions, the results from the pilot-scale and prototype-scale dryers confirmed the performance of the basic dryer design concept and provided the knowledge base needed to scale the process up to commercial size. Phase 2 of the GRE's Lignite Fuel Enhancement project included design, construction and integration of a full-scale commercial coal drying system (four FBDs per unit) with Coal Creek Units 1 and 2 heat sources and coal handling system. Two series of controlled tests were conducted at Coal Creek Unit 1 with wet and dried lignite to determine effect of dried lignite on unit performance and emissions. Wet lignite was fired during the first, wet baseline, test series conducted in September 2009. The second test series was performed

  10. Enhanced Micellar Catalysis LDRD.

    SciTech Connect

    Betty, Rita G.; Tucker, Mark David; Taggart, Gretchen; Kinnan, Mark K.; Glen, Crystal Chanea; Rivera, Danielle; Sanchez, Andres; Alam, Todd Michael

    2012-12-01

    The primary goals of the Enhanced Micellar Catalysis project were to gain an understanding of the micellar environment of DF-200, or similar liquid CBW surfactant-based decontaminants, as well as characterize the aerosolized DF-200 droplet distribution and droplet chemistry under baseline ITW rotary atomization conditions. Micellar characterization of limited surfactant solutions was performed externally through the collection and measurement of Small Angle X-Ray Scattering (SAXS) images and Cryo-Transmission Electron Microscopy (cryo-TEM) images. Micellar characterization was performed externally at the University of Minnesota's Characterization Facility Center, and at the Argonne National Laboratory Advanced Photon Source facility. A micellar diffusion study was conducted internally at Sandia to measure diffusion constants of surfactants over a concentration range, to estimate the effective micelle diameter, to determine the impact of individual components to the micellar environment in solution, and the impact of combined components to surfactant phase behavior. Aerosolized DF-200 sprays were characterized for particle size and distribution and limited chemical composition. Evaporation rates of aerosolized DF-200 sprays were estimated under a set of baseline ITW nozzle test system parameters.

  11. Waste water filtration enhancement

    SciTech Connect

    Martin, H.L.

    1989-01-01

    Removal of submicron particles from process solutions and waste water is now economically achievable using a new Tyvek{reg sign} media in conventional filtration equipment. This new product greatly enhances filtration and allows use of the much improved filter aids and polymers which were recently developed. It has reduced operating costs and ensures a clean effluent discharge to the environment. This significant technical development is especially important to those who discharge to a small stream with low 7Q10 flow and must soon routinely pass the Toxicity tests that are being required by many States for NPDES permit renewal. The Savannah River Plant produces special nuclear materials for the US Government. Aluminum forming and metal finishing operations in M-Area, that manufacture fuel and target assemblies for the nuclear reactors, discharge to a waste water treatment facility using BAT hydroxide precipitation and filtration. The new Tyvek{reg sign} media and filter aids have achieved 55% less solids in the filtrate discharged to Tims Branch Creek, 15% less hazardous waste (dry filter cake), 150%-370% more filtration capacity, 74% lower materials purchase cost, 10% lower total M-Area manufacturing cost, and have improved safety. Performance with the improved polymers is now being evaluated.

  12. Enhanced preliminary assessment

    SciTech Connect

    Not Available

    1992-02-01

    An Enhanced Preliminary Assessment was conducted at Fort Benjamin Harrison (FBH) Indiana, which is located approximately 12 miles from downtown Indianapolis in Lawrence Township, Marion County. FBH contains 2,501 acres, of which approximately 1,069 acres is covered by woodlands. Activities at FBH include administration, training, housing, and support. Sensitive environments at FBH include wetlands, habitat areas for the endangered Indiana bat, endangered plants, and historically and archeologically significant areas. FBH is a U.S. Army Soldier Support Center under the jurisdiction of the U.S. Army Training and Doctrine Command (TRADOC). Based on information obtained during and subsequent to a site visit (15 through 18 October 1991), 36 types of Areas Requiring Environmental Evaluation (AREEs) were identified and grouped by the following categories: Facility Operations; Maintenance/Fueling Operations; Water Treatment Operations; Training Areas; Hazardous Materials Storage/Waste Handling Areas; Sanitary Wastewater Treatment Plants; Storage Tanks; Landfills/Incinerators; Medical Facilities; Burn Pit Areas; Spill Areas; Ammunition Storage; Coal Storage; and Facility-wide AREEs. This report presents a summary of findings for each AREE and recommendations for further action.

  13. FRET enhanced fluorescent nanodiamonds.

    PubMed

    Fudala, Rafal; Raut, Sangram; Maliwal, Badri P; Zerda, T W; Gryczynski, Ignacy; Simanek, Eric; Borejdo, Julian; Rich, Ryan; Akopova, Irina; Gryczynski, Zygmunt

    2014-01-01

    Fluorescent nanodiamonds (FNDs) are one of the new and very promising biocompatible nanomaterials that can be used both as a fluorescence imaging agent and a highly versatile platform for controlled functionalization to target and deliver a wide spectrum of therapeutic agents. Among the remarkable fluorescence properties are excellent photostability, emission between 600-700nm, quantum yield of 1 and moderately long fluorescence lifetimes. However the low absorption cross section of fluorescent (N-V)(-) centers limits FNDs' brightness. In this work we show that an approach based on the Forster resonance energy transfer (FRET) may significantly enhance the fluorescence signal observed from a single ND. We demonstrate that organic dyes (fluorophores) attached to the FND surface can efficiently transfer the excitation energy to (N-V)(-) centers. Multiple dyes positioned in close proximity to the ND facile surface may serve as harvesting antennas transferring excitation energy to the fluorescent centers. We propose that, with the help of some of the functional groups present on the FND surface, we can either directly link flurophores or use scalable dendrimer chemistry to position many organic dyes at a calibrated distance. Also, the remaining multiple functional groups will be still available for particle targeting and drug delivery. This opens a new way for designing a new type of theranostics particles of ultrahigh brightness, high photostability, specific targeting, and high capacity for drug delivery. PMID:22394126

  14. Enhancing young people's awareness.

    PubMed

    Doan Thi Tien

    1995-01-01

    The role of the Vietnam Youth Union (21 million members) is to educate the youth aged 14-28 years about the movement at the grassroots level. Since 1995, it has been entrusted with information, education, and communication (IEC) activities (implemented through the Educational Center for Population, Health, and Development) concerning family planning, the environment, human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Mass media, direct communication, Youth Union leading staff, Youth Union cultural and arts activities, and advertisement have been used. 16 newspapers and magazines, a radio program, and a TV program disseminate information for the group. 1000 motivators' groups, 1370 Youth Clubs, and Youth Villages at the commune level work to enhance awareness and to change biased attitudes and habits. Leading staff speak at conferences and seminars that are attended by target groups. Art troupes perform at special local events; plays are organized and videos are shown. The HIV/AIDS information and prevention campaign is of great importance because research findings indicate that many young people believe that only prostitutes and drug addicts can be infected, and that condoms are bad and only for use with prostitutes. There are about 2300 persons infected with HIV in 14 provinces, mostly in the south and central regions. 131 are reported to have developed AIDS. PMID:12320323

  15. Enhancing chemical reactions

    DOEpatents

    Morrey, John R.

    1978-01-01

    Methods of enhancing selected chemical reactions. The population of a selected high vibrational energy state of a reactant molecule is increased substantially above its population at thermal equilibrium by directing onto the molecule a beam of radiant energy from a laser having a combination of frequency and intensity selected to pump the selected energy state, and the reaction is carried out with the temperature, pressure, and concentrations of reactants maintained at a combination of values selected to optimize the reaction in preference to thermal degradation by transforming the absorbed energy into translational motion. The reaction temperature is selected to optimize the reaction. Typically a laser and a frequency doubler emit radiant energy at frequencies of .nu. and 2.nu. into an optical dye within an optical cavity capable of being tuned to a wanted frequency .delta. or a parametric oscillator comprising a non-centrosymmetric crystal having two indices of refraction, to emit radiant energy at the frequencies of .nu., 2.nu., and .delta. (and, with a parametric oscillator, also at 2.nu.-.delta.). Each unwanted frequency is filtered out, and each desired frequency is focused to the desired radiation flux within a reaction chamber and is reflected repeatedly through the chamber while reactants are fed into the chamber and reaction products are removed therefrom.

  16. Enhanced local tomography

    DOEpatents

    Katsevich, Alexander J.; Ramm, Alexander G.

    1996-01-01

    Local tomography is enhanced to determine the location and value of a discontinuity between a first internal density of an object and a second density of a region within the object. A beam of radiation is directed in a predetermined pattern through the region of the object containing the discontinuity. Relative attenuation data of the beam is determined within the predetermined pattern having a first data component that includes attenuation data through the region. In a first method for evaluating the value of the discontinuity, the relative attenuation data is inputted to a local tomography function .function..sub..LAMBDA. to define the location S of the density discontinuity. The asymptotic behavior of .function..sub..LAMBDA. is determined in a neighborhood of S, and the value for the discontinuity is estimated from the asymptotic behavior of .function..sub..LAMBDA.. In a second method for evaluating the value of the discontinuity, a gradient value for a mollified local tomography function .gradient..function..sub..LAMBDA..epsilon. (x.sub.ij) is determined along the discontinuity; and the value of the jump of the density across the discontinuity curve (or surface) S is estimated from the gradient values.

  17. Enhancing geometric reasoning.

    PubMed

    Mistretta, R M

    2000-01-01

    Geometry is an important part of the mathematics curriculum. However, students are not demonstrating strong conceptual knowledge of this subject. The research of Van Hiele and Van Hiele-Geldof has focused on the concept of thinking levels in geometry and the role of instruction in raising levels of thinking. This paper describes a field trial of a supplemental geometry unit intended to raise Van Hiele thinking levels in a group of 23 eighth-grade students by having them become more adept at using higher order thinking skills. Sample questions assessing particular Van Hiele thinking levels and attitudes toward geometry, as well as field-tested activities yielding the most positive results, are presented. Educators can benefit from this application of the Van Hiele model of geometric thinking, since the thought processes involved in learning geometry are explained, along with teaching techniques and tools for assessment. By having teachers become more aware of their students' cognitive skills, attitudes, and misconceptions, teaching practices and student achievement can be enhanced. PMID:11019778

  18. Enhanced target factor analysis.

    PubMed

    Rostami, Akram; Abdollahi, Hamid; Maeder, Marcel

    2016-03-10

    Target testing or target factor analysis, TFA, is a well-established soft analysis method. TFA answers the question whether an independent target test vector measured at the same wavelengths as the collection of spectra in a data matrix can be excluded as the spectrum of one of the components in the system under investigation. Essentially, TFA cannot positively prove that a particular test spectrum is the true spectrum of one of the components, it can, only reject a spectrum. However, TFA will not reject, or in other words TFA will accept, many spectra which cannot be component spectra. Enhanced Target Factor Analysis, ETFA addresses the above problem. Compared with traditional TFA, ETFA results in a significantly narrower range of positive results, i.e. the chance of a false positive test result is dramatically reduced. ETFA is based on feasibility testing as described in Refs. [16-19]. The method has been tested and validated with computer generated and real data sets. PMID:26893084

  19. Analog enhancement of radiographic images

    NASA Technical Reports Server (NTRS)

    Baily, N. A.; Nachazel, R. J.

    1976-01-01

    The paper shows how analog methods for edge sharpening, contrast enhancement, and expansion of the range of gray levels of particular interest are effective for easy on-line application to video viewing of X-ray roentgenograms or to fluoroscopy. The technique for analog enhancement of radiographic images is a modified version of the system designed by Fuchs et al. (1972), whereby an all directional second derivative signal called detail signal is used to produce both vertical and horizontal enhancement of the image. Particular attention is given to noise filtration and contrast enhancement. Numerous radiographs supplement the text.

  20. Lignite Fuel Enhancement

    SciTech Connect

    Charles Bullinger

    2007-03-31

    This 11th quarterly Technical Progress Report for the Lignite Fuel Enhancement Project summarizes activities from January 1st through March 31st of 2007. It summarizes the completion of the Prototype testing activity and initial full-scale dryer design, Budget Period 2 activity during that time period. The Design Team completed process design and layouts of air, water, and coal systems. Heyl-Patterson completed dryer drawings and has sent RFPs to several fabricators for build and assembly. Several meetings were held with Barr engineers to finalize arrangement of the drying, air jig, and coal handling systems. Honeywell held meetings do discuss the control system logic and hardware location. By the end of March we had processed nearly 300,000 tons of lignite through the dryer. Outage preparation maintenance activities on a coal transfer hopper restricted operation of the dryer in February and March. The Outage began March 17th. We will not dry coal again until early May when the Outage on Unit No.2 completes. The Budget Period 1 (Phase 1) final report was submitted this quarter. Comments were received from NETL and are being reviewed. The Phase 2 Project Management Plan was submitted to NETL in January 2007. This deliverable also included the Financing Plan. An application for R&D 100 award was submitted in February. The project received an award from the Minnesota Professional Engineering Society's Seven Wonders of Engineering Award and Minnesota ACEC Grand Award in January. To further summarize, the focus this quarter has been on finalizing commercial design and the layout of four dryers behind each Unit. The modification to the coal handling facilities at Coal Creek and incorporation of air jigs to further beneficiate the segregated material the dryers will reject 20 to 30 % of the mercury and sulfur is segregated however this modification will recover the carbon in that stream.

  1. Plasmon Enhanced Photoemission

    SciTech Connect

    Polyakov, Aleksandr

    2012-05-08

    this work, the structure consisted of rectangular nano-grooves (NGs) arranged in a subwavelength grating on a metal surface is presented that provides a dramatic increase in the metal’s absorption, field localization, and field enhancement. When light is polarized perpendicular to the orientation of the grooves a standing SPP wave is excited along the vertical walls in the NGs, that act as Fabry-Perot resonators. By adjusting the geometry of the NGs and the period of the subwavelength grating the resonance can be fine tuned to a desired position, for example, the laser fundamental wavelength, anywhere from the UV to the near infrared (NIR). Two types of gratings are presented: (a) a gold grating with period of 600 nm, and (b) an aluminum-gold grating with a period of 100 nm; both with resonance at 720 nm. In each case, strong on-resonance absorption was observed, with over 98% for grating (b). Unlike the grating-coupled SPP waves, where the angle is well defined by the momentum matching condition, the resonant NGs allow coupling to the standing modes at a range of angles of incidence, referred to as the angular bandwidth. A new model for the on-resonance absorption based on the ensamble action of the NGs is presented that serves as the basis for a design of an NG grating with an ultrawide spectral as well as angular bandwidth. For sample (b), the angular bandwidth is 80 degrees, corresponding to an opening angle of 160 degrees. The photoemission enhancement for such a grating was measured to be seven orders of magnitude for a four-photon photoemission. This is an incredible result demonstrating the power of the plasmonic grating presented, which is an efficient light trapper and field enhancer for a non-linear processes. These results demonstrate that the metal photocathode prepared with a NG grating on the metal surface will provide sufficient pulse charge driven by a 1 μJ 15fs pulsed laser at 800 nm for the optimum FEL operation.

  2. SURFACE ENHANCED SECOND HARMONIC GENERATION

    SciTech Connect

    Chen, C. K.; de Castro, A. R.B.; Shen, Y. R.

    1980-09-01

    Second harmonic generation at a silver-air interface was enhanced due to surface roughness by a factor of 10{sup 4}. The local field enhancement is believed to be responsible for the effect. An unusually broad luminescence background extending far beyond the antiStokes side of the second harmonic was also observed.

  3. Strategies to Enhance Vocabulary Development.

    ERIC Educational Resources Information Center

    Teal, Tiffany

    Vocabulary knowledge provides a source of prior knowledge and word meaning that can be used to enhance reading comprehension. It is important that teachers be aware and knowledgeable of the many strategies available to enhance vocabulary growth, and also how to teach these strategies to students. These strategies can range from the use of context…

  4. Cohen's Conservatism and Human Enhancement.

    PubMed

    Pugh, Jonathan; Kahane, Guy; Savulescu, Julian

    2013-01-01

    In an intriguing essay, G. A. Cohen has defended a conservative bias in favour of existing value. In this paper, we consider whether Cohen's conservatism raises a new challenge to the use of human enhancement technologies. We develop some of Cohen's suggestive remarks into a new line of argument against human enhancement that, we believe, is in several ways superior to existing objections. However, we shall argue that on closer inspection, Cohen's conservatism fails to offer grounds for a strong sweeping objection to enhancement, and may even offer positive support for forms of enhancement that preserve valuable features of human beings. Nevertheless, we concede that Cohen's arguments may suggest some plausible and important constraints on the modality of legitimate and desirable enhancements. PMID:24683311

  5. The Misfortunes of Moral Enhancement.

    PubMed

    Azevedo, Marco Antonio

    2016-10-01

    In Unfit for the Future, Ingmar Persson and Julian Savulescu present a sophisticated argument in defense of the imperative of moral enhancement. They claim that without moral enhancement, the future of humanity is seriously compromised. The possibility of ultimate harm, caused by a dreadful terrorist attack or by a final unpreventable escalation of the present environmental crisis aggravated by the availability of cognitive enhancement, makes moral enhancement a top priority. It may be considered optimistic to think that our present moral capabilities can be successfully improved by means of moral education, moral persuasion, and fear of punishment. So, without moral enhancement, drastic restrictions on human freedom would become the only alternative to prevent those dramatic potential outcomes. In this article, I will try to show that we still have reason to be less pessimistic and that Persson & Savulescu's arguments are fortunately unconvincing. PMID:27473409

  6. One danger of biomedical enhancements.

    PubMed

    Rajczi, Alex

    2008-07-01

    In the near future, our society may develop a vast array of medical enhancements. There is a large debate about enhancements, and that debate has identified many possible harms. This paper describes a harm that has so far been overlooked. Because of some particular features of enhancements, we could come to place more value on them than we actually should. This over-valuation would lead us to devote time, energy, and resources to enhancements that could be better spent somewhere else. That mistake might not be trivial. By spending too much time, energy, and resources on enhancements, we could set back our pursuit of our deepest goals such as living happily and leading ethical lives. PMID:18522592

  7. Lignite Fuel Enhancement

    SciTech Connect

    Charles Bullinger

    2006-04-03

    This 7th quarterly Technical Progress Report for the Lignite Fuel Enhancement Project summarizes activities from January 1st through March 31st of 2006. It also summarizes the subsequent purchasing activity, dryer/process construction, and testing. The Design Team began conferencing again as construction completed and the testing program began. Primary focus this quarter was construction/installation completion. Phase 1 extension recommendation, and subsequent new project estimate, Forms 424 and 4600 were accepted by DOE headquarters. DOE will complete the application and amended contract. All major mechanical equipment was run, checked out, and tested this quarter. All water, air, and coal flow loops were run and tested. The system was run on January 30th, shut down to adjust equipment timing in the control system on the 31st, and run to 75 ton//hour on February 1st. It ran for seven to eight hours per day until March 20th when ''pairs'' testing ( 24 hour running) began. ''Pairs'' involves comparative testing of unit performance with seven ''wet'' pulverizers versus six ''wet'' and one ''dry''. During the interim, more operators were brought up to speed on system operation and control was shifted to the main Unit No.2 Control Room. The system is run now from the Unit control board operator and an equipment operator checks the system during regular rounds or when an alarm needs verification. The flawless start-up is unprecedented in the industry and credit should be made to the diligence and tenacity of Coal Creek maintenance/checkout staff. Great River Energy and Headwaters did not meet to discuss the Commercialization Plan this quarter. The next meeting is pending data from the drying system. Discussions with Basin Electric, Otter Tail, and Dairyland continue and confidentiality secured as we promote dryers in their stations. Lighting and fire protection were completed in January. Invoices No.12 through No.20 are completed and forwarded following preliminary

  8. Enhanced Elliptic Grid Generation

    NASA Technical Reports Server (NTRS)

    Kaul, Upender K.

    2007-01-01

    An enhanced method of elliptic grid generation has been invented. Whereas prior methods require user input of certain grid parameters, this method provides for these parameters to be determined automatically. "Elliptic grid generation" signifies generation of generalized curvilinear coordinate grids through solution of elliptic partial differential equations (PDEs). Usually, such grids are fitted to bounding bodies and used in numerical solution of other PDEs like those of fluid flow, heat flow, and electromagnetics. Such a grid is smooth and has continuous first and second derivatives (and possibly also continuous higher-order derivatives), grid lines are appropriately stretched or clustered, and grid lines are orthogonal or nearly so over most of the grid domain. The source terms in the grid-generating PDEs (hereafter called "defining" PDEs) make it possible for the grid to satisfy requirements for clustering and orthogonality properties in the vicinity of specific surfaces in three dimensions or in the vicinity of specific lines in two dimensions. The grid parameters in question are decay parameters that appear in the source terms of the inhomogeneous defining PDEs. The decay parameters are characteristic lengths in exponential- decay factors that express how the influences of the boundaries decrease with distance from the boundaries. These terms govern the rates at which distance between adjacent grid lines change with distance from nearby boundaries. Heretofore, users have arbitrarily specified decay parameters. However, the characteristic lengths are coupled with the strengths of the source terms, such that arbitrary specification could lead to conflicts among parameter values. Moreover, the manual insertion of decay parameters is cumbersome for static grids and infeasible for dynamically changing grids. In the present method, manual insertion and user specification of decay parameters are neither required nor allowed. Instead, the decay parameters are

  9. Excitation enhancement and extraction enhancement with photonic crystals

    SciTech Connect

    Shapira, Ofer; Soljacic, Marin; Zhen, Bo; Chua, Song-Liang; Lee, Jeongwon; Joannopoulos, John

    2015-03-03

    Disclosed herein is a system for stimulating emission from at least one an emitter, such as a quantum dot or organic molecule, on the surface of a photonic crystal comprising a patterned dielectric substrate. Embodiments of this system include a laser or other source that illuminates the emitter and the photonic crystal, which is characterized by an energy band structure exhibiting a Fano resonance, from a first angle so as to stimulate the emission from the emitter at a second angle. The coupling between the photonic crystal and the emitter may result in spectral and angular enhancement of the emission through excitation and extraction enhancement. These enhancement mechanisms also reduce the emitter's lasing threshold. For instance, these enhancement mechanisms enable lasing of a 100 nm thick layer of diluted organic molecules solution with reduced threshold intensity. This reduction in lasing threshold enables more efficient organic light emitting devices and more sensitive molecular sensing.

  10. Environmental engineering education enhancement

    NASA Astrophysics Data System (ADS)

    Caporali, E.

    2012-04-01

    Since higher education plays a central role in the development of both human beings and modern societies, enhancing social, cultural and economic development, active citizenship, ethical values and expertises for a sustainable growth, environment respectful, the European Commission promotes a wide range of programmes. Among the EC programmes, the TEMPUS - Trans European Mobility Programme for University Studies, with the support of the DG EAC of the European Commission, has contributed to many aspects of general interest for higher education. Curricula harmonization, LifeLong Learning Programme development, ICT use, quality assessment, accreditation, innovation learning methods, growth of networks of institutions trusting each other, are the focused aspects. Such a solid cooperation framework is surely among the main outcomes of the TEMPUS Projects leaded by the University of Firenze UNIFI (Italy), DEREC - Development of Environment and Resources Engineering Curriculum (2005-2008), and its spin-off DEREL - Development of Environment and Resources Engineering Learning (2010-2013), and VICES - Videoconferencing Educational Services (2009-2012). DEREC and DEREL TEMPUS projects, through the co-operation of Universities in Italy, Austria, Germany, Greece, Macedonia, Albania and Serbia, are aimed at the development of first and second level curricula in "Environment and Resources Engineering" at the Ss. Cyril and Methodius University - UKIM Skopje (MK). In the DEREC Project the conditions for offering a joint degree title in the field of Environmental Engineering between UNIFI and UKIM Skopje were fulfilled and a shared educational programme leading to the mutual recognition of degree titles was defined. The DEREL project, as logical continuation of DEREC, is aimed to introduce a new, up-to-date, postgraduate second level curriculum in Environment and Resources Engineering at UKIM Skopje, University of Novi Sad (RS) and Polytechnic University of Tirana (AL). following

  11. Ultrasound Despeckling for Contrast Enhancement

    PubMed Central

    Tay, Peter C.; Garson, Christopher D.; Acton, Scott T.; Hossack, John A.

    2010-01-01

    Images produced by ultrasound systems are adversely hampered by a stochastic process known as speckle. A despeckling method based upon removing outlier is proposed. The method is developed to contrast enhance B-mode ultrasound images. The contrast enhancement is with respect to decreasing pixel variations in homogeneous regions while maintaining or improving differences in mean values of distinct regions. A comparison of the proposed despeckling filter is compared with the other well known despeckling filters. The evaluations of despeckling performance are based upon improvements to contrast enhancement, structural similarity, and segmentation results on a Field II simulated image and actual B-mode cardiac ultrasound images captured in vivo. PMID:20227984

  12. Ultrasound despeckling for contrast enhancement.

    PubMed

    Tay, Peter C; Garson, Christopher D; Acton, Scott T; Hossack, John A

    2010-07-01

    Images produced by ultrasound systems are adversely hampered by a stochastic process known as speckle. A despeckling method based upon removing outlier is proposed. The method is developed to contrast enhance B-mode ultrasound images. The contrast enhancement is with respect to decreasing pixel variations in homogeneous regions while maintaining or improving differences in mean values of distinct regions. A comparison of the proposed despeckling filter is compared with the other well known despeckling filters. The evaluations of despeckling performance are based upon improvements to contrast enhancement, structural similarity, and segmentation results on a Field II simulated image and actual B-mode cardiac ultrasound images captured in vivo. PMID:20227984

  13. Male chest enhancement: pectoral implants.

    PubMed

    Benito-Ruiz, J; Raigosa, J M; Manzano-Surroca, M; Salvador, L

    2008-01-01

    The authors present their experience with the pectoral muscle implant for male chest enhancement in 21 patients. The markings and technique are thoroughly described. The implants used were manufactured and custom made. The candidates for implants comprised three groups: group 1 (18 patients seeking chest enhancement), group 2 (1 patient with muscular atrophy), and group 3 (2 patients with muscular injuries). Because of the satisfying results obtained, including significant enhancement of the chest contour and no major complications, this technique is used for an increasing number of male cosmetic surgeries. PMID:17676376

  14. Tip enhanced Raman scattering: plasmonic enhancements for nanoscale chemical analysis

    NASA Astrophysics Data System (ADS)

    Schultz, Zachary D.; Marr, James M.; Wang, Hao

    2014-04-01

    Tip enhanced Raman scattering (TERS) is an emerging technique that uses a metalized scanning probe microscope tip to spatially localize electric fields that enhances Raman scattering enabling chemical imaging on nanometer dimensions. Arising from the same principles as surface enhanced Raman scattering (SERS), TERS offers unique advantages associated with controling the size, shape, and location of the enhancing nanostructure. In this article we discuss the correlations between current understanding of SERS and how this relates to TERS, as well as how TERS provides new understanding and insights. The relationship between plasmon resonances and Raman enhancements is emphasized as the key to obtaining optimal TERS results. Applications of TERS, including chemical analysis of carbon nanotubes, organic molecules, inorganic crystals, nucleic acids, proteins, cells and organisms, are used to illustrate the information that can be gained. Under ideal conditions TERS is capable of single molecule sensitivity and sub-nanometer spatial resolution. The ability to control plasmonic enhancements for chemical analysis suggests new experiments and opportunities to understand molecular composition and interactions on the nanoscale.

  15. WEATHERABILITY OF ENHANCED DEGRADABLE PLASTICS

    EPA Science Inventory

    The main objective of this study was to assess the performance and the associated variability of several selected enhanced degradable plastic materials under a variety of different exposure conditions. ther objectives were to identify the major products formed during degradation ...

  16. Platelets enhance neutrophil transendothelial migration

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Platelets are increasingly recognized as important mediators of inflammation in addition to thrombosis. While platelets have been shown to promote neutrophil (PMN) adhesion to endothelium in various inflammatory models, it is unclear whether platelets enhance neutrophil transmigration across inflame...

  17. Geothermal Permeability Enhancement - Final Report

    SciTech Connect

    Joe Beall; Mark Walters

    2009-06-30

    The overall objective is to apply known permeability enhancement techniques to reduce the number of wells needed and demonstrate the applicability of the techniques to other undeveloped or under-developed fields. The Enhanced Geothermal System (EGS) concept presented in this project enhances energy extraction from reduced permeability zones in the super-heated, vapor-dominated Aidlin Field of the The Geysers geothermal reservoir. Numerous geothermal reservoirs worldwide, over a wide temperature range, contain zones of low permeability which limit the development potential and the efficient recovery of heat from these reservoirs. Low permeability results from poorly connected fractures or the lack of fractures. The Enhanced Geothermal System concept presented here expands these technologies by applying and evaluating them in a systematic, integrated program.

  18. Moderate eugenics and human enhancement.

    PubMed

    Selgelid, Michael J

    2014-02-01

    Though the reputation of eugenics has been tarnished by history, eugenics per se is not necessarily a bad thing. Many advocate a liberal new eugenics--where individuals are free to choose whether or not to employ genetic technologies for reproductive purposes. Though genetic interventions aimed at the prevention of severe genetic disorders may be morally and socially acceptable, reproductive liberty in the context of enhancement may conflict with equality. Enhancement could also have adverse effects on utility. The enhancement debate requires a shift in focus. What the equality and/or utility costs of enhancement will be is an empirical question. Rather than philosophical speculation, more social science research is needed to address it. Philosophers, meanwhile, should address head-on the question of how to strike a balance between liberty, equality, and utility in cases of conflict (in the context of genetics). PMID:23728949

  19. WEATHERABILITY OF ENHANCED DEGRADABLE PLASTICS

    EPA Science Inventory

    The main objective of this study was to assess the performance and the asociated variability of several selected enhanced degradable plastic materials under a variety of different exposure conditions. Other objectives were to identify the major products formed during degradation ...

  20. Ultrasonic enhancement of battery diffusion.

    PubMed

    Hilton, R; Dornbusch, D; Branson, K; Tekeei, A; Suppes, G J

    2014-03-01

    It has been demonstrated that sonic energy can be harnessed to enhance convection in Galvanic cells during cyclic voltammetry; however, the practical value of this approach is limited due to the lack of open volumes for convection patterns to develop in most batteries. This study evaluates the ability of ultrasonic waves to enhance diffusion in membrane separators commonly used in sandwich-architecture batteries. Studies include the measuring of open-circuit performance curves to interpret performances in terms of reductions in concentration overpotentials. The use of a 40 kHz sonicator bath can consistently increase the voltage of the battery and reduce overpotential losses up to 30%. This work demonstrates and quantifies battery enhancement due to enhanced diffusion made possible with ultrasonic energy. PMID:24210813

  1. Electret enhances transdermal drug permeation.

    PubMed

    Narasimha Sathyanarayana Murthy, Narasimha Sathyanarayana; Boguda, Vishwanath Anantharamaiah; Payasada, Kotrappa

    2008-01-01

    Electrets are polymeric discs that carry semi permanent electrostatic charge. These provide electrostatic potentials in the range of 500 to 3,000 V. In the current work, the effect of electret exposure on the skin permeability was investigated. Transdermal transport studies were carried out across porcine epidermis in Franz diffusion cells. Salicylic acid, fluorescein labeled dextrans (FD) and propofol were used as test diffusants. The ability of electret to enhance the transdermal permeation of salicylic acid was studied in vivo in Sprague Dawley rats. Electret enhanced the permeability of porcine epidermis to salicylic acid. The enhancement factor increased with the surface voltage, however it was independent of the nature of charge (+ or -). The enhancement by electret was cut-off at 1 kDa, as interpreted by studying the transport of FD. The electrets decreased the permeability of skin to propofol, a lipophilic diffusant. Pretreatment of porcine epidermis enhanced the iontophoretic transport of salicylic acid, whereas the same did not enhance the transport of salicylic acid by electroporation. It is most likely that electret exposure renders the lipid domains of stratum corneum more permeable to polar molecules and in turn hampers the diffusion of nonpolar diffusant. PMID:18175950

  2. Chemically enhanced in situ recovery

    SciTech Connect

    Sale, T.; Pitts, M.; Wyatt, K.

    1996-08-01

    Chemically enhanced recovery is a promising alternative to current technologies for management of subsurface releases of organic liquids. Through the inclusion of surfactants, solvents, polymers, and/or alkaline agents to a waterflood, the transport of targeted organic compounds can be increased and rates of recovery enhanced. By far, the vast majority of work done in the field of chemically enhanced recovery has been at a laboratory scale. The following text focuses on chemically enhanced recovery from a field application perspective with emphasis given to chlorinated solvents in a low permeability setting. While chlorinated solvents are emphasized, issues discussed are also relevant to organic liquids less dense than water such as petroleum products. Topics reviewed include: (1) Description of technology; (2) General technology considerations; (3) Low permeability media considerations; (4) Cost and reliability considerations; (5) Commercial availability; and (6) Case histories. Through this paper an appreciation is developed of both the potential and limitations of chemically enhanced recovery. Excluded from the scope of this paper is the in situ destruction of organic compounds through processes such as chemical or biological oxidation, chemically enhanced recovery of inorganic compounds, and ex situ soil treatment processes. 11 refs., 2 figs., 1 tab.

  3. Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) Binding: Strategic Use of a N → S (nN → σ*S-X) Interaction for Conformational Constraint.

    PubMed

    Pennington, Lewis D; Bartberger, Michael D; Croghan, Michael D; Andrews, Kristin L; Ashton, Kate S; Bourbeau, Matthew P; Chen, Jie; Chmait, Samer; Cupples, Rod; Fotsch, Christopher; Helmering, Joan; Hong, Fang-Tsao; Hungate, Randall W; Jordan, Steven R; Kong, Ke; Liu, Longbin; Michelsen, Klaus; Moyer, Carolyn; Nishimura, Nobuko; Norman, Mark H; Reichelt, Andreas; Siegmund, Aaron C; Sivits, Glenn; Tadesse, Seifu; Tegley, Christopher M; Van, Gwyneth; Yang, Kevin C; Yao, Guomin; Zhang, Jiandong; Lloyd, David J; Hale, Clarence; St Jean, David J

    2015-12-24

    The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 μM) was optimized to lead compound 32 (AMG-0696; hGK-hGKRP IC50 = 0.0038 μM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (nN → σ*S-X) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = -45%; 100 mg/kg po, 3 h). X-ray analyses of 32 and several precursors bound to GKRP were also obtained. This novel disrupter of GK-GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design. PMID:26551034

  4. Enhanced sludge washing evaluation plan

    SciTech Connect

    Jensen, R.D.

    1994-09-01

    The Tank Waste Remediation System (TWRS) Program mission is to store, treat, and immobilize highly radioactive Hanford Site waste (current and future tank waste and the strontium/cesium capsules) in an environmentally sound, safe, and cost-effective manner. The scope of the TWRS Waste Pretreatment Program is to treat tank waste and separate that waste into HLW and LLW fractions and provide additional treatment as required to feed LLW and HLW immobilization facilities. Enhanced sludge washing was chosen as the baseline process for separating Hanford tank waste sludge. Section 1.0 briefly discusses the purpose of the evaluation plan and provides the background that led to the choice of enhanced sludge washing as the baseline process. Section 2.0 provides a brief summary of the evaluation plan details. Section 3.0 discusses, in some detail, the technical work planned to support the evaluation of enhanced sludge washing. Section 4.0 briefly discusses the potential important of policy issues to the evaluation. Section 5.0 discusses the methodology to be used in the evaluation process. Section 6.0 summarizes the milestones that have been defined to complete the enhanced sludge washing evaluation and provides a summary schedule to evaluate the performance of enhanced sludge washing. References are identified in Section 7.0, and additional schedule and milestone information is provided in the appendices.

  5. Contrast-Enhanced Endoscopic Ultrasound

    PubMed Central

    Dietrich, Christoph F.; Sharma, M.; Hocke, M.

    2012-01-01

    The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) introduced guidelines on the use of contrast-enhanced ultrasound (CEUS) in 2004. This EFSUMB-document focused mainly on liver applications. However, new applications extending beyond the liver were developed thereafter. Increased interest in recent years in CEUS technique and in the application of CEUS in novel fields like endoscopic ultrasound (EUS) has revolutionized indications and applications. As a result, the EFSUMB initiated a new update of the guidelines in 2011 to include this additional knowledge. Some of the contrast-enhanced EUS (CE-EUS) indications are established, whereas others are preliminary; these latter indications are categorized as emergent CEUS applications since the available evidence is insufficient for general recommendation. This article focuses on the use of CE-EUS in various clinical settings. The reader will get an overview of current indications and possible applications of CE-EUS. This involves the introduction of different contrast studies including color Doppler techniques (known as contrast-enhanced high mechanical index endosonography or CEHMI-EUS) as well as more modern high-resolution contrast-enhanced techniques (known as contrast-enhanced low mechanical index endosonography or CELMI EUS). PMID:24949350

  6. Enhanced video viewing from metadata

    NASA Astrophysics Data System (ADS)

    Janevski, Angel; McGee, Thomas; Agnihotri, Lalitha; Dimitrova, Nevenka

    2001-11-01

    Current advanced television concepts envision data broadcasting along with the video stream, which is used by interactive applications at the client end. In this case, these applications do not proactively personalize the experience and may not allow user requests for additional information. We propose content enhancement using automatic retrieval of additional information based on video content and user interests. Our paper describes Video Retriever Genie, a system that enhances content with additional information based on metadata that provides semantics for the content. The system is based on a digital TV (Philips TriMedia) platform. We enhance content through user queries that define information extraction tasks that retrieve information from the Web. We present several examples of content enhancement such as additional movie character/actor information, financial information and weather alerts. Our system builds a bridge between the traditional TV viewing and the domain of personal computing and Internet. The boundaries between these domains are dissolving and this system demonstrates one effective approach for content enhancement. In addition, we illustrate our discussion with examples from two existing standards - MPEG-7 and TV-Anytime.

  7. Effects of piragliatin, a glucokinase activator, on fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus.

    PubMed

    Zhi, Jianguo; Zhai, Suoping

    2016-02-01

    To assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of piragliatin, a double-blind, randomized, placebo-controlled, multiple-ascending-doses study was conducted in patients with type 2 diabetes mellitus (T2D). Fifty-nine T2D patients were given piragliatin or placebo in a dose-escalation design as a single dose on day 1 followed by multiple doses on days 3 through 8 at doses of 10, 25, 50, 100, and 200 mg twice a day (BID) as well as 200 mg every day (QD). Blood and urine samples were collected for PK analysis. PD assessments included plasma glucose, insulin, C-peptide, glucagon, and GLP-1. Piragliatin exposure was dose proportional without appreciable accumulation or food effect. Piragliatin treatment at steady state yielded dose-dependent reductions up to 32.5% and 35.5% for the highest dose in fasting and postprandial plasma glucose. Piragliatin was well tolerated. Mild or moderate hypoglycemia with rapid recovery after sugar-containing drinks or scheduled meals was the only dose-limiting adverse event. It is concluded that multiple doses of piragliatin consistently showed rapid, dose-dependent glucose reduction of fasting and postprandial plasma glucose in T2D patients. PMID:26183686

  8. In vitro evidence supports the presence of glucokinase-independent glucosensing mechanisms in hypothalamus and hindbrain of rainbow trout.

    PubMed

    Otero-Rodiño, Cristina; Velasco, Cristina; Álvarez-Otero, Rosa; López-Patiño, Marcos A; Míguez, Jesús M; Soengas, José L

    2016-06-01

    We previously obtained evidence in rainbow trout for the presence and response to changes in circulating levels of glucose (induced by intraperitoneal hypoglycaemic and hyperglycaemic treatments) of glucosensing mechanisms based on liver X receptor (LXR), mitochondrial production of reactive oxygen species (ROS) leading to increased expression of uncoupling protein 2 (UCP2), and sweet taste receptor in the hypothalamus, and on sodium/glucose co-transporter 1 (SGLT-1) in hindbrain. However, these effects of glucose might be indirect. Therefore, we evaluated the response of parameters related to these glucosensing mechanisms in a first experiment using pooled sections of hypothalamus and hindbrain incubated for 6 h at 15°C in modified Hanks' medium containing 2, 4 or 8 mmol l(-1) d-glucose. The responses observed in some cases were consistent with glucosensing capacity. In a second experiment, pooled sections of hypothalamus and hindbrain were incubated for 6 h at 15°C in modified Hanks' medium with 8 mmol l(-1) d-glucose alone (control) or containing 1 mmol l(-1) phloridzin (SGLT-1 antagonist), 20 µmol l(-1) genipin (UCP2 inhibitor), 1 µmol l(-1) trolox (ROS scavenger), 100 µmol l(-1) bezafibrate (T1R3 inhibitor) and 50 µmol l(-1) geranyl-geranyl pyrophosphate (LXR inhibitor). The response observed in the presence of these specific inhibitors/antagonists further supports the proposal that critical components of the different glucosensing mechanisms are functioning in rainbow trout hypothalamus and hindbrain. PMID:27026717

  9. Piezoelectric enhancement under negative pressure

    NASA Astrophysics Data System (ADS)

    Kvasov, Alexander; McGilly, Leo J.; Wang, Jin; Shi, Zhiyong; Sandu, Cosmin S.; Sluka, Tomas; Tagantsev, Alexander K.; Setter, Nava

    2016-07-01

    Enhancement of ferroelectric properties, both spontaneous polarization and Curie temperature under negative pressure had been predicted in the past from first principles and recently confirmed experimentally. In contrast, piezoelectric properties are expected to increase by positive pressure, through polarization rotation. Here we investigate the piezoelectric response of the classical PbTiO3, Pb(Zr,Ti)O3 and BaTiO3 perovskite ferroelectrics under negative pressure from first principles and find significant enhancement. Piezoelectric response is then tested experimentally on free-standing PbTiO3 and Pb(Zr,Ti)O3 nanowires under self-sustained negative pressure, confirming the theoretical prediction. Numerical simulations verify that negative pressure in nanowires is the origin of the enhanced electromechanical properties. The results may be useful in the development of highly performing piezoelectrics, including lead-free ones.

  10. Microwave enhanced sintering of ceramics

    SciTech Connect

    Wroe, F.C.R.; Rowley, A.T.

    1995-12-31

    It is now well known that microwave dielectric heating can be used to increase the Wintering rates and to reduce the sintering times of ceramic materials. However, the nature of the mechanism causing this enhanced sintering is still far from understood, with many workers attributing the effect to a reduction in the activation energy even though there is no real physical basis for this assumption. Although the mechanism is not understood, many results have indicated that the effect is non thermal in nature, i.e. the enhancement would not be reproduced if conventional heat could be applied in exactly the same way (volumetrically) as microwave heat. By careful control of the relative proportions of microwave and conventional heating, it has been possible to separate the thermal (heating) effects from the non-thermal effects. This paper discusses the results obtained, and show that they are consistent with recent theories of enhanced diffusion.