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Sample records for hypercalciuric stone-forming ghs

  1. Pathophysiology of the Hypercalciuria in the Genetic Hypercalciuric Stone-Forming Rats

    NASA Astrophysics Data System (ADS)

    Bushinsky, David A.

    2007-04-01

    Given evidence for a genetic cause of hypercalciuria, we screened adult male and female Sprague-Dawley (SD) rats for hypercalciuria and used those with the highest urinary calcium excretion to breed the next generation, followed by subsequent selection and inbreeding of their most hypercalciuric progeny. By the 30th generation, and continuing to the present, the GHS rats (for Genetic Hypercalciuric Stone-forming rats) excrete 8-10 times as much calcium as simultaneously studied control rats The GHS rats were found to have defects in calcium transport in the intestine, kidneys and bone, similar to abnormalities found in many patients with idiopathic hypercalciuria. The GHS rats also form kidney stones. By the conclusion of an 18 wk study, all of the GHS rats formed stones, while there was no stone formation in similarly treated SD controls. The GHS rats, when fed a standard 1.2% calcium diet, form only poorly crystalline apatite stones. However, when 5% hydroxyproline is added to the diet of the GHS rats, they form only calcium oxalate stones.

  2. Integrative microRNA-gene expression network analysis in genetic hypercalciuric stone-forming rat kidney

    PubMed Central

    Lu, Yuchao; Qin, Baolong; Hu, Henglong; Zhang, Jiaqiao; Wang, Yufeng; Wang, Qing

    2016-01-01

    Background. MicroRNAs (miRNAs) influence a variety of biological functions by regulating gene expression post-transcriptionally. Aberrant miRNA expression has been associated with many human diseases. Urolithiasis is a common disease, and idiopathic hypercalciuria (IH) is an important risk factor for calcium urolithiasis. However, miRNA expression patterns and their biological functions in urolithiasis remain unknown. Methods and Results. A multi-step approach combining microarray miRNA and mRNA expression profile and bioinformatics analysis was adopted to analyze dysregulated miRNAs and genes in genetic hypercalciuric stone-forming (GHS) rat kidneys, using normal Sprague-Dawley (SD) rats as controls. We identified 2418 mRNAs and 19 miRNAs as significantly differentially expressed, over 700 gene ontology (GO) terms and 83 KEGG pathways that were significantly enriched in GHS rats. In addition, we constructed an miRNA-gene network that suggested that rno-miR-674-5p, rno-miR-672-5p, rno-miR-138-5p and rno-miR-21-3p may play important roles in the regulatory network. Furthermore, signal-net analysis suggested that NF-kappa B likely plays a crucial role in hypercalciuria urolithiasis. Conclusions. This study presents a global view of mRNA and miRNA expression in GHS rat kidneys, and suggests that miRNAs may be important in the regulation of hypercalciuria. The data provide valuable insights for future research, which should aim at validating the role of the genes featured here in the pathophysiology of hypercalciuria. PMID:27069814

  3. Increased biological response to 1,25(OH)2D3 in genetic hypercalciuric stone-forming rats

    PubMed Central

    Asplin, John R.; Favus, Murray J.; Culbertson, Christopher; Krieger, Nancy S.; Bushinsky, David A.

    2013-01-01

    Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (U) calcium (Ca) excretion, have increased intestinal Ca absorption and bone Ca resorption and reduced renal Ca reabsorption, leading to increased UCa compared with the Sprague-Dawley (SD) rats. GHS rats have increased vitamin D receptors (VDR) at each of these sites, with normal levels of 1,25(OH)2D3 (1,25D), indicating that their VDR is undersaturated with 1,25D. We tested the hypothesis that 1,25D would induce a greater increase in UCa in GHS rats by feeding both strains ample Ca and injecting 1,25D (25 ng · 100 g body wt−1 · day−1) or vehicle for 16 days. With 1,25D, UCa in SD increased from 1.7 ± 0.3 mg/day to 24.4 ± 1.2 (Δ = 22.4 ± 1.5) and increased more in GHS from 10.5 ± 0.7 to 41.9 ± 0.7 (Δ = 29.8 ± 1.8; P = 0.003). To determine the mechanism of the greater increase in UCa in GHS rats, we measured kidney RNA expression of components of renal Ca transport. Expression of transient receptor potential vanilloid (TRPV)5 and calbindin D28K were increased similarly in SD + 1,25D and GHS + 1,25D. The Na+/Ca2+ exchanger (NCX1) was increased in GHS + 1,25D. Klotho was decreased in SD + 1,25D and GHS + 1,25D. TRPV6 was increased in SD + 1,25D and increased further in GHS + 1,25D. Claudin 14, 16, and 19, Na/K/2Cl transporter (NKCC2), and secretory K channel (ROMK) did not differ between SD + 1,25D and GHS + 1,25D. Increased UCa with 1,25D in GHS exceeded that of SD, indicating that the increased VDR in GHS induces a greater biological response. This increase in UCa, which must come from the intestine and/or bone, must exceed any effect of 1,25D on TRPV6 or NCX1-mediated renal Ca reabsorption. PMID:23344574

  4. Persistence of 1,25D-induced hypercalciuria in alendronate-treated genetic hypercalciuric stone-forming rats fed a low-calcium diet

    PubMed Central

    Asplin, John R.; Culbertson, Christopher D.; Granja, Ignacio; Krieger, Nancy S.; Bushinsky, David A.

    2014-01-01

    Genetic hypercalciuric stone-forming (GHS) rats demonstrate increased intestinal Ca absorption, increased bone resorption, and reduced renal tubular Ca reabsorption leading to hypercalciuria and all form kidney stones. GHS have increased vitamin D receptors (VDR) at these sites of Ca transport. Injection of 1,25(OH)2D3 (1,25D) leads to a greater increase in urine (u)Ca in GHS than in control Sprague-Dawley (SD), possibly due to the additional VDR. In GHS the increased uCa persists on a low-Ca diet (LCD) suggesting enhanced bone resorption. We tested the hypothesis that LCD, coupled to inhibition of bone resorption by alendronate (alen), would eliminate the enhanced 1,25D-induced hypercalciuria in GHS. SD and GHS were fed LCD and half were injected daily with 1,25D. After 8 days all were also given alen until euthanasia at day 16. At 8 days, 1,25D increased uCa in SD and to a greater extent in GHS. At 16 days, alen eliminated the 1,25D-induced increase in uCa in SD. However, in GHS alen decreased, but did not eliminate, the 1,25D-induced hypercalciuria, suggesting maximal alen cannot completely prevent the 1,25D-induced bone resorption in GHS, perhaps due to increased VDR. There was no consistent effect on mRNA expression of renal transcellular or paracellular Ca transporters. Urine CaP and CaOx supersaturation (SS) increased with 1,25D alone in both SD and GHS. Alen eliminated the increase in CaP SS in SD but not in GHS. If these results are confirmed in humans with IH, the use of bisphosphonates, such as alen, may not prevent the decreased bone density observed in these patients. PMID:24573387

  5. 1,25(OH)2D3-enhanced hypercalciuria in genetic hypercalciuric stone-forming rats fed a low-calcium diet

    PubMed Central

    Asplin, John R.; Krieger, Nancy S.; Culbertson, Christopher D.; Asplin, Daniel M.; Bushinsky, David A.

    2013-01-01

    The inbred genetic hypercalciuric stone-forming (GHS) rats exhibit many features of human idiopathic hypercalciuria and have elevated levels of vitamin D receptors (VDR) in calcium (Ca)-transporting organs. On a normal-Ca diet, 1,25(OH)2D3 (1,25D) increases urine (U) Ca to a greater extent in GHS than in controls [Sprague-Dawley (SD)]. The additional UCa may result from an increase in intestinal Ca absorption and/or bone resorption. To determine the source, we asked whether 1,25D would increase UCa in GHS fed a low-Ca (0.02%) diet (LCD). With 1,25D, UCa in SD increased from 1.2 ± 0.1 to 9.3 ± 0.9 mg/day and increased more in GHS from 4.7 ± 0.3 to 21.5 ± 0.9 mg/day (P < 0.001). In GHS rats on LCD with or without 1,25D, UCa far exceeded daily Ca intake (2.6 mg/day). While the greater excess in UCa in GHS rats must be derived from bone mineral, there may also be a 1,25D-mediated decrease in renal tubular Ca reabsorption. RNA expression of the components of renal Ca transport indicated that 1,25D administration results in a suppression of klotho, an activator of the renal Ca reabsorption channel TRPV5, in both SD and GHS rats. This fall in klotho would decrease tubular reabsorption of the 1,25D-induced bone Ca release. Thus, the greater increase in UCa with 1,25D in GHS fed LCD strongly suggests that the additional UCa results from an increase in bone resorption, likely due to the increased number of VDR in the GHS rat bone cells, with a possible component of decreased renal tubular calcium reabsorption. PMID:23926184

  6. Regulation of renal calcium receptor gene expression by 1,25-dihydroxyvitamin D3 in genetic hypercalciuric stone-forming rats.

    PubMed

    Yao, Jim J; Bai, Shaochun; Karnauskas, Alexander J; Bushinsky, David A; Favus, Murray J

    2005-05-01

    Hypercalciuria in inbred genetic hypercalciuric stone-forming (GHS) rats is due, in part, to a decrease in renal tubule Ca reabsorption. Activation of the renal Ca receptor (CaR) may decrease renal tubule Ca reabsorption and cause hypercalciuria through suppression of Ca-sensitive potassium channel activity. Because the rat renal CaR gene is regulated by extracellular calcium and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and GHS rats have increased renal vitamin D receptor content, the current study was undertaken to determine the level of CaR gene expression in GHS rat kidney and whether CaR gene expression is regulated by 1,25(OH)2D3. Male GHS and normal control (NC) rats were fed a Ca-sufficient diet (0.6% Ca). Western blotting revealed a four-fold increase in CaR protein in GHS rat renal tissue, and 1,25(OH)2D3 administration increased renal CaR in both GHS and NC rats. Northern blot analysis of extracts of renal cortical tissue from GHS and NC rats revealed a major 7-kb transcript of CaR and a more modest 4-kb transcript, both of which were readily detectable. Both Northern blotting and real-time reverse transcription-PCR revealed increased basal CaR mRNA expression levels in GHS rat kidney. 1,25(OH)2D3 administration increased renal CaR mRNA levels 2.0- and 3.3-fold in GHS and NC rats, respectively. Despite the greater incremental increase by 1,25(OH)2D3 in NC rats, CaR mRNA levels remained higher in GHS rat kidney, and the elevation was more sustained. 1,25(OH)2D3 increased CaR mRNA through both elevated CaR gene expression and prolonged tissue half-life. These results demonstrate that GHS rats have high levels of CaR gene expression and CaR protein that may contribute to the hypercalciuria and calcium nephrolithiasis. PMID:15788476

  7. Pathogenesis and management of hypercalciuric nephrolithiasis.

    PubMed

    Breslau, N A

    1994-01-01

    Hypercalciuria has long been recognized as an important metabolic derangement associated with the formation of calcareous renal stones. Hypercalciuria increases the saturation of the urine with respect to stone-forming salts and reduces inhibitor activity. There is now ample evidence that 'idiopathic hypercalciuria' is a heterogeneous disorder, comprising several entities including absorptive, renal and resorptive forms of hypercalciuria. Absorptive hypercalciuria is the most common variety, and recent studies suggest that in a large subset of these patients, increased intestinal calcium absorption is caused by increased production of calcitriol or greater sensitivity to calcitriol (e.g. upregulation of vitamin D receptors). Reduced spinal bone density found in these patients may relate to increased action of calcitriol on bone or to other factors. Since patients with vitamin D-dependent absorptive hypercalciuria may develop negative calcium balance when placed on diets restricted in calcium, therapy is shifting from severe dietary calcium restriction and sodium cellulose phosphate (calcium-binding resin) to thiazides and orthophosphates, which promote calcium retention. For each form of hypercalciuria, selective therapy should provide the best results. PMID:7783695

  8. Integrating GHS into the Ghrelin System

    PubMed Central

    Veldhuis, Johannes D.; Bowers, Cyril Y.

    2010-01-01

    Oligopeptide derivatives of metenkephalin were found to stimulate growth-hormone (GH) release directly by pituitary somatotrope cells in vitro in 1977. Members of this class of peptides and nonpeptidyl mimetics are referred to as GH secretagogues (GHSs). A specific guanosine triphosphatate-binding protein-associated heptahelical transmembrane receptor for GHS was cloned in 1996. An endogenous ligand for the GHS receptor, acylghrelin, was identified in 1999. Expression of ghrelin and homonymous receptor occurs in the brain, pituitary gland, stomach, endothelium/vascular smooth muscle, pancreas, placenta, intestine, heart, bone, and other tissues. Principal actions of this peptidergic system include stimulation of GH release via combined hypothalamopituitary mechanisms, orexigenesis (appetitive enhancement), insulinostasis (inhibition of insulin secretion), cardiovascular effects (decreased mean arterial pressure and vasodilation), stimulation of gastric motility and acid secretion, adipogenesis with repression of fat oxidation, and antiapoptosis (antagonism of endothelial, neuronal, and cardiomyocyte death). The array of known and proposed interactions of ghrelin with key metabolic signals makes ghrelin and its receptor prime targets for drug development. PMID:20798846

  9. Prophylactic effects of quercetin and hyperoside in a calcium oxalate stone forming rat model.

    PubMed

    Zhu, Wei; Xu, Yun-fei; Feng, Yuan; Peng, Bo; Che, Jian-ping; Liu, Min; Zheng, Jun-hua

    2014-12-01

    Quercetin and hyperoside (QH) are the two main constituents of the total flavone glycosides of Flos Abelmoschus manihot, which has been prescribed for treating chronic kidney disease for decades. This study aimed to investigate the effect of QH on calcium oxalate (CaOx) formation in ethylene glycol (EG)-fed rats. Rats were divided into three groups: an untreated stone-forming group, a QH-treated stone-forming group (20 mg/kg/day) and a potassium citrate-treated stone-forming group (potassium citrate was a worldwide-recognized calculi-prophylactic medicine). Ethylene glycol (0.5 %) was administered to the rats during the last week, and vitamin D3 was force-fed to induce hyperoxaluria and kidney calcium oxalate crystal deposition. 24 h urine samples were collected before and after inducing crystal deposits. Rats were killed and both kidneys were harvested after 3 weeks. Bisected kidneys were examined under a polarized light microscope for semi-quantification of the crystal-formation. The renal tissue superoxide dismutase and catalase levels were measured by Western blot. QH and potassium citrate have the ability to alkalinize urine. The number of crystal deposits decreased significantly in the QH-treated stone-forming group as compared to the other groups. Superoxide dismutase and catalase levels also increased significantly in the QH-treated stone-forming group, as compared with the untreated stone-forming group. QH administration has an inhibitory effect on the deposition of CaOx crystal in EG-fed rats and may be effective for preventing stone-forming disease. PMID:25085199

  10. Assessing applicants to the NASA flight program for their renal stone-forming potential

    NASA Technical Reports Server (NTRS)

    Pak, Charles Y. C.; Hill, Kathy; Cintron, Nitza M.; Huntoon, Carolyn

    1989-01-01

    Because spaceflight can provoke the formation of kidney stones, 24-hour urine samples for 104 male applicants were analyzed for stone-forming risk factors prior to their selection into the NASA astronaut-mission specialist corps. A high level of supersaturation (with either calcium oxalate, brushite, or monosodium urate) was noted in these applicants which predisposes them to the crystallization of stone-forming calcium salts. It is suggested that most of the abnormal stone risk factors found were environmental, rather than metabolic, in origin.

  11. Biochemical changes in kidneys of normal and stone forming rats with sodium pentosan polysulphate.

    PubMed

    Subha, K; Baskar, R; Varalakshmi, P

    1992-02-01

    The influence of sodium pentosan polysulphate was studied on the deposition of stone forming constituents along with certain enzymes in the renal tissue of experimentally induced urolithiatic rats. Calcium, oxalate and phosphorus levels were elevated in kidneys of lithogenic rats, while SPP administration reduced these levels to near control values. The elevation in kidney LDH was significant in the stone forming groups and SPP had minimal effect. Increases in the activities of Na+, K(+)-and Ca(2+)-ATPases in the calculogenic groups was lowered considerably with SPP treatment. Inorganic pyrophosphatase activity was reduced significantly in the calculogenic as well as in the drug treated groups. Leucine aminopeptidase was decreased in the calculogenic group. SPP treatment elevated the enzyme activity in the treated groups. Reduction in kidney oxalate with SPP may prove useful in the medical management of urolithiasis. PMID:1373054

  12. Employee impact and attitude analysis for GHS implementation in Taiwan.

    PubMed

    Chang, Yi-Kuo; Su, Teh-Sheng; Ouyang, Yun; Tseng, Jo-Ming

    2013-01-01

    The employee impact and attitude analysis for GHS implementation in Taiwan was investigated in this study. An impact assessment on the new regulations or changes in regulations for government, potential costs, benefits, and the global trade in chemicals to industries and hazard communication program for workers was studied by the methods of the questionnaire design and Delphi expert method. A survey was conducted using questionnaires and taking 200 experts from government's expert database and 500 selected respondents from case company. Results from present study revealed that the barrier associated with GHS implementation is existed; it is feasible to overcome. Both experts and employees think that business entities are insufficient to test and classify chemicals on their own, and the technical guidance from the government is needed. Data analyzed by the logistic regression revealed that more hours an employee spends on education and trainings of new GHS systems; the employee thinks implementation of GHS will improve hazard awareness for transporters. The weak labeling ability affects deployment of the new GHS system. PMID:23385438

  13. Expert review for GHS classification of chemicals on health effects.

    PubMed

    Morita, Takeshi; Morikawa, Kaoru

    2011-01-01

    Intoxication as a result of chemical accidents is a major issue in industrial health. The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) provides a framework for hazard communication on chemicals using labelling or safety data sheets. The GHS will be expected to reduce the number of chemical accidents by communicating the hazards posed and prompting safety measures to be taken. One of the issues which may be a barrier to effective implementation of the GHS results from discrepancies in GHS classifications of chemicals across countries/regions. The main reasons are the differences in information sources used and in the expertise of people making the classification (Classifiers). The GHS requests expert judgment in a weight of evidence (WOE) approach in the application of the criteria of classification. A WOE approach is an assessment method that considers all available information bearing on the determination of toxicity. The quality and consistency of the data, study design, mechanism or mode of action, dose-effect relationships and biological relevance should be taken into account. Therefore, expert review should be necessary to classify chemicals accurately. However, the GHS does not provide any information on the required level of expertise of the Classifiers, definition of who qualifies as an expert, evaluation methods of WOE or data quality, and the timing of expert judgment and the need for updating/re-classification as new information becomes available. In this paper, key methods and issues in expert reviews are discussed. Examples of expert reviews and recommendations for harmonized classification are also presented. PMID:21804272

  14. Molecular cloning, regulation, and functional analysis of two GHS-R genes in zebrafish.

    PubMed

    Eom, Ji; Hong, Areum; Kang, Young-Ho; Yoo, Han-Ju; Chang, Eun-Ju; Kang, Sang-Wook; Yoon, Seung-Yong; Kim, Sang-Yeob; Song, Youngsup

    2014-08-01

    Mammalian ghrelin is derived from stomach and regulates growth hormone release and appetite by modulating GHS-R (Growth hormone secretagogue receptor) activity. Zebrafish has been developed as a forward genetic screening model system and previous screening identified a number of genes involved in multiple signaling pathways. In this system, ghrelin has been identified and its function and regulation have been shown to be highly conserved to that of mammals. Here, we identified three isoforms of zGHS-R1 and one of zGHS-R2 (zGHS-R2a), and characterized their expression, regulation and function. Three isoforms of zGHS-R1, which we named zGHS-R1a, zGHS-R1b, and zGHS-R1c, are generated by alternative splicing. The expression of zGHS-R1 is highly enriched in brain, intestine tissue, and skin tissues. Compared to zGHS-R1, the expression pattern of zGHS-R2a is rather evenly distributed. A 15 day fasting elevated expression of zGHS-R1 and zGHS-R2 transcripts in anterior intestine tissues, but not in brain. Whereas zGHS-R1a, zGHS-R1c, and zGHS-R2a appear to be presented on the plasma membrane, the localization of zGHS-R1b seems to be restricted in the intracellular region. Treatment of ghrelin agonist, L692,585 or goldfish ghrelin peptides but not rat ghrelin, elevated intracellular Ca(2+) level and phosphorylation of ERK in HEK-293 cells expressing zGHS-R1a, but not zGHS-R1b, zGHS-R1c, or zGHS-R2a. It appears that besides core ghrelin peptide sequence of GS/TSF additional amino acids are required for the activation of zGHS-R1a, as rat ghrelin induces neither intracellular Ca(2+) mobilization nor ERK phosphrylation. These results suggest that ghrelin system in zebrafish is highly conserved to that of mammals, and thus is an ideal in vivo model for dissecting ghrelin system. PMID:24928276

  15. Prevention of hypercalciuria and stone-forming propensity during prolonged bedrest by alendronate

    NASA Technical Reports Server (NTRS)

    Ruml, L. A.; Dubois, S. K.; Roberts, M. L.; Pak, C. Y.

    1995-01-01

    The bone loss and hypercalciuria induced by immobilization or the decreased gravitational forces of space are well described. Using a model of bedrest immobilization, the ability of a potent aminobisphosphonate, alendronate, to avert hypercalciuria and stone-forming propensity was tested. Sixteen male subjects participated in a randomized, placebo-controlled trial in which they received either 20 mg of alendronate or placebo 2 weeks prior to and during 3 weeks of strict bedrest. Parameters of bone and calcium metabolism and urinary crystallization of stone-forming salts were measured before and at the end of bedrest. In the placebo group, bedrest increased urinary calcium (209 +/- 47 to 267 +/- 60 mg/day, p < 0.01) and the saturation of calcium phosphate. Before bedrest, the alendronate group had a significantly lower serum calcium (8.8 +/- 0.4 vs. 9.6 +/- 0.5 mg/dl, p < 0.01) and higher serum PTH (62.4 +/- 33.1 vs. 23.1 +/- 7.5 pg/ml, p < 0.01) compared with the placebo group. Moreover, the alendronate group had a lower urinary calcium (75 +/- 41 mg/day) and saturation of calcium oxalate and calcium phosphate. These effects of alendronate were sustained during bedrest. Following bedrest in the alendronate group, urinary calcium rose to 121 +/- 50 mg/day, a value less than that in the placebo group before or during bedrest. Similarly, urinary saturation of calcium oxalate and calcium phosphate rose with bedrest in the alendronate-treated patients but remained lower than values obtained in placebo-treated patients before or during bedrest. Alendronate inhibits bone mineral loss and averts the hypercalciuria and increased propensity for the crystallization of stone-forming calcium salts which occurs during 3 weeks of strict bedrest.

  16. Assessing applicants to the NASA flight program for their renal stone-forming potential.

    PubMed

    Pak, C Y; Hill, K; Cintron, N M; Huntoon, C

    1989-02-01

    Spaceflight could provoke formation of kidney stones, in part by causing hypercalciuria and hyperphosphaturia. Applicants for spaceflight who have metabolic or environmental derangements to begin with might be particularly susceptible to stone formation in space. We, therefore, analyzed 24-h urine samples for stone-forming risk factors in 104 male applicants before their selection into the astronaut-mission specialist corps. The urinary environment was abnormally supersaturated with calcium oxalate in 25.0% of applicants, brushite in 36.5%, and monosodium urate in 66.3%, predisposing these applicants to crystallization of stone-forming calcium salts. This high level of supersaturation was caused by both "metabolic" and environmental disturbances. Thus, hypercalciuria was found in 11.5% of applicants, hyperoxaluria in 2.9%, hyperuricosuria in 18.3% and hypocitraturia in 5.8%. Environmental derangements were generally more prominent, as indicated by low urine volume of less than 2 L.d-1 in 84.6%, high urinary phosphate in 24.4%, and high urinary sodium in 10.6% of applicants. The results suggest that most of the abnormal stone risk factors disclosed among applicants for spaceflight programs were environmental in origin. PMID:2930428

  17. GHS Clock, a New Device for Precise Timing

    NASA Astrophysics Data System (ADS)

    Hayamizu, Tsutomu; Geshiro, Hiroyuki; Sôma, Mitsuru

    2000-12-01

    The Japanese shortwave time signals JJY will be shut down on 2001 March 31st. Astronomers who have been using JJY are seeking alternative methods for precise timing. The authors designed equipment, called the GHS Clock, that can be used with inexpensive GPS receivers to produce both an LED flash and a pip sound at the beginning of each second. Tests show that this device is accurate to about a microsecond.

  18. A Common Bile Duct Stone formed by Suture Material after Open Cholecystectomy

    PubMed Central

    Kim, Kook-Hyun; Jang, Byung-Ik

    2007-01-01

    The use of non-absorbable suture materials for cystic duct ligation after cholecystectomy can expose patients to the risk of recurrent stone formation in the common bile duct (CBD). However, in Korea suture materials have rarely been found to act as a nidus for common bile duct calculus formation. Recently, we experienced a case in which suture material, that had migrated from a previous cholecystectomy site into the CBD, probably served as a nidus for common bile duct stone formation. The stone was confirmed by endoscopic retrograde cholangiopancreatography (ERCP) and removed successfully using a basket. The authors report a case of surgical suture migration and discuss its subsequent role as a stone forming nucleus within the CBD in a patient who underwent open cholecystectomy; and include a review of the literature. PMID:18309688

  19. Biochemical effects in normal and stone forming rats treated with the ripe kernel juice of plantain (musa paradisiaca).

    PubMed

    Devi, V K; Baskar, R; Varalakshmi, P

    1993-01-01

    The effect of Musa paradisiaca stem kernel juice was investigated in experimental urolithiatic rats. Stone forming rats exhibited a significant elevation in the activities of two oxalate synthesizing enzymes - Glycollic acid oxidase and Lactate dehydrogenase. Deposition and excretion of stone forming constituents in kidney and urine were also increased in these rats. The enzyme activities and the level of crystalline components were lowered with the extract treatment. The extract also reduced the activities of urinary alkaline phosphatase, lactate dehydrogenase, r-glutamyl transferase, inorganic pyrophosphatase and β-glucuronidase in calculogenic rats. No appreciable changes were noticed with leucine amino peptidase activity in treated rats. PMID:22556626

  20. Risk factor analysis and relative supersaturation as tools for identifying calcium oxalate stone-forming dogs.

    PubMed

    Stevenson, A E; Robertson, W G; Markwell, P

    2003-11-01

    Twenty-four hour urine samples were collected from 17 calcium oxalate (CaOx) stone-forming (SF) dogs and 17 normal (N), age-, breed- and sex-matched dogs. Urinary CaOx relative supersaturation (RSS) was calculated and found to be significantly higher in the SF group than the N group. RSS measurement is not readily applicable to veterinary practice; thus, alternatives were explored. Discriminant analysis failed to identify key factors differentiating most SF from N dogs. Urinary calcium, oxalate and uric acid, which differed between the SF and N animals, were combined into a measure of relative probability of CaOx stone formation (PSF) to establish whether this approach could be used to assess the risk of CaOx stone formation in dogs. Although there was good correlation between the techniques, RSS more clearly discriminated between SF and N dogs. These data suggest that neither PSF nor discriminant analysis is preferable to RSS for assessing the risk of CaOx stone formation in dogs. PMID:14635961

  1. Prevention of nephrolithiasis by Lactobacillus in stone-forming rats: a preliminary study.

    PubMed

    Kwak, Cheol; Jeong, Byong Chang; Ku, Ja Hyeon; Kim, Hyeon Hoe; Lee, Jeong Jun; Huh, Chul Sung; Baek, Young Jin; Lee, Sang Eun

    2006-08-01

    Hyperoxaluria is a risk factor for renal stones. It appears to be sustained by increased dietary load or increased intestinal absorption. The aim of this study was to evaluate whether oral administration of lactobacilli could prevent urolithiasis in stone-forming rats. Oxalate-degrading activities of lactobacilli were evaluated by measuring the oxalate level in a culture medium after inoculation with lactobacilli. Only the strains of Lactobacillus having oxalate-degrading activity were used. Sprague-Dawley rats were fed a powdered standard diet containing 3% sodium oxalate and/or received 100 mg/kg of celecoxib for the first 8 days by gavage, before or after the beginning of this experiment (groups with previous treatment or with co-treatment). Rats were sacrificed after 4 weeks and kidneys were harvested for the assay of crystal formation under a dissecting microscope. Twenty-four-hour urine collections were performed before kidney harvest. Only two strains, Lactobacillus casei HY2743 and L. casei HY7201 out of 31 strains of Lactobacillus were able to degrade oxalate. In both groups of co-treatment and previous treatment with L. casei HY2743 and L. casei HY7201, urine oxalate excretion decreased compared to the group without lactobacilli. The dissecting microscope examination of kidneys in the rats in two previous treatment groups and the co-treatment group with L. casei HY7201 showed less abundant crystals than control groups. Our results show that lactobacilli may be used as a potential therapeutic strategy in the prevention of urinary stones. PMID:16633809

  2. Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists.

    PubMed

    McCoull, William; Barton, Peter; Brown, Alastair J H; Bowker, Suzanne S; Cameron, Jennifer; Clarke, David S; Davies, Robert D M; Dossetter, Alexander G; Ertan, Anne; Fenwick, Mark; Green, Clive; Holmes, Jane L; Martin, Nathaniel; Masters, David; Moore, Jane E; Newcombe, Nicholas J; Newton, Claire; Pointon, Helen; Robb, Graeme R; Sheldon, Christopher; Stokes, Stephen; Morgan, David

    2014-07-24

    Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a. PMID:24967667

  3. Similarity of urinary risk factors among stone-forming patients in five regions of the United States

    NASA Technical Reports Server (NTRS)

    Harvey, J. A.; Hill, K. D.; Pak, C. Y.

    1990-01-01

    Study Objective: To compare urinary biochemical risk factors among stone-forming patients in the Southeast (SE) or "stone belt" versus four other regions of the United States. Design: Prospective biochemical survey for regional comparisons. Setting: Referral-based nephrolithiasis clinics, urologists, nephrologists, and family practitioners. Patients: Consecutive sample of 3473 stone-forming patients who submitted 24-hour urine collections for biochemical analyses of stone-forming risk factors. Interventions: None. Subjects taking medication known to interfere with stone-forming risk factors were deleted from the final data compilation. Measurements and Main Results: Overall, the mean values for each urinary parameter spanned a narrow range without significant difference between the five regions. Among "metabolic" factors, 40% in the SE had hypercalciuria (> 6.25 mmol/d), compared to 35%-43% in other regions, and hyperuricosuria (> 4.2 mmol/d) was found in 16% in the SE versus 17%-19% elsewhere. Among "environmental" factors, low urine volume ( < 2 L/d) was found in 77% patients in the SE compared to 69%-78% elsewhere, and high sodium was encountered in 27% in the SE versus 24%-29% elsewhere. No differences were noted in occurrence of other abnormal risk factors: hyperoxaluria, hypocitraturia, low pH, high sulfate, high phosphorus, or low magnesium. Conclusions: Despite expected regional differences in nutritional and environmental influences, the results of this study showed a striking similarity in urinary biochemical risk factor profiles of stone-formers in all five regions of the United States.

  4. [Globally harmonized system of classification and labelling of chemicals (GHS) and its implementation in Japan].

    PubMed

    Miyagawa, Muneyuki

    2010-01-01

    The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) is a set of recommendations by the United Nations, first issued in 2003 as a communication tool for the sound management of chemicals, comprising harmonized classification criteria for physical, health and environmental hazards, a unified format for material safety data sheets (MSDS), and labeling elements including pictograms and hazard statements preassigned to each classification category. The GHS has been introduced into Japan and implemented in the regulatory framework for chemical safety. The Japanese Industrial Standards (JIS) adopted the GHS, and the GHS-based JIS rules have become the Japanese standards for labels and MSDS. The use of the JIS format for labels and MSDS is recommended by several competent authorities in Japan although mostly on a voluntary basis. In the workplace, however, GHS-based JIS labels and MSDS have become legal requirements by the Industrial Safety and Health Law since 2006; namely, issuing MSDS in such a format is mandatory for the 640 specified chemicals and also labeling for the 99 targeted chemicals*. Although the GHS provides definitions and classification criteria for 10 classes of health hazards (acute toxicity, skin and eye corrosion/irritation, sensitization, germ cell mutagenicity, carcinogenicity, reproductive toxicity, specific target organ toxicity single/repeated exposures, and aspiration hazard), it does not provide actual classification of chemicals, so that competent authorities and industries need to classify a number of chemicals and/or mixtures. Weight-of-evidence judgment and/or expert judgment would be necessary in many cases. In this paper, the outline of the GHS classification is described and problems of the GHS and its implementation are discussed. PMID:20134103

  5. The road to GHS: worker right-to-know in the 21st century.

    PubMed

    Karstadt, Myra L

    2012-01-01

    Of the three communications standards discussed, HI is definitely the outlier, as it emphasizes worker control of the process of identifying hazard and deemphasizes employer control of identification of hazards and dissemination of hazard information. GHS may not be as protective of American workers as HazCom is, but for workers in less-developed countries, where regulation of workplace health and safety is less strong than in the United States, Canada, many countries in Europe, and Japan, GHS--if adequately enforced-will likely represent an improvement in information on chemical hazards in the workplace. American workers may well see a decline in workplace protection against chemical hazards while protection may improve for workers in less-developed countries. This trade-off is part of the ongoing debate about globalization, of which worker protection from chemical hazards should be an important aspect. The next paper in this series will compare the proposed and final versions of GHS, and will discuss possible improvements to GHS to better serve American workers. As OSHA moves forward with the GHS rule, people and organizations concerned with worker right-to-know should consider possible improvements to GHS to better serve workers in the United States and worldwide. PMID:22550692

  6. GHS-R1a constitutive activity and its physiological relevance

    PubMed Central

    Mear, Yves; Enjalbert, Alain; Thirion, Sylvie

    2013-01-01

    Abundant evidences have shown that ghrelin, by its binding to GHS-R1a, plays an important role for fundamental physiological functions. Increasing attention is given to the GHS-R1a unusually high constitutive activity and its contribution to downstream signaling and physiological processes. Here, we review recent lines of evidences showing that the interaction between ligand-binding pocket TM domains and the ECL2 could be partially responsible for this high constitutive activity. Interestingly, GHSR-1a constitutive activity activates in turn the downstream PLC, PKC, and CRE signaling pathways and this activation is reversed by the inverse agonist [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P (MSP). Noteworthy, GHSR-1a exhibits a C-terminal-dependent constitutive internalization. Non-sense GHS-R1a mutation (Ala204Glu), first discovered in Moroccan patients, supports the role of GHSR-1a constitutive activity in physiological impairments. Ala204Glu-point mutation, altering exclusively the GHSR-1a constitutive activity, was associated with familial short stature syndrome. Altogether, these findings suggest that GHS-R1a constitutive activity could contribute to GH secretion or body weight regulation. Consequently, future research on basic and clinical applications of GHS-R1a inverse agonists will be challenging and potentially rewarding. PMID:23754971

  7. Nutrient intake and urine composition in calcium oxalate stone-forming dogs: comparison with healthy dogs and impact of dietary modification.

    PubMed

    Stevenson, Abigail E; Blackburn, Judith M; Markwell, Peter J; Robertson, William G

    2004-01-01

    Nutrient intake and urine composition were analyzed in calcium oxalate (CaOx)stone-forming and healthy control dogs to identify factors that contribute to CaOx urolithiasis. Stone-forming dogs had significantly lower intake of sodium, calcium, potassium, and phosphorus and significantly higher urinary calcium and oxalate concentrations, calcium excretion, and CaOx relative supersaturation (RSS). Feeding a diet used in the treatment of canine lower urinary tract disease for 1 month was associated with increased intake of moisture, sodium, and fat; reduced intake of potassium and calcium; and decreased urinary calcium and oxalate concentrations, calcium excretion, and CaOx RSS. No clinical signs of disease recurrence were observed in the stone-forming dogs when the diet was fed for an additional 11 months. The results suggest that hypercalciuria and hyperoxaluria contribute to the formation of CaOx uroliths in dogs and show that dietary modifications can alter this process. PMID:15578454

  8. Increased intestinal vitamin D receptor in genetic hypercalciuric rats. A cause of intestinal calcium hyperabsorption.

    PubMed

    Li, X Q; Tembe, V; Horwitz, G M; Bushinsky, D A; Favus, M J

    1993-02-01

    In humans, familial or idiopathic hypercalciuria (IH) is a common cause of hypercalciuria and predisposes to calcium oxalate nephrolithiasis. Intestinal calcium hyperabsorption is a constant feature of IH and may be due to either a vitamin D-independent process in the intestine, a primary overproduction of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], or a defect in renal tubular calcium reabsorption. Selective breeding of spontaneously hypercalciuric male and female Sprague-Dawley rats resulted in offspring with hypercalciuria, increased intestinal calcium absorption, and normal serum 1,25(OH)2D3 levels. The role of the vitamin D receptor (VDR) in the regulation of intestinal calcium absorption was explored in 10th generation male genetic IH rats and normocalciuric controls. Urine calcium excretion was greater in IH rats than controls (2.9 +/- 0.3 vs. 0.7 +/- 0.2 mg/24 h, P < 0.001). IH rat intestine contained twice the abundance of VDR compared with normocalciuric controls (536 +/- 73 vs. 243 +/- 42 nmol/mg protein, P < 0.001), with no difference in the affinity of the receptor for its ligand. Comparable migration of IH and normal intestinal VDR on Western blots and of intestinal VDR mRNA by Northern analysis suggests that the VDR in IH rat intestine is not due to large deletion or addition mutations of the wild-type VDR. IH rat intestine contained greater concentrations of vitamin D-dependent calbindin 9-kD protein. The present studies strongly suggest that increased intestinal VDR number and normal levels of circulating 1,25(OH)2D3 result in increased functional VDR-1,25(OH)2D3 complexes, which exert biological actions in enterocytes to increase intestinal calcium transport. Intestinal calcium hyperabsorption in the IH rat may be the first example of a genetic disorder resulting from a pathologic increase in VDR. PMID:8381825

  9. The usefulness of the validated SkinEthic™ RHE test method to identify skin corrosive UN GHS subcategories.

    PubMed

    Alépée, Nathalie; Robert, Clément; Tornier, Carine; Cotovio, José

    2014-06-01

    The SkinEthic™ Reconstructed Human Epidermis (RHE) test method has been adopted within the context of OECD TG 431 for distinguishing corrosive and non-corrosive chemicals. The EU CLP classification system requires subcategorising of corrosive chemicals into the three UN GHS subcategories 1A, 1B and 1C. Since the SkinEthic™ RHE method was originally validated to discriminate corrosives from non-corrosives, the present study was undertaken to investigate its usefulness to discriminate skin corrosive UN GHS subcategories. In total 84 substances were tested in three independent runs and two prediction models (PM) were assessed, representing a pre-defined validated prediction model (PM-A) and an alternative one defined post-hoc (PM-B). The results obtained with both PM were reproducible, as shown by the ⩾92.9% concordance of classification between runs for discriminating corrosives versus non-corrosives, and the ⩾85% concordance for discriminating the GHS subcategories versus non-corrosives. Moreover results confirmed a high sensitivity of the SkinEthic™ RHE method to predict corrosives (94.9%) and good specificity (⩾73.7%) independent of the PM applied. Regarding the identification of UN GHS corrosive subcategories, PM-A resulted in 86.1% correct classifications of the GHS subcategory 1A. When using the PM-B, the identification of GHS subcategory 1B-and-1C substances improved, with 63.4% correct sub-categorisation. If considering the 30 reference chemicals as recommended in the recently revised OECD TG 431 (2013), PM-A and PM-B achieved 78.9% and 83.3% accuracy respectively for the identification of GHS subcategories and non-corrosives. They correctly predicted 90% of GHS subcategory 1A and 80% of GHS non-corrosive substances independent of the PM used. In conclusion, the SkinEthic™ RHE test method is highly reproducible and sensitive for discriminating corrosive from non-corrosive substances. Furthermore it allows reliable identification of skin corrosive GHS subcategory 1B-and-1C substances using the PM-A and PM-B, and of GHS subcategories 1A using the PM-B. Due to its high sensitivity, the test method provides high safety standards for skin corrosion testing. PMID:24389111

  10. Extensive review of fish embryo acute toxicities for the prediction of GHS acute systemic toxicity categories.

    PubMed

    Scholz, Stefan; Ortmann, Julia; Klüver, Nils; Léonard, Marc

    2014-08-01

    Distribution and marketing of chemicals require appropriate labelling of health, physical and environmental hazards according to the United Nations global harmonisation system (GHS). Labelling for (human) acute toxicity categories is based on experimental findings usually obtained by oral, dermal or inhalative exposure of rodents. There is a strong societal demand for replacing animal experiments conducted for safety assessment of chemicals. Fish embryos are considered as alternative to animal testing and are proposed as predictive model both for environmental and human health effects. Therefore, we tested whether LC50s of the fish embryo acute toxicity test would allow effectively predicting of acute mammalian toxicity categories. A database of published fish embryo LC50 containing 641 compounds was established. For these compounds corresponding rat oral LD50 were identified resulting in 364 compounds for which both fish embryo LC50 and rat LD50 was available. Only a weak correlation of fish embryo LC50 and rat oral LD50 was obtained. Fish embryos were also not able to effectively predict GHS oral acute toxicity categories. We concluded that due to fundamental exposure protocol differences (single oral dose versus water-borne exposure) a reverse dosimetry approach is needed to explore the predictive capacity of fish embryos. PMID:24929227

  11. Integration of leprosy into GHS in India: a follow up study (2006-2007).

    PubMed

    Pandey, Aparna; Rathod, Harish

    2010-12-01

    In India leprosy services, were integrated into the General Health Services (GHS), in a phased manner, in different provinces, from 2001 to 2004. This study reports the findings from a follow-up operational research undertaken in 2006-2007, to assess the level of integration, on predetermined indicators related to: referral services, training of health functionaries, availability of diagnosis, treatment, MDT dispersal and counselling guidelines in health facilities, recording and reporting by GHS staff, MDT stock management and involvement of health sub-centres in different Indian provinces. Nine provinces, 18 districts, 88 health facilities and 108 sub-centres were selected, by using multistage stratified random sampling techniques. Reverse integration, as reflected by the training and deployment of vertical staff in GHS, was also assessed. Data was collected by medical officers experienced in leprosy, with the assistance of state health functionaries, and recorded on separate schedules for health facility and sub-centre levels. The study also touched on the issue of client perception towards MDT services by interviewing 149 under treatment/cured leprosy cases (who had completed treatment within the last year), in the community with the help of local interpreters. Results showed wide variations across the selected provinces in various parameters. District leprosy nuclei were understaffed in 12(66.7%) districts, and district hospitals were not working as referral institutions anywhere. The training status of medical officers and multi-purpose workers in leprosy was low in Andhra Pradesh (6.9 and 22.4%), Madhya Pradesh (26.3 and 14.5%), Rajasthan (19.7 and 40.9%) and Kerala (25.5 and 65.7%). MDT stock availability as per the National Leprosy Eradication Programme (NLEP) guidelines was not adequate in all provinces. Availability of patient counseling guidelines was nil/low in Kerala, Karnataka, West Bengal, Orissa, Rajasthan and Andhra Pradesh. The involvement of sub-centres, in case referral, recording and dispensing MDT was nil Kerala and Rajasthan and poor in Andhra Pradesh. Ninety percent of clients in Kerala and 38.0% in Andhra Pradesh and Madhya Pradesh did not get MDT in the nearest health facilities or sub-centres. PMID:21313976

  12. The expression of GHS-R in primary neurons is dependent upon maturation stage and regional localization.

    PubMed

    Lattuada, Donatella; Crotta, Katia; Tonna, Noemi; Casnici, Claudia; Benfante, Roberta; Fornasari, Diego; Bianco, Fabio; Longhi, Renato; Marelli, Ornella

    2013-01-01

    Ghrelin is a hormone with a crucial role in the regulation of appetite, regulation of inflammation, glucose metabolism and cell proliferation. In the brain ghrelin neurons are located in the cortex (sensorimotor area, cingular gyrus), and the fibres of ghrelin neurons in hypothalamus project directly to the dorsal vagal complex (DVC). Ghrelin binds the growth hormone secretagogue receptor (GHS-R) a G-protein-coupled receptor with a widespread tissue distribution, indeed these receptors are localized both in nonnervous, organs/tissues (i.e. adipose tissue, myocardium, adrenals, gonads, lung, liver, arteries, stomach, pancreas, thyroid, and kidney) as well as in central nervous system (CNS) and higher levels of expression in the pituitary gland and the hypothalamus and lower levels of expression in other organs, including brain. A GHS-R specific monoclonal antibody has been developed and characterized and through it we demonstrate that GHS-R is expressed in primary neurons and that its expression is dependent upon their developmental stage and shows differences according to the brain region involved, with a more pronounced expression in hippocampal rather than cortical neurons. A characterization of GHS-R within the central nervous system is of extreme importance in order to gain insights on its role in the modulation of neurodegenerative events such as Alzheimer's disease. PMID:23755116

  13. Hazard banding in compliance with the new Globally Harmonised System (GHS) for use in control banding tools.

    PubMed

    Arnone, Mario; Koppisch, Dorothea; Smola, Thomas; Gabriel, Stefan; Verbist, Koen; Visser, Remco

    2015-10-01

    Many control banding tools use hazard banding in risk assessments for the occupational handling of hazardous substances. The outcome of these assessments can be combined with advice for the required risk management measures (RMMs). The Globally Harmonised System of Classification and Labelling of Chemicals (GHS) has resulted in a change in the hazard communication elements, i.e. Hazard (H) statements instead of Risk-phrases. Hazard banding schemes that depend on the old form of safety information have to be adapted to the new rules. The purpose of this publication is to outline the rationales for the assignment of hazard bands to H statements under the GHS. Based on this, this publication proposes a hazard banding scheme that uses the information from the safety data sheets as the basis for assignment. The assignment of hazard bands tiered according to the severity of the underlying hazards supports the important principle of substitution. Additionally, the set of assignment rules permits an exposure-route-specific assignment of hazard bands, which is necessary for the proposed route-specific RMMs. Ideally, all control banding tools should apply the same assignment rules. This GHS-compliant hazard banding scheme can hopefully help to establish a unified hazard banding strategy in the various control banding tools. PMID:26206396

  14. Hypercalciuric Bone Disease

    NASA Astrophysics Data System (ADS)

    Favus, Murray J.

    2008-09-01

    Hypercalciuria plays an important causal role in many patients with calcium oxalate (CaOx) stones. The source of the hypercalciuria includes increased intestinal Ca absorption and decreased renal tubule Ca reabsorption. In CaOx stone formers with idiopathic hypercalciuria (IH), Ca metabolic balance studies have revealed negative Ca balance and persistent hypercalciuria in the fasting state and during low dietary Ca intake. Bone resorption may also contribute to the high urine Ca excretion and increase the risk of bone loss. Indeed, low bone mass by DEXA scanning has been discovered in many IH patients. Thiazide diuretic agents reduce urine Ca excretion and may increase bone mineral density (BMD), thereby reducing fracture risk. Dietary Ca restriction that has been used unsuccessfully in the treatment of CaOx nephrolithiasis in the past may enhance negative Ca balance and accelerate bone loss. DEXA scans may demonstrate low BMD at the spine, hip, or forearm, with no predictable pattern. The unique pattern of bone histologic changes in IH differs from other causes of low DEXA bone density including postmenopausal osteoporosis, male hypogonadal osteoporosis, and glucocorticoid-induced osteoporosis. Hypercalciuria appears to play an important pathologic role in the development of low bone mass, and therefore correction of urine Ca losses should be a primary target for treatment of the bone disease accompanying IH.

  15. Guidance on classification for reproductive toxicity under the globally harmonized system of classification and labelling of chemicals (GHS).

    PubMed

    Moore, Nigel P; Boogaard, Peter J; Bremer, Susanne; Buesen, Roland; Edwards, James; Fraysse, Benoit; Hallmark, Nina; Hemming, Helena; Langrand-Lerche, Carole; McKee, Richard H; Meisters, Marie-Louise; Parsons, Paul; Politano, Valerie; Reader, Stuart; Ridgway, Peter; Hennes, Christa

    2013-11-01

    The Globally Harmonised System of Classification (GHS) is a framework within which the intrinsic hazards of substances may be determined and communicated. It is not a legislative instrument per se, but is enacted into national legislation with the appropriate legislative instruments. GHS covers many aspects of effects upon health and the environment, including adverse effects upon sexual function and fertility or on development. Classification for these effects is based upon observations in humans or from properly designed experiments in animals, although only the latter is covered herein. The decision to classify a substance based upon experimental data, and the category of classification ascribed, is determined by the level of evidence that is available for an adverse effect on sexual function and fertility or on development that does not arise as a secondary non-specific consequence of other toxic effect. This document offers guidance on the determination of level of concern as a measure of adversity, and the level of evidence to ascribe classification based on data from tests in laboratory animals. PMID:24274377

  16. Ghrelin receptor (GHS-R1A) antagonism alters preference for ethanol and sucrose in a concentration-dependent manner in prairie voles.

    PubMed

    Stevenson, J R; Francomacaro, L M; Bohidar, A E; Young, K A; Pesarchick, B F; Buirkle, J M; McMahon, E K; O'Bryan, C M

    2016-03-01

    Ghrelin receptor (GHS-R1A) activity has been implicated in reward for preferred foods and drugs; however, a recent study in our laboratory indicated that GHS-R1A antagonism reduces early (after only four exposures) preference for 20% ethanol, but not 10% sucrose in prairie voles, a genetically diverse high alcohol-consuming species. The purpose of the present study was to determine if these effects of GHS-R1A antagonism depend on the concentration of the rewarding solution being consumed. We first characterized preference for varying concentrations of ethanol and sucrose. Two bottle tests of each ethanol concentration versus water indicated that 10% and 20% ethanol are less preferred than 3% ethanol, and a follow-up direct comparison of 10% vs. 20% showed that 10% was preferred over 20%. Direct two-bottle comparisons of 2% vs. 5%, 2% vs. 10%, and 5% vs. 10% sucrose showed that 10% sucrose was most preferred, and 2% sucrose was least preferred. The effects of JMV 2959, a GHS-R1A antagonist, on preference for each concentration of ethanol and sucrose were then tested. In a between groups design prairie voles were given four two-hour drinking sessions in which animals had access to ethanol (3, 10, or 20%) versus water, or sucrose (2, 5, or 10%) versus water every other day. Saline habituation injections were given 30 min before the third drinking session. JMV 2959 (i.p.; 9 mg/kg), a GHS-R1A antagonist, or saline was administered 30 min before the fourth drinking session. JMV 2959 reduced preference for 20% ethanol and 2% sucrose, but had no significant effect on preference for the other ethanol and sucrose concentrations. These data identify constraints on the role of GHS-R1A in early preference for ethanol and sucrose, and the concentration-dependent effects suggest strong preference for a reward may limit the importance of GHS-R1A activity. PMID:26723269

  17. Estradiol and testosterone modulate the tissue-specific expression of ghrelin, ghs-r, goat and nucb2 in goldfish.

    PubMed

    Bertucci, Juan Ignacio; Blanco, Ayelén Melisa; Canosa, Luis Fabián; Unniappan, Suraj

    2016-03-01

    Ghrelin, and nesfatin-1 (encoded by nucleobindin2/nucb2) are two metabolic peptides with multiple biological effects in vertebrates. While sex steroids are known to regulate endogenous ghrelin and NUCB2 in mammals, such actions by steroids in fish remain unknown. This study aimed to determine whether estradiol (E2) and testosterone (T) affects the expression of preproghrelin, ghrelin/growth hormone secretagogue receptor (GHS-R), ghrelin O-acyl transferase (GOAT) and NUCB2 in goldfish (Carassius auratus). First, a dose-response assay was performed in which fish were intraperitoneally (ip) implanted with pellets containing 25, 50 or 100μg/g body weight (BW) of E2 or T. It was found that sex steroids (100μg/g BW) administered for 2.5days achieved the highest E2 or T in circulation. In a second experiment, fish were ip implanted with pellets containing 100μg/g BW of E2, T or without hormone (control). RT-qPCR analyses at 2.5days post-administration show that gut preproghrelin and GOAT expression was upregulated by both E2 and T treatments, while the same effect was observed for GHS-R only in the pituitary. Both treatments also reduced hypothalamic preproghrelin mRNA expression. NUCB2 expression was increased in the forebrain of T treated group and reduced in the gut and pituitary under both treatments. These results show for the first time a modulation of preproghrelin and nucb2/nesfatin-1 by sex steroids in fish. The interaction between sex steroids and genes implicated in both metabolism and reproduction might help meeting the reproduction dependent energy demands in fish. PMID:26773340

  18. In Situ Localization and Rhythmic Expression of Ghrelin and ghs-r1 Ghrelin Receptor in the Brain and Gastrointestinal Tract of Goldfish (Carassius auratus)

    PubMed Central

    Unniappan, Suraj; Kah, Olivier; Gueguen, Marie-M.; Bertucci, Juan I.; Alonso-Gómez, Ángel L.; Valenciano, Ana I.; Isorna, Esther; Delgado, María J.

    2015-01-01

    Ghrelin is a gut-brain peptide hormone, which binds to the growth hormone secretagogue receptor (GHS-R) to regulate a wide variety of biological processes in fish. Despite these prominent physiological roles, no studies have reported the anatomical distribution of preproghrelin transcripts using in situ hybridization in a non-mammalian vertebrate, and its mapping within the different encephalic areas remains unknown. Similarly, no information is available on the possible 24-h variations in the expression of preproghrelin and its receptor in any vertebrate species. The first aim of this study was to investigate the anatomical distribution of ghrelin and GHS-R1a ghrelin receptor subtype in brain and gastrointestinal tract of goldfish (Carassius auratus) using immunohistochemistry and in situ hybridization. Our second aim was to characterize possible daily variations of preproghrelin and ghs-r1 mRNA expression in central and peripheral tissues using real-time reverse transcription-quantitative PCR. Results show ghrelin expression and immunoreactivity in the gastrointestinal tract, with the most abundant signal observed in the mucosal epithelium. These are in agreement with previous findings on mucosal cells as the primary synthesizing site of ghrelin in goldfish. Ghrelin receptor was observed mainly in the hypothalamus with low expression in telencephalon, pineal and cerebellum, and in the same gastrointestinal areas as ghrelin. Daily rhythms in mRNA expression were found for preproghrelin and ghs-r1 in hypothalamus and pituitary with the acrophase occurring at nighttime. Preproghrelin, but not ghs-r1a, displayed a similar daily expression rhythm in the gastrointestinal tract with an amplitude 3-fold higher than the rest of tissues. Together, these results described for the first time in fish the mapping of preproghrelin and ghrelin receptor ghs-r1a in brain and gastrointestinal tract of goldfish, and provide the first evidence for a daily regulation of both genes expression in such locations, suggesting a possible connection between the ghrelinergic and circadian systems in teleosts. PMID:26506093

  19. Ghrelin Receptor (GHS-R1A) Antagonism Suppresses Both Alcohol Consumption and the Alcohol Deprivation Effect in Rats following Long-Term Voluntary Alcohol Consumption

    PubMed Central

    Fredriksson, Ida; Engel, Jörgen A.; Jerlhag, Elisabet

    2013-01-01

    Alcohol dependence is a heterogeneous disorder where several signalling systems play important roles. Recent studies implicate that the gut-brain hormone ghrelin, an orexigenic peptide, is a potential mediator of alcohol related behaviours. Ghrelin increases whereas a ghrelin receptor (GHS-R1A) antagonist decreases alcohol consumption as well as operant self-administration of alcohol in rodents that have consumed alcohol for twelve weeks. In the present study we aimed at investigating the effect of acute and repeated treatment with the GHS-R1A antagonist JMV2959 on alcohol intake in a group of rats following voluntarily alcohol consumption for two, five and eight months. After approximately ten months of voluntary alcohol consumption the expression of the GHS-R1A gene (Ghsr) as well as the degree of methylation of a CpG island found in Ghsr was examined in reward related brain areas. In a separate group of rats, we examined the effect of the JMV2959 on alcohol relapse using the alcohol deprivation paradigm. Acute JMV2959 treatment was found to decrease alcohol intake and the effect was more pronounced after five, compared to two months of alcohol exposure. In addition, repeated JMV2959 treatment decreased alcohol intake without inducing tolerance or rebound increase in alcohol intake after the treatment. The GHS-R1A antagonist prevented the alcohol deprivation effect in rats. There was a significant down-regulation of the Ghsr expression in the ventral tegmental area (VTA) in high- compared to low-alcohol consuming rats after approximately ten months of voluntary alcohol consumption. Further analysis revealed a negative correlation between Ghsr expression in the VTA and alcohol intake. No differences in methylation degree were found between high- compared to low-alcohol consuming rats. These findings support previous studies showing that the ghrelin signalling system may constitute a potential target for development of novel treatment strategies for alcohol dependence. PMID:23977009

  20. Short Time Exposure (STE) test in conjunction with Bovine Corneal Opacity and Permeability (BCOP) assay including histopathology to evaluate correspondence with the Globally Harmonized System (GHS) eye irritation classification of textile dyes.

    PubMed

    Oliveira, Gisele Augusto Rodrigues; Ducas, Rafael do Nascimento; Teixeira, Gabriel Campos; Batista, Aline Carvalho; Oliveira, Danielle Palma; Valadares, Marize Campos

    2015-09-01

    Eye irritation evaluation is mandatory for predicting health risks in consumers exposed to textile dyes. The two dyes, Reactive Orange 16 (RO16) and Reactive Green 19 (RG19) are classified as Category 2A (irritating to eyes) based on the UN Globally Harmonized System for classification (UN GHS), according to the Draize test. On the other hand, animal welfare considerations and the enforcement of a new regulation in the EU are drawing much attention in reducing or replacing animal experiments with alternative methods. This study evaluated the eye irritation of the two dyes RO16 and RG19 by combining the Short Time Exposure (STE) and the Bovine Corneal Opacity and Permeability (BCOP) assays and then comparing them with in vivo data from the GHS classification. The STE test (first level screening) categorized both dyes as GHS Category 1 (severe irritant). In the BCOP, dye RG19 was also classified as GHS Category 1 while dye RO16 was classified as GHS no prediction can be made. Both dyes caused damage to the corneal tissue as confirmed by histopathological analysis. Our findings demonstrated that the STE test did not contribute to arriving at a better conclusion about the eye irritation potential of the dyes when used in conjunction with the BCOP test. Adding the histopathology to the BCOP test could be an appropriate tool for a more meaningful prediction of the eye irritation potential of dyes. PMID:26026500

  1. Sex Modifies Genetic Effects on Residual Variance in Urinary Calcium Excretion in Rat (Rattus norvegicus)

    PubMed Central

    Perry, Guy M. L.; Nehrke, Keith W.; Bushinsky, David A.; Reid, Robert; Lewandowski, Krista L.; Hueber, Paul; Scheinman, Steven J.

    2012-01-01

    Conventional genetics assumes common variance among alleles or genetic groups. However, evidence from vertebrate and invertebrate models suggests that residual genotypic variance may itself be under partial genetic control. Such a phenomenon would have great significance: high-variability alleles might confound the detection of classically acting genes or scatter predicted evolutionary outcomes among unpredicted trajectories. Of the few works on this phenomenon, many implicate sex in some aspect of its control. We found that female genetic hypercalciuric stone-forming (GHS) rats (Rattus norvegicus) had higher coefficients of variation (CVs) for urinary calcium (CV = 0.14) than GHS males (CV = 0.06), and the reverse in normocalciuric WistarKyoto rats (WKY) (CV? = 0.14; CV? = 0.09), suggesting sex-by-genotype interaction on residual variance. We therefore investigated the effect of sex on absolute-transformed residuals in urinary calcium in an F2 GHS WKY mapping cohort. Absolute residuals were associated with genotype at two microsatellites, D3Rat46 (RNO3, 33.9 Mb) and D4Mgh1 (RNO4, 84.8 MB) at Bonferroni thresholds across the entire cohort, and with the microsatellites D3Rat46, D9Mgh2 (RNO9, 84.4 Mb), and D12Rat25 (RNO12, 40.4 Mb) in females (P < 0.05) but not males. In GHS chromosome 1 congenic lines bred onto a WKY genomic background, we found that congenic males had significantly (P < 0.0001) higher CVs for urinary calcium (CV = 0.25) than females (CV = 0.15), supporting the hypothesis of the inheritance of sex-by-genotype interaction on this effect. Our findings suggest that genetic effects on residual variance are sex linked; heritable, sex-specific residuals might have great potential implications for evolution, adaptation, and genetic analysis. PMID:22554889

  2. Ghrelin induces colon cancer cell proliferation through the GHS-R, Ras, PI3K, Akt, and mTOR signaling pathways.

    PubMed

    Lien, Gi-Shih; Lin, Chien-Huang; Yang, You-Lan; Wu, Ming-Shun; Chen, Bing-Chang

    2016-04-01

    Colon cancer is the third most common malignancy worldwide. Recently, some interesting associations between ghrelin and cancer were reported, and it may participate in colon cancer development. In the present report, we explored the role of the growth hormone secretagogue receptor (GHS-R), Ras, phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) pathways in the ghrelin-induced proliferation of human colon cancer cells. Ghrelin-caused HT-29 proliferation was reduced by [D-Lys3]-GHRP-6 (a GHS-R inhibitor). We also found that a dominant negative mutant of Ras (Ras DN), a PI3K inhibitor (LY 294002), an Akt DN, and an mTOR inhibitor (rapamycin) attenuated ghrelin-caused colon cancer cell proliferation. We found that ghrelin induced time-dependent increases in Ras activity. Moreover, ghrelin-mediated Akt Ser473 phosphorylation was attenuated by a Ras DN and LY 294002. Furthermore, a Ras DN, LY 294002, and an Akt DN all inhibited ghrelin-caused mTOR Ser2448 phosphorylation. These results indicate that the Ras/PI3K/Akt/mTOR cascade plays a critical role in ghrelin-induced colon cancer cell proliferation. PMID:26879868

  3. Inotropic and lusitropic effects of ghrelin and their modulation by the endocardial endothelium, NO, prostaglandins, GHS-R1a and KCa channels.

    PubMed

    Soares, João-Bruno; Rocha-Sousa, Amândio; Castro-Chaves, Paulo; Henriques-Coelho, Tiago; Leite-Moreira, Adelino F

    2006-07-01

    Contractile effects of ghrelin (10(-9) to 10(-6) M) were tested in rat papillary muscles of normal (n = 50) and hypertrophic (n = 16) right ventricles (RV). RV hypertrophy was induced by pulmonary hypertension using monocrotaline. In normal muscles, ghrelin was added either alone (n = 9) or after pre-treatment with indomethacin (cycloxygenase inhibitor, 10(-5) M; n = 10), L-nitro-L-arginin (NO synthase inhibitor, 10(-4) M; n = 9), D-Lys(3)-GHRP-6 (GHS-R1a antagonist; 10(-4) M; n = 8) or apamin+charybdotoxin (KCa channels blockers; 10(-6) M, n =7 ), as well as after damaging the endocardial endothelium (n = 7). In hypertrophic muscles, ghrelin was added either alone (n = 9) or after pre-treatment with apamin+charybdotoxin (10(-6 M, n=7). Ghrelin concentration-dependently decreased active tension (AT) and maximal velocity of tension rise (negative inotropic effect), as well as, maximal velocity of tension decay (negative lusitropic effect) and time to AT (onset of relaxation). These effects were maximal at 10(-6) M, similar in normal and hypertrophic muscles and were significantly altered only by apamin+charybdotoxin, indomethacin and L-nitro-L-arginin. Apamin+charybdotoxin attenuated the negative inotropic effect, while indomethacin and L-nitro-L-arginin, respectively, blunted and exacerbated the premature onset of relaxation. In conclusion, ghrelin induces negative inotropic and lusitropic effects and an earlier onset of relaxation in normal and hypertrophic myocardium, which are independent of GHS-R1a, since they were not affected by D-Lys(3)-GHRP-6. The negative inotropic effect is partly mediated by KCa channels, while the earlier onset of relaxation is modulated by prostaglandins and NO. PMID:16417945

  4. A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice.

    PubMed

    Engel, Jörgen A; Nylander, Ingrid; Jerlhag, Elisabet

    2015-12-01

    Gut-brain hormones such as ghrelin have recently been suggested to have a role in reward regulation. Ghrelin was traditionally known to regulate food intake and body weight homoeostasis. In addition, recent work has pin-pointed that this peptide has a novel role in drug-induced reward, including morphine-induced increase in the extracellular levels of accumbal dopamine in rats. Herein the effect of the ghrelin receptor (GHS-R1A) antagonist, JMV2959, on morphine-induced activation of the mesolimbic dopamine system was investigated in mice. In addition, the effects of JMV2959 administration on opioid peptide levels in reward related areas were investigated. In the present series of experiment we showed that peripheral JMV2959 administration, at a dose with no effect per se, attenuates the ability of morphine to cause locomotor stimulation, increase the extracellular levels of accumbal dopamine and to condition a place preference in mice. JMV2959 administration significantly increased tissue levels of Met-enkephalin-Arg(6)Phe(7) in the ventral tegmental area, dynorphin B in hippocampus and Leu-enkephalin-Arg(6) in striatum. We therefore hypothesise that JMV2959 prevents morphine-induced reward via stimulation of delta receptor active peptides in striatum and ventral tegmental areas. In addition, hippocampal peptides that activate kappa receptor may be involved in JMV2959׳s ability to regulate memory formation of reward. Given that development of drug addiction depends, at least in part, of the effects of addictive drugs on the mesolimbic dopamine system the present data suggest that GHS-R1A antagonists deserve to be elucidated as novel treatment strategies of opioid addiction. PMID:26508707

  5. Ghrelin and GHS-R1A signaling within the ventral and laterodorsal tegmental area regulate sexual behavior in sexually naïve male mice.

    PubMed

    Prieto-Garcia, Luna; Egecioglu, Emil; Studer, Erik; Westberg, Lars; Jerlhag, Elisabet

    2015-12-01

    In addition to food intake and energy balance regulation, ghrelin mediate the rewarding and motivational properties of palatable food as well as addictive drugs. The ability of ghrelin to regulate reinforcement involves the cholinergic-dopaminergic reward link, which encompasses a cholinergic projection from the laterodorsal tegmental area (LDTg) to the ventral tegmental area (VTA) together with mesolimbic dopaminergic projections from the VTA to the nucleus accumbens (NAc). Recently, systemic ghrelin was shown to regulate sexual behavior and motivation in male mice via dopamine neurotransmission. The present study therefore elucidates the role of ghrelin and ghrelin receptor (GHS-R1A) antagonist treatment within NAc, VTA or LDTg for sexual behavior in sexually naïve male mice. Local administration of the GHSR-1A antagonist, JMV2959, into the VTA or LDTg was found to reduce the preference for female mice, the number of mounts and the duration of mounting as well as to prolong the latency to mount. This was further substantiated by the findings that ghrelin administration into the VTA or LDTg increased the number of mounts and the duration of mounting and decreased the latency to mount. Moreover, ghrelin administered into the LDTg increased the preference for female mice. Accumbal administration of ghrelin increased whereas GHS-R1A antagonist decreased the intake of palatable food, but did not alter sexual behavior. In males exposed to sexual interaction, systemic administration of ghrelin increases whereas JMV2959 decreases the turnover of dopamine in the VTA. These data suggest that ghrelin signaling within the tegmental areas is required for sexual behavior in sexually naïve male mice. PMID:26398679

  6. Determining the Depth of Injury in Bioengineered Tissue Models of Cornea and Conjunctiva for the Prediction of All Three Ocular GHS Categories

    PubMed Central

    Zorn-Kruppa, Michaela; Houdek, Pia; Wladykowski, Ewa; Engelke, Maria; Bartok, Melinda; Mewes, Karsten R.; Moll, Ingrid; Brandner, Johanna M.

    2014-01-01

    The depth of injury (DOI) is a mechanistic correlate to the ocular irritation response. Attempts to quantitatively determine the DOI in alternative tests have been limited to ex vivo animal eyes by fluorescent staining for biomarkers of cell death and viability in histological cross sections. It was the purpose of this study to assess whether DOI could also be measured by means of cell viability detected by the MTT assay using 3-dimensional (3D) reconstructed models of cornea and conjunctiva. The formazan-free area of metabolically inactive cells in the tissue after topical substance application is used as the visible correlate of the DOI. Areas of metabolically active or inactive cells are quantitatively analyzed on cryosection images with ImageJ software analysis tools. By incorporating the total tissue thickness, the relative MTT-DOI (rMTT-DOI) was calculated. Using the rMTT-DOI and human reconstructed cornea equivalents, we developed a prediction model based on suitable viability cut-off values. We tested 25 chemicals that cover the whole range of eye irritation potential based on the globally harmonized system of classification and labelling of chemicals (GHS). Principally, the MTT-DOI test method allows distinguishing between the cytotoxic effects of the different chemicals in accordance with all 3 GHS categories for eye irritation. Although the prediction model is slightly over-predictive with respect to non-irritants, it promises to be highly valuable to discriminate between severe irritants (Cat. 1), and mild to moderate irritants (Cat. 2). We also tested 3D conjunctiva models with the aim to specifically address conjunctiva-damaging substances. Using the MTT-DOI method in this model delivers comparable results as the cornea model, but does not add additional information. However, the MTT-DOI method using reconstructed cornea models already provided good predictability that was superior to the already existing established in vitro/ex vivo methods. PMID:25494045

  7. Sub-categorisation of skin corrosive chemicals by the EpiSkin™ reconstructed human epidermis skin corrosion test method according to UN GHS: revision of OECD Test Guideline 431.

    PubMed

    Alépée, N; Grandidier, M H; Cotovio, J

    2014-03-01

    The EpiSkin™ skin corrosion test method was formally validated and adopted within the context of OECD TG 431 for identifying corrosive and non-corrosive chemicals. The EU Classification, Labelling and Packaging Regulation (EU CLP) system requires the sub-categorisation of corrosive chemicals into the three UN GHS optional subcategories 1A, 1B and 1C. The present study was undertaken to investigate the usefulness of the validated EpiSkin™ test method to identify skin corrosive UN GHS Categories 1A, 1B and 1C using the original and validated prediction model and adapted controls for direct MTT reduction. In total, 85 chemicals selected by the OECD expert group on skin corrosion were tested in three independent runs. The results obtained were highly reproducible both within (>80%) and between (>78%) laboratories when compared with historical data. Moreover the results obtained showed that the EpiSkin™ test method is highly sensitive (99%) and specific (80%) in discriminating corrosive from non-corrosive chemicals and allows reliable and relevant identification of the different skin corrosive UN GHS subcategories, with high accuracies being obtained for both UN GHS Categories 1A (83%) and 1B/1C (76%) chemicals. The overall accuracy of the test method to subcategorise corrosive chemicals into three or two UN GHS subcategories ranged from 75% to 79%. Considering those results, the revised OECD Test Guideline 431 permit the use of EpiSkin™ for subcategorising corrosive chemicals into at least two classes (Category 1A and Category 1B/1C). PMID:24211528

  8. The Role of Claudin in Hypercalciuric Nephrolithiasis

    PubMed Central

    2013-01-01

    Calcium nephrolithiasis is a common condition. Family-based genetic linkage studies and genome-wide association studies (GWASs) have uncovered a run of important candidate genes involved in renal Ca++ disorders and kidney stone diseases. The susceptible genes include NKCC2, ROMK and ClCkb/Barttin that underlie renal salt excretion; claudin-14, -16 and -19 that underlie renal Ca++ excretion; and CaSR that provides a sensing mechanism for the kidney to regulate salt, water and Ca++ homeostasis. Biological and physiological analyses have revealed the cellular mechanism for transepithelial Ca++ transport in the kidney that depends on the concerted action of these gene products. Although the individual pathogenic weight of the susceptible genes in nephrolithiasis remains unclear, perturbation of their expression or function compromises the different steps within the integrated pathway for Ca++ reabsorption, providing a physiological basis for diagnosing and managing kidney stone diseases. PMID:23180343

  9. Reduced vertebral bone density in hypercalciuric nephrolithiasis

    NASA Technical Reports Server (NTRS)

    Pietschmann, F.; Breslau, N. A.; Pak, C. Y.

    1992-01-01

    Dual-energy x-ray absorptiometry and single-photon absorptiometry were used to determine bone density at the lumbar spine and radial shaft in 62 patients with absorptive hypercalciuria, 27 patients with fasting hypercalciuria, and 31 nonhypercalciuric stone formers. Lumbar bone density was significantly lower in patients with absorptive (-10%) as well as in those with fasting hypercalciuria (-12%), with 74 and 92% of patients displaying values below the normal mean, whereas only 48% of the nonhypercalciuric stone formers had bone density values below the normal mean. In contrast, radial bone density was similar in all three groups of renal stone formers investigated. The comparison of urinary chemistry in patients with absorptive hypercalciuria and low normal bone density compared to those with high normal bone density showed a significantly increased 24 h urinary calcium excretion on random diet and a trend toward a higher 24 h urinary uric acid excretion and a higher body mass index in patients with low normal bone density. Moreover, among the patients with absorptive hypercalciuria we found a statistically significant correlation between the spinal bone density and the 24 h sodium and sulfate excretion and the urinary pH. These results gave evidence for an additional role of environmental factors (sodium and animal proteins) in the pathogenesis of bone loss in absorptive hypercalciuria. In conclusion, our data suggest an osteopenia of trabecular-rich bone tissues in patients with fasting and absorptive hypercalciurias.

  10. The Wnt11 Signaling Pathway in Potential Cellular EMT and Osteochondral Differentiation Progression in Nephrolithiasis Formation

    PubMed Central

    He, Deng; Lu, Yuchao; Hu, Henglong; Zhang, Jiaqiao; Qin, Baolong; Wang, Yufeng; Xing, Shuai; Xi, Qilin; Wang, Shaogang

    2015-01-01

    The molecular events leading to nephrolithiasis are extremely complex. Previous studies demonstrated that calcium and transforming growth factor-β1 (TGF-β1) may participate in the pathogenesis of stone formation, but the explicit mechanism has not been defined. Using a self-created genetic hypercalciuric stone-forming (GHS) rat model, we observed that the increased level of serous/uric TGF-β1 and elevated intracellular calcium in primary renal tubular epithelial cells (PRECs) was associated with nephrolithiasis progression in vivo. In the setting of high calcium plus high TGF-β1 in vitro, PRECs showed great potential epithelial to mesenchymal transition (EMT) progression and osteochondral differentiation properties, representing the multifarious increased mesenchymal and osteochondral phenotypes (Zeb1, Snail1, Col2A1, OPN, Sox9, Runx2) and decreased epithelial phenotypes (E-cadherin, CK19) bythe detection of mRNAs and corresponding proteins. Moreover, TGF-β-dependent Wnt11 knockdown and L-type Ca2+ channel blocker could greatly reverse EMT progression and osteochondral differentiation in PRECs. TGF-β1 alone could effectively promote EMT, but it had no effect on osteochondral differentiation in NRK cells (Rat kidney epithelial cell line). Stimulation with Ca2+ alone did not accelerate differentiation of NRK. Co-incubation of extracellular Ca2+ and TGF-β1 synergistically promotes EMT and osteochondral differentiation in NRK control cells. Our data supplied a novel view that the pathogenesis of calcium stone development may be associated with synergic effects of TGF-β1 and Ca2+, which promote EMT and osteochondral differentiation via Wnt11 and the L-type calcium channel. PMID:26193266

  11. Hypercalciuria: lessons from studies of genetic hypercalciuric rats.

    PubMed

    Favus, M J

    1994-11-01

    Human idiopathic hypercalciuria (IH) is a common cause of hypercalciuria that contributes to calcium oxalate nephrolithiasis. The disorder is characterized by normocalcemia, increased intestinal Ca absorption, and normal or elevated circulating 1,25(OH)2D3. Intestinal Ca hyperabsorption, which is a source of excess urine Ca excretion, may result from either a primary increase in renal 1,25(OH)2D3 production; a primary, vitamin D-independent defect in enterocyte regulation of Ca transport; or a secondary increase in 1,25(OH)2D3 production in response to a defect in renal tubular Ca reabsorption. Breeding male and female Sprague Dawley rats with spontaneous hypercalciuria has resulted in offspring with hypercalciuria, increased intestinal Ca absorption, and normal serum 1,25(OH)2D3. In male IH rats, vitamin D receptor (VDR) content measured by saturation binding and western blotting revealed a twofold increase in VDR number in the duodenum, kidney cortex, and splenic monocytes. The molecular basis for the increase in VDR appears not to be due to increased VDR gene expression, but may result from increased efficiency of translation of the VDR message or prolongation of the half-life of VDR. Comparable migration of normal and IH intestinal VDR on western blots and of intestinal VDR mRNA on northern blots suggests that the abundant VDR in IH rat intestine is not a mutation of the wild-type VDR. These observations strongly suggest that, in IH rats, normal serum 1,25(OH)2D3 and increased VDR results in increased VDR-1,25(OH)2D3 complexes and enhanced biologic actions of 1,25(OH)2D3, including increased intestinal Ca transport. IH in rats may be the first genetic disorder due to a pathologic increase in the VDR. PMID:7873746

  12. Predicting GHS toxicity using RTCA and discrete-time Fourier transform.

    PubMed

    Chen, Jiao; Pan, Tianhong; Pu, Tianqing; Huang, Biao; Huang, Dorothy Yu; Zhang, Weiping; Gabos, Stephan; Jin, Can

    2016-02-01

    In order to promote the acceptance of cell-based toxicity testings, the accuracy of cytotoxicity test must be determined when compared to in vivo results. Traditional methods of cytotoxicity analysis, such as LC[Formula: see text] (concentration where 50% of the cells are killed) can be problematic since they have been found to vary with time. Technological advances in cytotoxicity testing make it easy to record the dynamic data on changes in cell proliferation, morphology, and damage. To effectively and reasonably analyze the dynamic data, we present a new in vitro toxicity assessed method using the discrete-time Fourier transform (DTFT) which maps the measured cell index from the time domain to the frequency domain. The direct current (DC) component of the DTFT is extracted as a feature which reflects the intensity of cytotoxicity. The smaller the value, the higher the cytotoxicity. Then, a novel toxicity index, as expressed in terms of DC[Formula: see text], is calculated. Results generated with selected test chemicals are compared favorably with data obtained from The Interagency Coordinating Committee on the Validation of Alternative Method (ICCVAM) report concerning the prediction of acute systemic toxicity in rodents. The method can be applied with the standard and high throughput to estimate acute rodent oral toxicity which reduces the number of animals required in subsequent pharmacological/toxicological studies. PMID:26708053

  13. Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi Syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of the Snord116 small nucleolar RNA cluster has been identified as the major contributor to PWS symptoms. The Snord116 deletion (Snord116del) mouse model manifested a subset of PWS symptoms ...

  14. Effect of Potassium Citrate on Calcium Phosphate Stones in a Model of Hypercalciuria.

    PubMed

    Krieger, Nancy S; Asplin, John R; Frick, Kevin K; Granja, Ignacio; Culbertson, Christopher D; Ng, Adeline; Grynpas, Marc D; Bushinsky, David A

    2015-12-01

    Potassium citrate is prescribed to decrease stone recurrence in patients with calcium nephrolithiasis. Citrate binds intestinal and urine calcium and increases urine pH. Citrate, metabolized to bicarbonate, should decrease calcium excretion by reducing bone resorption and increasing renal calcium reabsorption. However, citrate binding to intestinal calcium may increase absorption and renal excretion of both phosphate and oxalate. Thus, the effect of potassium citrate on urine calcium oxalate and calcium phosphate supersaturation and stone formation is complex and difficult to predict. To study the effects of potassium citrate on urine supersaturation and stone formation, we utilized 95th-generation inbred genetic hypercalciuric stone-forming rats. Rats were fed a fixed amount of a normal calcium (1.2%) diet supplemented with potassium citrate or potassium chloride (each 4 mmol/d) for 18 weeks. Urine was collected at 6, 12, and 18 weeks. At 18 weeks, stone formation was visualized by radiography. Urine citrate, phosphate, oxalate, and pH levels were higher and urine calcium level was lower in rats fed potassium citrate. Furthermore, calcium oxalate and calcium phosphate supersaturation were higher with potassium citrate; however, uric acid supersaturation was lower. Both groups had similar numbers of exclusively calcium phosphate stones. Thus, potassium citrate effectively raises urine citrate levels and lowers urine calcium levels; however, the increases in urine pH, oxalate, and phosphate levels lead to increased calcium oxalate and calcium phosphate supersaturation. Potassium citrate induces complex changes in urine chemistries and resultant supersaturation, which may not be beneficial in preventing calcium phosphate stone formation. PMID:25855777

  15. The Gene Transfer Agent RcGTA Contains Head Spikes Needed for Binding to the Rhodobacter capsulatus Polysaccharide Cell Capsule.

    PubMed

    Westbye, Alexander B; Kuchinski, Kevin; Yip, Calvin K; Beatty, J Thomas

    2016-01-29

    Viruses and bacteriophages recognize cell surface proteins using receptor-binding proteins. In most tailed bacteriophages, receptor-binding proteins are located on the bacteriophage tail. The gene transfer agent of Rhodobacter capsulatus, RcGTA, morphologically resembles a tailed bacteriophage and binds to a capsular polysaccharide covering R. capsulatus cells. Here, we report that the RcGTA capsid (head) is decorated by spikes that are needed for binding to the capsule. The triangular spikes measured ~12nm and appeared to be attached at the capsid vertices. Head spike production required the putative carbohydrate-binding protein ghsB (rcc01080) previously thought to encode a side tail fiber protein. We found that ghsB is likely co-transcribed with ghsA (rcc01079) and that ghsA/ghsB is regulated by the CckA-ChpT-CtrA phosphorelay homologues and a quorum-sensing system. GhsA and GhsB were found to be CckA-dependent RcGTA maturation factors, as GhsA- and GhsB-deficient particles were found to have altered native-gel electrophoresis migration. Additionally, we provide electron microscopy images showing that RcGTA contains side tail fibers and a baseplate-like structure near the tip of the tail, which are independent of ghsB. PMID:26711507

  16. Development of a Geriatric Scale of Hopelessness: Implications for Counseling and Intervention with the Depressed Elderly.

    ERIC Educational Resources Information Center

    Fry, P. S.

    1984-01-01

    Evaluated hopelessness, depression, and self-esteem among depressed elderly people (N=78) and developed a Geriatric Hopelessness Scale (GHS). As predicted, elderly subjects who scored high on the GHS showed significantly higher depression and lower self-esteem scores. (JAC)

  17. Characteristics of Participants in Australia's Get Healthy Telephone-Based Lifestyle Information and Coaching Service: Reaching Disadvantaged Communities and Those Most at Need

    ERIC Educational Resources Information Center

    O'Hara, Blythe J.; Phongsavan, Philayrath; Venugopal, Kamalesh; Bauman, Adrian E.

    2011-01-01

    To address increasing rates of overweight and obesity, a population-based telephone intervention was introduced in New South Wales, Australia. The Get Healthy Information and Coaching Service[R] (GHS) offered participants a 6-month coaching program or detailed self-help information. Determining the population reach of GHS is of public health…

  18. Thermogenic characterization of ghrelin receptor null mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is the only known circulating orexigenic hormone that increases food intake and promotes adiposity, and these physiological functions of ghrelin are mediated through its receptor growth hormone secretagogue receptor (GHS-R). Ghrelin/GHS-R signaling plays a crucial role in energy homeostasis....

  19. Sequence, genomic organization and expression of ghrelin receptor in grass carp, Ctenopharyngodon idellus.

    PubMed

    Cai, Wen-jing; Yuan, Xiao-chen; Yuan, Yong-chao; Xie, Shou-qi; Gong, Yuan; Su, Hang; Qiao, Yang

    2015-01-01

    The growth hormone secretagogue-receptor (GHS-R) is an endogenous receptor for the gut hormone ghrelin. Here we report the identification and characterization of GHS-R1a in grass carp, Ctenopharyngodon idellus. The full-length GHS-R1a cDNA contained a 1803-bp coding domain sequence which encoded a peptide of 360 amino acid residues. Comparison analysis revealed that the amino acid sequences of GHS-R1a were highly conserved in vertebrates and shared 97% amino acid identity with zebrafish (Danio rerio), 96% with jian carp (Cyprinus carpio var. Jian) and 93% with goldfish (Carassius auratus). The GHS-R1a showed the highest level of mRNA expression in the pituitary, followed by the brain and liver, and the lowest expression was observed in the hindgut. Intraperitoneally injected with grass carp ghrelin (50, 100 and 150ng/g body weight (BW)), grass carp showed greater mRNA expression of GHS-R1a in the pituitary compared with saline injected at 0.5h postinjection. It was observed that food deprivation could promote the expression of ghrelin and GHS-R1a in the pituitary, demonstrating that nutritional status can influence the expression of both ghrelin and GHS-R1a in the pituitary. After a 2- or 4-week fast, plasma growth hormone (GH) increased, was positively correlated with ghrelin and GHS-R1a mRNA expression levels in the pituitary. These results suggested that the involvement of ghrelin/GHS-R1a systems in mediating the effects of nutritional status and ghrelin on growth processes in grass carp. PMID:25242546

  20. Diversification and coevolution of the ghrelin/growth hormone secretagogue receptor system in vertebrates.

    PubMed

    Tine, Mbaye; Kuhl, Heiner; Teske, Peter R; Tschöp, Matthias H; Jastroch, Martin

    2016-04-01

    The gut hormone ghrelin is involved in numerous metabolic functions, such as the stimulation of growth hormone secretion, gastric motility, and food intake. Ghrelin is modified by ghrelin O-acyltransferase (GOAT) or membrane-bound O-acyltransferase domain-containing 4 (MBOAT4) enabling action through the growth hormone secretagogue receptors (GHS-R). During the course of evolution, initially strong ligand/receptor specificities can be disrupted by genomic changes, potentially modifying physiological roles of the ligand/receptor system. Here, we investigated the coevolution of ghrelin, GOAT, and GHS-R in vertebrates. We combined similarity search, conserved synteny analyses, phylogenetic reconstructions, and protein structure comparisons to reconstruct the evolutionary history of the ghrelin system. Ghrelin remained a single-gene locus in all vertebrate species, and accordingly, a single GHS-R isoform was identified in all tetrapods. Similar patterns of the nonsynonymous (dN) and synonymous (dS) ratio (dN/dS) in the vertebrate lineage strongly suggest coevolution of the ghrelin and GHS-R genes, supporting specific functional interactions and common physiological pathways. The selection profiles do not allow confirmation as to whether ghrelin binds specifically to GOAT, but the ghrelin dN/dS patterns are more similar to those of GOAT compared to MBOAT1 and MBOAT2 isoforms. Four GHS-R isoforms were identified in teleost genomes. This diversification of GHS-R resulted from successive rounds of duplications, some of which remained specific to the teleost lineage. Coevolution signals are lost in teleosts, presumably due to the diversification of GHS-R but not the ghrelin gene. The identification of the GHS-R diversity in teleosts provides a molecular basis for comparative studies on ghrelin's physiological roles and regulation, while the comparative sequence and structure analyses will assist translational medicine to determine structure-function relationships of the ghrelin/GHS-R system. PMID:27066235

  1. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors.

    PubMed

    McKee, K K; Palyha, O C; Feighner, S D; Hreniuk, D L; Tan, C P; Phillips, M S; Smith, R G; Van der Ploeg, L H; Howard, A D

    1997-04-01

    GH release is thought to occur under the reciprocal regulation of two hypothalamic peptides, GH releasing hormone (GHRH) and somatostatin, via their engagement with specific cell surface receptors on the anterior pituitary somatotroph. In addition, GH-releasing peptides, such as GHRP-6 and the nonpeptide mimetics, L-692,429 and MK-0677, stimulate GH release through their activation of a distinct receptor, the GH secretagogue receptor (GHS-R). The recent cloning of the GHS-R from human and swine pituitary gland identifies yet a third G protein-coupled receptor (GPC-R) involved in the control of GH release and further supports the existence of an undiscovered hormone that may activate this receptor. Using the human GHS-R as a probe, we report the isolation of a rat pituitary GHS-R cDNA derived from an unspliced, precursor mRNA. The rat cDNA encodes a protein of 364 amino acids containing seven transmembrane domains (7-TM) with >90% sequence identity to both the human and swine GHS-Rs. A single intron of approximately 2 kb divides the open reading frame into two exons encoding TM 1-5 and TM 6-7, thus placing the GHS-R into the intron-containing class of GPC-Rs. The intron maps to the site of sequence divergence between the human and swine type 1a and 1b GHS-R mRNAs. In addition, determination of the nucleotide sequence for the human GHS-R gene confirmed the position of an intron in the human GHS-R gene at this position. A full-length contiguous cDNA from rat hypothalamus was isolated and shown to be identical in its nucleotide and deduced amino acid sequence to the rat pituitary GHS-R. The cloned rat GHS-R binds [35S]MK-0677 with high affinity [dissociation constant (K(D)) = 0.7 nM] and is functionally active when expressed in HEK-293 cells. Expression of the rat GHS-R was observed specifically in the pituitary and hypothalamus when compared with control tissues. PMID:9092793

  2. [The conservative therapy of urolithiasis (author's transl)].

    PubMed

    Matouschek, E; Huber, R

    1979-07-01

    Some common conservative treating methods of urolithiasis are critically discussed. Based on physico-chemical relationships of solubility and cristallisation of stone-forming compounds our own methods of conservative treatment of urolithiasis is presented. PMID:473452

  3. Acute and chronic suppression of the central ghrelin signaling system reveals a role in food anticipatory activity.

    PubMed

    Verhagen, Linda A W; Egecioglu, Emil; Luijendijk, Mieneke C M; Hillebrand, Jacquelien J G; Adan, Roger A H; Dickson, Suzanne L

    2011-05-01

    Using the rodent activity-based anorexia (ABA) model that mimics clinical features of anorexia nervosa that include food restriction-induced hyperlocomotion, we found that plasma ghrelin levels are highly associated with food anticipatory behaviour, measured by running wheel activity in rats. Furthermore, we showed that ghrelin receptor (GHS-R1A) knockout mice do not anticipate food when exposed to the ABA model, unlike their wild type littermate controls. Likewise, food anticipatory activity in the ABA model was suppressed by a GHS-R1A antagonist administered either by acute central (ICV) injection to rats or by chronic peripheral treatment to mice. Interestingly, the GHS-R1A antagonist did not alter food intake in any of these models. Therefore, we hypothesize that suppression of the central ghrelin signaling system via GHS-R1A provides an interesting therapeutic target to treat hyperactivity in patients suffering from anorexia nervosa. PMID:20620030

  4. Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro

    PubMed Central

    Kitazawa, T; De Smet, B; Verbeke, K; Depoortere, I; Peeters, T L

    2005-01-01

    Background and aims: The gastroprokinetic activities of ghrelin, the natural ligand of the growth hormone secretagogue receptor (GHS-R), prompted us to compare the effect of ghrelin with that of synthetic peptide (growth hormone releasing peptide 6 (GHRP-6)) and non-peptide (capromorelin) GHS-R agonists both in vivo and in vitro. Methods: In vivo, the dose dependent effects (1–150 nmol/kg) of ghrelin, GHRP-6, and capromorelin on gastric emptying were measured by the 14C octanoic breath test which was adapted for use in mice. The effect of atropine, NG-nitro-L-arginine methyl ester hydrochloride (l-NAME), or D-Lys3-GHRP-6 (GHS-R antagonist) on the gastroprokinetic effect of capromorelin was also investigated. In vitro, the effect of the GHS-R agonists (1 µM) on electrical field stimulation (EFS) induced responses was studied in fundic strips in the absence and presence of L-NAME. Results: Ghrelin, GHRP-6, and capromorelin accelerated gastric emptying in an equipotent manner, with bell-shaped dose-response relationships. In the presence of atropine or l-NAME, which delayed gastric emptying, capromorelin failed to accelerate gastric emptying. D-Lys3-GHRP-6 also delayed gastric emptying but did not effectively block the action of the GHS-R agonists, but this may be related to interactions with other receptors. EFS of fundic strips caused frequency dependent relaxations that were not modified by the GHS-R agonists. L-NAME turned EFS induced relaxations into cholinergic contractions that were enhanced by ghrelin, GHRP-6, and capromorelin. Conclusion: The 14C octanoic breath test is a valuable technique to evaluate drug induced effects on gastric emptying in mice. Peptide and non-peptide GHS-R agonists accelerate gastric emptying of solids in an equipotent manner through activation of GHS receptors, possibly located on local cholinergic enteric nerves. PMID:15843418

  5. Agonism, Antagonism, and Inverse Agonism Bias at the Ghrelin Receptor Signaling.

    PubMed

    M'Kadmi, Céline; Leyris, Jean-Philippe; Onfroy, Lauriane; Galés, Céline; Saulière, Aude; Gagne, Didier; Damian, Marjorie; Mary, Sophie; Maingot, Mathieu; Denoyelle, Séverine; Verdié, Pascal; Fehrentz, Jean-Alain; Martinez, Jean; Banères, Jean-Louis; Marie, Jacky

    2015-11-01

    The G protein-coupled receptor GHS-R1a mediates ghrelin-induced growth hormone secretion, food intake, and reward-seeking behaviors. GHS-R1a signals through Gq, Gi/o, G13, and arrestin. Biasing GHS-R1a signaling with specific ligands may lead to the development of more selective drugs to treat obesity or addiction with minimal side effects. To delineate ligand selectivity at GHS-R1a signaling, we analyzed in detail the efficacy of a panel of synthetic ligands activating the different pathways associated with GHS-R1a in HEK293T cells. Besides β-arrestin2 recruitment and ERK1/2 phosphorylation, we monitored activation of a large panel of G protein subtypes using a bioluminescence resonance energy transfer-based assay with G protein-activation biosensors. We first found that unlike full agonists, Gq partial agonists were unable to trigger β-arrestin2 recruitment and ERK1/2 phosphorylation. Using G protein-activation biosensors, we then demonstrated that ghrelin promoted activation of Gq, Gi1, Gi2, Gi3, Goa, Gob, and G13 but not Gs and G12. Besides, we identified some GHS-R1a ligands that preferentially activated Gq and antagonized ghrelin-mediated Gi/Go activation. Finally, we unambiguously demonstrated that in addition to Gq, GHS-R1a also promoted constitutive activation of G13. Importantly, we identified some ligands that were selective inverse agonists toward Gq but not of G13. This demonstrates that bias at GHS-R1a signaling can occur not only with regard to agonism but also to inverse agonism. Our data, combined with other in vivo studies, may facilitate the design of drugs selectively targeting individual signaling pathways to treat only the therapeutically relevant function. PMID:26363071

  6. Longer term impact of the mass media campaign to promote the Get Healthy Information and Coaching Service®: increasing the saliency of a new public health program.

    PubMed

    O'Hara, Blythe J; Phongsavan, Philayrath; Gebel, Klaus; Banovic, Debbie; Buffett, Kym M; Bauman, Adrian E

    2014-11-01

    The Get Healthy Information and Coaching Service® (GHS) was introduced in New South Wales in February 2009. It used mass reach media advertising and direct mail and/or proactive marketing to recruit participants. This article reports on the long-term impact of the campaign on GHS participation from July 2011 to June 2012. A stand-alone population survey collected awareness, knowledge, and behavioral variables before the first advertising phase, (n = 1,544, August-September 2010), during the advertising period (n = 1,500, February-March 2011; n = 1,500, June-July 2011; n = 1,500, February 2012), and after the advertising period (n = 1,500, June-July 2012). GHS usage data (n = 6,095) were collated during July 2011-June 2012. Unprompted and prompted awareness of GHS mass media significantly increased (0% to 8.0%, p < .001; and 14.1% to 43.9%, p < .001, respectively) as well as knowledge and perceived effectiveness of the GHS. Those from the lowest three quintiles of socioeconomic disadvantage and respondents who were overweight or obese were significantly more likely to report prompted campaign awareness. The majority (84.4%) of new GHS calls occurred when television advertising was present. Participants who cited mass media as their referral source were significantly more likely to enroll in the intensive coaching program. Mass media campaigns remain an effective method of promoting a telephone-based statewide lifestyle program. PMID:24662895

  7. Characteristics of participants in Australia's Get Healthy telephone-based lifestyle information and coaching service: reaching disadvantaged communities and those most at need.

    PubMed

    O'Hara, Blythe J; Phongsavan, Philayrath; Venugopal, Kamalesh; Bauman, Adrian E

    2011-12-01

    To address increasing rates of overweight and obesity, a population-based telephone intervention was introduced in New South Wales, Australia. The Get Healthy Information and Coaching Service® (GHS) offered participants a 6-month coaching program or detailed self-help information. Determining the population reach of GHS is of public health importance to ensure that the program reaches disadvantaged groups. This paper describes the socio-demographic and risk profile of participants (n = 4828) in the first 18 months of operations, determines how representative they are of the population, assesses changes in participants' socio-demographic profile and compares 'information-only' and 'coaching' participants. The results show that GHS users are representative of the adult population in relation to education, employment status, Aboriginal status, fruit and vegetable consumption and alcohol use. However, more female, middle-aged, English-speaking, rural and socially disadvantaged adults participated in GHS. Coaching Participants were more likely to be overweight and to be ex-smokers than the general population. There was substantial variability in GHS recruitment, when mass-reach television advertising was used, participants enrolled from a major city and from more disadvantaged communities. The GHS has broader population reach than many local interventions, but further efforts are needed to increase reach by Aboriginal communities, other minorities and men. PMID:21987479

  8. The suppression of ghrelin signaling mitigates age-associated thermogenic impairment

    PubMed Central

    Bongmba, Odelia Y. N.; Ma, Xiaojun; Zhu, Xiongwei; Sheikh-Hamad, David; Sun, Yuxiang

    2014-01-01

    Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), attenuates age-associated obesity and insulin resistance. Ghrelin and obestatin are derived from the same preproghrelin gene. Here we showed that in brown adipocytes, ghrelin decreases the expression of thermogenic regulator but obestatin increases it, thus showing the opposite effects. We also found that during aging, plasma ghrelin and GHS-R expression in brown adipose tissue (BAT) are increased, but plasma obestatin is unchanged. Increased plasma ghrelin and unchanged obestatin during aging may lead to an imbalance of thermogenic regulation, which may in turn exacerbate thermogenic impairment in aging. Moreover, we found that GHS-R ablation activates thermogenic signaling, enhances insulin activation, increases mitochondrial biogenesis, and improves mitochondrial dynamics of BAT. In addition, we detected increased norepinephrine in the circulation, and observed that GHS-R knockdown in brown adipocytes directly stimulates thermogenic activity, suggesting that GHS-R regulates thermogenesis via both central and peripheral mechanisms. Collectively, our studies demonstrate that ghrelin signaling is an important thermogenic regulator in aging. Antagonists of GHS-R may serve as unique anti-obesity agents, combating obesity by activating thermogenesis. PMID:25543537

  9. The suppression of ghrelin signaling mitigates age?associated thermogenic impairment.

    PubMed

    Lin, Ligen; Lee, Jong Han; Bongmba, Odelia Y N; Ma, Xiaojun; Zhu, Xiongwei; Sheikh-Hamad, David; Sun, Yuxiang

    2014-12-01

    Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS?R), attenuates age?associated obesity and insulin resistance. Ghrelin and obestatin are derived from the same preproghrelin gene. Here we showed that in brown adipocytes, ghrelin decreases the expression of thermogenic regulator but obestatin increases it, thus showing the opposite effects. We also found that during aging, plasma ghrelin and GHS?R expression in brown adipose tissue (BAT) are increased, but plasma obestatin is unchanged. Increased plasma ghrelin and unchanged obestatin during aging may lead to an imbalance of thermogenic regulation, which may in turn exacerbate thermogenic impairment in aging. Moreover, we found that GHS?R ablation activates thermogenic signaling, enhances insulin activation, increases mitochondrial biogenesis, and improves mitochondrial dynamics of BAT. In addition, we detected increased norepinephrine in the circulation, and observed that GHS?R knockdown in brown adipocytes directly stimulates thermogenic activity, suggesting that GHS?R regulates thermogenesis via both central and peripheral mechanisms.Collectively, our studies demonstrate that ghrelin signaling is an important thermogenic regulator in aging. Antagonists of GHS?R may serve as unique anti?obesity agents, combating obesity by activating thermogenesis. PMID:25543537

  10. Tissue-specific expression of ghrelinergic and NUCB2/nesfatin-1 systems in goldfish (Carassius auratus) is modulated by macronutrient composition of diets.

    PubMed

    Blanco, Ayelén M; Bertucci, Juan I; Delgado, María J; Valenciano, Ana I; Unniappan, Suraj

    2016-05-01

    The macronutrient composition of diets is a very important factor in the regulation of body weight and metabolism. Several lines of research in mammals have shown that macronutrients differentially regulate metabolic hormones, including ghrelin and nesfatin-1 that have opposing effects on energy balance. This study aimed to determine whether macronutrients modulate the expression of ghrelin and the nucleobindin-2 (NUCB2) encoded nesfatin-1 in goldfish (Carassius auratus). Fish were fed once daily on control, high-carbohydrate, high-protein, high-fat and very high-fat diets for 7 (short-term) or 28 (long-term) days. The expression of preproghrelin, ghrelin O-acyl transferase (goat), growth hormone secretagogue receptor 1 (ghs-r1) and nucb2/nesfatin-1 mRNAs was quantified in the hypothalamus, pituitary, gut and liver. Short-term feeding with fat-enriched diets significantly increased nucb2 mRNA levels in hypothalamus and liver, preproghrelin, goat and ghs-r1 expression in pituitary, and ghs-r1 expression in gut. Fish fed on a high-protein diet exhibited a significant reduction in preproghrelin and ghs-r1 mRNAs in the liver. After long-term feeding, fish fed on high-carbohydrate and very high-fat diets had significantly increased preproghrelin, goat and ghs-r1 expression in pituitary. Feeding on a high-carbohydrate diet also upregulated goat and ghs-r1 transcripts in gut, while feeding on a high-fat diet elicited the same effect only for ghs-r1 in liver. Nucb2 expression increased in pituitary, while it decreased in gut after long-term feeding of a high-protein diet. Collectively, these results show for the first time in fish that macronutrients differentially regulate the expression of ghrelinergic and NUCB2/nesfatin-1 systems in central and peripheral tissues of goldfish. PMID:26805937

  11. Ghrelin Receptor in Two Species of Anuran Amphibian, Bullfrog (Rana catesbeiana), and Japanese Tree Frog (Hyla japonica)

    PubMed Central

    Kaiya, Hiroyuki; Koizumi, Yasushi; Konno, Norifumi; Yamamoto, Kazutoshi; Uchiyama, Minoru; Kangawa, Kenji; Miyazato, Mikiya

    2011-01-01

    We have identified cDNA encoding a functional growth hormone secretagogue-receptor 1a (GHS-R1a, ghrelin receptor) in two species of anuran amphibian, the bullfrog (Rana catesbeiana), and the Japanese tree frog (Hyla japonica). Deduced receptor protein for bullfrog and Japanese tree frog (tree frog) was comprised of 374- and 371-amino acids, respectively. The two receptors shared 86% identity, and are grouped to the clade of the tetrapod homologs by phylogenetic analysis. In functional analyses, ghrelin and GHS-R1a agonists increased intracellular Ca2+ concentration in GHS-R1a-transfected-HEK293 cell, but ligand selectivity of ghrelin with Ser3 and Thr3 was not observed between the two receptors. Bullfrog GHS-R1a mRNA was mainly expressed in the brain, stomach, and testis. In the brain, the gene expression was detected in the diencephalon and mesencephalon, but not in the pituitary. Tree frog GHS-R1a mRNA was predominantly expressed in the gastrointestinal tract and ovary, but not detected in the pituitary. In bullfrog stomach but not the brain, GHS-R1a mRNA expression increased after 10 days of fasting. For tree frog, GHS-R1a mRNA expression was increased in the brain, stomach and ventral skin by 10 days of fasting, and in the stomach and ventral skin by a dehydration treatment. Intracerebroventricular injection of ghrelin in dehydrated tree frog did not affect water absorption from the ventral skin. These results suggest that ghrelin is involved in energy homeostasis and possibly in osmoregulation in frogs. PMID:22654801

  12. Combined vitamin D and calcium supplementation in vitamin D inadequate patients with urolithiasis: Impact on hypercalciuria and de novo stone formation

    PubMed Central

    Hesswani, Charles; Noureldin, Yasser A.; Elkoushy, Mohamed A.; Andonian, Sero

    2015-01-01

    Introduction: We examined the effect of combined vitamin D and calcium supplementation (VDCS) on urinary calcium excretion and de novo stone formation in vitamin D inadequate (VDI) urolithiasis patients. Methods: We retrospectively reviewed the data of VDI patients (serum 25-hydroxyvitamin D <75 nmol/L) followed at a tertiary stone centre between September 2009 and December 2014. VDI patients with history of urolithiasis, who were placed on VDCS for abnormal bone mineral density or hyperoxaluria, were included. Hypercalciuric patients and patients on thiazide diuretics were excluded. Metabolic stone workup and two 24-hour urine collections were performed before and after VDCS. Results: In total, we included 34 patients, with a mean age of 54.8 years and a mean body mass index of 25.7 kg/m2. After VDCS, there was a significant increase in the mean serum 25-hydroxyvitamin D (52.0 vs. 66.4 nmol/L, p < 0.001) and the mean urinary calcium excretion (3.80 vs. 5.64 mmol/d, p < 0.001). Eight (23.5%) patients developed de novo hypercalciuria. After a median follow-up of 39 (range: 7–60) months, 50% of hypercalciuric patients developed stones compared with 11.5% of non-hypercalciuric patients (p = 0.038). Conclusion: This study showed a significant effect of combined VDCS on mean urinary calcium excretion, de novo hypercalciuria, and stone development in VDI patients with history of urolithiasis. Therefore, VDI urolithiasis patients receiving VDCS are advised to have monitoring with 24-hour urine collections and imaging studies. Although small, our sample size was good enough to validate the statistical outcomes. Prospective studies are needed to confirm these results. PMID:26788229

  13. Of Mice and Men: Experimental Induction of Calcium Oxalate Nephrolithiasis in Mice

    PubMed Central

    Khan, Saeed R.; Glenton, Patricia A.

    2013-01-01

    Purpose Availability of various transgenic and knockout mice provides an excellent opportunity to better understand the pathophysiology of calcium oxalate (CaOx) stone disease. However attempts to produce CaOx nephrolithiasis in mice have not been very successful. We have hypothesized that CaOx nephrolithiasis in mice requires increasing the urinary excretion of calcium as well as oxalate and that experimentally induced hyperoxaluria alone is not sufficient. To provide evidence we induced hyperoxaluria by administering hyperoxaluria inducing agents to normocalciuric as well as hypercalciuric mice and investigated various aspects of nephrolithiasis. Materials and Methods Ethylene glycol (EG), glyoxylate (GOx) or hydroxyl proline (HLP) were administered through diet to male and female normocalciuric B6 mice as well as hypercalciuric Npt2a −/− mice for 4 weeks. 24 hour urine samples were collected on 0.3,7,14,21 and 28 days and analyzed for pH, creatinine, lactate dehydrogensae (LDH) calcium and oxalate. Kidneys were examined using light microscopy. Urine was examined for crystals using both light and scanning electron microscopy. Results Hypercalciuric mice on HLP did not tolerate the treatment and had to be sacrificed before 28 days. All mice receiving EG, GOx or HLP became hyperoxaluric and demonstrated CaOx crystalluria. None of the female mice, normo or hypercalciuric developed renal CaOx crystal deposits. All mice on Gox and some on EG developed CaOx nephrolithiais. Kidneys of all mice showed epithelial injury. Male mice particularly on GOx showed more renal injury and migration of inflammatory cells into the interstitium around the crystal deposits. Conclusions Results confirm that induction of hyperoxaluria alone is not sufficient for CaOx nephrolithiais in mice. Hypercalciuria is also required. Kidneys of male mice are more prone to injury than those of female mice and are susceptible to CaOx crystal deposition. Perhaps epithelial injury promotes crystal retention. Thus CaOx nephrolithiais in mice is gender dependent and requires both hypercalciuria and hyperoxaluria. PMID:20663521

  14. Inferred gas hydrate and permafrost stability history models linked to climate change in the Beaufort-Mackenzie Basin, Arctic Canada

    NASA Astrophysics Data System (ADS)

    Majorowicz, J.; Safanda, J.; Osadetz, K.

    2012-03-01

    Atmospheric methane from episodic gas hydrate (GH) destabilization, the "clathrate gun" hypothesis, is proposed to affect past climates, possibly since the Phanerozoic began or earlier. In the terrestrial Beaufort-Mackenzie Basin (BMB), GHs occur commonly below thick ice-bearing permafrost (IBP), but they are rare within it. Two end-member GH models, where gas is either trapped conventionally (Case 1) or where it is trapped dynamically by GH formation (Case 2), were simulated using profile (1-D) models and a 14 Myr ground surface temperature (GST) history based on marine isotopic data, adjusted to the study setting, constrained by deep heat flow, sedimentary succession conductivity, and observed IBP and Type I GH contacts in Mallik wells. Models consider latent heat effects throughout the IBP and GH intervals. Case 1 GHs formed at ~0.9 km depth only ~1 Myr ago by in situ transformation of conventionally trapped natural gas. Case 2 GHs begin to form at ~290-300 m ~6 Myr ago in the absence of lithological migration barriers. During glacial intervals Case 2 GH layers expand both downward and upward as the permafrost grows downward through and intercalated with GHs. The distinctive model results suggest that most BMB GHs resemble Case 1 models, based on the observed distinct and separate occurrences of GHs and IBP and the lack of observed GH intercalations in IBP. Case 2 GHs formed >255 m, below a persistent ice-filled permafrost layer that is as effective a seal to upward methane migration as are Case 1 lithological seals. All models respond to GST variations, but in a delayed and muted manner such that GH layers continue to grow even as the GST begins to increase. The models show that the GH stability zone history is buffered strongly by IBP during the interglacials. Thick IBP and GHs could have persisted since ~1.0 Myr ago and ~4.0 Myr ago for Cases 1 and 2, respectively. Offshore BMB IBP and GHs formed terrestrially during Pleistocene sea level low stands. Where IBP is sufficiently thick, both IBP and GHs persist even where inundated by a Holocene sea level rise and both are also expected to persist into the next glacial even if atmospheric CO2 doubles. We do not address the "clathrate gun" hypothesis directly, but our models show that sub-IBP GHs respond to, rather than cause GST changes, due to both how GST changes propagates with depth and latent heat effects. Models show that many thick GH accumulations are prevented from contributing methane to the atmosphere, because they are almost certainly trapped below either ice-filled IBP or lithological barriers. Where permafrost is sufficiently thick, combinations of geological structure, thermal processes and material properties make sub-IBP GHs unlikely sources for significant atmospheric methane fluxes. Our sub-IBP GH model histories suggest that similar models applied to other GH settings could improve the understanding of GHs and their potential to affect climate.

  15. Taking two to tango: a role for ghrelin receptor heterodimerization in stress and reward

    PubMed Central

    Schellekens, Harriët; Dinan, Timothy G.; Cryan, John F.

    2013-01-01

    The gut hormone, ghrelin, is the only known peripherally derived orexigenic signal. It activates its centrally expressed receptor, the growth hormone secretagogue receptor (GHS-R1a), to stimulate food intake. The ghrelin signaling system has recently been suggested to play a key role at the interface of homeostatic control of appetite and the hedonic aspects of food intake, as a critical role for ghrelin in dopaminergic mesolimbic circuits involved in reward signaling has emerged. Moreover, enhanced plasma ghrelin levels are associated with conditions of physiological stress, which may underline the drive to eat calorie-dense “comfort-foods” and signifies a role for ghrelin in stress-induced food reward behaviors. These complex and diverse functionalities of the ghrelinergic system are not yet fully elucidated and likely involve crosstalk with additional signaling systems. Interestingly, accumulating data over the last few years has shown the GHS-R1a receptor to dimerize with several additional G-protein coupled receptors (GPCRs) involved in appetite signaling and reward, including the GHS-R1b receptor, the melanocortin 3 receptor (MC3), dopamine receptors (D1 and D2), and more recently, the serotonin 2C receptor (5-HT2C). GHS-R1a dimerization was shown to affect downstream signaling and receptor trafficking suggesting a potential novel mechanism for fine-tuning GHS-R1a receptor mediated activity. This review summarizes ghrelin's role in food reward and stress and outlines the GHS-R1a dimer pairs identified to date. In addition, the downstream signaling and potential functional consequences of dimerization of the GHS-R1a receptor in appetite and stress-induced food reward behavior are discussed. The existence of multiple GHS-R1a heterodimers has important consequences for future pharmacotherapies as it significantly increases the pharmacological diversity of the GHS-R1a receptor and has the potential to enhance specificity of novel ghrelin-targeted drugs. PMID:24009547

  16. Exhumation of the Greater Himalayan Sequence Along the Zanskar Shear Zone, NW India

    NASA Astrophysics Data System (ADS)

    Basta, S.; Beck, E.; Burlick, T.

    2013-12-01

    The Zanskar Shear Zone (ZSZ), the western extent of the South Tibetan Detachment System, exposes high-grade metamorphic rocks of the Greater Himalayan Sequence (GHS) in its footwall. Granites and metapelites collected along the the ZSZ in the Suru River valley provide how and when the GHS rocks exhumed and were deformed. There are two suits of Paleozoic granites deformed within the ZSZ: Pan-African Cambrian-Ordovician granites at the cores of gneiss domes and Mississippian-Permian granites related to Panjal Traps magmatism. Age of Himalayan granites indicates 28-16 Ma which is concurrent with anatectic leucogranite crystallization. The metamorphic mineral assemblage indicates increasing metamorhic grade from NE to SW and comprises Qtz × Kfs + Pl + Bt × Ms × Sil × Ky × Grt × St × Chl × Tur × Rt. In addition to macroscopic evidence, strongly deformed quartz grains, deformation twins, pressure shadows, and kink bands have been observed to demonstrate micro-tectonics evidence. There are two different method to explain exhumation and deformation of the GHS metapelites: Electron backscatter diffraction (EBSD) crystallographic mapping and pseudosection modeling. While EBSD indicates the potential temperature of deformation, pseudosection modeling with Perple_X specifically presents the exhumation path of the GHS rocks. Pseudosection modeling with Perple_X , based on whole-rock geochemical analysis, is set pressure and temperature to 0.4-1.2 GPa and 300-900°C, and uses specific solution models, Bio(TCC), Chl(HP), St(HP), feldspar, Mica(CHA), Gt(HP), and hCrd, namely. These two methods are used by combining with geo/thermochronology data from U-Pb, 40Ar/39Ar, and (U-Th)/He, constraining the age of metamorphism, the cooling and exhumation time of the GHS rocks, and the end of shearing of deformation, respectively. 40Ar/39Ar dating on muscovite and biotite constrains cooling and exhumation ages of the GHS as ~20-19 Ma and 15 Ma, respectively. A metamorphic pressure-temperature-time-deformation (P-T-t-d) history of the GHS rocks, generated in the light of these combining data using multi methods, fills gaps in data to understand tectonic and metamorphic evolution of the GHS rocks, deformed within the ZSZ, in the Suru River valley which has less-clarified data compared to the eastern part of the GHS.

  17. Ghrelin receptor in Japanese fire belly newt, Cynops pyrrhogaster.

    PubMed

    Kaiya, Hiroyuki; Kangawa, Kenji; Miyazato, Mikiya

    2015-11-01

    We identified cDNA encoding a functional ghrelin receptor (growth hormone secretagogue-receptor 1a (GHS-R1a)) in a urodele amphibian, the Japanese fire belly newt (Cynops pyrrhogaster). Two functional receptor proteins, composed of 378- and 362-amino acids, were deduced from the identified cDNA because two candidate initiation methionine sites were found. The long-chain receptor protein shared 80%, 69%, and 59% identities with the bullfrog GHS-R1a, human GHS-R1a and tilapia GHS-R1a-like receptor, respectively. Phylogenetic analysis suggested that the newt receptor is grouped to the clade of the tetrapod homologs, and very closed to anuran amphibians. In functional analyses, homologous newt ghrelin, heterologous bullfrog and rat ghrelin, and a GHS-R1a agonist, GHRP-6 increased intracellular Ca(2+) concentration in human embryonic kidney (HEK) 293 cells stably expressed newt GHS-R1a. The responsiveness was much greater in the short-chain receptor than in the long-chain receptor. Both receptors preferred to bind Ser(3)-ghrelin including newt and rat ghrelin than Thr(3)-ghrelin with bullfrog ghrelin. GHRP-6 has a similar affinity to bullfrog ghrelin. GHS-R1a mRNA was expressed in the brain, pituitary, intestine, pancreas, testis and fat body with high level, and eyes, heart, stomach, liver, gall bladder, kidney and dorsal skin with low level. In a fasting experiment, gene expression of GHS-R1a in the brain and pituitary increased 4days after fasting, and the increased level decreased to the initial level 2weeks after fasting. These changes are consistent with the change in ghrelin mRNA. In contrast, expression of ghrelin and GHS-R1a mRNA in the stomach decreased on day 4 after fasting, and increased 2weeks after fasting. These results indicate that ghrelin and its receptor system are present and altered by energy states in this newt. PMID:26172570

  18. Thermodynamic Relationships with Processivity in Serratia marcescens Family 18 Chitinases.

    PubMed

    Hamre, Anne Grethe; Jana, Suvamay; Holen, Matilde Mengkrog; Mathiesen, Geir; Väljamäe, Priit; Payne, Christina M; Sørlie, Morten

    2015-07-30

    The enzymatic degradation of recalcitrant polysaccharides is accomplished by synergistic enzyme cocktails of glycoside hydrolases (GHs) and accessory enzymes. Many GHs are processive which means that they remain attached to the substrate in between subsequent hydrolytic reactions. Chitinases are GHs that catalyze the hydrolysis of chitin (β-1,4-linked N-acetylglucosamine). Previously, a relationship between active site topology and processivity has been suggested while recent computational efforts have suggested a link between the degree of processivity and ligand binding free energy. We have investigated these relationships by employing computational (molecular dynamics (MD)) and experimental (isothermal titration calorimetry (ITC)) approaches to gain insight into the thermodynamics of substrate binding to Serratia marcescens chitinases ChiA, ChiB, and ChiC. We show that increased processive ability indeed corresponds to more favorable binding free energy and that this likely is a general feature of GHs. Moreover, ligand binding in ChiB is entropically driven; in ChiC it is enthalpically driven, and the enthalpic and entropic contributions to ligand binding in ChiA are equal. Furthermore, water is shown to be especially important in ChiA-binding. This work provides new insight into oligosaccharide binding, getting us one step closer to understand how GHs efficiently degrade recalcitrant polysaccharides. PMID:26154587

  19. Ghrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus

    PubMed Central

    Ribeiro, Luís F.; Catarino, Tatiana; Santos, Sandra D.; Benoist, Marion; van Leeuwen, J. Fiona; Esteban, José A.; Carvalho, Ana Luísa

    2014-01-01

    Ghrelin is a peptide mainly produced by the stomach and released into circulation, affecting energy balance and growth hormone release. These effects are guided largely by the expression of the ghrelin receptor growth hormone secretagogue type 1a (GHS-R1a) in the hypothalamus and pituitary. However, GHS-R1a is expressed in other brain regions, including the hippocampus, where its activation enhances memory retention. Herein we explore the molecular mechanism underlying the action of ghrelin on hippocampal-dependent memory. Our data show that GHS-R1a is localized in the vicinity of hippocampal excitatory synapses, and that its activation increases delivery of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic-type receptors (AMPARs) to synapses, producing functional modifications at excitatory synapses. Moreover, GHS-R1a activation enhances two different paradigms of long-term potentiation in the hippocampus, activates the phosphatidylinositol 3-kinase, and increases GluA1 AMPAR subunit and stargazin phosphorylation. We propose that GHS-R1a activation in the hippocampus enhances excitatory synaptic transmission and synaptic plasticity by regulating AMPAR trafficking. Our study provides insights into mechanisms that may mediate the cognition-enhancing effect of ghrelin, and suggests a possible link between the regulation of energy metabolism and learning. PMID:24367106

  20. Analysis of the comprehensibility of chemical hazard communication tools at the industrial workplace.

    PubMed

    Ta, Goh Choo; Mokhtar, Mazlin Bin; Mohd Mokhtar, Hj Anuar Bin; Ismail, Azmir Bin; Abu Yazid, Mohd Fadhil Bin Hj

    2010-01-01

    Chemical classification and labelling systems may be roughly similar from one country to another but there are significant differences too. In order to harmonize various chemical classification systems and ultimately provide consistent chemical hazard communication tools worldwide, the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) was endorsed by the United Nations Economic and Social Council (ECOSOC). Several countries, including Japan, Taiwan, Korea and Malaysia, are now in the process of implementing GHS. It is essential to ascertain the comprehensibility of chemical hazard communication tools that are described in the GHS documents, namely the chemical labels and Safety Data Sheets (SDS). Comprehensibility Testing (CT) was carried out with a mixed group of industrial workers in Malaysia (n=150) and factors that influence the comprehensibility were analysed using one-way ANOVA. The ability of the respondents to retrieve information from the SDS was also tested in this study. The findings show that almost all the GHS pictograms meet the ISO comprehension criteria and it is concluded that the underlying core elements that enhance comprehension of GHS pictograms and which are also essential in developing competent persons in the use of SDS are training and education. PMID:20616463

  1. Ghrelin receptor regulates adipose tissue inflammation in aging

    PubMed Central

    Buras, Eric D.; Yu, Kaijiang; Wang, Ruitao; Smith, C. Wayne; Wu, Huaizhu; Sheikh-Hamad, David; Sun, Yuxiang

    2016-01-01

    Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr−/− mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsr−/− mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsr−/− mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance. PMID:26837433

  2. Genetic control of the humoral immune response to avian egg white lysozymes in the chicken

    SciTech Connect

    Flanagan, M.P.

    1987-01-01

    Chickens from two closely related sublines, GHs-B6 and GHs-B13, differing serologically at the major histocompatibility complex, were significantly different in their humoral response to three avian egg white lysozymes. Specific antisera levels were measured by radioimmunoassay using /sup 125/I-labeled lysozymes. Antibodies elicited in response to these lysozymes are assumed to be directed against sites on these lysozymes where their amino acid sequence differs from that of the recipient G. domesticus egg white lysozyme (HEL). GHs-B6 birds produced a high level of antibody in response to immunization of turkey (TEL), pheasant (PhL) and guinea hen (GHL) lysozymes. GHs-B13 birds produced no detectable antibody to TEL, were intermediate in their response to PhL and equaled the antibody production of GHs-B6 birds in response to GHL. Antisera to each lysozyme were examined for crossreactivity with all other lysozymes by use of a competitive binding assay.

  3. Telescoping of isotherms beneath the South Tibetan Detachment System, Mount Everest Massif

    NASA Astrophysics Data System (ADS)

    Law, R. D.; Jessup, M. J.; Searle, M. P.; Francsis, M. K.; Waters, D. J.; Cottle, J. M.

    2011-11-01

    Petrologic and microstructural/crystal fabric data indicate that isotherms recorded in Greater Himalayan Series (GHS) schists and gneisses in the footwall to the South Tibetan Detachment System (STDS) have undergone extreme telescoping during penetrative flow associated with southward extrusion of the GHS. In the Rongbuk Valley, to the north of Mount Everest, we have made three vertical sampling traverses from the STDS down into the GHS and estimated temperatures associated with penetrative deformation using the opening angles of quartz c-axis fabrics measured on dynamically recrystallized grains. From north to south, the deformation temperature data indicate apparent thermal field gradients of 369, 385 and 420 °C per km for our three traverses, traced over a maximum vertical sampling distance of 0.5 km. Adopting a differential flow path model, simple geometric analysis using sections drawn parallel to the local transport direction indicates that detachment-parallel transport magnitudes of 25-170 km are needed to explain the extreme telescoping of isotherms in the immediate footwall to the STDS, depending on assumed original geothermal gradient, dip of detachment, etc. These particle transport estimates are similar to those previously calculated from barometry data of GHS rocks in the Everest region and are compatible with channel flow models for extrusion and exhumation of the GHS.

  4. Growth hormone secretagogues and ghrelin: an update on physiology and clinical relevance.

    PubMed

    Petersenn, S

    2002-01-01

    The pulsatile release of growth hormone (GH) by the anterior pituitary is stimulated by small synthetic molecules termed GH secretagogues (GHS). The receptor for GHS (GHS-R) belongs to the family of G-protein-coupled receptors. An endogenous specific ligand of 28 amino acids has recently been purified from rat stomach, it has been termed 'ghrelin'. Ghrelin demonstrates potent and reproducible GH-releasing activity, as well as significant prolactin-, ACTH- and cortisol-releasing activity. However, its major physiological relevance may relate to energy homeostasis. Peripheral daily administration of ghrelin caused weight gain by reducing fat utilization in mice and rats. In man, intravenous ghrelin was shown to stimulate food intake. The pathophysiological role and the potential clinical use of ghrelin are reviewed. PMID:12435899

  5. Towards a molecular-level theory of carbohydrate processivity in glycoside hydrolases.

    PubMed

    Beckham, Gregg T; Ståhlberg, Jerry; Knott, Brandon C; Himmel, Michael E; Crowley, Michael F; Sandgren, Mats; Sørlie, Morten; Payne, Christina M

    2014-06-01

    Polysaccharide depolymerization in nature is primarily accomplished by processive glycoside hydrolases (GHs), which abstract single carbohydrate chains from polymer crystals and cleave glycosidic linkages without dissociating after each catalytic event. Understanding the molecular-level features and structural aspects of processivity is of importance due to the prevalence of processive GHs in biomass-degrading enzyme cocktails. Here, we describe recent advances towards the development of a molecular-level theory of processivity for cellulolytic and chitinolytic enzymes, including the development of novel methods for measuring rates of key steps in processive action and insights gained from structural and computational studies. Overall, we present a framework for developing structure-function relationships in processive GHs and outline additional progress towards developing a fundamental understanding of these industrially important enzymes. PMID:24863902

  6. Using mass-media communications to increase population usage of Australia’s Get Healthy Information and Coaching Service®

    PubMed Central

    2012-01-01

    Background Global obesity prevalence is increasing and population health programs are required to support changes to modifiable lifestyle risk factors. Such interventions benefit from mass-communications to promote their use. The Get Healthy Information and Coaching Service ® (GHS) utilised mass-reach media advertising to recruit participants to an Australian state-wide program. Methods A stand alone population survey collected awareness, knowledge and behavioural variables before the first advertising phase, (n = 1,544; August -September 2010), during (n = 1,500; February - March 2011) and after the advertising period (n = 1,500; June-July 2011). GHS usage data (n = 6,375) was collated during July 2010 – June 2011. Results The results showed that television-lead mass-media significantly increased unprompted awareness (0% to 31.8%, p < 0.001); prompted awareness (2.5% to 23.7%, p < 0.001); and understanding (10.2% to 32.2%, p < 0.001). Mass-media (television, print and mail out information) was more often cited as the source of referral by males, those aged 18 – 49 years, employed, and from the lowest socio-economic groups. During the weeks when mass-media advertising was present, 4 and 2.5 times more information and coaching participants respectively registered than when there was no advertising present. Participants who cited television and print were less likely to enrol in GHS coaching, but this was not the case for mail out information and secondary referral sources. Conclusions GHS mass-communications campaigns are effective at increasing awareness and usage of the GHS, especially among hard-to-reach population groups. Television advertising provides universal reach, but should be supplemented by health professional referrals and targeted mail-out information to recruit participants to the intensive GHS coaching program. PMID:22967230

  7. Constraints on brittle field exhumation of the Everest-Makalu section of the Greater Himalayan Sequence: Implications for models of crustal flow

    NASA Astrophysics Data System (ADS)

    Streule, Michael J.; Carter, Andrew; Searle, Michael P.; Cottle, John M.

    2012-06-01

    New apatite and zircon fission track (FT) data from the summit slopes of Everest and along the Barun, Arun, Dudh Kosi, and Kangshung valleys that drain the Everest and Makalu massifs cover a vertical sample transect of almost 8000 m of the Eastern Nepal Greater Himalayan Sequence (GHS). Apatite FT ages range from 0.9 ± 0.3 Ma to 3.1 ± 0.3 Ma in the GHS with ages increasing systematically with elevation. Apatite FT ages in the Everest Series and summit Ordovician limestones are much older, up to 30.5 ± 5.1 Ma. Zircon FT ages from the GHS range from 3.8 ± 0.4 Ma to 16.3 ± 0.8 Ma. The brittle exhumation rates calculated from these data show the GHS was exhumed, since ˜9 Ma, at an average rate of 1.0 ± 0.2 mm/a. Pliocene exhumation rates are higher at 1.7 ± 0.3 mm/a. These values are not significantly different from the estimate of ductile exhumation rates of 1.8 mm/a recorded by metamorphic minerals undergoing decompression between 18.7 and 15.6 Ma but are well below the values (up to 10 mm/a) used by thermomechanical models for ductile channel flow in the GHS. If representative of the GHS these models will therefore require further `tuning'. Higher exhumation rates in the Pliocene have also been observed in other parts of the Himalaya and points to a regional cause, likely increased erosion due to the onset of late Pliocene-Pleistocene glaciation of the high Himalaya.

  8. Identification and localization of gastrointestinal hormones in the skin of the bullfrog Rana catesbeiana during periods of activity and hibernation.

    PubMed

    Wang, Huan; Zhou, Naizhen; Zhang, Rui; Wu, Yuanyuan; Zhang, Ruidong; Zhang, Shengzhou

    2014-10-01

    Amphibian skin and its secretions contain a wide variety of biogenic amines and biologically active peptides, some of which are either identical or highly homologous to gastrointestinal hormones (GHs) of higher vertebrates. This study investigated the distribution density and immunoreactive (IR) intensity of 5-hydroxytryptamine (5-HT), gastrin (GAS), somatostatin (SS), pancreatic polypeptide (PP), neuropeptide Y (NPY) and glucagon (GLU) IR cells in the skin of the bullfrog Rana catesbeiana during periods of activity and hibernation. The results indicated that the six types of GHs were all present in the bullfrog skin and were most predominant in the epidermis and mucous glands. In dorsal skin, the density of the GHs-IR cells in mucous glands was higher than that in epidermis except for GAS-IR cells. In ventral skin, the density of 5-HT, PP and NPY-IR cells in mucous glands was also higher than that in the epidermis. During hibernation, the density of the six types of GHs-IR cells and the IR intensity of GAS, SS, NPY and GLU-IR cells in the epidermis of dorsal skin increased significantly. The IR intensity of SS, PP and NPY-IR cells in granular glands of ventral skin also increased significantly during hibernation. These results suggested that multiple types of GHs-IR cells present in the skin of R. catesbeiana, may play important roles in the regulation of the physiological functions of skin. Also, adaptive changes in the density and IR intensity of GHs-IR cells occurred during hibernation. PMID:25440532

  9. Design and characterization of a fluorescent ghrelin analog for imaging the growth hormone secretagogue receptor 1a.

    PubMed

    McGirr, Rebecca; McFarland, Mark S; McTavish, Jillian; Luyt, Leonard G; Dhanvantari, Savita

    2011-12-10

    Ghrelin is a 28-amino acid peptide hormone produced in the stomach. It binds to the growth hormone secretagogue receptor 1a (GHS-R1a), a class A G-protein-coupled receptor. In the present study, we describe the design, synthesis and characterization of a truncated, 18-amino acid analog of ghrelin conjugated to a fluorescent molecule, fluorocein isothiocyanate (FITC), through the addition of a lysine at its C terminus ([Dpr(octanoyl)(3), Lys(fluorescein)(19)]ghrelin(1-19)). Receptor binding affinity of this novel fluorescein-ghrelin(1-18) was similar to that of wild-type ghrelin and a synthetic GHS-R1a ligand, hexarelin. Live cell imaging in CHO/GHS-R1a cells demonstrated cell surface receptor labeling and internalization, and agonist activity of fluorescein-ghrelin(1-18) was confirmed by increased phosphorylation of ERK1/2. We also show that GHS-R1a protein is expressed primarily in the heart when compared to all other organs, suggesting high receptor density in the left ventricle. Finally, we demonstrate that fluorescein-ghrelin(1-18) binds specifically to heart tissue in situ, and its binding is displaced by both wt ghrelin and hexarelin. We have therefore developed a novel imaging probe, fluorescein-ghrelin(1-18), that can be used to image GHS-R1a in situ, for the purposes of investigating mechanisms of receptor trafficking or pharmacological agents that target GHS-R1a. PMID:21893106

  10. Comparison of the domain of validity of several approximate surface scatter theories

    NASA Astrophysics Data System (ADS)

    Choi, Narak; Harvey, James E.

    2012-10-01

    A new generalized Harvey-Shack (GHS) surface scatter theory is numerically compared to the classical small perturbation method (SPM), the Kirchhoff approximation method (KM) and the rigorous method of moment (MoM) for one-dimensional ideally conducting surfaces whose surface power spectral density function is Gaussian or abc-function. In spite of its simple analytic form, our numerical comparison shows that the new GHS theory is valid (with reasonable accuracy) over a broader range of surface parameter space than either of the two classical surface scatter theories.

  11. Episodic exhumation of the Greater Himalayan Sequence since the Miocene constrained by fission track thermochronology in Nyalam, central Himalaya

    NASA Astrophysics Data System (ADS)

    Wang, An; Garver, John I.; Wang, Guocan; Smith, Jacqueline A.; Zhang, Kexin

    2010-12-01

    The Greater Himalayan Sequence (GHS), which makes up the core of the Himalayan orogen, has an uppermost tectonic contact defined by the South Tibetan Detachment System (STDS) and a lower tectonic contact defined by the Main Central Thrust (MCT). The GHS occurs as one of the most important tectostratigraphic units for deciphering processes related to tectonic and climatic exhumation across the orogen. Zircon and apatite fission track (ZFT, AFT) dating were carried out along a transect in Nyalam, central Himalaya in southern Tibet to constrain cooling driven by orogenic process since the middle Miocene. The hanging wall of the STDS yields an essentially unreset Jurassic ZFT age in the Jurassic strata. However, below the STDS within the GHS there is a clear and distinct thermal signal of cooling related to exhumation. In the footwall and within the GHS, the rocks have ZFT ages of middle Miocene to Pliocene, and AFT ages of late Miocene to Quaternary that get younger downward and away from the STDS. In combination with thermal structure modeling, a two-part episodic model, which is widely compatible with existing thermochronological data, is proposed for cooling and exhumation of the GHS since the middle Miocene: [1] middle Miocene; and [2] Pliocene to Quaternary (Recent). The middle Miocene cooling is suggested to have resulted from a rapid tectonic unroofing by down-to-the-north slip on the STDS. The tectonic exhumation was also recorded by several other thermochronological systems (e.g. biotite 40Ar/ 39Ar) with concordant middle Miocene cooling ages in different structural positions across the GHS. Post middle Miocene ZFT and AFT cooling ages in the lower part of the GHS suggest accelerated cooling by climate-enhanced erosional exhumation, which was initiated in the late Miocene to Pliocene and was dramatic in the Quaternary to Recent. Thermochronological data and modeling further imply that the present Himalayan topographic front may have been shaped essentially by surface erosion since the late Miocene, when the Himalayan divide might have been some 20-30 km to the south of its present position. However, these data do not preclude the possibility that the intense erosional exhumation may have triggered rock uplift to approach and/or maintain a steady topography in the GHS.

  12. Identifying the Himalayan Hinterland-Foreland Transition in Central Nepal

    NASA Astrophysics Data System (ADS)

    Larson, K. P.; Godin, L.; Price, R. A.

    2008-12-01

    Recumbent isoclinal folds and orogen transport direction-parallel stretching lineations indicative of extending flow commonly characterize orogenic hinterlands. Strain preserved in orogenic forelands, in contrast, is typified by thrust faulting and related folding characteristic of compressing flow. Exhumed mid-crustal rocks exposed in central Nepal, which are mapped as part of the Greater Himalayan sequence (GHS), record a progressive, multi-stage metamorphic and deformation history. The GHS comprises material in the hanging wall of the Main Central thrust (MCT), here mapped at the base of Tertiary pervasive deformation and metamorphism. In the study area the GHS is separated into two distinct tectonometamorphic domains. Metamorphism and deformation of the migmatitic upper domain is interpreted to have occurred synchronously at ca. 20 Ma. Metamorphic depth estimates define an apparent field gradient of 62 MPa/km, twice that expected for pelitic gneiss density. The distorted pressure field gradient of the upper domain is interpreted to reflect post-metamorphic vertical thinning. Assuming plane strain conditions, as indicated by petrofabric data, vertical thinning of the GHS would have been paired with horizontal stretching. In contrast, metamorphism and strain in the lower domain is diachronous, younging away from the migmatitic core toward the MCT. The lower domain is interpreted to comprise thrust slices added to the hanging wall of the MCT while the fault migrated downward structurally beneath the base of the migmatitic rocks after ca. 20 Ma. The net effect of the migration of the MCT was to vertically thicken and horizontally shorten the GHS. The vertical thinning and horizontal stretching of the upper domain of the GHS indicates hinterland-style extending flow. In contrast, the vertical thickening and horizontal shortening of the lower domain of the GHS is more typical of compressing flow commonly observed in foreland regions. The transition between the upper and lower domains, therefore, represents the change from hinterland-style deformation to foreland-style deformation as the mid-crustal material was extruded laterally from the back of the Himalayan orogenic wedge. The identification of the Himalayan hinterland-foreland transition may serve to reconcile some of the current contrasting interpretations of the GHS.

  13. Dominant simple-shear deformation during peak metamorphism for the lower portion of the Greater Himalayan Sequence in West Nepal: New implications for hybrid channel flow-type mechanisms in the Dolpo region

    NASA Astrophysics Data System (ADS)

    Frassi, Chiara

    2015-12-01

    I conducted new vorticity and deformation temperatures studies to test competing models of the exhumation of the mid-crustal rocks exposed in the Dolpo region (West Nepal). My results indicate that the Main Central Thrust is located ˜5 km structurally below the previous mapped locations. Deformation temperature increasing up structural section from ˜450 °C to ˜650 °C and overlap with peak metamorphic temperature indicating that penetrative shearing was responsible for the exhumation of the GHS occurred at "close" to peak metamorphic conditions. I interpreted the telescoping and the inversion of the paleo-isotherms at the base of the GHS as produced mainly by a sub-simple shearing (Wm = 0.88-1) pervasively distributed through the lower portion of the GHS. My results are consistent with hybrid channel flow-type models where the boundary between lower and upper portions of the GHS, broadly corresponding to the tectonometamorphic discontinuity recently documented in west Nepal, represents the limit between buried material, affected by dominant simple shearing, and exhumed material affected by a general flow dominates by pure shearing. This interpretation is consistent with the recent models suggesting the simultaneous operation of channel flow- and critical wedge-type processes at different structural depth.

  14. 75 FR 12718 - Hazard Communication; Meetings Notice

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-17

    ... Communication Standard in Washington, DC; Pittsburgh, PA; and Los Angeles, CA (74 FR 68756). OSHA will hold the... Classification and Labelling of Chemicals (GHS) (74 FR 50280). OSHA published a correction notice for the Notice of Proposed Rulemaking (NPRM) on November 5, 2009 (74 FR 57278). The deadline for submitting...

  15. Physiological roles revealed by ghrelin and ghrelin receptor deficient mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is a hormone made in the stomach and known primarily for its growth hormone releasing and orexigenic properties. Nevertheless, ghrelin through its receptor, the GHS-R1a, has been shown to exert many roles including regulation of glucose homeostasis, memory & learning, food addiction and neur...

  16. Ghrelin receptor regulates appetite and satiety during aging in mice by regulating meal frequency and portion size but not total food intake

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aging is often associated with overweight and obesity. There exists a long-standing debate about whether meal pattern also contributes to the development of obesity. The orexigenic hormone ghrelin regulates appetite and satiety by activating its receptor, growth hormone secretagogue receptor (GHS-R)...

  17. 49 CFR 172.401 - Prohibited labeling.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Recommendations (IBR, see § 171.7 of this subchapter); (2) The IMDG Code (IBR, see § 171.7 of this subchapter); (3) The ICAO Technical Instructions (IBR, see § 171.7 of this subchapter); (4) The TDG Regulations (IBR... Chemicals (GHS) (IBR, see § 171.7 of this subchapter). (d) The provisions of paragraph (a) of this...

  18. Ghrelin: much more than a hunger hormone

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is a multifaceted gut hormone that activates its receptor, growth hormone secretagogue receptor (GHS-R). Ghrelin's hallmark functions are its stimulatory effects on growth hormone release, food intake and fat deposition. Ghrelin is famously known as the 'hunger hormone'. However, ample recen...

  19. Requirement of central ghrelin signaling for alcohol reward

    PubMed Central

    Jerlhag, Elisabet; Egecioglu, Emil; Landgren, Sara; Salomé, Nicolas; Heilig, Markus; Moechars, Diederik; Datta, Rakesh; Perrissoud, Daniel; Dickson, Suzanne L.; Engel, Jörgen A.

    2009-01-01

    The stomach-derived hormone ghrelin interacts with key CNS circuits regulating energy balance and body weight. Here we provide evidence that the central ghrelin signaling system is required for alcohol reward. Central ghrelin administration (to brain ventricles or to tegmental areas involved in reward) increased alcohol intake in a 2-bottle (alcohol/water) free choice limited access paradigm in mice. By contrast, central or peripheral administration of ghrelin receptor (GHS-R1A) antagonists suppressed alcohol intake in this model. Alcohol-induced locomotor stimulation, accumbal dopamine release and conditioned place preference were abolished in models of suppressed central ghrelin signaling: GHS-R1A knockout mice and mice treated with 2 different GHS-R1A antagonists. Thus, central ghrelin signaling, via GHS-R1A, not only stimulates the reward system, but is also required for stimulation of that system by alcohol. Our data suggest that central ghrelin signaling constitutes a potential target for treatment of alcohol-related disorders. PMID:19564604

  20. Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference

    PubMed Central

    Egecioglu, Emil; Dickson, Suzanne L.; Engel, Jörgen A.

    2010-01-01

    Introduction Recently we demonstrated that genetic or pharmacological suppression of the central ghrelin signaling system, involving the growth hormone secretagogue receptor 1A (GHS-R1A), lead to a reduced reward profile from alcohol. As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine. Results We found that amphetamine—as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist. Moreover, the ability of these drugs to condition a place preference was also attenuated by the GHS-R1A antagonist. Conclusions Thus GHS-R1A appears to be required not only for alcohol-induced reward, but also for reward induced by psychostimulant drugs. Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence. PMID:20559820

  1. Twisting of glycosidic bonds by hydrolases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Patterns of scissile bond twisting have been found in crystal structures of glycoside hydrolases (GHs) that are complexed with substrates and inhibitors. To estimate the increased potential energy in the substrates that results from this twisting, we have plotted torsion angles for the scissile bond...

  2. The suppression of ghrelin signaling mitigates age-associated thermogenic impairment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), attenuates age-associated obesity and insulin resistance. Ghrelin and obestatin are ...

  3. An integrated testing strategy for in vitro skin corrosion and irritation assessment using SkinEthic™ Reconstructed Human Epidermis.

    PubMed

    Alépée, Nathalie; Grandidier, Marie-Hélène; Tornier, Carine; Cotovio, José

    2015-10-01

    The SkinEthic™ Reconstructed Human Epidermis (RHE) method has been formally adopted for the regulatory assessment of skin irritation (OECD TG 439) and corrosion (OECD TG 431). Recently, the OECD adopted an Integrated Approach on Testing and Assessment (IATA) for skin corrosion and skin irritation (OECD GD 203), which provides guidance on the integration of existing and new information in a modular approach for classification and labelling. The present study aimed to evaluate the use of the SkinEthic™ RHE model within the proposed OECD IATA. Data on 86 substances were integrated in a bottom-up and top-down testing strategy to assess their capacity for EU CLP and UN GHS classifications. For EU CLP, strategies showed an accuracy of 84.8% to discriminate non-classified from classified substances, 94.4% to discriminate corrosive from non-corrosive substances, and 68.5% to discriminate the four (sub)-categories. For UN GHS, strategies showed an accuracy of 89.5% to discriminate non-classified from classified substances, 93.4% to discriminate corrosive from non-corrosive substances, and 74.2% to discriminate four GHS (sub)-categories (excluding Category 3). In conclusion, the integration of SkinEthic™ RHE irritation and corrosion data in a bottom-up and top-down testing strategy allows the classification of substances according to EU CLP and UN GHS. PMID:26187475

  4. Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is a hallmark of aging in many Western societies, and is a precursor to numerous serious age-related diseases. Ghrelin ("Ghrl"), via its receptor (growth hormone secretagogue receptor, GHS-R), is shown to stimulate GH secretion and appetite. Surprisingly, our previous studies showed that "Gh...

  5. Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin and the ghrelin receptor (GH secretagogue receptor, GHS-R) are believed to have important roles in energy homeostasis. We describe results from the first studies to be conducted in congenic (N10) adult ghrelin(-/-) and Ghsr(-/-) mice under conditions of both positive (high-fat diet) and nega...

  6. Methane Hydrate Dissociation and Gas Seepage on Global Upper Continental Slopes Driven by Intermediate Ocean Warming

    NASA Astrophysics Data System (ADS)

    Ruppel, C. D.; Weber, T.; Kessler, J. D.; Pohlman, J.; Skarke, A. D.

    2014-12-01

    Evidence suggests that the short-term temporal pattern of seafloor gas emissions may be largely driven by tidal/barometric pressure fluctuations. However, thermal perturbations in the overlying intermediate waters are a key factor leading to gas hydrate dissociation that liberates methane to feed cold seeps near the updip limit of gas hydrate stability (GHS) on upper continental slopes. Over the past 5 years, studies have documented temperature-driven methane release at intraseasonal to century-long timescales on the West Spitsbergen margin. Our data on the US Arctic margin show that bottom water temperature (BWT) perturbations over ~2.5 months cause the theoretical updip GHS limit to migrate ~1.5 km upslope, a level of dynamism that may manifest as the observed elevated methane concentrations over the upper slope. Given the documented decades-long increase in oceanic heat content due to global warming, it is not surprising that evidence is emerging that upper slope hydrate dissociation is a global, not merely arctic, phenomenon. On the northern US Atlantic margin, most of the ~600 newly-discovered methane seeps mapped between Cape Hatteras and Georges Bank occur on the upper continental slope near the updip limit of GHS (505-575 m). A BWT database based on ~35,000 CTD casts reveals subtle along-margin variations in the theoretical updip GHS limit and first-order agreement with the observed onset of seepage. Other historical datasets provide evidence for short-term BWT variations of >1ºC on the upper slope. Hudson Canyon, the largest US Atlantic margin shelf-break canyon, has reversing current patterns that amplify short-term BWT variations, making this location an apt laboratory for study of possible gas hydrate degradation processes. Hudson Canyon surveys conducted in 2014 identified dozens more seeps than the ~50 described in Skarke et al. (Fall Meeting 2013), particularly at the updip limit of GHS At this depth, CTDs show that BWTs were initially within GHS conditions and had warmed outside the GHS limit in <2 days. Such rapid BWT fluctuations have important implications for the upper slope gas hydrate dynamics, variations in the amount of previously-sequestered methane available for release at seeps, and periodic clogging and re-opening of seep conduits as gas hydrate forms and breaks down.

  7. Th-Pb Monazite-in-Garnet Ages From the Greater Himalayan Sequence of Central Nepal

    NASA Astrophysics Data System (ADS)

    Gehrels, G.; Decelles, P.; Martin, A.

    2007-12-01

    431 new Th-Pb ages have been determined from rocks of the Greater Himalayan Sequence (GHS) of central Nepal. Some of these ages are reported by Martin et al. (2007, Chem. Geol.), most have not been reported previously. 42 samples were collected from transects along Kali Gandaki, Modi Khola, Seti Nadi, Madi Nadi, Nayu Ridge, and Marsyangdi Nadi in the Annapurna region, with three transects extending across the GHS and three transects concentrated near the base of the sequence. Garnet crystals were extracted from the samples, and monazite inclusions were identified by BSE imaging and then analyzed by LA-MC-ICPMS with a 10 micron laser beam. Where possible, inclusions were sampled from both cores and rims of the garnet crystals. The resulting ages belong to four groups: (1) 3 ages (all cores) between 801 Ma and 1407 Ma that are inherited from GHS protoliths, (2) 42 ages (all cores) from 550 Ma to 400 Ma (peak age of 487 Ma) that record early Paleozoic prograde metamorphism, (3) 102 ages (nearly all cores) scattered between 400 Ma and ~50 Ma that are interpreted as early Paleozoic grains which have experienced either Pb loss or overgrowth of Tertiary monazite, and (4) 284 ages (2/3 cores, 1/3 rims) between ca. 50 Ma and ca. 10 Ma, with cores only slightly (avg of 1.5 m.y.) older than rims. The Tertiary ages consistently young northward/upsection from ca. 35 to ca. 18 Ma, and in Marsyangdi Nadi define two separate panels that are interpreted to be imbricated along a north-dipping thrust fault. This fault is near the base of sillimanite-bearing rocks, similar to the Langtang thrust (Kohn et al. 2005, JMG), and may be partly responsible for the inverted metamorphic gradient discussed by many previous workers. Our preferred structural scenario is that the Tertiary monazite ages record progressive burial of the GHS by shortening in the Tethyan thrust belt between ca. 35 and ca. 18 Ma, termination of this metamorphism due to onset of motion along the MCT, and ca. 10 Ma imbrication of the GHS along the fault described above. This fault operated either as an out-of-sequence south-vergent thrust that merges with the MCT to the north, or a south- dipping backthrust that formed the roof of a south-vergent tectonic wedge of GHS. Argon-muscovite cooling ages in GHS and upper Lesser Himalayan rocks are consistent with either scenario, but geological evidence favors the second explanation.

  8. From cessation of south-directed mid-crust extrusion to onset of orogen-parallel extension, NW Nepal Himalaya

    NASA Astrophysics Data System (ADS)

    Nagy, Carl

    Field mapping and, structural, microstructural, and chronological analyses confirm the existence of a segment of the Gurla-Mandhata-Humla fault, an orogen-parallel strike-slip dominated shear zone in the upper Karnali valley of northwestern Nepal. This shear zone forms the upper contact of, and cuts obliquely across the Greater Himalayan Sequence (GHS). Data from this study reveal two phases of GHS deformation. Phase 1 is characterized by U-Th-Pb monazite crystallization ages (˜26--12 Ma, peak ˜18--15 Ma), consistent with typical Neohimalayan metamorphic ages, and the final stages of south-directed extrusion of the GHS. Phase 2 is characterized by south-dipping high-strain foliations and intensely developed ESE-WNW trending, shallowly plunging mineral elongation lineations, indicating orogen-parallel extension. Thermochronology of muscovite defining these fabrics implies that the area was cooling and experiencing orogen-parallel extension by ˜15--9 Ma. Mineral deformation mechanisms and quartz c-axis patterns of these fabrics record a rapid increase in temperature from ˜350°C along the shear zone, to ˜650°C at ˜2.5 structural km below the shear zone. Such temperature gradients may be remnants of telescoped and/or flattened isotherms generated during south-directed extrusion of the GHS. Overprinting ESE-WNW fabrics record progressive deformation of the GHS at lower temperatures. Progressive deformation included a significant component of pure shear, as indicated by symmetric high-temperature quartz c-axis fabrics and a lower-temperature vorticity estimate (˜59% pure shear). A transition in c-axis fabrics from type I to type II cross-girdles at ˜ 1.2 km below the fault could indicate a transition from plane strain towards constriction. Together, these data suggest orogen-parallel extension was occurring as a result of transtension. This study reveals a transition from south-directed extrusion of the GHS to orogen-parallel extension between ˜15--13 Ma. Comparing these data with tectonic events across the Himalaya reveals an orogen-wide middle Miocene transition, coeval with the uplift of eastern Tibet. This is consistent with interpretations invoking radial spreading of Tibet and east-directed lower-crustal flow to explain orogen-parallel extension. Our study leads to the suggestion that a transition affecting mid- to lower-crustal processes may be responsible for the cessation of south-directed extrusion of the GHS and onset of east-directed lower-crustal flow.

  9. Kinematic evolution, metamorphism, and exhumation of the Greater Himalayan Series, Sutlej River and Zanskar regions of NW India

    NASA Astrophysics Data System (ADS)

    Stahr, Donald William, III

    The Himalayan orogen provides a natural laboratory to test models of orogenic development due to large-scale continental collision. The Greater Himalayan Series (GHS), a lithotectonic unit continuous along the entire length of the belt, comprises the metamorphic core of the Himalayan orogen and underlies the highest topography. GHS rocks are exposed as a moderately northdipping slab bounded below by the Main Central Thrust (MCT) and above by the South Tibetan Detachment System (STDS) of normal faults. Coeval reverse- and normal-sense motion on the crustal-scale MCT and STDS ductile shear zones allows the GHS to be modeled as an extruded wedge or channel of mid-crustal material. Due to this unique tectonic setting, the deformation path of rocks within the bounding shear zones and throughout the core of the GHS profoundly influences the efficiency of extrusion and exhumation processes. Attempts to quantify GHS deformation and metamorphic evolution have provided significant insight into Himalayan orogenic development, but these structural and petrologic studies are often conducted in isolation. Penetrative deformation fabrics developed under mid-upper amphibolite facies conditions within the GHS argue that deformation and metamorphism were coupled, and this should be considered in studies aimed at quantifying GHS teconometamorphic evolution. This work focuses on two projects related to the coupled deformation, thermal and metamorphic evolution during extrusion and exhumation of the GHS, focused on the lower and upper margins of the slab. A detailed examination of the P--T history of a schist collected from within the MCT zone of the Sutlej River, NW India, provides insight into the path experienced by these rocks as they traveled through the crust in response to the extreme shortening related to India-Asia collision. Combined forward thermodynamic and diffusion modeling indicates compositional zoning preserved in garnet has remained unmodified since growth and can be related directly to the P--T--X evolution of rocks from this zone. Classic porphyroblast-matrix relationships coupled with the above models provide a structural framework within which to interpret the microstructures and provide additional constraints on the relative timing of metamorphic and deformation events. A combined microstructural and quartz petrofabric study of rocks from the highest structural levels of the GHS in the Zanskar region was completed. This work provides the first quantitative estimate of temperatures attending normal-sense shearing along the Zanskar Shear Zone, the westernmost strand of the STDS. Results indicate penetrative top-N (extensional) deformation occurred at elevated temperatures and resulted in the telescoping of isothermal surfaces present during shearing and extrusion of GHS rocks. Simple geometric models invoking heterogeneous simple shear parallel to the overlying detachment require dip-slip displacement magnitudes on the order of 15--40 km, identical to estimates derived from nearby barometric analyses. Finally, focus is given to the rotational behavior of rigid inclusions suspended in a flowing viscous matrix from a theoretical perspective. Predictions of clast rotational behavior have been used to construct several kinematic vorticity estimation techniques that have become widely adopted for quantitative studies of naturally deformed rocks. Despite the popularity of the techniques, however, basic questions regarding clast-based analyses remain open. Therefore a numerical model was constructed and a systematic investigation of 2- and 3D clasts suspended in steady and non-steady plane-strain flows was undertaken to determine likely sources of error and the intrinsic strengths and limitations of the techniques.

  10. Interactions of growth hormone secretagogues and growth hormone-releasing hormone/somatostatin.

    PubMed

    Tannenbaum, G S; Bowers, C Y

    2001-02-01

    The class of novel synthetic compounds termed growth hormone secretagogues (GHSs) act in the hypothalamus through, as yet, unknown pathways. We performed physiologic and histochemical studies to further understand how the GHS system interacts with the well-established somatostatin (SRIF)/growth hormone-releasing hormone (GHRH) neuroendocrine system for regulating pulsatile GH secretion. Comparison of the GH-releasing activities of the hexapeptide growth hormone-releasing peptide-6 (GHRP-6) and GHRH administered intravenously to conscious adult male rats showed that the pattern of GH responsiveness to GHRP-6 was markedly time-dependent, similar to that observed with GHRH. Immunoneutralization of endogenous SRIF reversed the blunted GH response to GHRP-6 at trough times, suggesting that GHRP-6 neither disrupts nor inhibits the cyclical release of endogenous hypothalamic SRIF. By striking contrast, passive immunization with anti-GHRH serum virtually obliterated the GH responses to GHRP-6, irrespective of the time of administration. These findings suggest that the GHSs do not act by altering SRIF release but, rather, stimulate GH release via GHRH-dependent pathways. Our dual chromogenic and autoradiographic in situ hybridization experiments revealed that a subpopulation of GHRH mRNA-containing neurons in the arcuate (Arc) nucleus and ventromedial nucleus (VMN) of the hypothalamus expressed the GHS receptor (GHS-R) gene. These results provide strong anatomic evidence that GHSs may directly stimulate GHRH release into hypophyseal portal blood, and thereby influence GH secretion, through interaction with the GHS-R on GHRH- containing neurons. Altogether, these findings support the notion that an additional neuroendocrine pathway may exist to regulate pulsatile GH secretion, possibly through the influence of the newly discovered GHS natural peptide, ghrelin. PMID:11322498

  11. Hazard Classification of Household Chemical Products in Korea according to the Globally Harmonized System of Classification and labeling of Chemicals

    PubMed Central

    2013-01-01

    Objectives This study was conducted to review the validity of the need for the application of the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) to household chemical products in Korea. The study also aimed to assess the severity of health and environmental hazards of household chemical products using the GHS. Methods 135 products were classified as ‘cleaning agents and polishing agents’ and 98 products were classified as ‘bleaches, disinfectants, and germicides.’ The current status of carcinogenic classification of GHS and carcinogenicity was examined for 272 chemical substances contained in household chemical products by selecting the top 11 products for each of the product categories. In addition, the degree of toxicity was assessed through analysis of whether the standard of the Republic of Korea’s regulations on household chemical products had been exceeded or not. Results According to GHS health and environmental hazards, “acute toxicity (oral)” was found to be the highest for two product groups, ‘cleaning agents and polishing agents’, and ‘bleaches, disinfectants, and germicides’ (result of classification of 233 household chemical products) at 37.8% and 52.0% respectively. In an analysis of carcinogenicity assuming a threshold of IARC 2B for the substances in household chemical products, we found ‘cleaning agents and polishing agents’ to contain 12 chemical substances and ‘bleaches, disinfectants, and germicides’ 11 chemical substances. Conclusion Some of the household chemical products were found to have a high hazard level including acute toxicity and germ cell mutagenicity, carcinogenicity, and reproductive toxicity. Establishing a hazard information delivery system including the application of GHS to household chemical products in Korea is urgent as well. PMID:24472347

  12. Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues.

    PubMed

    Lin, Ligen; Saha, Pradip K; Ma, Xiaojun; Henshaw, Iyabo O; Shao, Longjiang; Chang, Benny H J; Buras, Eric D; Tong, Qiang; Chan, Lawrence; McGuinness, Owen P; Sun, Yuxiang

    2011-12-01

    Aging is associated with increased adiposity in white adipose tissues and impaired thermogenesis in brown adipose tissues; both contribute to increased incidences of obesity and type 2 diabetes. Ghrelin is the only known circulating orexigenic hormone that promotes adiposity. In this study, we show that ablation of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) improves insulin sensitivity during aging. Compared to wild-type (WT) mice, old Ghsr(-/-) mice have reduced fat and preserve a healthier lipid profile. Old Ghsr(-/-) mice also exhibit elevated energy expenditure and resting metabolic rate, yet have similar food intake and locomotor activity. While GHS-R expression in white and brown adipose tissues was below the detectable level in the young mice, GHS-R expression was readily detectable in visceral white fat and interscapular brown fat of the old mice. Gene expression profiles reveal that Ghsr ablation reduced glucose/lipid uptake and lipogenesis in white adipose tissues but increased thermogenic capacity in brown adipose tissues. Ghsr ablation prevents age-associated decline in thermogenic gene expression of uncoupling protein 1 (UCP1). Cell culture studies in brown adipocytes further demonstrate that ghrelin suppresses the expression of adipogenic and thermogenic genes, while GHS-R antagonist abolishes ghrelin's effects and increases UCP1 expression. Hence, GHS-R plays an important role in thermogenic impairment during aging. Ghsr ablation improves aging-associated obesity and insulin resistance by reducing adiposity and increasing thermogenesis. Growth hormone secretagogue receptor antagonists may be a new means of combating obesity by shifting the energy balance from obesogenesis to thermogenesis. PMID:21895961

  13. ‘Get Healthy, Stay Healthy’: protocol for evaluation of a lifestyle intervention delivered by text-message following the Get Healthy Information and Coaching Service®

    PubMed Central

    2014-01-01

    Background Behavioural lifestyle interventions can be effective at promoting initial weight loss and supporting physical activity and dietary behaviour change, however maintaining improvements in these outcomes is often more difficult to achieve. Extending intervention contact to reinforce learnt behavioural skills has been shown to improve maintenance of behaviour change and weight loss. This trial aims to evaluate the feasibility, acceptability and efficacy of a text message-delivered extended contact intervention to enhance or maintain change in physical activity, dietary behaviour and weight loss among participants who have completed a six month Government-funded, population-based telephone coaching lifestyle program: the Get Healthy Information and Coaching Service (GHS). Methods/Design GHS completers will be randomised to the 6-month extended contact intervention (Get Healthy, Stay Healthy, GHSH) or a no contact control group (standard practice following GHS completion). GHSH participants determine the timing and frequency of the text messages (3–13 per fortnight) and content is tailored to their behavioural and weight goals and support preferences. Two telephone tailoring calls are made (baseline, 12-weeks) to facilitate message tailoring. Primary outcomes, anthropometric (body weight and waist circumference via self-report) and behavioural (moderate-vigorous physical activity via self-report and accelerometer, fruit and vegetable intake via self-report), will be assessed at baseline (at GHS completion), 6-months (end of extended contact intervention) and 12-months (6-months post intervention contact). Secondary aims include evaluation of: the feasibility of program delivery; the acceptability for participants; theoretically-guided, potential mediators and moderators of behaviour change; dose-responsiveness; and, costs of program delivery. Discussion Findings from this trial will inform the delivery of the GHS in relation to the maintenance of behaviour change and weight loss, and will contribute to the broader science of text message lifestyle interventions delivered in population health settings. Trial registration ACTRN12613000949785 PMID:24495781

  14. Claudins and the Kidney Volume 75: Annual Review of Physiology

    PubMed Central

    Hou, Jianghui; Rajagopal, Madhumitha; Yu, Alan S. L.

    2013-01-01

    Claudins are tight junction membrane proteins that regulate paracellular permeability of renal epithelia to small ions, solutes and water. Claudins interact within the cell membrane and between neighboring cells to form tight junction strands and constitute both the paracellular barrier and pore. The first extracellular domain of claudins is thought to be the pore-lining domain and contains the determinants of charge selectivity. Multiple claudins are expressed in different nephron segments and this likely determines the permeability properties of each segment. Recent evidence has identified claudin-2 as constituting the cation-reabsorptive pathway in the proximal tubule, claudin-14, -16 and -19 as forming a complex that regulates calcium transport in the thick ascending limb of the loop of Henle, and claudin-4, -7 and -8 as determinants of collecting duct choride permeability. Mutations in claudin-16 and -19 cause familial hypercalciuric hypomagnesemia. The roles of other claudins in kidney diseases remain to be fully elucidated. PMID:23140368

  15. Function and Regulation of Claudins in the Thick Ascending Limb of Henle

    PubMed Central

    Günzel, Dorothee; Yu, Alan S. L.

    2008-01-01

    SUMMARY The thick ascending limb of Henle mediates transcellular reabsorption of NaCl while generating a lumen-positive voltage that drives passive paracellular reabsorption of divalent cations. Disturbance of paracellular reabsorption leads to Ca2+ and Mg2+ wasting in patients with the rare inherited disorder of familial hypercalciuric hypomagnesemia with nephrocalcinosis (FHHNC). Recent work has shown that the claudin family of tight junction proteins form paracellular pores and determine the ion selectivity of paracellular permeability. Importantly, FHHNC has been found to be caused by mutations in two of these genes, claudin-16 and -19, and mice with knockdown of claudin-16 reproduce many of the features of FHHNC. Here, we review the physiology of TAL ion transport, present the current view of the role and mechanism of claudins in determining paracellular permeability, and discuss the possible pathogenic mechanisms responsible for FHHNC. PMID:18795318

  16. A Transect Across the Greater Himalayan Sequence of Bhutan: Evidence for a Minimum of 10 Ma of Ductile Flow Between the Outer South Tibetan Detachment and the Main Central Thrust

    NASA Astrophysics Data System (ADS)

    Daniel, C. G.; Kim, Y.; Grujic, D.; Hollister, L. S.

    2011-12-01

    Unique features of the Bhutan Himalaya are klippen of Tethyan sediments that overlie sillimanite and kyanite gneisses of the Greater Himalayan Sequence (GHS). The contact is strongly sheared, and referred to as the Outer South Tibetan Detachment (O-STD). Five such klippen are preserved in Bhutan and give insight into the Miocene displacement (ca. 24-11 Ma) of the STD system and on the evolution of the uppermost GHS. The base of the klippen are characterized by strongly sheared Grt-Bt±St±Sil schists of the Chekha Formation that appear to grade continuously upward into the black slates and weakly- to unmetamorphosed rocks of the Tethyan Sedimentary Sequence (TSS). Leucogranites intrude the Chekha Fm and the GHS in the vicinity of the contact, but not the TSS. New metamorphic, structural and geochronologic data from the western side of the Tang Chu klippe show that deformation and metamorphism within the Chekha Fm. were underway prior to 17.6 Ma, and that ductile shearing clearly overprints peak metamorphic mineral assemblages and continued until after 14 Ma. These data, when combined with previously reported data from adjacent klippen and the Main Central Thrust Zone to the south, provide a record of fairly continuous ductile flow of the GHS between 25-23 Ma and 13-11 Ma, at which point displacement transfers north of the klippen, to the Kakhtang thrust and the Inner-STD. Samples for this study were collected along a 10 km traverse and include four samples of Chekha Fm. and two samples of GHS collected across an ~ 80 m structural section that straddles the O-STD. The top of the interval starts in the Chekha Fm. and is characterized by the assemblage Grt-Bt-St, with a peak temperature near 600 °C. The base of the Chekha Fm. preserves Grt-Bt-Ms, with minor Sil, and peak temperatures near 650 °C; no evidence of partial melting is observed. The GHS samples are characterized by Grt-Bt-Ms-Sil and were partially melted. Peak metamorphic temperatures are estimated to be 650-750 °C. No pressure break is observed across the O-STD, and all peak temperatures correspond to a pressure of 6-7 kbar. In-situ, monazite SHRIMP U-Pb ages for the Chekha Fm. range from about 16.58 Ma ± 0.22 Ma (2σ) at the top of the interval to about 17.58 Ma ± 0.47 Ma (2σ) near its base. Apparent ages from monazite in the GHS range from 21.0 Ma ± 0.7 Ma (1σ) to 13.9 Ma ± 0.4 Ma (1σ). Deformation outlasts metamorphism, as indicated by pre- to syn-kinematic porphyroblasts overprinted by shear bands. Samples from the Chekha Fm. show top-to-north extensional displacement at the top of the interval and conjugate top-to-north and top-to-south shearing indicative of flattening at the base. The GHS samples show dominantly top-to-south shearing overprinted by minor top-to-north shearing. The simultaneous displacement across the GHS and O-STD, the compression of isotherms, and the absence of a discrete pressure break across the O-STD are consistent with a model of ductile flow and extrusion.

  17. When and how to evaluate a patient with nephrolithiasis.

    PubMed

    Rivers, K; Shetty, S; Menon, M

    2000-05-01

    Nephrolithiasis is a common disorder that afflicts up to 12% of the population and continues to be a significant cause of patient injury. Evaluation of these patients should include the assessment of their comorbidities and underlying medical conditions. Patients who form stones can undergo a streamlined evaluation. A cause can be found in more than 90% of these patients. With medical treatment, stone-recurrence rates can be decreased by 85% for calcium oxalate stone formation, which affects a large proportion of patients. Introduction of nonspecific medical therapy in uncomplicated calcium stone disease may improve the quality of life for these patients and allow utilization a simple diagnostic protocol. This is in contrast to the previous recommendations of disease-specific therapy. Because patients without complications represent the majority of those who form stones, a simplified approach greatly reduces the cost of evaluation and treatment. Underlying medical conditions, however, require disease-specific therapy. The protocol represented here should aid physicians and patients in the approach to management of stone disease. The fasting calcium-load test is not required, and the entire evaluation can be performed in an ambulatory setting in two visits. Two 24-hour urine samples should be obtained on a random and restricted diet. Patients who form calcium stones can be subdivided into those who form hypercalciuric and normocalciuric stones. Patients who form normocalciuric stones are treated with conservative measures (increased fluid intake) and potassium and magnesium citrate. Patients who form hypercalciuric stones are treated with a combination of thiazides and potassium and magnesium citrate. PMID:10778464

  18. The role of vitamin D receptor gene polymorphisms in Turkish infants with urolithiasis.

    PubMed

    Goknar, Nilufer; Öktem, Faruk; Torun, Emel; Gok, Ozlem; Demir, Aysegul Dogan; Kucukkoc, Mehmet; Kilic, Ulkan

    2016-05-01

    Polymorphisms in the vitamin D receptor (VDR) gene have recently been reported to be associated with urinary calculi in pediatric and adult cases, but no studies have looked at the youngest period of life. The purpose of this study was to investigate the role of VDR gene polymorphisms in infantile urolithiasis in a Turkish population. We compared a study group of 104 infants (55 girls and 49 boys, mean age 6.94 ± 3.81 months) with a control group of 96 infants (51 girls and 45 boys, mean age 7.51 ± 3.23) to evaluate their demographics and metabolic risk factors. PCR-based restriction analysis of the polymorphisms on the VDR gene (BsmI and TaqI) showed statistically significant differences between study and control groups (p = 0.001 and 0.043, respectively). In addition, the prevalence of the BsmI genotype was significantly different between the hypercalciuric and normocalciuric stone formers (p = 0.007). Allelic frequencies were similar between the urolithiasis and control groups (p > 0.05). The B allele of BsmI and the A allele of ApaI were more prevalent in the hypercalciuric stone formers than in the normocalciuric stone formers (p = 0.018 vs.0.036, respectively). These results suggest that the BsmI and TaqI VDR genotypes could be candidate genes leading to infantile urolithiasis. PMID:26908058

  19. Spatial and Temporal Relationships Between Anatexis and Deformation in the Himalayan Mid-Crust (Invited)

    NASA Astrophysics Data System (ADS)

    Cottle, J. M.; Jessup, M. J.

    2010-12-01

    Partial melting of mid- to lower-crustal rocks within collisional orogens, such as the Himalaya, has the potential to dramatically alter the rheology (effective bulk viscosity) and therefore strength of the crust. Understanding the processes that lead to generation and mobilization of anatectic melts is important in defining the spatial and temporal scales over which flow or extrusion of crustal material can occur as well as defining the linkages and potential feedbacks between melting and other fundamental orogenic processes such as deformation and exhumation. To gain a more complete picture of the magmatic history of the Himalayan mid-crust we compare and contrast the thermobarometric, geochronologic and geochemical record of melting and its relationship to deformation in the three spatially distinct, yet ultimately related, geologic components of the Himalaya: the Greater Himalayan Series (GHS); North Himalayan domes; and younger domes exhumed during orogen-parallel extension. Within the GHS, as exemplified by the Mt. Everest transect in central Nepal / Southern Tibet and the Leo Pargil Dome in NW India, the magmatic history is protracted, with multiple phases of melt-generation via muscovite dehydration of metapelitic source rocks over the period 26 - 12 Ma. The northern most exposures of GHS equivalent rocks - the North Himalayan domes - also record a complex melting history with leucogranite crystallization ages ranging from Oligocene to as young as ~8 Ma. Our ongoing petrologic work indicates that in addition to muscovite dehydration, early melt production via biotite dehydration appears to be volumetrically important in generating leucogranites. The age and petrogenesis of leucogranites within the domes imply that they potentially record an earlier part of the melting history than is preserved in the majority of the GHS to the south. In contrast to the GHS rocks, orogen-parallel domes such as the Ama Drime Massif (ADM) record melting over a relatively restricted time interval of 2 - 3 Ma. Within the ADM, syn-kinematic melting of granitic orthogneiss at granulite-facies Pressure-Temperature (P-T) conditions of 750°C and 0.8GPA occurred between 13 and 12 Ma. This was immediately followed by emplacement of post-kinematic dykes along steep semi-brittle structures at 12-11 Ma. Observations from these three tectonic domains suggest that the timing, duration and sources of melt generation varied considerably throughout the history of the orogen. Significantly, during the late Miocene, as a result of a fundamental shift in the kinematic configuration, the locus of melting migrated from widespread anatexis and associated south-directed extrusion of the mid-crust (GHS) to structurally controlled isolated zones of melting within the lower-crust (ADM) during east-west extension.

  20. Who Benefits from Government Healthcare Subsidies? An Assessment of the Equity of Healthcare Benefits Distribution in China

    PubMed Central

    Chen, Mingsheng; Fang, Guixia; Wang, Lidan; Wang, Zhonghua; Zhao, Yuxin; Si, Lei

    2015-01-01

    Background Improving the equitable distribution of government healthcare subsidies (GHS), particularly among low-income citizens, is a major goal of China’s healthcare sector reform in China. Objectives This study investigates the distribution of GHS in China between socioeconomic populations at two different points in time, examines the comparative distribution of healthcare benefits before and after healthcare reforms in Northwest China, compares the parity of distribution between urban and rural areas, and explores factors that influence equitable GHS distribution. Methods Benefit incidence analysis of GHS progressivity was performed, and concentration and Kakwani indices for outpatient, inpatient, and total healthcare were calculated. Two rounds of household surveys that used multistage stratified samples were conducted in 2003 (13,564 respondents) and 2008 (12,973 respondents). Data on socioeconomics, healthcare payments, and healthcare utilization were collected using household interviews. Results High-income individuals generally reap larger benefits from GHS, as reflected by positive concentration indices, which indicates a regressive system. Concentration indices for inpatient care were 0.2199 (95% confidence interval [CI], 0.0829 to 0.3568) and 0.4445 (95% CI, 0.3000 to 0.5890) in 2002 (urban vs. rural, respectively), and 0.3925 (95% CI, 0.2528 to 0.5322) and 0.4084 (95% CI, 0.2977 to 0.5190) in 2007. Outpatient healthcare subsidies showed different distribution patterns in urban and rural areas following the redesign of rural healthcare insurance programs (urban vs. rural: 0.1433 [95% CI, 0.0263 to 0.2603] and 0.3662 [95% CI, 0.2703 to 0.4622] in 2002, respectively; 0.3063 [95% CI, 0.1657 to 0.4469] and −0.0273 [95% CI, −0.1702 to 0.1156] in 2007). Conclusions Our study demonstrates an inequitable distribution of GHS in China from 2002 to 2007; however, the inequity was reduced, especially in rural outpatient services. Future healthcare reforms in China should not only focus on expanding the coverage, but also on improving the equity of distribution of healthcare benefits. PMID:25781163

  1. Renal function in space: the link between osteoporosis, hypercalciuria, and aquaporins.

    PubMed

    Gaspare De Santo, Natale; Cirillo, Massimo; Valenti, Giovanna; Perna, Alessandra; Anastasio, Pietro; Drummer, Christian

    2005-01-01

    This article reviews bone adaptation to microgravity, during manned space missions, in humans undergoing Head Down Tilt (HDT) and in Hind-Limb-Suspended Rats. Under microgravity conditions, bone loss occurs in association with hypercalciuria, which in turn modulates Aquaporin 2 (AQP2) excretion in urine, thus avoiding stone forming in space. This report discloses the need to prevent bone loss in order to prepare for long stays at lunar bases or voyages to Mars. PMID:15648031

  2. Evaluation of Musa (Paradisiaca Linn. cultivar)--"Puttubale" stem juice for antilithiatic activity in albino rats.

    PubMed

    Prasad, K V; Bharathi, K; Srinivasan, K K

    1993-10-01

    The fresh juice of Musa stem (Puttubale) was tested for its antilithiatic activity. Zinc discs were implanted in the urinary bladder of albino rats to induce urolithiasis. The stones formed were mainly of magnesium ammonium phosphate with traces of calcium oxalate. Musa stem juice (3 mL/rat/day orally) was found to be effective in reducing the formation and also in dissolving the pre-formed stones. PMID:8112813

  3. Preclinical safety and effectiveness studies of ultrasonic propulsion of kidney stones

    PubMed Central

    Harper, Jonathan D.; Dunmire, Barbrina; Wang, Yak-Nam; Simon, Julianna C.; Liggitt, H. Denny; Paun, Marla; Cunitz, Bryan W.; Starr, Frank; Bailey, Michael R.; Penniston, Kristina; Lee, Franklin Chong-Ho; Hsi, Ryan S.; Sorensen, Mathew D.

    2014-01-01

    Objective To provide an update on a research device to ultrasonically reposition kidney stones transcutaneously. This paper reports preclinical safety and effectiveness studies, survival data, modifications of the system, and testing in a stone-forming porcine model. These data formed the basis for regulatory approval to test the device in humans. Materials and Methods The ultrasound burst was shortened to 50ms from previous investigations with 1s bursts. Focused ultrasound was used to expel 2–5mm calcium oxalate monohydrate stones placed ureteroscopically in five pigs. Additionally, de novo stones were imaged and repositioned in a stone-forming porcine model. Acute safety studies were performed targeting two kidneys (6 sites) and three pancreases (8 sites). Survival studies followed 10 animals for one week after simulated treatment. Serum and urine analyses were performed and tissues were evaluated histologically. Results All ureteroscopically-implanted stones (6/6) were repositioned out of the kidney in 14 ± 8 minutes with 13 ± 6 bursts. On average, three bursts moved a stone more than 4mm and collectively accounted for the majority of relocation. Stones (3mm) were detected and repositioned in the 200-kg stone-forming model. No injury was detected in the acute or survival studies. Conclusions Ultrasonic propulsion is safe and effective in the porcine model. Stones were expelled from the kidney. De novo stones formed in a large porcine model were repositioned. No adverse effects were identified with the acute studies directly targeting kidney or pancreatic tissue or during the survival studies indicating no evidence of delayed tissue injury. PMID:24975708

  4. Alternative methods for the replacement of eye irritation testing.

    PubMed

    Lotz, Christian; Schmid, Freia F; Rossi, Angela; Kurdyn, Szymon; Kampik, Daniel; De Wever, Bart; Walles, Heike; Groeber, Florian K

    2016-01-01

    In the last decades significant regulatory attempts were made to replace, refine and reduce animal testing to assess the risk of consumer products for the human eye. As the original in vivo Draize eye test has been criticized for limited predictivity, costs and ethical issues, several animal-free test methods have been developed to categorize substances according to the global harmonized system (GHS) for eye irritation.This review summarizes the progress of alternative test methods for the assessment of eye irritation. Based on the corneal anatomy and the current knowledge of the mechanisms causing eye irritation, different ex vivo and in vitro methods will be presented and discussed in regard of possible limitations and their status of regulatory acceptance. In addition to established in vitro models, this review will also highlight emerging, full thickness cornea models that might be applicable to predict all GHS categories. PMID:26626125

  5. Recent Advances in Potential Clinical Application of Ghrelin in Obesity

    PubMed Central

    Delporte, Christine

    2012-01-01

    Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a 28 amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by ghrelin O-acyltransferase (GOAT). Ghrelin stimulates growth hormone secretion, but also appetite, food intake, weight gain, and gastric emptying. Ghrelin is involved in weight regulation, obesity, type 2 diabetes, and metabolic syndrome. Furthermore, a better understanding of ghrelin biology led to the identification of molecular targets modulating ghrelin levels and/or its biological effects: GOAT, ghrelin, and GHS-R1a. Furthermore, a recent discovery, showing the involvement of bitter taste receptor T2R in ghrelin secretion and/or synthesis and food intake, suggested that T2R could represent an additional interesting molecular target. Several classes of ghrelin-related pharmacological tools for the treatment of obesity have been or could be developed to modulate the identified molecular targets. PMID:22523666

  6. Ghrelin in Female and Male Reproduction

    PubMed Central

    Dupont, Joëlle; Maillard, Virginie; Coyral-Castel, Stéphanie; Ramé, Christelle; Froment, Pascal

    2010-01-01

    Ghrelin and one of its functional receptors, GHS-R1a (Growth Hormone Secretagogue Receptor 1a), were firstly studied about 15 years. Ghrelin is a multifunctional peptide hormone that affects several biological functions including food intake, glucose release, cell proliferation… Ghrelin and GHS-R1a are expressed in key cells of both male and female reproductive organs in several species including fishes, birds, and mammals suggesting a well-conserved signal through the evolution and a role in the control of fertility. Ghrelin could be a component of the complex series of nutrient sensors such as adipokines, and nuclear receptors, which regulate reproduction in function of the energy stores. The objective of this paper was to report the available information about the ghrelin system and its role at the level of the hypothalamic-pituitary-gonadal axis in both sexes. PMID:20700403

  7. CLP Regulation and the transport of dangerous goods.

    PubMed

    Benassai, Sergio

    2011-01-01

    Regulations concerning different modes of transport of dangerous goods are well harmonized at global level: they were then looked at as a model for developing Globally Harmonized System of Classification and Labelling of Chemicals (GHS), (on which CLP Regulations is based). Transport regulations do not cover some hazard classes, such as germ cell mutagenicity, carcinogenicity, reproductive toxicity, having been evaluated that such hazards are not relevant in transport because in general, in case of accident, no repeated and prolonged exposure takes place. Other differences with CLP Regulation are related to the use of "building block approach". Transport labels, which were used as a basis for GHS, can be used, instead of CLP pictograms, on packages during transport. PMID:21709384

  8. Biologic activities of growth hormone secretagogues in humans.

    PubMed

    Ghigo, E; Arvat, E; Giordano, R; Broglio, F; Gianotti, L; Maccario, M; Bisi, G; Graziani, A; Papotti, M; Muccioli, G; Deghenghi, R; Camanni, F

    2001-02-01

    Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules with strong, dose-dependent, and reproducible growth hormone (GH)-releasing activity even after oral administration. GHSs release GH via actions on specific receptors (GHS-R) at the pituitary and, mainly, at the hypothalamic levels. GHSs likely act as functional somatostatin antagonists and meantime enhance the activity of GH-releasing hormone (GHRH)-secreting neurons. The GH-releasing effect of GHSs is independent of gender but undergoes marked age-related variations. Estrogens play a major role in enhancing the GH response to GHSs at puberty, which GHRH hypoactivity, somatostatinergic hyperactivity and impaired activity of the putative GHS-like ligand and receptors probably explain the reduced GH-releasing effect of GHSs in aging. The activity of GHSs is not fully specific for GH. Their slight prolactin-releasing activity probably comes from direct pituitary action. In physiological conditions, the ACTH-releasing activity of GHSs is dependent on central actions; a direct action on GHS-R in pituitary ACTH-secreting tumors likely explains the peculiar ACTH and cortisol hyperresponsiveness to GHSs in Cushing disease. GHSs have specific receptor subtypes in other central and peripheral endocrine and nonendocrine tissues mediating GH-independent biologic activities. GHSs influence sleep pattern, stimulate food intake, and have cardiovascular activities. GHs have specific binding in normal and neoplastic follicular derived human thyroid tissue and inhibit the proliferation of follicular-derived neoplastic cell lines. The discovery of ghrelin, a 28 amino acid peptide synthesized in the stomach but also in other tissues, has opened new fascinating perspectives of research in this field. PMID:11322506

  9. Upregulation of voltage-gated Na+ channels by long-term activation of the ghrelin-growth hormone secretagogue receptor in clonal GC somatotropes.

    PubMed

    Dominguez, Belisario; Felix, Ricardo; Monjaraz, Eduardo

    2009-05-01

    A central question in adenohypophyseal cell physiology concerns the role of transmembrane ionic fluxes in the initiation of the hormone secretion process. In the current report, we investigated the effects of the growth hormone (GH) secretagogues ghrelin and GH-releasing peptide-6 (GHRP-6) on the regulation of the functional expression of voltage-gated Na(+) channels using the tumoral somatotrope GC cell line as a model. Cells were cultured under control conditions or in presence of the GH secretagogues (GHS) for 96 h, and Na(+) currents (I(Na)) were characterized in whole cell patch-clamp experiments. GHS treatment significantly increased I(Na) density in a dose-dependent manner. The effects of GHRP-6 were accompanied by an augment in conductance without changes in the kinetics and the voltage dependence of the currents, suggesting an increase in the number of channels in the cell membrane. Sustained inhibition of L-type Ca(2+) channel activity decreased I(Na) density and prevented the effects of the GHS, whereas long-term exposure to an L-channel agonist increased I(Na) density and enhanced the actions of GHRP-6, indicating that Ca(2+) entry through these channels plays a role in the regulation of Na(+) channel expression. Likewise, GHRP-6 failed to enhance Na(+) channel expression in the presence of membrane-permeable inhibitors of protein kinases A and C, as well as the Ca(2+)/calmodulin-dependent kinase II. Conversely, treatment with a cAMP analog or a protein kinase C activator enhanced both basal and GHS-induced secretion of GH measured by enzyme-linked immunoassay, suggesting that GHRP-6 acting through the ghrelin receptor and different signaling pathways enhances Na(+) channel membrane expression, which favors hormone release from GC somatotropes. PMID:19223651

  10. Exploring the use of social network analysis to measure communication between disease programme and district managers at sub-national level in South Africa.

    PubMed

    Kawonga, Mary; Blaauw, Duane; Fonn, Sharon

    2015-06-01

    With increasing interest in maximising synergies between disease control programmes (DCP) and general health services (GHS), methods are needed to measure interactions between DCP and GHS actors. In South Africa, administrative integration reforms make GHS managers at decentralised level (district managers) responsible for the oversight of DCP operations within districts, with DCP managers (programme managers) providing specialist support. The reforms necessitate interdependence, but these actors work together ineffectively. Communication is crucial for joint working, but no research to assess communication between these actors has been done. This study explores the use of social network analysis (SNA) to measure the extent to which programme and district managers in South Africa communicate, using HIV monitoring and evaluation (M&E) as an exemplar. Data were collected from fifty one managers in two provinces during 2010-2011, to measure: a) one-on-one task-related communication - talking about the collation (verification, reporting) and use of HIV data for monitoring HIV interventions; and b) group communication through co-participating in management committees where HIV data are used for monitoring HIV interventions in districts. SNA measures were computed to describe actor centrality, network density (cohesion), and communication within and between respective manager groups. Block modelling was applied to identify management committees that connect respective manager groups. Results show HIV programme managers located at higher level communicated largely amongst themselves as a group (homophily), seldom talked to the district managers to whom they are supposed to provide specialist HIV M&E support, and rarely participated with them in management committees. This research demonstrates the utility of SNA as a tool for measuring the extent of communication between DCP and GHS actors at sub-national level. Actions are needed to bridge observed communication gaps in order to promote collaborative monitoring of HIV programme interventions within districts. PMID:25931377

  11. Multidomain, Surface Layer-associated Glycoside Hydrolases Contribute to Plant Polysaccharide Degradation by Caldicellulosiruptor Species.

    PubMed

    Conway, Jonathan M; Pierce, William S; Le, Jaycee H; Harper, George W; Wright, John H; Tucker, Allyson L; Zurawski, Jeffrey V; Lee, Laura L; Blumer-Schuette, Sara E; Kelly, Robert M

    2016-03-25

    The genome of the extremely thermophilic bacteriumCaldicellulosiruptor kronotskyensisencodes 19 surface layer (S-layer) homology (SLH) domain-containing proteins, the most in anyCaldicellulosiruptorspecies genome sequenced to date. These SLH proteins include five glycoside hydrolases (GHs) and one polysaccharide lyase, the genes for which were transcribed at high levels during growth on plant biomass. The largest GH identified so far in this genus, Calkro_0111 (2,435 amino acids), is completely unique toC. kronotskyensisand contains SLH domains. Calkro_0111 was produced recombinantly inEscherichia colias two pieces, containing the GH16 and GH55 domains, respectively, as well as putative binding and spacer domains. These displayed endo- and exoglucanase activity on the β-1,3-1,6-glucan laminarin. A series of additional truncation mutants of Calkro_0111 revealed the essential architectural features required for catalytic function. Calkro_0402, another of the SLH domain GHs inC. kronotskyensis, when produced inE. coli, was active on a variety of xylans and β-glucans. Unlike Calkro_0111, Calkro_0402 is highly conserved in the genusCaldicellulosiruptorand among other biomass-degrading Firmicutes but missing fromCaldicellulosiruptor bescii As such, the gene encoding Calkro_0402 was inserted into theC. besciigenome, creating a mutant strain with its S-layer extensively decorated with Calkro_0402. This strain consequently degraded xylans more extensively than wild-typeC. bescii The results here provide new insights into the architecture and role of SLH domain GHs and demonstrate that hemicellulose degradation can be enhanced through non-native SLH domain GHs engineered into the genomes ofCaldicellulosiruptorspecies. PMID:26814128

  12. Evaluation and synthesis of polar aryl- and heteroaryl spiroazetidine-piperidine acetamides as ghrelin inverse agonists.

    PubMed

    Orr, Suvi T M; Beveridge, Ramsay; Bhattacharya, Samit K; Cameron, Kimberly O; Coffey, Steven; Fernando, Dilinie; Hepworth, David; Jackson, Margaret V; Khot, Vishal; Kosa, Rachel; Lapham, Kimberly; Loria, Paula M; McClure, Kim F; Patel, Jigna; Rose, Colin; Saenz, James; Stock, Ingrid A; Storer, Gregory; von Volkenburg, Maria; Vrieze, Derek; Wang, Guoqiang; Xiao, Jun; Zhang, Yingxin

    2015-02-12

    Several polar heteroaromatic acetic acids and their piperidine amides were synthesized and evaluated as ghrelin or type 1a growth hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts to improve pharmacokinetic and safety profile was achieved by modulating physicochemical properties and, more specifically, emphasizing increased polarity of our chemical series. ortho-Carboxamide containing compounds provided optimal physicochemical, pharmacologic, and safety profile. pH-dependent chemical stability was also assessed with our series. PMID:25699143

  13. Devil's Claw to Suppress Appetite—Ghrelin Receptor Modulation Potential of a Harpagophytum procumbens Root Extract

    PubMed Central

    Torres-Fuentes, Cristina; Theeuwes, Wessel F.; McMullen, Michael K.; McMullen, Anna K.; Dinan, Timothy G.; Cryan, John F.; Schellekens, Harriët

    2014-01-01

    Ghrelin is a stomach-derived peptide that has been identified as the only circulating hunger hormone that exerts a potent orexigenic effect via activation of its receptor, the growth hormone secretagogue receptor (GHS-R1a). Hence, the ghrelinergic system represents a promising target to treat obesity and obesity-related diseases. In this study we analysed the GHS-R1a receptor activating potential of Harpagophytum procumbens, popularly known as Devil's Claw, and its effect on food intake in vivo. H. procumbens is an important traditional medicinal plant from Southern Africa with potent anti-inflammatory and analgesic effects. This plant has been also used as an appetite modulator but most evidences are anecdotal and to our knowledge, no clear scientific studies relating to appetite modulation have been done to this date. The ghrelin receptor activation potential of an extract derived from the dried tuberous roots of H. procumbens was analysed by calcium mobilization and receptor internalization assays in human embryonic kidney cells (Hek) stably expressing the GHS-R1a receptor. Food intake was investigated in male C57BL/6 mice following intraperitoneal administration of H. procumbens root extract in ad libitum and food restricted conditions. Exposure to H. procumbens extract demonstrated a significant increased cellular calcium influx but did not induce subsequent GHS-R1a receptor internalization, which is a characteristic for full receptor activation. A significant anorexigenic effect was observed in male C57BL/6 mice following peripheral administration of H. procumbens extract. We conclude that H. procumbens root extract is a potential novel source for potent anti-obesity bioactives. These results reinforce the promising potential of natural bioactives to be developed into functional foods with weight-loss and weight maintenance benefits. PMID:25068823

  14. The influence of the Goos-Hänchen effect on seismic data processing and AVO in attenuating media

    NASA Astrophysics Data System (ADS)

    Wang, Zhiyong

    2015-11-01

    The Goos-Hänchen (GH) effect induced by the total reflection of an incident beam of P-wave from a low-impedance medium to a high-impedance medium at near- and post-critical angles was theoretically simulated and discussed. For both PP- and PSV-waves, there may be large GH shifts (GHS) and penetration depths (PD) for both lossless and attenuating media. As the Q-factor increases, or the frequency of the seismic wave decreases, the GH effect is increased. However, in attenuating media, there may be non-zero GHS and PD at all non-zero incident angles, not just post-critical angles. GHS may be either positive or negative, while PD is positive only. Compared to the Q-factor in the incident medium, the Q-factor in the transmission medium may play a more dominant role in the determination of reflection coefficients, GHS, and PD. The GH-induced normal moveout (NMO) discrepancy of the PSV-wave may be larger than that of the PP-wave. Due to the GH effect, there may be an angle discrepancy (at fixed offset) between the GH-modified incident angle and the traditional incident angle. In addition, the GH effect at a given offset may produce two or three reflected waves, from different incident angles. These results suggest that, within their assumptions, the GH effect may lead to errors in NMO estimates and the vertical location of the reflector. Furthermore, there may be errors in offsets, incident angles, and reflection amplitudes, in the analyses of the amplitude variation with offset (AVO). These GH effects might be more important for seismic data at fixed offsets and shallow layers, and for sonic log data, which might fall into the post-critical angle regime. Therefore, there may be a necessity to take into account the GH effect in the interpretation of wide-angle reflection data in NMO and AVO analyses.

  15. Crustal channel flows: 2. Numerical models with implications for metamorphism in the Himalayan-Tibetan orogen

    NASA Astrophysics Data System (ADS)

    Jamieson, Rebecca A.; Beaumont, Christopher; Medvedev, Sergei; Nguyen, Mai H.

    2004-06-01

    Results from a thermal-mechanical model (HT1) that includes midcrustal channel flow are compatible with many features of the Himalayan-Tibetan system. Radioactive self-heating and rheological weakening of thickened model orogenic crust lead to the formation of a hot, low-viscosity midcrustal channel and a broad plateau. Channel material, corresponding to the Greater Himalayan Sequence (GHS), flows outward from beneath the plateau in response to topographically induced differential pressure. At the plateau flank it is exhumed by focused surface denudation and juxtaposed with cooler, newly accreted material corresponding to the Lesser Himalayan Sequence (LHS). The model channel is bounded by coeval thrust and normal sense ductile shear zones, interpreted to represent the Main Central Thrust (MCT) zone and South Tibetan Detachment system, respectively. Inverted metamorphism associated with the model MCT zone results from distributed ductile shear along the MCT and extrusion of the hot channel. A variety of model P-T-t path styles, resembling those observed in the GHS and LHS, are produced for points traveling through contrasting tectonic regimes that coexist in different parts of the model. Predicted times of peak metamorphism, cooling, and erosion of metamorphic facies are generally compatible with observations, although model GHS cooling ages are too young. The times of M1 and M2 metamorphic "events" observed in the GHS correspond to model times of maximum burial and maximum heating, respectively. The results highlight the need to integrate tectonics and metamorphism in continental collision models and demonstrate the importance of lateral transport of both heat and material in large hot orogens.

  16. Caldicellulosiruptor Core and Pangenomes Reveal Determinants for

    SciTech Connect

    Blumer-Schuette, Sara E.; Giannone, Richard J; Zurawski, Jeffrey V; Ozdemir, Inci; Ma, Qin; Yin, Yanbin; Xu, Ying; Kataeva, Irena; Poole, Farris; Adams, Michael W. W.; Hamilton-Brehm, Scott; Elkins, James G; Larimer, Frank W; Land, Miriam L; Hauser, Loren John; Cottingham, Robert W; Hettich, Robert {Bob} L; Kelly, Robert M

    2012-01-01

    Extremely thermophilic bacteria of the genus Caldicellulosiruptor utilize carbohydrate components of plant cell walls, including cellulose and hemicellulose, facilitated by a diverse set of glycoside hydrolases (GHs). From a biofuel perspective, this capability is crucial for deconstruction of plant biomass into fermentable sugars. While all species from the genus grow on xylan and acidpretreated switchgrass, growth on crystalline cellulose is variable. The basis for this variability was examined using microbiological, genomic, and proteomic analyses of eight globally diverse Caldicellulosiruptor species. The open Caldicellulosiruptor pangenome (4,009 open reading frames [ORFs]) encodes 106 GHs, representing 43 GH families, but only 26 GHs from 17 families are included in the core (noncellulosic) genome (1,543 ORFs). Differentiating the strongly cellulolytic Caldicellulosiruptor species from the others is a specific genomic locus that encodes multidomain cellulases from GH families 9 and 48, which are associated with cellulose-binding modules. This locus also encodes a novel adhesin associated with type IV pili, which was identified in the exoproteome bound to crystalline cellulose. Taking into account the core genomes, pangenomes, and individual genomes, the ancestral Caldicellulosiruptor was likely cellulolytic and evolved, in some cases, into species that lost the ability to degrade crystalline cellulose while maintaining the capacity to hydrolyze amorphous cellulose and hemicellulose.

  17. Obesity in MENX Rats Is Accompanied by High Circulating Levels of Ghrelin and Improved Insulin Sensitivity.

    PubMed

    Wiedemann, Tobias; Bielohuby, Maximilian; Müller, Timo D; Bidlingmaier, Martin; Pellegata, Natalia S

    2016-02-01

    Ghrelin, the natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing ε-cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7.5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin's proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion in MENX rats, while insulin sensitivity is improved. In summary, we provide a novel nontransgenic rat model with high endogenous ghrelin plasma levels and, interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases, including type 2 diabetes. PMID:26512025

  18. Diversity of Glycosyl Hydrolases from Cellulose-Depleting Communities Enriched from Casts of Two Earthworm Species▿ †

    PubMed Central

    Beloqui, Ana; Nechitaylo, Taras Y.; López-Cortés, Nieves; Ghazi, Azam; Guazzaroni, María-Eugenia; Polaina, Julio; Strittmatter, Axel W.; Reva, Oleg; Waliczek, Agnes; Yakimov, Michail M.; Golyshina, Olga V.; Ferrer, Manuel; Golyshin, Peter N.

    2010-01-01

    The guts and casts of earthworms contain microbial assemblages that process large amounts of organic polymeric substrates from plant litter and soil; however, the enzymatic potential of these microbial communities remains largely unexplored. In the present work, we retrieved carbohydrate-modifying enzymes through the activity screening of metagenomic fosmid libraries from cellulose-depleting microbial communities established with the fresh casts of two earthworm species, Aporrectodea caliginosa and Lumbricus terrestris, as inocula. Eight glycosyl hydrolases (GHs) from the A. caliginosa-derived community were multidomain endo-β-glucanases, β-glucosidases, β-cellobiohydrolases, β-galactosidase, and β-xylosidases of known GH families. In contrast, two GHs derived from the L. terrestris microbiome had no similarity to any known GHs and represented two novel families of β-galactosidases/α-arabinopyranosidases. Members of these families were annotated in public databases as conserved hypothetical proteins, with one being structurally related to isomerases/dehydratases. This study provides insight into their biochemistry, domain structures, and active-site architecture. The two communities were similar in bacterial composition but significantly different with regard to their eukaryotic inhabitants. Further sequence analysis of fosmids and plasmids bearing the GH-encoding genes, along with oligonucleotide usage pattern analysis, suggested that those apparently originated from Gammaproteobacteria (pseudomonads and Cellvibrio-like organisms), Betaproteobacteria (Comamonadaceae), and Alphaproteobacteria (Rhizobiales). PMID:20622123

  19. Effects of ghrelin and des-acyl ghrelin on neurogenesis of the rat fetal spinal cord

    SciTech Connect

    Sato, Miho; Nakahara, Keiko; Goto, Shintaro; Kaiya, Hiroyuki; Miyazato, Mikiya . E-mail: a0d201u@cc.miyazaki-u.ac.jp; Date, Yukari; Nakazato, Masamitsu; Kangawa, Kenji; Murakami, Noboru

    2006-11-24

    Expressions of the growth hormone secretagogue receptor (GHS-R) mRNA and its protein were confirmed in rat fetal spinal cord tissues by RT-PCR and immunohistochemistry. In vitro, over 3 nM ghrelin and des-acyl ghrelin induced significant proliferation of primary cultured cells from the fetal spinal cord. The proliferating cells were then double-stained using antibodies against the neuronal precursor marker, nestin, and the cell proliferation marker, 5-bromo-2'-deoxyuridine (BrdU), and the nestin-positive cells were also found to be co-stained with antibody against GHS-R. Furthermore, binding studies using [{sup 125}I]des-acyl ghrelin indicated the presence of a specific binding site for des-acyl ghrelin, and confirmed that the binding was displaced with unlabeled des-acyl ghrelin or ghrelin. These results indicate that ghrelin and des-acyl ghrelin induce proliferation of neuronal precursor cells that is both dependent and independent of GHS-R, suggesting that both ghrelin and des-acyl ghrelin are involved in neurogenesis of the fetal spinal cord.

  20. A new approach for continuous estimation of baseflow using discrete water quality data: Method description and comparison with baseflow estimates from two existing approaches

    NASA Astrophysics Data System (ADS)

    Miller, Matthew P.; Johnson, Henry M.; Susong, David D.; Wolock, David M.

    2015-03-01

    Understanding how watershed characteristics and climate influence the baseflow component of stream discharge is a topic of interest to both the scientific and water management communities. Therefore, the development of baseflow estimation methods is a topic of active research. Previous studies have demonstrated that graphical hydrograph separation (GHS) and conductivity mass balance (CMB) methods can be applied to stream discharge data to estimate daily baseflow. While CMB is generally considered to be a more objective approach than GHS, its application across broad spatial scales is limited by a lack of high frequency specific conductance (SC) data. We propose a new method that uses discrete SC data, which are widely available, to estimate baseflow at a daily time step using the CMB method. The proposed approach involves the development of regression models that relate discrete SC concentrations to stream discharge and time. Regression-derived CMB baseflow estimates were more similar to baseflow estimates obtained using a CMB approach with measured high frequency SC data than were the GHS baseflow estimates at twelve snowmelt dominated streams and rivers. There was a near perfect fit between the regression-derived and measured CMB baseflow estimates at sites where the regression models were able to accurately predict daily SC concentrations. We propose that the regression-derived approach could be applied to estimate baseflow at large numbers of sites, thereby enabling future investigations of watershed and climatic characteristics that influence the baseflow component of stream discharge across large spatial scales.

  1. Caldicellulosiruptor Core and Pangenomes Reveal Determinants for Noncellulosomal Thermophilic Deconstruction of Plant Biomass

    PubMed Central

    Blumer-Schuette, Sara E.; Giannone, Richard J.; Zurawski, Jeffrey V.; Ozdemir, Inci; Ma, Qin; Yin, Yanbin; Xu, Ying; Kataeva, Irina; Poole, Farris L.; Adams, Michael W. W.; Hamilton-Brehm, Scott D.; Elkins, James G.; Larimer, Frank W.; Land, Miriam L.; Hauser, Loren J.; Cottingham, Robert W.; Hettich, Robert L.

    2012-01-01

    Extremely thermophilic bacteria of the genus Caldicellulosiruptor utilize carbohydrate components of plant cell walls, including cellulose and hemicellulose, facilitated by a diverse set of glycoside hydrolases (GHs). From a biofuel perspective, this capability is crucial for deconstruction of plant biomass into fermentable sugars. While all species from the genus grow on xylan and acid-pretreated switchgrass, growth on crystalline cellulose is variable. The basis for this variability was examined using microbiological, genomic, and proteomic analyses of eight globally diverse Caldicellulosiruptor species. The open Caldicellulosiruptor pangenome (4,009 open reading frames [ORFs]) encodes 106 GHs, representing 43 GH families, but only 26 GHs from 17 families are included in the core (noncellulosic) genome (1,543 ORFs). Differentiating the strongly cellulolytic Caldicellulosiruptor species from the others is a specific genomic locus that encodes multidomain cellulases from GH families 9 and 48, which are associated with cellulose-binding modules. This locus also encodes a novel adhesin associated with type IV pili, which was identified in the exoproteome bound to crystalline cellulose. Taking into account the core genomes, pangenomes, and individual genomes, the ancestral Caldicellulosiruptor was likely cellulolytic and evolved, in some cases, into species that lost the ability to degrade crystalline cellulose while maintaining the capacity to hydrolyze amorphous cellulose and hemicellulose. PMID:22636774

  2. Growing degree hours - a simple, accurate, and precise protocol to approximate growing heat summation for grapevines

    NASA Astrophysics Data System (ADS)

    Gu, S.

    2015-11-01

    Despite its low accuracy and consistency, growing degree days (GDD) has been widely used to approximate growing heat summation (GHS) for regional classification and phenological prediction. GDD is usually calculated from the mean of daily minimum and maximum temperatures (GDDmm) above a growing base temperature (T gb). To determine approximation errors and accuracy, daily and cumulative GDDmm was compared to GDD based on daily average temperature (GDDavg), growing degree hours (GDH) based on hourly temperatures, and growing degree minutes (GDM) based on minute-by-minute temperatures. Finite error, due to the difference between measured and true temperatures above T gb is large in GDDmm but is negligible in GDDavg, GDH, and GDM, depending only upon the number of measured temperatures used for daily approximation. Hidden negative error, due to the temperatures below T gb when being averaged for approximation intervals larger than measuring interval, is large in GDDmm and GDDavg but is negligible in GDH and GDM. Both GDH and GDM improve GHS approximation accuracy over GDDmm or GDDavg by summation of multiple integration rectangles to reduce both finite and hidden negative errors. GDH is proposed as the standardized GHS approximation protocol, providing adequate accuracy and high precision independent upon T gb while requiring simple data recording and processing.

  3. Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP.

    PubMed

    Shi, Chang-He; Schisler, Jonathan C; Rubel, Carrie E; Tan, Song; Song, Bo; McDonough, Holly; Xu, Lei; Portbury, Andrea L; Mao, Cheng-Yuan; True, Cadence; Wang, Rui-Hao; Wang, Qing-Zhi; Sun, Shi-Lei; Seminara, Stephanie B; Patterson, Cam; Xu, Yu-Ming

    2014-02-15

    Gordon Holmes syndrome (GHS) is a rare Mendelian neurodegenerative disorder characterized by ataxia and hypogonadism. Recently, it was suggested that disordered ubiquitination underlies GHS though the discovery of exome mutations in the E3 ligase RNF216 and deubiquitinase OTUD4. We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1 (NM_005861) c.737C→T, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus of HSC70-interacting protein). CHIP plays a central role in regulating protein quality control, in part through its ability to function as an E3 ligase. Loss of CHIP function has long been associated with protein misfolding and aggregation in several genetic mouse models of neurodegenerative disorders; however, a role for CHIP in human neurological disease has yet to be identified. Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism. We conclude that GHS can be caused by a loss-of-function mutation in CHIP. Our findings further highlight the role of disordered ubiquitination and protein quality control in the pathogenesis of neurodegenerative disease and demonstrate the utility of combining whole-exome sequencing with molecular analyses and animal models to define causal disease polymorphisms. PMID:24113144

  4. A novel GH secretagogue, A233, exhibits enhanced growth activity and innate immune system stimulation in teleosts fish.

    PubMed

    Martinez, Rebeca; Ubieta, Kenia; Herrera, Fidel; Forellat, Alina; Morales, Reynold; de la Nuez, Ania; Rodriguez, Rolando; Reyes, Osvaldo; Oliva, Ayme; Estrada, Mario P

    2012-09-01

    In teleosts fish, secretion of GH is regulated by several hypothalamic factors that are influenced by the physiological state of the animal. There is an interaction between immune and endocrine systems through hormones and cytokines. GH in fish is involved in many physiological processes that are not overtly growth related, such as saltwater osmoregulation, antifreeze synthesis, and the regulation of sexual maturation and immune functions. This study was conducted to characterize a decapeptide compound A233 (GKFDLSPEHQ) designed by molecular modeling to evaluate its function as a GH secretagogue (GHS). In pituitary cell culture, the peptide A233 induces GH secretion and it is also able to increase superoxide production in tilapia head-kidney leukocyte cultures. This effect is blocked by preincubation with the GHS receptor antagonist [d-Lys(3)]-GHRP6. Immunoneutralization of GH by addition of anti-tilapia GH monoclonal antibody blocked the stimulatory effect of A233 on superoxide production. These experiments propose a GH-mediated mechanism for the action of A233. The in vivo biological action of the decapeptide was also demonstrated for growth stimulation in goldfish and tilapia larvae (P<0.001). Superoxide dismutase levels, antiprotease activity, and lectin titer were enhanced in tilapia larvae treated with this novel molecule. The decapeptide A233 designed by molecular modeling is able to function as a GHS in teleosts and enhance parameters of the innate immune system in the fish larvae. PMID:22707376

  5. Thermo-kinematic evolution of the Annapurna-Dhaulagiri Himalaya, central Nepal: The Composite Orogenic System

    NASA Astrophysics Data System (ADS)

    Parsons, A. J.; Law, R. D.; Lloyd, G. E.; Phillips, R. J.; Searle, M. P.

    2016-04-01

    The Himalayan orogen represents a "Composite Orogenic System" in which channel flow, wedge extrusion, and thrust stacking operate in separate "Orogenic Domains" with distinct rheologies and crustal positions. We analyze 104 samples from the metamorphic core (Greater Himalayan Sequence, GHS) and bounding units of the Annapurna-Dhaulagiri Himalaya, central Nepal. Optical microscopy and electron backscatter diffraction (EBSD) analyses provide a record of deformation microstructures and an indication of active crystal slip systems, strain geometries, and deformation temperatures. These data, combined with existing thermobarometry and geochronology data are used to construct detailed deformation temperature profiles for the GHS. The profiles define a three-stage thermokinematic evolution from midcrustal channel flow (Stage 1, >700°C to 550-650°C), to rigid wedge extrusion (Stage 2, 400-600°C) and duplexing (Stage 3, <280-400°C). These tectonic processes are not mutually exclusive, but are confined to separate rheologically distinct Orogenic Domains that form the modular components of a Composite Orogenic System. These Orogenic Domains may be active at the same time at different depths/positions within the orogen. The thermokinematic evolution of the Annapurna-Dhaulagiri Himalaya describes the migration of the GHS through these Orogenic Domains and reflects the spatial and temporal variability in rheological boundary conditions that govern orogenic systems.

  6. Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis.

    PubMed

    Dezaki, Katsuya; Sone, Hedeyuki; Yada, Toshihiko

    2008-05-01

    Ghrelin, an acylated 28-amino acid peptide, was isolated from the stomach as the endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R). Circulating ghrelin is produced predominantly in the oxyntic mucosa of stomach. Ghrelin potently stimulates GH release and feeding, and exhibits positive cardiovascular effects, suggesting a possible clinical application. Low plasma ghrelin levels are associated with elevated fasting insulin levels and insulin resistance, suggesting both physiological and pathophysiological roles for ghrelin in glucose metabolism. Here, we review the physiological role of ghrelin in the regulation of insulin release and glucose metabolism, and a potential therapeutic avenue to treat type 2 diabetes by manipulating ghrelin and/or its signaling. Ghrelin inhibits insulin release in mice, rats and humans. The signal transduction mechanisms of ghrelin in islet beta-cells are distinct from those utilized in GH-releasing and/or GHS-R-expressing cells. Ghrelin is expressed in pancreatic islets and released into pancreatic microcirculations. Pharmacological and genetic blockades of islet-derived ghrelin markedly augment glucose-induced insulin release in vitro. In high-fat diet-induced mildly obese mice, ghrelin-deficiency enhances insulin release and prevents impaired glucose tolerance. Thus, manipulation of insulinostatic function of ghrelin--GHS-R system, particularly that in islets, could optimize the amount of insulin release to meet the systemic demand, providing a potential therapeutic application to prevent type 2 diabetes. PMID:18433874

  7. Fungal glycoside hydrolases for saccharification of lignocellulose: outlook for new discoveries fueled by genomics and functional studies

    SciTech Connect

    Jovanovic, Iva; Magnuson, Jon K.; Collart, Frank R.; Robbertse, Barbara; Adney, William S.; Himmel, Michael E.; Baker, Scott E.

    2009-08-01

    Genome sequencing of a variety of fungi is a major initiative currently supported by the Department of Energy’s Joint Genome Institute. Encoded within the genomes of many fungi are upwards of 200+ enzymes called glycoside hydrolases (GHs). GHs are known for their ability to hydrolyze the polysaccharide components of lignocellulosic biomass. Production of ethanol and “next generation” biofuels from lignocellulosic biomass represents a sustainable route to biofuels production. However this process has to become more economical before large scale operations are put into place. Identifying and characterizing GHs with improved properties for biomass degradation is a key factor for the development of cost effective processes to convert biomass to fuels and chemicals. With the recent explosion in the number of GH encoding genes discovered by fungal genome sequencing projects, it has become apparent that improvements in GH gene annotation processes have to be developed. This will enable more informed and efficient decision making with regard to selection and utilization of these important enzymes in bioprocess that produce fuels and chemicals from lignocellulosic feedstocks.

  8. Rudaibacter terrae gen. nov., sp. nov., isolated from greenhouse soil.

    PubMed

    Kim, Soo-Jin; Moon, Ji-Young; Hamada, Moriyuki; Tamura, Tomohiko; Weon, Hang-Yeon; Suzuki, Ken-ichiro; Kwon, Soon-Wo

    2013-11-01

    A novel Gram-stain-positive, non-motile, rod-shaped bacterium, designated 5GHs34-4(T), was isolated from greenhouse soil in Yongin, Republic of Korea. Growth occurred in the temperature range of 10-37 °C (optimum 28-30 °C) and at pH 5.0-9.0 (optimum pH 7.0). It can tolerate up to 3 % (w/v) NaCl. The strain showed 16S rRNA gene sequence similarity levels of 95.1-97.0 % with species of the genus Leifsonia, 95.7-96.7 % with species of the genus Herbiconiux, 95.1-96.4 % with species of the genus Salinibacterium and 96.1 % with Labedella gwakjiensis and Homoserinimonas aerilata. The highest sequence similarities (97.0 %) were with Leifsonia aquatica JCM 1368(T), Leifsonia poae VKM Ac-1401(T) and Leifsonia psychrotolerans LI1(T). The peptidoglycan type determined for strain 5GHs34-4(T) was B2γ with dl-2,4-diaminobutyric acid at position 3. The murein was of the acetyl type. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol and two unknown glycolipids. The menaquinones detected were MK-13, MK-12 and MK-14, and the major fatty acids were summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c), anteiso-C17 : 0 and anteiso-C15 : 0. The phenotypic and phylogenetic traits of strain 5GHs34-4(T) differed in some respects from those of members of the family Microbacteriaceae. Therefore, strain 5GHs34-4(T) is considered to represent a novel species of a new genus in the family Microbacteriaceae, for which the name Rudaibacter terrae gen. nov., sp. nov. is proposed. The type strain is 5GHs34-4(T) ( = KACC 15523(T) = NBRC 108754(T)). PMID:23728372

  9. Prevalence and Cardiovascular Associations of Diabetic Retinopathy and Maculopathy: Results from the Gutenberg Health Study

    PubMed Central

    Raum, Philipp; Lamparter, Julia; Ponto, Katharina A.; Peto, Tunde; Hoehn, René; Schulz, Andreas; Schneider, Astrid; Wild, Philipp S.; Pfeiffer, Norbert; Mirshahi, Alireza

    2015-01-01

    Objective Diabetic retinopathy (DR) is the leading cause of blindness in people of working age. The purpose of this paper is to report the prevalence and cardiovascular associations of diabetic retinopathy and maculopathy (DMac) in Germany. Research Design and Methods The Gutenberg Health Study (GHS) is a population-based study with 15,010 participants aged between 35 at 74 years from the city of Mainz and the district of Mainz-Bingen. We determined the weighted prevalence of DR and DMac by assessing fundus photographs of persons with diabetes from the GHS data base. Diabetes was defined as HbA1c ≥ 6.5%, known diagnosis diabetes mellitus or known diabetes medication. Furthermore, we analysed the association between DR and cardiovascular risk factors and diseases. Results Overall, 7.5% (1,124/15,010) of the GHS cohort had diabetes. Of these, 27.7% were unaware of their disease and thus were newly diagnosed by their participation in the GHS. The prevalence of DR and DMac was 21.7% and 2.3%, respectively among patients with diabetes. Vision-threatening disease was present in 5% of the diabetic cohort. In the multivariable analysis DR (all types) was associated with age (Odds Ratio [95% confidence interval]: 0.97 [0.955–0.992]; p = 0.006) arterial hypertension (1.90 [1.190–3.044]; p = 0.0072) and vision-threatening DR with obesity (3.29 [1.504–7.206]; p = 0.0029). DR (all stages) and vision-threatening DR were associated with duration of diabetes (1.09 [1.068–1.114]; p<0.0001 and 1.18 [1.137–1.222]; p<0.0001, respectively). Conclusions Our calculations suggest that more than a quarter-million persons have vision-threatening diabetic retinal disease in Germany. Prevalence of DR was lower in the GHS compared to East-Asian studies. Associations were found with age, arterial hypertension, obesity, and duration of diabetes mellitus. PMID:26075604

  10. Chemical evolution of Himalayan leucogranites based on an O, U-Pb and Hf study of zircon

    NASA Astrophysics Data System (ADS)

    Hopkinson, Thomas N.; Warren, Clare J.; Harris, Nigel B. W.; Hammond, Samantha J.; Parrish, Randall R.

    2015-04-01

    Crustal melting is a characteristic process at convergent plate margins, where crustal rocks are heated and deformed. Miocene leucogranite sheets and plutons are found intruded into the high-grade metasedimentary core (the Greater Himalayan Sequence, GHS) across the Himalayan orogen. Previously-published Himalayan whole-rock data suggest that these leucogranites formed from a purely meta-sedimentary source, isotopically similar to those into which they now intrude. Bulk rock analyses carry inherent uncertainties, however: they may hide contributions from different contributing sources, and post-crystallization processes such as fluid interaction may significantly alter the original chemistry. In contrast, zircon is more able to retain precise information of the contributing sources of the melt from which it crystallises whilst its resistant nature is impervious to post-magmatic processes. This multi-isotope study of Oligocene-Miocene leucogranite zircons from the Bhutan Himalaya, seeks to differentiate between various geochemical processes that contribute to granite formation. Hf and O isotopes are used to detect discrete changes in melt source while U-Pb isotopes provide the timing of zircon crystallisation. Our data show that zircon rims of Himalayan age yield Hf-O signatures that lie within the previously reported whole-rock GHS field, confirming the absence of a discernible mantle contribution to the leucogranite source. Importantly, we document a decrease in the minimum ɛHf values during Himalayan orogenesis through time, correlating to a change in Hf model age from 1.4 Ga to 2.4 Ga. Nd model ages for the older Lesser Himalayan metasediments (LHS) that underthrust the GHS are significantly older than those for the GHS (2.4-2.9 Ga compared with 1.4-2.2 Ga), and as such even minor contributions of LHS material incorporated into a melt would significantly increase the resulting Hf model age. Hence our leucogranite data suggest either a change of source within the GHS over time, or an increasing contribution from older Lesser Himalayan (LHS) material in the melt. This is the first time that an evolutionary trend in the chemistry of Himalayan crustal melts has been recognized. Thus these new data show that, at least in the Himalaya, accessory phase geochemistry can provide more detailed insight into tectonic processes than bulk rock geochemistry.

  11. A new approach to the hazard classification of alloys based on transformation/dissolution.

    PubMed

    Skeaff, James M; Hardy, David J; King, Pierrette

    2008-01-01

    Most of the metals produced for commercial application enter into service as alloys which, together with metals and all other chemicals in commerce, are subject to a hazard identification and classification initiative now being implemented in a number of jurisdictions worldwide, including the European Union Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) initiative, effective 1 June 2007. This initiative has considerable implications for environmental protection and market access. While a method for the hazard identification and classification of metals is available in the recently developed United Nations (UN) guidance document on the Globally Harmonized System of Hazard Classification and Labelling (GHS), an approach for alloys has yet to be formulated. Within the GHS, a transformation/dissolution protocol (T/ DP) for metals and sparingly soluble metal compounds is provided as a standard laboratory method for measuring the rate and extent of the release of metals into aqueous media from metal-bearing substances. By comparison with ecotoxicity reference data, T/D data can be used to derive UN GHS classification proposals. In this study we applied the T/DP for the 1st time to several economically important metals and alloys: iron powder, nickel powder, copper powder, and the alloys Fe-2Cu-0.6C (copper = 2%, carbon = 0.6%), Fe-2Ni-0.6C, Stainless Steel 304, Monel, brass, Inconel, and nickel-silver. The iron and copper powders and the iron and nickel powders had been sintered to produce the Fe-2Me-0.6C (Me = copper or nickel) alloys which made them essentially resistant to reaction with the aqueous media, so they would not classify under the GHS, although their component copper and nickel metal powders would. Forming a protective passivating film, chromium in the Stainless Steel 304 and Inconel alloys protected them from reaction with the aqueous media, so that their metal releases were minimal and would not result in GHS classification. For the other alloys, we developed a new critical surface area-toxic units (CSA-TU) approach to derive their GHS classification proposals. The CSA-TU approach can be readily applied to other multicomponent alloy systems, without the need to arbitrarily select a particular component among several as the determinant of toxicity. This paper shows how regulatory obligations, such as those mandated by REACH, can be met with a laboratory-based CSA-TU method for deriving hazard classification proposals for alloys, linking to attendant environmental protection management decisions. Drawing on T/D data derived from laboratory testing of the alloy itself, the CSA-TU approach can be applied to establish scientifically defensible decisions on hazard classification proposals for an alloy of interest. The resulting decisions can then be incorporated into environmental management measures in such jurisdictions as the European Union. Based on an approach developed specifically for alloys, the hazard classification decisions can be regarded as relevant, credible, and protective of the environment. Since alloys are usually more resistant to chemical attack than their components, this approach is a considerable improvement over the possibility provided for in the GHS of calculating a hazard classification level for an alloy from the classification levels of its components. PMID:17944545

  12. Impaired bone formation in male idiopathic osteoporosis: further reduction in the presence of concomitant hypercalciuria

    NASA Technical Reports Server (NTRS)

    Zerwekh, J. E.; Sakhaee, K.; Breslau, N. A.; Gottschalk, F.; Pak, C. Y.

    1992-01-01

    We present iliac bone histomorphometric data and related biochemical data from 16 nonalcoholic men (50 +/- 11 (SD) years) referred for evaluation of spontaneous skeletal and/or appendicular fractures and reduced spinal bone density. All men were eugonadal and had no known underlying disorder associated with osteopenia. For the group, mean serum chemistry values were within normal limits including immunoreactive parathyroid hormone, osteocalcin and serum 1,25-dihydroxyvitamin D [1,25(OH)2D]. Nine men demonstrated hypercalciuria (greater than or equal to 0.1 mmol/kg per day) while on a constant metabolic diet of 20 mmol/day Ca. Their 24-hour urinary calcium was significantly greater than that for the remaining 7 men (7.4 +/- 1.6 vs. 5.0 +/- 0.8 mmol/day, p = 0.003), as was their calciuric response to a 1 g oral calcium load (0.23 +/- 0.06 vs. 0.15 +/- 0.05 Ca/creatinine, p = 0.042). Serum parameters (including parathyroid hormone and 1,25(OH)2D) of hypercalciuric and normocalciuric men were not significantly different. Histomorphometric indices for cancellous bone demonstrated significant differences between the entire group of osteoporotic men and age-adjusted normal values for bone volume (11.4 +/- 4.0% vs. 23.2 +/- 4.4%), osteoid surface (5.6 +/- 3.9% vs. 12.1 +/- 4.6%), osteoblastic surface (2.0 +/- 2.3% vs. 3.9 +/- 1.9%), and mineralizing surface (1.9 +/- 2.4% vs. 5.1 +/- 2.7%); there were also significant differences in bone formation rate (total surface referent) (0.004 +/- 0.001 vs. 0.011 +/- 0.006 mm3/mm2 per year). Compared with the normocalciuric group the 9 hypercalciuric men had significantly lower osteoblastic surfaces (1.6 +/- 1.9% vs. 2.5 +/- 2.6%) and mineralizing surfaces (1.4 +/- 1.5% vs. 2.7 +/- 3.2%).(ABSTRACT TRUNCATED AT 250 WORDS).

  13. Role of 1,25-Dihydroxy Vitamin D3 and Parathyroid Hormone in Urinary Calcium Excretion in Calcium Stone Formers

    PubMed Central

    Kim, Won Tae; Kim, Yong-June; Yun, Seok Joong; Shin, Kyung-Sub; Choi, Young Deuk; Kim, Wun-Jae

    2014-01-01

    Purpose To find out the possible role of 1,25(OH)2 vitamin D3 [1,25(OH)2D3] and parathyroid hormone (PTH) as intrinsic factors in urinary calcium stone formers (SFs), we investigated their relationship with serum and urinary biochemical parameters. Materials and Methods A total of 326 calcium SFs (male: 204, female: 122) were enrolled and underwent outpatient metabolic evaluations including 1,25(OH)2D3 and PTH as well as serum and 24-hour urinary biochemical parameters. As control, 163 age- and sex-matched (2:1) individuals (non-SFs) who have never urinary stone episode were included. Results 1,25(OH)2D3 level was positively correlated with urinary calcium excretion (r=0.347, p<0.001). The hypercalciuric group and recurrent SFs had higher serum 1,25(OH)2D3 levels than the normocalciuric group (p<0.001) and first SFs (p=0.050). In the adjusted multiple linear regression analysis, serum 1,25(OH)2D3 level (β=0.259, p<0.001) and serum PTH level (β=-0.160, p<0.001) were significantly correlated with urinary calcium excretion. The patients in highest tertile of 1,25(OH)2D3 had a more than 3.1 fold risk of hypercalciuria than those in the lowest tertile (odds ratio=3.14, 95% confidence interval: 1.431-6.888, p=0.004). No correlation was observed between PTH and 1,25(OH)2D3 (R=0.005, p=0.929) in calcium SFs, while a negative correlation was found in controls (R=-0.269, p=0.001). Conclusion 1,25(OH)2D3 was closely correlated with urinary calcium excretion, and high 1,25(OH)2D3 levels were detected in the hypercalciuric group and in recurrent SFs. However, 1,25(OH)2D3 was not correlated with PTH in calcium SFs. These findings suggest that 1,25(OH)2D3 might be important intrinsic factor for altered calcium regulation in SFs. PMID:25048492

  14. Simulating calcium salt precipitation in the nephron using chemical speciation.

    PubMed

    Rodgers, Allen L; Allie-Hamdulay, Shameez; Jackson, Graham; Tiselius, Hans-Göran

    2011-08-01

    Theoretical modeling of urinary crystallization processes affords opportunities to create and investigate scenarios which would be extremely difficult or impossible to achieve in in vivo experiments. Researchers have previously hypothesized that calcium renal stone formation commences in the nephron. In the present study, concentrations of urinary components and pH ranges in different regions of the nephron were estimated from concentrations in blood combined with a knowledge of the renal handling of individual ions. These were used in the chemical speciation program JESS to determine the nature of the solution complexes in the different regions of the nephron and the saturation index (SI) of the stone-forming salts calcium oxalate (CaOx), brushite (Bru), hydroxyapatite (HAP) and octacalcium phosphate (OCP). The effect of independent precipitation of each of the latter on the SI values of other salts was also investigated. HAP was the only salt which was supersaturated throughout the nephron. All of the other salts were supersaturated only in the middle and distal regions of the collecting duct. Supersaturations were pH sensitive. When precipitation of CaOx, Bru and OCP was simulated in the distal part of the collecting duct, little or no effect on the SI values of the other stone forming salts was observed. However, simulation of HAP precipitation caused all other salts to become unsaturated. This suggests that if HAP precipitates, a pure stone comprising this component will ensue while if any of the other salts precipitates, a mixed CaOx/CaP stone will be formed. Application of Ostwald's Rule of Stages predicts that the mixed stone is likely to be CaOx and Bru. Our modelling demonstrates that precipitation of stone-forming salts in the nephron is highly dependent on the delicate nature of the chemical equilibria which prevail and which are themselves highly dependent on pH and component concentrations. PMID:21249493

  15. Renal-Stone Risk Assessment During Space Shuttle Flights

    NASA Technical Reports Server (NTRS)

    Whitson, Peggy A.; Pietrzyk, Robert A.; Pak, Charles Y. C.

    1996-01-01

    The metabolic and environmental factors influencing renal stone formation before, during, and after Space Shuttle flights were assessed. We established the contributing roles of dietary factors in relationship to the urinary risk factors associated with renal stone formation. 24-hr urine samples were collected prior to, during space flight, and following landing. Urinary factors associated with renal stone formation were analyzed and the relative urinary supersaturation ratios of calcium oxalate, calcium phosphate (brushite), sodium urate, struvite and uric acid were calculated. Food and fluid consumption was recorded for a 48-hr period ending with the urine collection. Urinary composition changed during flight to favor the crystallization of stone-forming salts. Factors that contributed to increased potential for stone formation during space flight were significant reductions in urinary pH and increases in urinary calcium. Urinary output and citrate, a potent inhibitor of calcium-containing stones, were slightly reduced during space flight. Dietary intakes were significantly reduced for a number of variables, including fluid, energy, protein, potassium, phosphorus and magnesium. This is the first in-flight characterization of the renal stone forming potential in astronauts. With the examination of urinary components and nutritional factors, it was possible to determine the factors that contributed to increased risk or protected from risk. In spite of the protective components, the negative contributions to renal stone risk predominated and resulted in a urinary environment that favored the supersaturation of stone-forming salts. The importance of the hypercalciuria was noted since renal excretion was high relative to the intake.

  16. [MICROBIAL COMMUNITIES ON KIDNEY STONES].

    PubMed

    Romanova, Yu M; Mulabaev, N S; Tolordava, E R; Seregin, A V; Seregin, I V; Alexeeva, N V; Stepanova, T V; Levina, G A; Barhatova, O I; Gamova, N A; Goncharova, S A; Didenko, L V; Rakovskaya, I V

    2015-01-01

    The clinical material obtained surgically in patients with kidney stone disease (KSD) was tested for content of the stone microflora using PCR and standard microbiological methods. It was demonstrated that about 50% of stones in patients with KSD were infected with various infection agents as observed using standard microbiological and molecular genetic methods. The percentage of detection of the Mycoplasma hominis using cultural method is lower than the percentage detected using PCR, which is due to difficult isolation and cultivation, as well as DNA fragments of mycoplasma observed after antibiotic therapy. Studies based on modern microscopy methods showed that microorganisms on the surface of the kidney stone formed multispecies biofilms. PMID:26182663

  17. Carcass composition of market weight pigs subjected to heat stress in utero and during finishing.

    PubMed

    Cruzen, S M; Boddicker, R L; Graves, K L; Johnson, T P; Arkfeld, E K; Baumgard, L H; Ross, J W; Safranski, T J; Lucy, M C; Lonergan, S M

    2015-05-01

    Objectives were to investigate the effects of prolonged gestational and/or postnatal heat stress on performance and carcass composition of market weight pigs. Pregnant gilts were exposed to gestational heat stress (GHS, 28°C to 34°C, diurnal) or thermal neutral (18°C to 22°C, diurnal) conditions during the entire gestation or during the first or second half of gestation. At 14 wk of age (58 ± 5 kg), barrows were housed in heat stress (32°C, HS) or thermal neutral (21°C, TN) conditions. Feed intake and BW were recorded weekly, and body temperature parameters were monitored twice weekly until slaughter (109 ± 5 kg). Organs were removed and weighed, and loin eye area (LEA) and back fat thickness (BF) were measured after carcass chilling. Carcass sides were separated into lean, separable fat, bone, and skin components and were weighed. Moisture, lipid, and protein content were determined in the LM at the 10th rib. Data were analyzed using a split plot with random effect of dam nested within gestational treatment. Carcass measurements included HCW as a covariate to control for weight. Planned orthogonal contrast statements were used to evaluate the overall effect of GHS in the first half, second half, or any part of gestation. Gestational heat stress did not alter postnatal performance or most body temperature parameters (P > 0.10). However, ADFI in the finishing period was increased (P < 0.05) in response to GHS, particularly in pigs receiving GHS in the first half of gestation. Gestational heat stress during the first half of gestation decreased head weight as a percent of BW (P = 0.02), whereas GHS in the second half of gestation decreased bone weight as a percent of BW (P = 0.02). Heat stress reduced ADG, BW, and HCW (P < 0.0001). Lean tissue was increased in HS pigs on both a weight and percentage basis (P < 0.0001), but LEA was similar to TN carcasses (P = 0.38). Carcasses from HS barrows also had less carcass separable fat (P < 0.01) and tended to have less BF (P = 0.06) compared with those from TN barrows, even after controlling for HCW. However, percent intramuscular fat did not differ between treatments (P = 0.48). The LM from HS carcasses had a greater moisture to protein ratio (P = 0.04). HS barrows also had decreased heart (P < 0.001) and kidney (P < 0.0001) as a percent of BW compared with TN pigs. In summary, GHS may affect head and bone development, subsequently affecting carcass composition. Chronic HS during finishing results in longer times to reach market weight and a leaner carcass once market weight is achieved. PMID:26020353

  18. Expression of the ghrelin and neurotensin systems is altered in the temporal lobe of Alzheimer's disease patients.

    PubMed

    Gahete, Manuel D; Rubio, Alicia; Crdoba-Chacn, Jos; Gracia-Navarro, Francisco; Kineman, Rhonda D; Avila, Jess; Luque, Ral M; Castao, Justo P

    2010-01-01

    Ghrelin and neurotensin (NTS) are neuroendocrine peptides that exert opposite effects on food intake and energy homeostasis, but share comparable actions in improving memory and learning. Ghrelin and NTS mediate their effects via receptors with high evolutionary identity: two ghrelin G-protein coupled receptors (GPCRs; GHS-R1a/1b) and three NTS-receptors, two GPCRs (NTSR1/2) and one non-GPCR (NTSR3). Because ghrelin and NTS systems are tightly linked to energy balance regulation and cognitive processes, they have been proposed to be altered in Alzheimer's disease (AD), a dementia syndrome markedly influenced by the metabolic status. Although it has been demonstrated that ghrelin and NTS can attenuate AD-related cognitive impairment, a comprehensive analysis of these systems in AD has not been conducted. Here, we used quantitative real time-RT-PCR to analyze expression of the ghrelin/NTS axis in one of the cortical regions most affected in AD, the temporal gyrus. Results unveiled a striking reduction of mRNA levels for ghrelin, and its newly discovered In2-ghrelin variant, as well as for the enzyme responsible for ghrelin acylation, ghrelin-O-acyltransferase and GHS-R1a, while expression of GHS-R1b was markedly increased. In addition, expression levels of NTSR1 and NTSR2 were profoundly decreased in AD, whereas mRNA levels of NTS only declined slightly, and those of NTSR3 (which is involved in neuronal apoptosis) did not vary. Taken together, our results provide the first quantitative evidence showing that ghrelin/NTS systems are markedly altered in the brain of AD patients, thereby suggesting that these systems may contribute to the severe cognitive deficit observed in this pathology. PMID:20858966

  19. A role of ghrelin in canine mammary carcinoma cells proliferation, apoptosis and migration

    PubMed Central

    2012-01-01

    Background Ghrelin is a natural ligand of the growth hormone secretagogue receptor (GHS-R). They are often co-expressed in multiple human tumors and related cancer cell lines what can indicate that the ghrelin/GHS-R axis may have an important role in tumor growth and progression. However, a role of ghrelin in canine tumors remains unknown. Thus, the aim of our study was two-fold: (1) to assess expression of ghrelin and its receptor in canine mammary cancer and (2) to examine the effect of ghrelin on carcinoma cells proliferation, apoptosis, migration and invasion. The expression of ghrelin and its receptor in canine mammary cancer tissues and cell lines (isolated from primary tumors and their metastases) was examined using Real-time qPCR and immunohistochemistry. For apoptosis analysis the Annexin V and propidium iodide dual staining was applied whereas cell proliferation was evaluated by MTT assay and BrdU incorporation test. The influence of ghrelin on cancer cells migration and invasion was assessed using Boyden chamber assays and wound healing assay. Results The highest expression of ghrelin was observed in metastatic cancers whereas the lowest expression of ghrelin receptor was detected in tumors of the 3rd grade of malignancy. Higher expression of ghrelin and its receptor was detected in cancer cell lines isolated from metastases than in cell lines isolated from primary tumors. In vitro experiments demonstrated that exposure to low doses of ghrelin stimulates cellular proliferation, inhibits apoptosis and promotes motility and invasion of canine mammary cancer cells. Growth hormone secretagogue receptor inhibitor ([D-Lys3]-GHRP6) as well as RNA interference enhances early apoptosis. Conclusion The presence of ghrelin and GHS-R in all of the examined canine mammary tumors may indicate their biological role in cancer growth and development. Our experiments conducted in vitro confirmed that ghrelin promotes cancer development and metastasis. PMID:22999388

  20. The Ophthalmic Branch of the Gutenberg Health Study: Study Design, Cohort Profile and Self-Reported Diseases

    PubMed Central

    Höhn, René; Kottler, Ulrike; Peto, Tunde; Blettner, Maria; Münzel, Thomas; Blankenberg, Stefan; Lackner, Karl J.; Beutel, Manfred

    2015-01-01

    Purpose This paper describes the study design, methodology, cohort profile and self-reported diseases in the ophthalmological branch of the Gutenberg Health Study (GHS). Methods The GHS is an ongoing, prospective, interdisciplinary, single-center, population-based cohort study in Germany. The main goals of the ophthalmological section are to assess the prevalence and incidence of ocular diseases and to explore risk factors, genetic determinants and associations with systemic diseases and conditions. The eye examination at baseline included a medical history, self-reported eye diseases, visual acuity, refractive errors, intraocular pressure, visual field, pachymetry, keratometry, fundus photography and tear sampling. The 5-year follow-up visit additionally encompassed optical coherence tomography, anterior segment imaging and optical biometry. The general examination included anthropometry; blood pressure measurement; carotid artery ultrasound; electrocardiogram; echocardiography; spirometry; cognitive tests; questionnaires; assessment of mental conditions; and DNA, RNA, blood and urine sampling. Results Of 15,010 participants (aged 35-74 years at the time of inclusion), ocular data are available for 14,700 subjects (97.9%). The mean visual acuity (standard deviation), mean spherical equivalent, median decimal visual acuity, and mean intraocular pressure were 0.08 (0.17) logMar, -0.42 (2.43) diopters, 0.9 and 14.24 (2.79) mm Hg, respectively. The frequencies of self-reported strabismus, glaucoma, surgery for retinal detachment and retinal vascular occlusions were 2.7%, 2.3%, 0.2% and 0.4%, respectively. Conclusions The GHS is the most extensive dataset of ophthalmic diseases and conditions and their risk factors in Germany and one of the largest cohorts worldwide. This dataset will provide new insight in the epidemiology of ophthalmic diseases and related medical specialties. PMID:25775251

  1. Ghrelin promotes renal cell carcinoma metastasis via Snail activation and is associated with poor prognosis.

    PubMed

    Lin, Tsung-Chieh; Liu, Yu-Peng; Chan, Yung-Chieh; Su, Chia-Yi; Lin, Yuan-Feng; Hsu, Shih-Lan; Yang, Chung-Shi; Hsiao, Michael

    2015-09-01

    Ghrelin is an appetite-regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS-R). Recently, high ghrelin levels have been detected in various types of human cancer. Ghrelin expression is observed in proximal and distal renal tubules, where renal cell carcinoma (RCC) arises. However, whether ghrelin is up-regulated and promotes renal cell carcinogenesis remains obscure. In this study, we observed that ghrelin was highly expressed in renal tumours, especially in metastatic RCC. In addition, high ghrelin levels correlated with poor outcome, lymph node and distant metastasis. The addition of ghrelin promoted the migration ability of RCC cell lines 786-0, ACHN and A-498. Furthermore, knockdown of ghrelin expression reduced in vitro migration and in vivo metastasis, suggesting a requirement for ghrelin accumulation in the microenvironment for RCC metastasis. Analysis of microarray signatures using Ingenuity Pathway Analysis (IPA) and MetaCore pointed to the potential regulation by ghrelin of Snail, a transcriptional repressor of E-cadherin. We further observed that Ghrelin increased the expression, nuclear translocation and promoter-binding activity of Snail. Snail silencing blocked the ghrelin-mediated effects on E-cadherin repression and cell migration. Snail-E-cadherin regulation was mediated by GHS-R-triggered Akt phosphorylation at Ser473 and Thr308. Pretreatment with PI3K inhibitors, LY294002 and wortmannin, as well as Akt siRNA, decreased ghrelin-induced Akt phosphorylation, Snail promoter binding activity and migration. Taken together, our findings indicate that ghrelin can activate Snail function via the GHS-R-PI3K-Akt axis, which may contribute to RCC metastasis. The microarray raw data were retrieved from the Cancer Genome Atlas (TCGA) [KIRC gene expression (IlluminaHiSeq) dataset]. PMID:25925728

  2. Ghrelin gene products and the regulation of food intake and gut motility.

    PubMed

    Chen, Chih-Yen; Asakawa, Akihiro; Fujimiya, Mineko; Lee, Shou-Dong; Inui, Akio

    2009-12-01

    A breakthrough using "reverse pharmacology" identified and characterized acyl ghrelin from the stomach as the endogenous cognate ligand for the growth hormone (GH) secretagogue receptor (GHS-R) 1a. The unique post-translational modification of O-n-octanoylation at serine 3 is the first in peptide discovery history and is essential for GH-releasing ability. Des-acyl ghrelin, lacking O-n-octanoylation at serine 3, is also produced in the stomach and remains the major molecular form secreted into the circulation. The third ghrelin gene product, obestatin, a novel 23-amino acid peptide identified from rat stomach, was found by comparative genomic analysis. Three ghrelin gene products actively participate in modulating appetite, adipogenesis, gut motility, glucose metabolism, cell proliferation, immune, sleep, memory, anxiety, cognition, and stress. Knockdown or knockout of acyl ghrelin and/or GHS-R1a, and overexpression of des-acyl ghrelin show benefits in the therapy of obesity and metabolic syndrome. By contrast, agonism of acyl ghrelin and/or GHS-R1a could combat human anorexia-cachexia, including anorexia nervosa, chronic heart failure, chronic obstructive pulmonary disease, liver cirrhosis, chronic kidney disease, burn, and postsurgery recovery, as well as restore gut dysmotility, such as diabetic or neurogenic gastroparesis, and postoperative ileus. The ghrelin acyl-modifying enzyme, ghrelin O-Acyltransferase (GOAT), which attaches octanoate to serine-3 of ghrelin, has been identified and characterized also from the stomach. To date, ghrelin is the only protein to be octanylated, and inhibition of GOAT may have effects only on the stomach and is unlikely to affect the synthesis of other proteins. GOAT may provide a critical molecular target in developing novel therapeutics for obesity and type 2 diabetes. PMID:20038570

  3. Noninflammatory upregulation of nerve growth factor underlies gastric hypersensitivity induced by neonatal colon inflammation.

    PubMed

    Li, Qingjie; Winston, John H; Sarna, Sushil K

    2016-02-01

    Gastric hypersensitivity is one of the key contributors to the postprandial symptoms of epigastric pain/discomfort, satiety, and fullness in functional dyspepsia patients. Epidemiological studies found that adverse early-life experiences are risk factors for the development of gastric hypersensitivity. Preclinical studies found that neonatal colon inflammation elevates plasma norepinephrine (NE), which upregulates expression of nerve growth factor (NGF) in the muscularis externa of the gastric fundus. Our goal was to investigate the cellular mechanisms by which NE upregulates the expression of NGF in gastric hypersensitive (GHS) rats, which were subjected previously to neonatal colon inflammation. Neonatal colon inflammation upregulated NGF protein, but not mRNA, in the gastric fundus of GHS rats. Western blotting showed upregulation of p110γ of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), pAKT(Ser473), and phosphorylated 4E-binding protein (p4E-BP1)(Thr70), suggesting AKT activation and enhanced NGF protein translation. AKT inhibitor MK-2206 blocked the upregulation of NGF in the fundus of GHS rats. Matrix metalloproteinase 9 (MMP-9), the major NGF-degrading protease, was suppressed, indicating that NGF degradation was impeded. Incubation of fundus muscularis externa with NE upregulated NGF by modulating the protein translation and degradation pathways. Yohimbine, an α2-adrenergic receptor antagonist, upregulated plasma NE and NGF expression by activating the protein translation and degradation pathways in naive rats. In contrast, a cocktail of adrenergic receptor antagonists suppressed the upregulation of NGF by blocking the activation of the protein translation and degradation pathways. Our findings provide evidence that the elevation of plasma NE induces NGF expression in the gastric fundus. PMID:26608656

  4. Analysis of Draize eye irritation testing and its prediction by mining publicly available 2008-2014 REACH data.

    PubMed

    Luechtefeld, Thomas; Maertens, Alexandra; Russo, Daniel P; Rovida, Costanza; Zhu, Hao; Hartung, Thomas

    2016-01-01

    Public data from ECHA online dossiers on 9,801 substances encompassing 326,749 experimental key studies and additional information on classification and labeling were made computable. Eye irritation hazard, for which the rabbit Draize eye test still represents the reference method, was analyzed. Dossiers contained 9,782 Draize eye studies on 3,420 unique substances, indicating frequent retesting of substances. This allowed assessment of the test's reproducibility test based on all substances tested more than once. There was a 10% chance of a non-irritant evaluation given after a prior severe-irritant result as given by UN GHS classification criteria. The most reproducible outcomes were the results negative (94% reproducible) and severe eye irritant (73% reproducible). To evaluate whether other GHS categorizations predict eye irritation we built a dataset of 5,629 substances (1,931 'irritant' and 3,698 'non-irritant'). The two best decision trees with up to three other GHS classifications resulted in balanced accuracies of 68% and 73%, i.e., in the rank order of the Draize rabbit eye test itself, but both use inhalation toxicity data ("May cause respiratory irritation"), which is not typically available. Next, a dataset of 929 substances with at least one Draize study was mapped to PubChem to compute chemical similarity using 2D conformational fingerprints and Tanimoto similarity. Using a minimum similarity of 0.7 and simple classification by the closest chemical neighbor resulted in balanced accuracy from 73% over 737 substances to 100% at a threshold of 0.975 over 41 substances. This represents a strong support of read-across and (Q)SAR approaches in this area. PMID:26863293

  5. Non-medical use of prescription pain relievers among high school students in China: a multilevel analysis

    PubMed Central

    Guo, Lan; Xu, Yan; Deng, Jianxiong; He, Yuan; Gao, Xue; Li, Pengsheng; Wu, Hong; Zhou, Jinhua; Lu, Ciyong

    2015-01-01

    Objectives Given the differences between general high school (GHS) and vocational high school (VHS) students, this study aimed to investigate the lifetime prevalence of non-medical use of prescription pain relievers (NMUPPR) among high school students as well as the associations between NMUPPR and individual-level factors and school category. Methods A cross-sectional study was conducted in GHS and VHS students in 2012 in Chongqing, and 11 906 students’ questionnaires were completed and qualified for the survey. Self-reported NMUPPR and information regarding individual-level determinants and school category were collected. A multilevel multivariate logistic regression model was fitted to explore independent predictors of NMUPPR. Results The total lifetime prevalence of NMUPPR was 11.3%, and NMUPPR was more prevalent among VHS students (15.8%) compared with GHS students (9.8%). Overall, the results indicated that VHS students were more likely to be involved in NMUPPR (adjusted OR (AOR)=1.64, 95% CI 1.42 to 1.89). Regarding the individual-level predictors of NMUPPR, below-average family economic status was negatively correlated with NMUPPR (AOR=0.77, 95% CI 0.60 to 0.98), and students with more pocket money were more likely to be engaged in NMUPPR. Students who had difficult family relationships, had poor relationships with teachers, had parents or friends who engaged in non-medical prescription drug use, and considered or attempted suicide were more likely to be engaged in NMUPPR. Conclusions NMUPPR among high school students is a multidetermined phenomenon. The current findings indicate that VHS students are an important subgroup of adolescents and highlight the need for additional research as well as targeted prevention and intervention programmes for NMUPPR. PMID:26169805

  6. The role of ghrelin signalling for sexual behaviour in male mice.

    PubMed

    Egecioglu, Emil; Prieto-Garcia, Luna; Studer, Erik; Westberg, Lars; Jerlhag, Elisabet

    2016-03-01

    Ghrelin, a gut-brain signal, is well known to regulate energy homeostasis, food intake and appetite foremost via hypothalamic ghrelin receptors (GHS-R1A). In addition, ghrelin activates the reward systems in the brain, namely the mesolimbic dopamine system, and regulates thereby the rewarding properties of addictive drugs as well as of palatable foods. Given that the mesolimbic dopamine system mandates the reinforcing properties of addictive drugs and natural rewards, such as sexual behaviour, we hypothesize that ghrelin plays an important role for male sexual behaviour, a subject for the present studies. Herein we show that ghrelin treatment increases, whereas pharmacological suppression (using the GHSR-1A antagonist JMV2959) or genetic deletion of the GHS-R1A in male mice decreases the sexual motivation for as well as sexual behaviour with female mice in oestrus. Pre-treatment with L-dopa (a dopamine precursor) prior to treatment with JMV2959 significantly increased the preference for female mouse compared with vehicle treatment. On the contrary, treatment with 5-hydroxythyptohan (a precursor for serotonin) prior to treatment with JMV2959 decreased the sexual motivation compared to vehicle. In separate experiments, we show that ghrelin and GHS-R1A antagonism do not affect the time spent over female bedding as measured in the androgen-dependent bedding test. Collectively, these data show that the hunger hormone ghrelin and its receptor are required for normal sexual behaviour in male mice and that the effects of the ghrelin signalling system on sexual behaviour involve dopamine neurotransmission. PMID:25475101

  7. Piloting proactive marketing to recruit disadvantaged adults to a community-wide obesity prevention program.

    PubMed

    O'Hara, Blythe J; Eggins, Dianne; Phongsavan, Philayrath; Milat, Andrew J; Bauman, Adrian E; Wiggers, John

    2015-01-01

    Population-wide obesity prevention and treatment programs are fundamental to addressing the increasing overweight and obesity rates in socioeconomically disadvantaged populations. Innovative recruitment strategies, including proactive marketing strategies, are needed to ensure such programs have universal reach and target vulnerable populations. This study aimed to determine the success of proactive recruitment to Australia's Get Healthy Information and Coaching Service® (GHS) and to assess whether the recruitment strategy influenced participants' outcomes. Sociodemographic information was collected from all GHS participants who joined the service between February 2009 and August 2013, and anthropometric information regarding behavioural risk factors was collected from all GHS coaching participants at baseline and six months. Data were analysed according to the participants' referral source (self-referral and secondary referral versus proactive recruitment). Participants recruited through proactive marketing were more likely to be male, aged 50 years or older, have high school education, not be in paid employment and be from the lowest three quintiles of socioeconomic advantage. The risk factor profile of coaching participants recruited through proactive marketing did not vary significantly from those recruited via other mechanisms, although they were less likely to be obese and less likely to have a higher 'at risk' waist circumference measurement. Proactively recruited coaching participants reported significant improvements from baseline to six months (consistent with improvements made by participants recruited through other strategies), although they were significantly more likely to withdraw from coaching before they completed the six-month program.Proactive marketing facilitated use of an obesity prevention service; similar services may have greater reach if proactive marketing recruitment strategies are used. These strategies could be encouraged to assist such services to achieve optimal population impact among hard-to-reach populations. PMID:25848739

  8. Strengthening global health security capacity--Vietnam demonstration project, 2013.

    PubMed

    Tran, Phu Dac; Vu, Long Ngoc; Nguyen, Hien Tran; Phan, Lan Trong; Lowe, Wayne; McConnell, Michelle S; Iademarco, Michael F; Partridge, Jeffrey M; Kile, James C; Do, Trang; Nadol, Patrick J; Bui, Hien; Vu, Diep; Bond, Kyle; Nelson, David B; Anderson, Lauren; Hunt, Kenneth V; Smith, Nicole; Giannone, Paul; Klena, John; Beauvais, Denise; Becknell, Kristi; Tappero, Jordan W; Dowell, Scott F; Rzeszotarski, Peter; Chu, May; Kinkade, Carl

    2014-01-31

    Over the past decade, Vietnam has successfully responded to global health security (GHS) challenges, including domestic elimination of severe acute respiratory syndrome (SARS) and rapid public health responses to human infections with influenza A(H5N1) virus. However, new threats such as Middle East respiratory syndrome coronavirus (MERS-CoV) and influenza A(H7N9) present continued challenges, reinforcing the need to improve the global capacity to prevent, detect, and respond to public health threats. In June 2012, Vietnam, along with many other nations, obtained a 2-year extension for meeting core surveillance and response requirements of the 2005 International Health Regulations (IHR). During March-September 2013, CDC and the Vietnamese Ministry of Health (MoH) collaborated on a GHS demonstration project to improve public health emergency detection and response capacity. The project aimed to demonstrate, in a short period, that enhancements to Vietnam's health system in surveillance and early detection of and response to diseases and outbreaks could contribute to meeting the IHR core capacities, consistent with the Asia Pacific Strategy for Emerging Diseases. Work focused on enhancements to three interrelated priority areas and included achievements in 1) establishing an emergency operations center (EOC) at the General Department of Preventive Medicine with training of personnel for public health emergency management; 2) improving the nationwide laboratory system, including enhanced testing capability for several priority pathogens (i.e., those in Vietnam most likely to contribute to public health emergencies of international concern); and 3) creating an emergency response information systems platform, including a demonstration of real-time reporting capability. Lessons learned included awareness that integrated functions within the health system for GHS require careful planning, stakeholder buy-in, and intradepartmental and interdepartmental coordination and communication. PMID:24476979

  9. Ghrelin and the endocrine pancreas.

    PubMed

    Broglio, Fabio; Gottero, Cristina; Benso, Andrea; Prodam, Flavia; Volante, Marco; Destefanis, Silvia; Gauna, Carlotta; Muccioli, Giampiero; Papotti, Mauro; van der Lely, Aart Jan; Ghigo, Ezio

    2003-10-01

    Ghrelin is a 28-amino-acid peptide predominantly produced by the stomach, while substantially lower amounts derive from other tissues including the pancreas. It is a natural ligand of the GH secretagogue (GHS) receptor (GHS-R1a) and strongly stimulates GH secretion, but acylation in serine 3 is needed for its activity. Ghrelin also possesses other endocrine and nonendocrine actions reflecting central and peripheral GHS-R distribution including the pancreas. The wide spectrum of ghrelin activities includes orexigenic effect, control of energy expenditure, and peripheral gastroenteropancreatic actions. Circulating ghrelin levels mostly reflect gastric secretion as indicated by evidence that they are reduced by 80% after gastrectomy and even after gastric by-pass surgery. Ghrelin secretion is increased in anorexia and cachexia but reduced in obesity, a notable exception being Prader-Willi syndrome. The negative association between ghrelin secretion and body weight is emphasized by evidence that weight increase and decrease reduces and augments circulating ghrelin levels in anorexia and obesity, respectively, and agrees with the clear negative association between ghrelin and insulin levels. In fact, ghrelin secretion is increased by fasting whereas it is decreased by glucose load as well as during euglycemic clamp but not after arginine or free fatty acid load in normal subjects; in physiological conditions, however, the most remarkable inhibitory input on ghrelin secretion is represented by somatostatin as well as by its natural analog cortistatin that concomitantly reduce beta-cell secretion. This evidence indicates that the endocrine pancreas plays a role in directly or indirectly modulating ghrelin secretion. PMID:14610295

  10. Involvements of the lateral hypothalamic area in gastric motility and its regulation by the lateral septum.

    PubMed

    Gong, Yanling; Xu, Luo; Wang, Hongbo; Guo, Feifei; Sun, Xiangrong; Gao, Shengli

    2013-12-01

    Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) pre-dominantly produced in the stomach. Recent studies have shown that it may promote food intake and gastric motility. We aim to explore effects of ghrelin on the gastric distension (GD) sensitive neurons and gastric motility in the lateral hypothalamic area (LHA), and the possible regulation by the lateral septum. Extracellular single unit discharges were recorded and the gastric motility was monitored by administration of ghrelin into LHA and electrical stimulation of lateral septum. Expression of GHS-R was determined by polymerase chain reaction (PCR), western blot and immunohistochemistry staining. Projection of nerve fiber and expression of ghrelin were observed by retrograde tracer and fluo-immunohistochemistry staining. Results revealed that there were GD neurons in the LHA, and administration of ghrelin could excite both GD-excitatory (GD-E) and GD-inhibited (GD-I) neurons in the LHA. The gastric motility was significantly promoted by administration of ghrelin into LHA with a dose dependent manner, which could be completely abolished by treatment with ghrelin receptor antagonist [D-Lys-3]-GHRP-6 or BIM-28163. c-Fos expression was significantly increased after ghrelin administration to the LHA. Electrical stimulation of the lateral septum could significantly excite GD neurons responsive to ghrelin in the LHA as well as promote gastric motility. However, those effects could be absorbed by pre-treatment of [D-Lys-3]-GHRP-6. GHSR-1a expression in the LHA had no change after ghrelin administration to the LHA or electrical stimulating lateral septum. Electrical lesion of the LHA resulted in the decrease of gastric motility. GHS-R and Ghrelin/FG-double labeled neurons were observed in the LHA and lateral septum, respectively. It is suggested that the LHA may involve in promoting gastric motility via ghrelin. The Lateral septum projects to the LHA and exerts some regulating function on the LHA. PMID:24100167

  11. Claudin-14 regulates renal Ca++ transport in response to CaSR signalling via a novel microRNA pathway

    PubMed Central

    Gong, Yongfeng; Renigunta, Vijayaram; Himmerkus, Nina; Zhang, Jiaqi; Renigunta, Aparna; Bleich, Markus; Hou, Jianghui

    2012-01-01

    The paracellular claudin channel of the thick ascending limb (TAL) of Henle is critical for Ca++ reabsorption in the kidney. Genome-wide association studies (GWASs) have identified claudin-14 associated with hypercalciuric nephrolithiasis. Here, we show that claudin-14 promoter activity and transcript are exclusively localized in the TAL. Under normal dietary condition, claudin-14 proteins are suppressed by two microRNA molecules (miR-9 and miR-374). Both microRNAs directly target the 3′-UTR of claudin-14 mRNA; induce its mRNA decay and translational repression in a synergistic manner. Through physical interaction, claudin-14 blocks the paracellular cation channel made of claudin-16 and -19, critical for Ca++ reabsorption in the TAL. The transcript and protein levels of claudin-14 are upregulated by high Ca++ diet, while downregulated by low Ca++ diet. Claudin-14 knockout animals develop hypermagnesaemia, hypomagnesiuria, and hypocalciuria under high Ca++ dietary condition. MiR-9 and miR-374 transcript levels are regulated by extracellular Ca++ in a reciprocal manner as claudin-14. The Ca++ sensing receptor (CaSR) acts upstream of the microRNA-claudin-14 axis. Together, these data have established a key regulatory role for claudin-14 in renal Ca++ homeostasis. PMID:22373575

  12. Ghrelin Decreases Firing Activity of Gonadotropin-Releasing Hormone (GnRH) Neurons in an Estrous Cycle and Endocannabinoid Signaling Dependent Manner

    PubMed Central

    Farkas, Imre; Vastagh, Csaba; Sárvári, Miklós; Liposits, Zsolt

    2013-01-01

    The orexigenic peptide, ghrelin is known to influence function of GnRH neurons, however, the direct effects of the hormone upon these neurons have not been explored, yet. The present study was undertaken to reveal expression of growth hormone secretagogue receptor (GHS-R) in GnRH neurons and elucidate the mechanisms of ghrelin actions upon them. Ca2+-imaging revealed a ghrelin-triggered increase of the Ca2+-content in GT1-7 neurons kept in a steroid-free medium, which was abolished by GHS-R-antagonist JMV2959 (10µM) suggesting direct action of ghrelin. Estradiol (1nM) eliminated the ghrelin-evoked rise of Ca2+-content, indicating the estradiol dependency of the process. Expression of GHS-R mRNA was then confirmed in GnRH-GFP neurons of transgenic mice by single cell RT-PCR. Firing rate and burst frequency of GnRH-GFP neurons were lower in metestrous than proestrous mice. Ghrelin (40nM-4μM) administration resulted in a decreased firing rate and burst frequency of GnRH neurons in metestrous, but not in proestrous mice. Ghrelin also decreased the firing rate of GnRH neurons in males. The ghrelin-evoked alterations of the firing parameters were prevented by JMV2959, supporting the receptor-specific actions of ghrelin on GnRH neurons. In metestrous mice, ghrelin decreased the frequency of GABAergic mPSCs in GnRH neurons. Effects of ghrelin were abolished by the cannabinoid receptor type-1 (CB1) antagonist AM251 (1µM) and the intracellularly applied DAG-lipase inhibitor THL (10µM), indicating the involvement of retrograde endocannabinoid signaling. These findings demonstrate that ghrelin exerts direct regulatory effects on GnRH neurons via GHS-R, and modulates the firing of GnRH neurons in an ovarian-cycle and endocannabinoid dependent manner. PMID:24124622

  13. Measurement of Clathrate Hydrate Thermodynamic Stability in the Presence of Ammonia

    NASA Technical Reports Server (NTRS)

    Dunham, Marc

    2012-01-01

    There is a lack of data available for the stability of clathrate hydrates in the presence of ammonia for low-to-moderate pressures in the 0-10 MPa range. Providing such data will allow for a better understanding of natural mass transfer processes on celestial bodies like Titan and Enceladus, on which destabilization of clathrates may be responsible for replenishment of gases in the atmosphere. The experimental process utilizes a custom-built gas handling system (GHS) and a cryogenic calorimeter to allow for the efficient testing of samples under varying pressures and gas species.

  14. Ghrelin Receptors in Non-Mammalian Vertebrates

    PubMed Central

    Kaiya, Hiroyuki; Kangawa, Kenji; Miyazato, Mikiya

    2012-01-01

    The growth hormone secretagogue-receptor (GHS-R) was discovered in humans and pigs in 1996. The endogenous ligand, ghrelin, was discovered 3 years later, in 1999, and our understanding of the physiological significance of the ghrelin system in vertebrates has grown steadily since then. Although the ghrelin system in non-mammalian vertebrates is a subject of great interest, protein sequence data for the receptor in non-mammalian vertebrates has been limited until recently, and related biological information has not been well organized. In this review, we summarize current information related to the ghrelin receptor in non-mammalian vertebrates. PMID:23882259

  15. Strain distribution across the Greater Himalayan Sequence, Annapurna-Dhaulagiri, Nepal

    NASA Astrophysics Data System (ADS)

    Parsons, A. J.; Phillips, R. J.; Lloyd, G. E.; Searle, M. P.; Law, R. D.; Ferre, E. C.

    2012-12-01

    The Himalaya provides a unique natural laboratory to observe orogenic processes at a variety of temporal and spatial scales. The potential for these observations to serve as kinematic and geodynamic analogues for past orogens relies on a robust understanding of the evolution of the Himalayan mountain belt. Field structural data, supported by thermobaromety, geochronology and thermodynamic modelling, generally support a channel flow model in which a partially molten middle crust layer, the Greater Himalaya Sequence (GHS), was extruded to the south during Miocene time bounded by high-strain ductile shears above and below. This model suggests that the GHS, the metamorphic core of the orogen, represents an exhumed, rheologically weak, mid-crustal channel. Lateral flow of the channel was driven southwards by the lithostatic pressure gradient between the 5 km high Tibetan plateau and the < 1 km elevation and average crustal thickness of the Indian plate. The vertical distribution of strain across the GHS is one element of the channel flow hypothesis that is yet to be fully investigated. This project considers this issue by examining specifically, the vertical distribution and evolution of strain across the GHS and bounding units. A variety of techniques, that include SEM electron back scattered diffraction (EBSD) and anisotropy of magnetic susceptibility (AMS) will be used to analyse samples collected during recent field work in the Annapurna-Dhaulagiri Himal, central Nepal. These samples were collected from two transects along the Modi Khola valley and the Kali Gandaki valley. EBSD will be used to measure the lattice preferred orientation of individual mineral phases of these samples, providing a proxy for strain and valuable information on deformation mechanisms. Given specific magnetic carriers, AMS will be used to provide a proxy for finite strain in samples that are too heterogeneous for EBSD. Combined EBSD and AMS data will be augmented by additional strain and vorticity data collected via optical microscopy. The resulting strain data set will be used to determine a vertical strain profile for the Himalayan orogen. This profile will be coupled with existing geochronometric and thermobarometric data to determine the kinematics of the Greater Himalayan Sequence and will provide a means of critically assessing the strain distribution predicted by current channel flow models for the Himalayan orogen.

  16. Thermal metamorphism of the Arunachal Himalaya, India: Raman thermometry and thermochronological constraints on the tectono-thermal evolution

    NASA Astrophysics Data System (ADS)

    Mathew, George; De Sarkar, Sharmistha; Pande, Kanchan; Dutta, Suryendu; Ali, Shakir; Rai, Apritam; Netrawali, Shilpa

    2013-05-01

    Determination of the peak thermal condition is vital in order to understand tectono-thermal evolution of the Himalayan belt. The Lesser Himalayan Sequence (LHS) in the Western Arunachal Pradesh, being rich in carbonaceous material (CM), facilitates the determination of peak metamorphic temperature based on Raman spectroscopy of carbonaceous material (RSCM). In this study, we have used RSCM method of Beyssac et al. (J Metamorph Geol 20:859-871, 2002a) and Rahl et al. (Earth Planet Sci Lett 240:339-354, 2005) to estimate the thermal history of LHS and Siwalik foreland from the western Arunachal Pradesh. The study indicates that the temperature of 700-800 °C in the Greater Himalayan Sequence (GHS) decreases to 650-700 °C in the main central thrust zone (MCTZ) and decreases further to <200 °C in the Mio-Pliocene sequence of Siwaliks. The work demonstrates greater reliability of Rahl et al.'s (Earth Planet Sci Lett 240:339-354, 2005) RSCM method for temperatures >600 and <340 °C. We show that the higher and lower zones of Bomdila Gneiss (BG) experienced temperature of ~600 °C and exhumed at different stages along the Bomdila Thrust (BT) and Upper Main Boundary Thrust (U.MBT). Pyrolysis analysis of the CM together with the Fission Track ages from upper Siwaliks corroborates the RSCM thermometry estimate of ~240 °C. The results indicate that the Permian sequence north of Lower MBT was deposited at greater depths (>12 km) than the upper Siwalik sediments to its south at depths <8 km before they were exhumed. The 40Ar/39Ar ages suggest that the upper zones of Se La evolved ~13-15 Ma. The middle zone exhumed at ~11 Ma and lower zone close to ~8 Ma indicating erosional unroofing of the MCT sheet. The footwall of MCTZ cooled between 6 and 8 Ma. Analyses of P-T path imply that LHS between MCT and U.MBT zone falls within the kyanite stability field with near isobaric condition. At higher structural level, the temperatures increase gradually with P-T conditions in the sillimanite stability field. The near isothermal (700-800 °C) condition in the GHS, isobaric condition in the MCTZ together with T-t path evidence of GHS that experienced relatively longer duration of near peak temperatures and rapid cooling towards MCTZ, compares the evolution of GHS and inverted metamorphic gradient closely to channel flow predictions.

  17. Physiological significance of ghrelin revealed by studies using genetically engineered mouse models with modifications in the ghrelin system.

    PubMed

    Ariyasu, Hiroyuki; Akamizu, Takashi

    2015-01-01

    Ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R or ghrelin receptor), is a 28-amino acid acylated peptide mainly produced in the stomach. The pharmacological administration of ghrelin is known to exert diverse effects, such as stimulating GH secretion, promoting food intake, and increasing adiposity. In recent years, genetically engineered mouse models have provided important insights into the physiology of various hormones. In this review, we discuss current knowledge regarding the physiological significance of ghrelin on the basis of studies using genetically engineered mouse models with modifications in the ghrelin system. PMID:26226836

  18. Identifying the ionically bound cell wall and intracellular glycoside hydrolases in late growth stage Arabidopsis stems: implications for the genetic engineering of bioenergy crops

    PubMed Central

    Wei, Hui; Brunecky, Roman; Donohoe, Bryon S.; Ding, Shi-You; Ciesielski, Peter N.; Yang, Shihui; Tucker, Melvin P.; Himmel, Michael E.

    2015-01-01

    Identifying the cell wall-ionically bound glycoside hydrolases (GHs) in Arabidopsis stems is important for understanding the regulation of cell wall integrity. For cell wall proteomics studies, the preparation of clean cell wall fractions is a challenge since cell walls constitute an open compartment, which is more likely to contain a mixture of intracellular and extracellular proteins due to cell leakage at the late growth stage. Here, we utilize a CaCl2-extraction procedure to isolate non-structural proteins from Arabidopsis whole stems, followed by the in-solution and in-gel digestion methods coupled with Nano-LC-MS/MS, bioinformatics and literature analyses. This has led to the identification of 75 proteins identified using the in-solution method and 236 proteins identified by the in-gel method, among which about 10% of proteins predicted to be secreted. Together, eight cell wall proteins, namely AT1G75040, AT5G26000, AT3G57260, AT4G21650, AT3G52960, AT3G49120, AT5G49360, and AT3G14067, were identified by the in-solution method; among them, three were the GHs (AT5G26000, myrosinase 1, GH1; AT3G57260, β-1,3-glucanase 2, GH17; AT5G49360, bifunctional XYL 1/α-L-arabinofuranosidase, GH3). Moreover, four more GHs: AT4G30270 (xyloglucan endotransferase, GH16), AT1G68560 (bifunctional α-l-arabinofuranosidase/XYL, GH31), AT1G12240 (invertase, GH32) and AT2G28470 (β-galactosidase 8, GH35), were identified by the in-gel solution method only. Notably, more than half of above identified GHs are xylan- or hemicellulose-modifying enzymes, and will likely have an impact on cellulose accessibility, which is a critical factor for downstream enzymatic hydrolysis of plant tissues for biofuels production. The implications of these cell wall proteins identified at the late growth stage for the genetic engineering of bioenergy crops are discussed. PMID:26029221

  19. Development of a new device for precise timing

    NASA Astrophysics Data System (ADS)

    Hayamizu, Tsutomu; Soma, Mitsuru; Geshiro, Hiroyuki; Hashiguchi, Takashi

    2001-09-01

    The Japanese shortwave time signals JJY were shut down on 2001 March 31st. Astronomers who have been using JJY are seeking alternative methods for precise timing. We designed equipment, called the GHS Clock, that can be used with inexpensive GPS receivers to produce both an LED flash and a pip sound at the beginning of each second. According to the GPS receiver manual, this device has an accuracy better than 500 nano-seconds, and our tests show that it usually has an accuracy better than 200 nano-seconds.

  20. Is increasing MB ratio a positive indicator of declining leprosy?

    PubMed

    Kumar, Anil; Girdhar, B K

    2006-03-01

    In recent years, an increasing MB ratio-trend has been seen in most state reported leprosy data in India and elsewhere. The programme of leprosy all over the world has been integrated with general health system (GHS). This has given rise to gross under reporting of leprosy cases and increasing MB ratio. This paper examines this critical issue and attempt to find out the causes of this trend. The findings suggest clearly that increasing MB ratio is the result of early cases of leprosy being missed out. This can be to the extent of 73% when MB ratio is reached to 47.5%. PMID:17370687

  1. Developing an inverted Barrovian sequence; insights from monazite petrochronology

    NASA Astrophysics Data System (ADS)

    Mottram, Catherine M.; Warren, Clare J.; Regis, Daniele; Roberts, Nick M. W.; Harris, Nigel B. W.; Argles, Tom W.; Parrish, Randall R.

    2014-10-01

    In the Himalayan region of Sikkim, the well-developed inverted metamorphic sequence of the Main Central Thrust (MCT) zone is folded, thus exposing several transects through the structure that reached similar metamorphic grades at different times. In-situ LA-ICP-MS U-Th-Pb monazite ages, linked to pressure-temperature conditions via trace-element reaction fingerprints, allow key aspects of the evolution of the thrust zone to be understood for the first time. The ages show that peak metamorphic conditions were reached earliest in the structurally highest part of the inverted metamorphic sequence, in the Greater Himalayan Sequence (GHS) in the hanging wall of the MCT. Monazite in this unit grew over a prolonged period between ∼37 and 16 Ma in the southerly leading-edge of the thrust zone and between ∼37 and 14.5 Ma in the northern rear-edge of the thrust zone, at peak metamorphic conditions of ∼790 °C and 10 kbar. Monazite ages in Lesser Himalayan Sequence (LHS) footwall rocks show that identical metamorphic conditions were reached ∼4-6 Ma apart along the ∼60 km separating samples along the MCT transport direction. Upper LHS footwall rocks reached peak metamorphic conditions of ∼655 °C and 9 kbar between ∼21 and 16 Ma in the more southerly-exposed transect and ∼14.5-12 Ma in the northern transect. Similarly, lower LHS footwall rocks reached peak metamorphic conditions of ∼580 °C and 8.5 kbar at ∼16 Ma in the south, and 9-10 Ma in the north. In the southern transect, the timing of partial melting in the GHS hanging wall (∼23-19.5 Ma) overlaps with the timing of prograde metamorphism (∼21 Ma) in the LHS footwall, confirming that the hanging wall may have provided the heat necessary for the metamorphism of the footwall. Overall, the data provide robust evidence for progressively downwards-penetrating deformation and accretion of original LHS footwall material to the GHS hanging wall over a period of ∼5 Ma. These processes appear to have occurred several times during the prolonged ductile evolution of the thrust. The preserved inverted metamorphic sequence therefore documents the formation of sequential ‘paleo-thrusts’ through time, cutting down from the original locus of MCT movement at the LHS-GHS protolith boundary and forming at successively lower pressure and temperature conditions. The petrochronologic methods applied here constrain a complex temporal and thermal deformation history, and demonstrate that inverted metamorphic sequences can preserve a rich record of the duration of progressive ductile thrusting.

  2. Novel expression and functional role of ghrelin in chicken ovary.

    PubMed

    Sirotkin, A V; Grossmann, R; María-Peon, M T; Roa, J; Tena-Sempere, M; Klein, S

    2006-09-26

    Ghrelin has recently emerged as pleiotropic regulator of a wide array of endocrine and non-endocrine functions. The former likely includes the control of gonadal function, as expression of ghrelin and its putative receptor, the GH secretagogue receptor type 1a (GHS-R1a), has been described in mammalian gonads, and direct effects of ghrelin in the control of testicular secretion and cell proliferation have been reported. Yet, the expression and/or functional role of ghrelin in gonads from non-mammalian species remain to be analyzed. The present study aimed to evaluate the expression of ghrelin and GHS-R genes in the chicken ovary, and to assess the potential involvement of ghrelin in the direct control of chick ovarian function. To this end, RT-PCR assays for ghrelin and GHS-R1a mRNAs were performed in ovarian tissue, and cultures of chicken ovarian cells were conducted in the presence of increasing doses (1, 10 or 100 ng/ml) of the ghrelin analog, ghrelin 1-18. Our results demonstrate that both ghrelin and GHS-R1a mRNAs are expressed in chick ovarian tissue. Moreover, challenge of ovarian granulosa cells with ghrelin 1-18 was able to induce markers of proliferation (i.e. expression of both PCNA and cyclin), and to modulate markers of apoptosis (i.e. decreased expression of caspase-3, bax, bcl-2 and TUNEL-positive cells). Moreover, ghrelin 1-18 increased the expression of PCNA, cyclin, bax and p53 in cultures of ovarian follicular fragments, where it also stimulated the release of progesterone, estradiol, arginine-vasotocin (AVT) and IGF-I, but not of testosterone. In conclusion, our study provides novel evidence for the gonadal expression of the genes encoding ghrelin and its cognate receptor in a non-mammalian species, i.e. the chicken ovary, and unravels the potential involvement of this newly discovered molecule in the control of key gonadal functions in the chick, such as proliferation, apoptosis, and hormone release. PMID:16891055

  3. Empirical constraints on extrusion mechanisms from the upper margin of an exhumed high-grade orogenic core, Sutlej valley, NW India

    NASA Astrophysics Data System (ADS)

    Chambers, Jennifer; Caddick, Mark; Argles, Tom; Horstwood, Matthew; Sherlock, Sarah; Harris, Nigel; Parrish, Randall; Ahmad, Talat

    2009-11-01

    The Early-Middle Miocene exhumation of the crystalline core of the Himalaya is a relatively well-understood process compared to the preceding phase of burial and prograde metamorphism in the Eocene-Oligocene. Highly deformed rocks of the Greater Himalayan Sequence (GHS) dominate the crystalline core, and feature a strong metamorphic and structural overprint related to the younger exhumation. The Tethyan Sedimentary Series was tectonically separated from the underlying GHS during the Miocene by the South Tibetan Detachment, and records a protracted and complex history of Cenozoic deformation. Unfortunately these typically low-grade or unmetamorphosed rocks generally yield little quantitative pressure-temperature-time information to accompany this deformation history. In parts of the western Himalaya, however, the basal unit of the Tethyan Sedimentary Series (the Haimanta Group) includes pelites metamorphosed to amphibolite facies. This presents a unique opportunity to explore the tectono-thermal evolution of crystalline rocks which record the early history of the orogen. Pressure-temperature-time-deformation ( P-T-t-d) paths modelled for two Haimanta Group pelitic rocks reveal three distinct stages of metamorphism: (1) prograde Barrovian metamorphism to 610-620 °C at c. 7-8 kbars, with garnet growing over an early tectonic fabric (S 1); (2) initial decompression during heating to 640-660 °C at c. 6-7 kbars, with development of a pervasive crenulation cleavage (S 2) and staurolite and kyanite porphyroblast growth; (3) further exhumation during cooling, with minor retrograde metamorphism and modification of the pervasive S 2 fabric. Monazite growth ages constrain the timing of initial garnet growth (> 34 Ma), the start of D 2 and maximum burial (c. 30 Ma), and the termination of garnet growth (c. 28 Ma). Muscovite Ar/Ar ages indicate cooling through c. 300 °C at c. 13 Ma, from which we derive an initial exhumation rate of c. 1.3 mm year - 1 for the Haimanta Group. The underlying GHS was exhumed at a rate of 2.2 to 3 mm year - 1 during this time. The difference in exhumation rate between these two units is considered to reflect Early Miocene displacement on the intervening South Tibetan Detachment. Slower exhumation (c. 0.6 mm year - 1 ) of both units after c. 13 Ma followed the cessation of major displacement on this structure, after which time the Haimanta Group and the GHS were exhumed as one relatively coherent tectonic block.

  4. A generalized hard-sphere model for Monte Carlo simulation

    NASA Technical Reports Server (NTRS)

    Hassan, H. A.; Hash, David B.

    1993-01-01

    A new molecular model, called the generalized hard-sphere, or GHS model, is introduced. This model contains, as a special case, the variable hard-sphere model of Bird (1981) and is capable of reproducing all of the analytic viscosity coefficients available in the literature that are derived for a variety of interaction potentials incorporating attraction and repulsion. In addition, a new procedure for determining interaction potentials in a gas mixture is outlined. Expressions needed for implementing the new model in the direct simulation Monte Carlo methods are derived. This development makes it possible to employ interaction models that have the same level of complexity as used in Navier-Stokes calculations.

  5. Visit the journal at http://www.elsevier.nl/locate/jnlnr/00212 Geologic control of Sr and major element chemistry in Himalayan Rivers, Nepal

    NASA Astrophysics Data System (ADS)

    English, N. B.; Quade, J.; DeCelles, P. G.; Garzione, C. N.

    2000-08-01

    Our study of the Seti River in far western Nepal shows that the solute chemistry of the river and its tributaries is strongly controlled by geology. The Seti flows through four distinct terranes, starting with the Tethyan sedimentary series (TSS) and Greater Himalayan series (GHS). TSS/GHS waters display 87Sr/ 86Sr ratios of <0.73 and high Sr and Ca, consistent with the composition of limestone and marble common in these terranes. The 87Sr/ 86Sr ratio and Mg increase markedly as the river passes into the Lesser Himalayan series (LHS), where tributaries have 87Sr/ 86Sr ratios from 0.75 to 1.02 and high Sr, Ca, and Mg. The high Mg in LHS waters correlate with high 87Sr/ 86Sr ratios, which we attribute to weathering of highly radiogenic (0.71-0.82) dolostones. Tributaries to the Seti River draining the largely carbonate-free Dadeldhura thrust sheet (DTS) have ratios near 0.74, but low Sr, Ca, and Mg and therefore have little impact on Seti mainstem chemistry. Mass balance calculations and CaMg-weathering indices show that carbonate weathering accounts for >70% of total dissolved solids to the Seti River. Sr/Ca ratios of river waters provide a minimum estimate of the %-carbonate weathering contribution to Sr, due to partitioning of Sr and Ca during incongruent dissolution and reprecipitation of calcite. Overall, we attribute high 87Sr/ 86Sr ratios in the Seti River and its tributaries to the weathering of metacarbonates (especially dolostones in the upper Nawakhot Group) which have exchanged Sr with silicates during metamorphism. Our modeling of Sr fluxes in the Seti River indicates that the TSS/GHS accounts for 36-39% of the Sr, the LHS for 40-53%, and 8-23% for the DTS. Prior to exposure of LHS rocks at ˜12 Ma, TSS and GHS carbonates with low 87Sr/ 86Sr ratios dominated Himalayan rivers. We attribute the elevated 87Sr/ 86Sr ratios of Himalayan paleorivers during the late Miocene and Pliocene to exposure and weathering of LHS metacarbonates.

  6. Nephrolithiasis: Molecular Mechanism of Renal Stone Formation and the Critical Role Played by Modulators

    PubMed Central

    Aggarwal, Kanu Priya; Narula, Shifa; Kakkar, Monica

    2013-01-01

    Urinary stone disease is an ailment that has afflicted human kind for many centuries. Nephrolithiasis is a significant clinical problem in everyday practice with a subsequent burden for the health system. Nephrolithiasis remains a chronic disease and our fundamental understanding of the pathogenesis of stones as well as their prevention and cure still remains rudimentary. Regardless of the fact that supersaturation of stone-forming salts in urine is essential, abundance of these salts by itself will not always result in stone formation. The pathogenesis of calcium oxalate stone formation is a multistep process and essentially includes nucleation, crystal growth, crystal aggregation, and crystal retention. Various substances in the body have an effect on one or more of the above stone-forming processes, thereby influencing a person's ability to promote or prevent stone formation. Promoters facilitate the stone formation while inhibitors prevent it. Besides low urine volume and low urine pH, high calcium, sodium, oxalate and urate are also known to promote calcium oxalate stone formation. Many inorganic (citrate, magnesium) and organic substances (nephrocalcin, urinary prothrombin fragment-1, osteopontin) are known to inhibit stone formation. This review presents a comprehensive account of the mechanism of renal stone formation and the role of inhibitors/promoters in calcium oxalate crystallisation. PMID:24151593

  7. Clinical, demographic, and laboratory characteristics of children with nephrolithiasis.

    PubMed

    Sas, David J; Becton, Lauren J; Tutman, Jeffrey; Lindsay, Laura A; Wahlquist, Amy H

    2016-06-01

    While the incidence of pediatric kidney stones appears to be increasing, little is known about the demographic, clinical, laboratory, imaging, and management variables in this patient population. We sought to describe various characteristics of our stone-forming pediatric population. To that end, we retrospectively reviewed the charts of pediatric patients with nephrolithiasis confirmed by imaging. Data were collected on multiple variables from each patient and analyzed for trends. For body mass index (BMI) controls, data from the general pediatrics population similar to our nephrolithiasis population were used. Data on 155 pediatric nephrolithiasis patients were analyzed. Of the 54 calculi available for analysis, 98 % were calcium based. Low urine volume, elevated supersaturation of calcium phosphate, elevated supersaturation of calcium oxalate, and hypercalciuria were the most commonly identified abnormalities on analysis of 24-h urine collections. Our stone-forming population did not have a higher BMI than our general pediatrics population, making it unlikely that obesity is a risk factor for nephrolithiasis in children. More girls presented with their first stone during adolescence, suggesting a role for reproductive hormones contributing to stone risk, while boys tended to present more commonly at a younger age, though this did not reach statistical significance. These intriguing findings warrant further investigation. PMID:26467033

  8. Prophylactic and therapeutic properties of a sodium citrate preparation in the management of calcium oxalate urolithiasis: randomized, placebo-controlled trial.

    PubMed

    Allie-Hamdulay, Shameez; Rodgers, Allen L

    2005-05-01

    The purpose of this study was to investigate the prophylactic and therapeutic effects of a hitherto untested preparation containing sodium citrate in the management of calcium oxalate urolithiasis. In this study, a host of calcium oxalate kidney stone risk factors was investigated using a randomised, placebo controlled, "within-patient" clinical trial. The trial involved four groups of subjects: healthy male controls, healthy female controls , calcium oxalate stone-forming males and calcium oxalate stone-forming females. There were 30 subjects in each group. Twenty subjects in each group ingested the preparation containing sodium citrate and ten subjects in each group ingested a placebo for 7 days. Collection of 24 h urines were carried out at baseline, at day 7 and day 10 (i.e. 3 days after suspension of drug/placebo ingestion). These were analysed for biochemical and physicochemical risk factors. They were also tested for their inhibitory properties in crystallization experiments. Data were statistically analyzed using analysis of variance (ANOVA). Key risk factors were significantly and beneficially altered across all groups after ingestion of the preparation. The pH and urinary citrate excretion increased while urinary oxalate and calcium excretions decreased, as did relative supersaturations of calcium oxalate and uric acid. In addition, inhibition of calcium oxalate crystallization increased. Beneficial carryover effects were observed for some risk factors. The results of this study have demonstrated, for the first time, that a sodium citrate-containing preparation favourably alters the risk factors for calcium oxalate urolithiasis. PMID:15871014

  9. Effect of renal insufficiency on stone recurrence in patients with urolithiasis.

    PubMed

    Kang, Ho Won; Seo, Sung Phil; Kim, Won Tae; Kim, Yong-June; Yun, Seok-Joong; Lee, Sang-Cheol; Kim, Wun-Jae

    2014-08-01

    The study was designed to assess the relationship between glomerular filtration rate (GFR) and urinary stone-forming constituents, and to assess the effect of renal insufficiency on stone recurrence risk in first stone formers (SF). Baseline serum creatinine levels were obtained, and renal insufficiency was defined as creatinine clearance ≤60 mL/min (Cockroft-Gault). This retrospective case-control study consists of 342 first SF; 171 SF with normal renal function were selected with 1:1 propensity scores matched to 171 SF with renal insufficiency. Urinary metabolic evaluation was compared to renal function. GFR was positively correlated with urinary calcium, uric acid, and citrate excretion. Subjects with renal insufficiency had significantly lower urinary calcium, uric acid, and citrate excretion than those with normal renal function, but not urine volume. With regard to urinary metabolic abnormalities, similar results were obtained. SF with renal insufficiency had lower calcium oxalate supersaturation indexes and stone recurrence rates than SF with normal renal function. Kaplan-Meier curves showed similar results. In conclusion, GFR correlates positively with urinary excretion of stone-forming constituents in SF. This finding implies that renal insufficiency is not a risk factor for stone recurrence. PMID:25120325

  10. Mathematical model to estimate risk of calcium-containing renal stones

    NASA Technical Reports Server (NTRS)

    Pietrzyk, R. A.; Feiveson, A. H.; Whitson, P. A.

    1999-01-01

    BACKGROUND/AIMS: Astronauts exposed to microgravity during the course of spaceflight undergo physiologic changes that alter the urinary environment so as to increase the risk of renal stone formation. This study was undertaken to identify a simple method with which to evaluate the potential risk of renal stone development during spaceflight. METHOD: We used a large database of urinary risk factors obtained from 323 astronauts before and after spaceflight to generate a mathematical model with which to predict the urinary supersaturation of calcium stone forming salts. RESULT: This model, which involves the fewest possible analytical variables (urinary calcium, citrate, oxalate, phosphorus, and total volume), reliably and accurately predicted the urinary supersaturation of the calcium stone forming salts when compared to results obtained from a group of 6 astronauts who collected urine during flight. CONCLUSIONS: The use of this model will simplify both routine medical monitoring during spaceflight as well as the evaluation of countermeasures designed to minimize renal stone development. This model also can be used for Earth-based applications in which access to analytical resources is limited.

  11. Renal stone risk assessment during Space Shuttle flights

    NASA Technical Reports Server (NTRS)

    Whitson, P. A.; Pietrzyk, R. A.; Pak, C. Y.

    1997-01-01

    PURPOSE: The metabolic and environmental factors influencing renal stone formation before, during, and after Space Shuttle flights were assessed. We established the contributing roles of dietary factors in relationship to the urinary risk factors associated with renal stone formation. MATERIALS AND METHODS: 24-hr. urine samples were collected prior to, during space flight, and following landing. Urinary and dietary factors associated with renal stone formation were analyzed and the relative urinary supersaturation of calcium oxalate, calcium phosphate (brushite), sodium urate, struvite and uric acid were calculated. RESULTS: Urinary composition changed during flight to favor the crystallization of calcium-forming salts. Factors that contributed to increased potential for stone formation during space flight were significant reductions in urinary pH and increases in urinary calcium. Urinary output and citrate, a potent inhibitor of calcium-containing stones, were slightly reduced during space flight. Dietary intakes were significantly reduced for a number of variables, including fluid, energy, protein, potassium, phosphorus and magnesium. CONCLUSIONS: This is the first in-flight characterization of the renal stone forming potential in astronauts. With the examination of urinary components and nutritional factors, it was possible to determine the factors that contributed to increased risk or protected from risk. In spite of the protective components, the negative contributions to renal stone risk predominated and resulted in a urinary environment that favored the supersaturation of stone-forming salts. Dietary and pharmacologic therapies need to be assessed to minimize the potential for renal stone formation in astronauts during/after space flight.

  12. Effect of Renal Insufficiency on Stone Recurrence in Patients with Urolithiasis

    PubMed Central

    2014-01-01

    The study was designed to assess the relationship between glomerular filtration rate (GFR) and urinary stone-forming constituents, and to assess the effect of renal insufficiency on stone recurrence risk in first stone formers (SF). Baseline serum creatinine levels were obtained, and renal insufficiency was defined as creatinine clearance ≤60 mL/min (Cockroft-Gault). This retrospective case-control study consists of 342 first SF; 171 SF with normal renal function were selected with 1:1 propensity scores matched to 171 SF with renal insufficiency. Urinary metabolic evaluation was compared to renal function. GFR was positively correlated with urinary calcium, uric acid, and citrate excretion. Subjects with renal insufficiency had significantly lower urinary calcium, uric acid, and citrate excretion than those with normal renal function, but not urine volume. With regard to urinary metabolic abnormalities, similar results were obtained. SF with renal insufficiency had lower calcium oxalate supersaturation indexes and stone recurrence rates than SF with normal renal function. Kaplan-Meier curves showed similar results. In conclusion, GFR correlates positively with urinary excretion of stone-forming constituents in SF. This finding implies that renal insufficiency is not a risk factor for stone recurrence. Graphical Abstract PMID:25120325

  13. Recombinant protein production facility for fungal biomass-degrading enzymes using the yeast Pichia pastoris

    PubMed Central

    Haon, Mireille; Grisel, Sacha; Navarro, David; Gruet, Antoine; Berrin, Jean-Guy; Bignon, Christophe

    2015-01-01

    Filamentous fungi are the predominant source of lignocellulolytic enzymes used in industry for the transformation of plant biomass into high-value molecules and biofuels. The rapidity with which new fungal genomic and post-genomic data are being produced is vastly outpacing functional studies. This underscores the critical need for developing platforms dedicated to the recombinant expression of enzymes lacking confident functional annotation, a prerequisite to their functional and structural study. In the last decade, the yeast Pichia pastoris has become increasingly popular as a host for the production of fungal biomass-degrading enzymes, and particularly carbohydrate-active enzymes (CAZymes). This study aimed at setting-up a platform to easily and quickly screen the extracellular expression of biomass-degrading enzymes in P. pastoris. We first used three fungal glycoside hydrolases (GHs) that we previously expressed using the protocol devised by Invitrogen to try different modifications of the original protocol. Considering the gain in time and convenience provided by the new protocol, we used it as basis to set-up the facility and produce a suite of fungal CAZymes (GHs, carbohydrate esterases and auxiliary activity enzyme families) out of which more than 70% were successfully expressed. The platform tasks range from gene cloning to automated protein purifications and activity tests, and is open to the CAZyme users’ community. PMID:26441929

  14. A Novel Member of GH16 Family Derived from Sugarcane Soil Metagenome.

    PubMed

    Alvarez, Thabata Maria; Liberato, Marcelo Vizoná; Cairo, João Paulo L Franco; Paixão, Douglas A A; Campos, Bruna M; Ferreira, Marcel R; Almeida, Rodrigo F; Pereira, Isabela O; Bernardes, Amanda; Ematsu, Gabriela C G; Chinaglia, Mariana; Polikarpov, Igor; de Oliveira Neto, Mario; Squina, Fabio Marcio

    2015-09-01

    Glycoside hydrolases (GHs) are enzymes found in all living kingdoms that are involved in multiple physiological functions. Due to their multiple enzymatic activities, GHs are broadly applied in bioethanol, food, and paper industry. In order to increase the productivity of these industrial processes, a constant search for novel and efficient enzymes has been proved to be necessary. In this context, metagenomics is a powerful approach to achieve this demand. In the current study, we describe the discovery and characterization of a novel member of GH16 family derived from the sugarcane soil metagenome. The enzyme, named SCLam, has 286 amino acid residues and displays sequence homology and activity properties that resemble known laminarases. SCLam is active against barley beta-glucan, laminarin, and lichenan (72, 33, and 10 U mg(-1), respectively). The optimal reaction conditions were identified as 40 °C and pH 6.5. The low-resolution structure was determined using the small-angle X-ray scattering technique, revealing that SCLam is a monomer in solution with a radius of gyration equal to 19.6 Å. To the best of our knowledge, SCLam is the first nonspecific (1,3/1,3:1,4)-β-D-glucan endohydrolase (EC 3.2.1.6) recovered by metagenomic approach to be characterized. PMID:26242386

  15. Lignocellulose degradation mechanisms across the Tree of Life.

    PubMed

    Cragg, Simon M; Beckham, Gregg T; Bruce, Neil C; Bugg, Timothy D H; Distel, Daniel L; Dupree, Paul; Etxabe, Amaia Green; Goodell, Barry S; Jellison, Jody; McGeehan, John E; McQueen-Mason, Simon J; Schnorr, Kirk; Walton, Paul H; Watts, Joy E M; Zimmer, Martin

    2015-12-01

    Organisms use diverse mechanisms involving multiple complementary enzymes, particularly glycoside hydrolases (GHs), to deconstruct lignocellulose. Lytic polysaccharide monooxygenases (LPMOs) produced by bacteria and fungi facilitate deconstruction as does the Fenton chemistry of brown-rot fungi. Lignin depolymerisation is achieved by white-rot fungi and certain bacteria, using peroxidases and laccases. Meta-omics is now revealing the complexity of prokaryotic degradative activity in lignocellulose-rich environments. Protists from termite guts and some oomycetes produce multiple lignocellulolytic enzymes. Lignocellulose-consuming animals secrete some GHs, but most harbour a diverse enzyme-secreting gut microflora in a mutualism that is particularly complex in termites. Shipworms however, house GH-secreting and LPMO-secreting bacteria separate from the site of digestion and the isopod Limnoria relies on endogenous enzymes alone. The omics revolution is identifying many novel enzymes and paradigms for biomass deconstruction, but more emphasis on function is required, particularly for enzyme cocktails, in which LPMOs may play an important role. PMID:26583519

  16. Molten sodium-induced graphitization towards highly crystalline and hierarchical porous graphene frameworks

    NASA Astrophysics Data System (ADS)

    Wang, Huanwen; Zhang, Yu; Wu, Xing-Long; Fan, Haosen; Luo, Zhong-Zhen; Madhavi, Srinivasan; Yan, Qingyu

    2015-09-01

    Mass production of high quality graphene platelets has attracted considerable interest for potential applications in various fields. Nevertheless, in literature, the graphite oxide (GO)-derived graphene is always lacking high crystallinity and hierarchical porosity. Herein, we report a new molten sodium-induced graphitization for mass-fabricating highly crystalline and porous graphene sheets. The 3D graphene hydrogels (GHs) obtained from GO by the hydrothermal self-assembly are directly annealed in molten sodium at 800 °C. As a result, the D band intensity in Raman spectroscopy is reduced significantly, while 2D band intensity is increased prominently, which is a typical characteristic of highly crystalline graphene. More importantly, the resulting Na-GFs-800 sample exhibits increased surface area and narrow mesopore size distribution (∼3.6 nm). The excellent supercapacitive performance of Na-GFs-800 has been demonstrated in an organic symmetric system. Meanwhile, the possible interaction mechanism between molten sodium and GHs has been proposed in the text.

  17. Gene-targeted metagenomic analysis of glucan-branching enzyme gene profiles among human and animal fecal microbiota

    PubMed Central

    Lee, Sunghee; Cantarel, Brandi; Henrissat, Bernard; Gevers, Dirk; Birren, Bruce W; Huttenhower, Curtis; Ko, GwangPyo

    2014-01-01

    Glycoside hydrolases (GHs), the enzymes that breakdown complex carbohydrates, are a highly diversified class of key enzymes associated with the gut microbiota and its metabolic functions. To learn more about the diversity of GHs and their potential role in a variety of gut microbiomes, we used a combination of 16S, metagenomic and targeted amplicon sequencing data to study one of these enzyme families in detail. Specifically, we employed a functional gene-targeted metagenomic approach to the 1-4-α-glucan-branching enzyme (gBE) gene in the gut microbiomes of four host species (human, chicken, cow and pig). The characteristics of operational taxonomic units (OTUs) and operational glucan-branching units (OGBUs) were distinctive in each of hosts. Human and pig were most similar in OTUs profiles while maintaining distinct OGBU profiles. Interestingly, the phylogenetic profiles identified from 16S and gBE gene sequences differed, suggesting the presence of different gBE genes in the same OTU across different vertebrate hosts. Our data suggest that gene-targeted metagenomic analysis is useful for an in-depth understanding of the diversity of a particular gene of interest. Specific carbohydrate metabolic genes appear to be carried by distinct OTUs in different individual hosts and among different vertebrate species' microbiomes, the characteristics of which differ according to host genetic background and/or diet. PMID:24108330

  18. A Trapped Covalent Intermediate of a Glycoside Hydrolase on the Pathway to Transglycosylation. Insights from Experiments and Quantum Mechanics/Molecular Mechanics Simulations.

    PubMed

    Raich, Lluís; Borodkin, Vladimir; Fang, Wenxia; Castro-López, Jorge; van Aalten, Daan M F; Hurtado-Guerrero, Ramón; Rovira, Carme

    2016-03-16

    The conversion of glycoside hydrolases (GHs) into transglycosylases (TGs), i.e., from enzymes that hydrolyze carbohydrates to enzymes that synthesize them, represents a promising solution for the large-scale synthesis of complex carbohydrates for biotechnological purposes. However, the lack of knowledge about the molecular details of transglycosylation hampers the rational design of TGs. Here we present the first crystallographic structure of a natural glycosyl-enzyme intermediate (GEI) of Saccharomyces cerevisiae Gas2 in complex with an acceptor substrate and demonstrate, by means of quantum mechanics/molecular mechanics metadynamics simulations, that it is tuned for transglycosylation (ΔG(⧧) = 12 kcal/mol). The 2-OH···nucleophile interaction is found to be essential for catalysis: its removal raises the free energy barrier significantly (11 and 16 kcal/mol for glycosylation and transglycosylation, respectively) and alters the conformational itinerary of the substrate (from (4)C1 → [(4)E](⧧) → (1,4)B/(4)E to (4)C1 → [(4)H3](⧧) → (4)C1). Our results suggest that changes in the interactions involving the 2-position could have an impact on the transglycosylation activity of several GHs. PMID:26859322

  19. Acute Toxicity Comparison of Single-Walled Carbon Nanotubes in Various Freshwater Organisms

    PubMed Central

    Chung, Young Shin; Kim, Tae Gyu; Kim, Jin Kwon; Lee, Ji Hyun; Lee, Yong Hwa; Kang, Sung Wook

    2015-01-01

    While the commercialization of single-walled carbon nanotubes (SWCNTs) is rapidly expanding, the environmental impact of this nanomaterial is not well understood. Therefore, the present study evaluates the acute aquatic toxicity of SWCNTs towards two freshwater microalgae (Raphidocelis subcapitata and Chlorella vulgaris), a microcrustacean (Daphnia magna), and a fish (Oryzias latipes) based on OECD test guidelines (201, 202, and 203). According to the results, the SWCNTs inhibited the growth of the algae R. subcapitata and C. vulgaris with a median effective concentration (EC50) of 29.99 and 30.96 mg/L, respectively, representing “acute category 3” in the Globally Harmonized System (GHS) of classification and labeling of chemicals. Meanwhile, the acute toxicity test using O. latipes and D. magna did not show any mortality/immobilizing effects up to a concentration of 100.00 mg/L SWCNTs, indicating no hazard category in the GHS classification. In conclusion, SWCNTs were found to induce acute ecotoxicity in freshwater microalgae, yet not in D. magna and medaka fish. PMID:25654094

  20. Ghrelin, food intake, and botanical extracts: A Review

    PubMed Central

    Rezaie, Peyman; Mazidi, Mohsen; Nematy, Mohsen

    2015-01-01

    A kind of growth hormone secretagogue (GHS), ghrelin, was first isolated from the rat stomach and plays a major role in the activation of the growth hormone secretagogue receptor 1a (GHS-R1a) resulting the release of growth hormone (GH). The preproghrelin gene is placed on chromosome 3, at locus 3p25 –2 in humans and constitutes five exons and three introns. Ghrelin is most plentifully expressed in particular cells in the oxyntic glands of the gastric epithelium, initially named X/A-like cells. Almost 60-70% of circulating ghrelin is secreted by the stomach. Plasma ghrelin concentration alters throughout the day. Ghrelin has been suggested to act as a meal initiator because of its appetite-stimulating influences in free feeding rats in short period. In addition to ghrelin’s function as a meal motivator, it seems to contribute in long-term energy balance and nutritional status. In addition, many studies have been carried out in order to investigate the effects of natural and medicinal plants and botanical extracts on appetite, food intake, energy hemostasis, and the level of related hormones including ghrelin. Due to the importance of ghrelin in nutritional and medical sciences, this review was performed to understand new aspects of this hormone’s function. PMID:26445708

  1. Quality of Life in Cancer Patients Undergoing Chemotherapy in a Tertiary Care Center in Malwa Region of Punjab

    PubMed Central

    Singh, Harminder; Kaur, Kamalpreet; Banipal, Raja Paramjeet Singh; Singh, Shaminder; Bala, Ritu

    2014-01-01

    Objective: The objective of this prospective, non-interventional, 4-month observational study was to analyze and compare patient-reported quality of life (QOL) and their physical/psychosocial symptom burden during their respective chemotherapy sessions. Materials and Methods: A prospective and descriptive study was carried out jointly by Pharmacology and Oncology Departments of a tertiary care center in Malwa region of Punjab. The data collection was performed by administering validated questionnaire/response after taking informed consent. Results: A total of 131 cancer patients were recruited with the mean age of 49.05 ± 14.35 (SD (standard deviation)) years. As per the QOL scoring of Global Health Status (GHS) and four items of symptom scale, that is, insomnia, pain, appetite loss, and constipation, and financial difficulties attained a significance difference. GHS significantly improved in group three as compared to group one, indicating that the patient's overall health/QOL improved as the chemotherapy session progressed. Conclusion: Although QOL scoring system did not show significant improvement in all areas (except insomnia, pain, appetite loss, constipation, and financial difficulties) with reference to their respective chemotherapy cycles, but a judicious diagnosis with an appropriate treatment including chemotherapy may lessen the negative perception of cancer as a deadly and fatal disease in our rural population. PMID:25125867

  2. Lignocellulose Degradation Mechanisms Across the Tree of Life

    SciTech Connect

    Cragg, Simon M.; Beckham, Gregg T.; Bruce, Neil C.; Bugg, Timothy D. H.; Distel, Daniel L.; Dupree, Paul; Etxabe, Amaia Green; Goodell, Barry S.; Jellison, Jody; McGeehan, John E.; McQueen-Mason, Simon J.; Schnorr, Kirk; Walton, Paul H.; Watts, Joy E. M.; Zimmer, Martin

    2015-11-14

    Organisms use diverse mechanisms involving multiple complementary enzymes, particularly glycoside hydrolases (GHs), to deconstruct lignocellulose. Lytic polysaccharide monooxygenases (LPMOs) produced by bacteria and fungi facilitate deconstruction as does the Fenton chemistry of brown-rot fungi. Lignin depolymerisation is achieved by white-rot fungi and certain bacteria, using peroxidases and laccases. Meta-omics is now revealing the complexity of prokaryotic degradative activity in lignocellulose-rich environments. Protists from termite guts and some oomycetes produce multiple lignocellulolytic enzymes. We found that the Lignocellulose-consuming animals secrete some GHs, but most harbour a diverse enzyme-secreting gut microflora in a mutualism that is particularly complex in termites. Shipworms however, house GH-secreting and LPMO-secreting bacteria separate from the site of digestion and the isopod Limnoria relies on endogenous enzymes alone. Moreover, the omics revolution is identifying many novel enzymes and paradigms for biomass deconstruction, but more emphasis on function is required, particularly for enzyme cocktails, in which LPMOs may play an important role.

  3. Lignocellulose Degradation Mechanisms Across the Tree of Life

    DOE PAGESBeta

    Cragg, Simon M.; Beckham, Gregg T.; Bruce, Neil C.; Bugg, Timothy D. H.; Distel, Daniel L.; Dupree, Paul; Etxabe, Amaia Green; Goodell, Barry S.; Jellison, Jody; McGeehan, John E.; et al

    2015-11-14

    Organisms use diverse mechanisms involving multiple complementary enzymes, particularly glycoside hydrolases (GHs), to deconstruct lignocellulose. Lytic polysaccharide monooxygenases (LPMOs) produced by bacteria and fungi facilitate deconstruction as does the Fenton chemistry of brown-rot fungi. Lignin depolymerisation is achieved by white-rot fungi and certain bacteria, using peroxidases and laccases. Meta-omics is now revealing the complexity of prokaryotic degradative activity in lignocellulose-rich environments. Protists from termite guts and some oomycetes produce multiple lignocellulolytic enzymes. We found that the Lignocellulose-consuming animals secrete some GHs, but most harbour a diverse enzyme-secreting gut microflora in a mutualism that is particularly complex in termites. Shipworms however,more » house GH-secreting and LPMO-secreting bacteria separate from the site of digestion and the isopod Limnoria relies on endogenous enzymes alone. Moreover, the omics revolution is identifying many novel enzymes and paradigms for biomass deconstruction, but more emphasis on function is required, particularly for enzyme cocktails, in which LPMOs may play an important role.« less

  4. Carbohydrate-binding module assisting glycosynthase-catalysed polymerizations.

    PubMed

    Codera, Victoria; Gilbert, Harry J; Faijes, Magda; Planas, Antoni

    2015-08-15

    Carbohydrate-binding modules (CBMs) are found within multi-modular polysaccharide degrading enzymes [glycoside hydrolases (GHs)]. CBMs play a critical role in the recognition of plant cell-wall polysaccharides and enhance the hydrolase activity of their cognate catalytic domains by increasing enzyme substrate proximity. Mimicking their role in Nature, we, in the present study, propose that CBMs may assist in vitro glycosynthase-catalysed polymerization reactions to produce artificial polysaccharides. Glycosynthases are GHs that have been engineered to catalyse glycoside bond formation for the synthesis of oligosaccharides, glycoconjugates and glycans. The degree of polymerization (DP) of the glycans generated is limited by the solubility of the polymeric product. In the present study, we have targeted the synthesis of artificial 1,3-1,4-β-glucans with a regular sequence using the glycosynthase E(134)S derived from a Bacillus licheniformis lichenase. We show that the addition of CBM11, which binds mixed-linked β-glucans, either as an isolated protein or fused to the glycosynthase E(134)S, has an effect on the DP of the polysaccharide products that is dependent on the rate of polymerization. The mechanism by which CBM influences the DP of the synthesized glycans is discussed. PMID:26251443

  5. U(-Th)-Pb age Constraints on the Timing and Duration of Channel Flow in the Mt. Everest Region, Eastern Himalaya

    NASA Astrophysics Data System (ADS)

    Cottle, J. M.; Searle, M. P.; Horstwood, M. S.; Waters, D. J.; Noble, S. R.; Parrish, R. R.

    2007-12-01

    U(-Th)-Pb dating of accessory phases from metamorphic and igneous rocks at two outcrops along a north-south transect in the Mt. Everest region of southern Tibet provides new constraints on the timing and duration of thermal events associated with ductile extrusion of the Greater Himalayan Series (GHS). At the southern-most outcrop in the Kangshung valley, Th-Pb ages from monazite indicate that prograde metamorphism associated with crustal thickening following the India - Asia collision, peaked at least as early as ~39 Ma, ~7 Ma earlier than previously recognized in the GHS of southern Tibet. A subsequent sillimanite grade metamorphic event at ~28 Ma was followed by two phases of leucogranite emplacement at ~21 Ma and ~17 Ma. At Thongmön, 40 km in the down-tectonic transport direction relative to Kangshung valley, prograde metamorphism was occurring at ~25 Ma and lasted until ~16 Ma, reaching ~740°C and 5 kbar at ~22 Ma. Immediately following metamorphism, two phases of leucogranite were emplaced at ~15 Ma and ~12 Ma, with an intervening phase of ductile deformation. These two outcrops record a northward propagation of metamorphic, magmatic and structural events that are ~5-7 Ma younger in the down-tectonic transport direction. This diachroneity in thermal history provides quantitative geological support for previously proposed models of south-directed mid-crustal channel flow, but suggests that the time-scales over which this process operated require significant revision.

  6. Gene-targeted metagenomic analysis of glucan-branching enzyme gene profiles among human and animal fecal microbiota.

    PubMed

    Lee, Sunghee; Cantarel, Brandi; Henrissat, Bernard; Gevers, Dirk; Birren, Bruce W; Huttenhower, Curtis; Ko, GwangPyo

    2014-03-01

    Glycoside hydrolases (GHs), the enzymes that breakdown complex carbohydrates, are a highly diversified class of key enzymes associated with the gut microbiota and its metabolic functions. To learn more about the diversity of GHs and their potential role in a variety of gut microbiomes, we used a combination of 16S, metagenomic and targeted amplicon sequencing data to study one of these enzyme families in detail. Specifically, we employed a functional gene-targeted metagenomic approach to the 1-4-α-glucan-branching enzyme (gBE) gene in the gut microbiomes of four host species (human, chicken, cow and pig). The characteristics of operational taxonomic units (OTUs) and operational glucan-branching units (OGBUs) were distinctive in each of hosts. Human and pig were most similar in OTUs profiles while maintaining distinct OGBU profiles. Interestingly, the phylogenetic profiles identified from 16S and gBE gene sequences differed, suggesting the presence of different gBE genes in the same OTU across different vertebrate hosts. Our data suggest that gene-targeted metagenomic analysis is useful for an in-depth understanding of the diversity of a particular gene of interest. Specific carbohydrate metabolic genes appear to be carried by distinct OTUs in different individual hosts and among different vertebrate species' microbiomes, the characteristics of which differ according to host genetic background and/or diet. PMID:24108330

  7. Episodic molecular evolution of pituitary growth hormone in Cetartiodactyla.

    PubMed

    Maniou, Zoitsa; Wallis, O Caryl; Wallis, Michael

    2004-06-01

    The sequence of growth hormone (GH) is generally strongly conserved in mammals, but episodes of rapid change occurred during the evolution of primates and artiodactyls, when the rate of GH evolution apparently increased substantially. As a result the sequences of higher primate and ruminant GHs differ markedly from sequences of other mammalian GHs. In order to increase knowledge of GH evolution in Cetartiodactyla (Artiodactyla plus Cetacea) we have cloned and characterized GH genes from camel (Camelus dromedarius), hippopotamus (Hippopotamus amphibius), and giraffe (Giraffa camelopardalis), using genomic DNA and a polymerase chain reaction technique. As in other mammals, these GH genes comprise five exons and four introns. Two very similar GH gene sequences (encoding identical proteins) were found in each of hippopotamus and giraffe. The deduced sequence for the mature hippopotamus GH is identical to that of dolphin, in accord with current ideas of a close relationship between Cetacea and Hippopotamidae. The sequence of camel GH is identical to that reported previously for alpaca GH. The sequence of giraffe GH is very similar to that of other ruminants but differs from that of nonruminant cetartiodactyls at about 18 residues. The results demonstrate that the apparent burst of rapid evolution of GH occurred largely after the separation of the line leading to ruminants from other cetartiodactyls. PMID:15461431

  8. Transitional change in rat fetal cell proliferation in response to ghrelin and des-acyl ghrelin during the last stage of pregnancy

    SciTech Connect

    Inoue, Yoshiyuki; Nakahara, Keiko; Kangawa, Kenji; Murakami, Noboru

    2010-03-12

    Expression of mRNA for the ghrelin receptor, GHS-R1a, was detected in various peripheral and central tissues of fetal rats, including skin, bone, heart, liver, gut, brain and spinal cord, on embryonic day (ED)15 and ED17. However, its expression in skin, bone, heart and liver, but not in gut, brain and spinal cord, became relatively weak on ED19 and disappeared after birth (ND2). Ghrelin and des-acyl ghrelin facilitated the proliferation of cultured fetal (ED17, 19), but not neonatal (ND2), skin cells. On the other hand, with regard to cells from the spinal cord and hypothalamus, the proliferative effect of ghrelin continued after birth, whereas the effect of des-acyl ghrelin on neurogenesis in these tissues was lost at the ED19 fetal and ND2 neonatal stages. Immunohistochemistry revealed that the cells in the hypothalamus induced to proliferate by ghrelin at the ND2 stage were positive for nestin and glial fibrillary acidic protein. These results suggest that in the period immediately prior to, and after birth, rat fetal cells showing proliferation in response to ghrelin and des-acyl ghrelin are at a transitional stage characterized by alteration of the expression of GHS-R1a and an undefined des-acyl ghrelin receptor, their responsiveness varying among different tissues.

  9. The utility of scores in the decision to salvage or amputation in severely injured limbs.

    PubMed

    Shanmuganathan, Rajasekaran

    2008-10-01

    The decision to amputate or salvage a severely injured limb can be very challenging to the trauma surgeon. A misjudgment will result in either an unnecessary amputation of a valuable limb or a secondary amputation after failed salvage. Numerous scores have been proposed to provide guidelines to the treating surgeon, the notable of which are Mangled extremity severity score (MESS); the predictive salvage index (PSI); the Limb Salvage Index (LSI); the Nerve Injury, Ischemia, Soft tissue injury, Skeletal injury, Shock and Age of patient (NISSSA) score; and the Hannover fracture scale-97 (HFS-97). These scores have all been designed to evaluate limbs with combined orthopaedic and vascular injuries and have a poor sensitivity and specificity in evaluating IIIB injuries. Recently the Ganga Hospital Score (GHS) has been proposed which is specifically designed to evaluate a IIIB injury. Another notable feature of GHS is that it offers guidelines in the choice of the appropriate reconstruction protocol. The basis of the commonly used scores with their utility have been discussed in this paper. PMID:19753223

  10. 'Translational formative evaluation': critical in up-scaling public health programmes.

    PubMed

    O'Hara, Blythe J; Phongsavan, Philayrath; King, Lesley; Develin, Elizabeth; Milat, Andrew J; Eggins, Dianne; King, Elizabeth; Smith, Joanne; Bauman, Adrian E

    2014-03-01

    The process of generating evidence-based public health interventions is understood to include steps that define the issue, generate and test solutions in controlled settings, replicate and then disseminate more widely. However, to date models have not considered the types and scale of formative evaluation tasks that are needed to up-scale interventions, from efficacy to population-wide dissemination in the real world. In this paper, we propose that an additional stage of 'translational formative evaluation' is necessary for the translation of effectiveness evidence into wide-scale public health practice. We illustrate the utility of translational formative evaluation, through a case study of the Get Healthy Information and Coaching Service(®) (GHS), a population-based telephone service designed to assist adults change lifestyle-related behaviours. The additional translational formative evaluation steps comprised synthesis of efficacy studies, qualitative research with the wider target audience, environmental analysis and stakeholder consultation. They produced precise recommendations to refine GHS design and implementation. Translational formative evaluation is a necessary intermediate step, following efficacy studies and a precursor to population-wide implementation of public health programmes. PMID:23630131

  11. Ghrelin Receptor Ligands Reaching Clinical Trials: From Peptides to Peptidomimetics; from Agonists to Antagonists.

    PubMed

    Vodnik, M; Štrukelj, B; Lunder, M

    2016-01-01

    In the recent decades, great progress has been made in the development of ghrelin receptor ligands. The discovery of the first in vitro only active peptide growth hormone secretagogue derived from Met-enkephalin was the foundation for later discoveries of the receptor and the endogenous ligand ghrelin. Since then, the scope of peptides, peptidomimetics, and small-molecules targeting the ghrelin receptor, GHS-R1a, has expanded dramatically. Numerous agonists have been tested in animals and several in humans, and a handful have progressed to clinical trials for indications such as growth hormone release, gastric emptying, and cachexia. However, with the exception of the approval of GHRP-2 for diagnostic purposes in Japan, none of the candidates have been successfully introduced into the market. More recently, the attention of researchers has been concentrated on developing antagonists and inverse agonists for pharmacological treatment of the ever-expanding obese and overweight population. In this review, we describe the development of GHS-R1a targeting agonists, antagonists, and inverse agonists. We focus on current and completed clinical trials and the therapeutic potential of currently available ligands. PMID:26551992

  12. Molecular evolution of GPCRs: Ghrelin/ghrelin receptors.

    PubMed

    Kaiya, Hiroyuki; Kangawa, Kenji; Miyazato, Mikiya

    2014-06-01

    After the discovery in 1996 of the GH secretagogue-receptor type-1a (GHS-R1a) as an orphan G-protein coupled receptor, many research groups attempted to identify the endogenous ligand. Finally, Kojima and colleagues successfully isolated the peptide ligand from rat stomach extracts, determined its structure, and named it ghrelin. The GHS-R1a is now accepted to be the ghrelin receptor. The existence of the ghrelin system has been demonstrated in many animal classes through biochemical and molecular biological strategies as well as through genome projects. Our work, focused on identifying the ghrelin receptor and its ligand ghrelin in laboratory animals, particularly nonmammalian vertebrates, has provided new insights into the molecular evolution of the ghrelin receptor. In mammals, it is assumed that the ghrelin receptor evolution is in line with the plate tectonics theory. In contrast, the evolution of the ghrelin receptor in nonmammalian vertebrates differs from that of mammals: multiplicity of the ghrelin receptor isoforms is observed in nonmammalian vertebrates only. This multiplicity is due to genome duplication and polyploidization events that particularly occurred in Teleostei. Furthermore, it is likely that the evolution of the ghrelin receptor is distinct from that of its ligand, ghrelin, because only one ghrelin isoform has been detected in all species examined so far. In this review, we summarize current knowledge related to the molecular evolution of the ghrelin receptor in mammalian and nonmammalian vertebrates. PMID:24353285

  13. Ghrelin, peptide YY and their receptors: gene expression in brain from subjects with and without Prader-Willi syndrome.

    PubMed

    Talebizadeh, Zohreh; Kibiryeva, Nataliya; Bittel, Douglas C; Butler, Merlin G

    2005-04-01

    Ghrelin and peptide YY (PYY) are peptides generally produced by the gastrointestinal organs which are involved in appetite regulation via highly specialized centers in the brain. Abnormal plasma ghrelin and PYY levels compared with controls have been reported for subjects with Prader-Willi syndrome (PWS) which is characterized by infantile hypotonia, poor suck reflex and failure to thrive followed by hyperphagia and marked obesity in early childhood. We studied gene expression of ghrelin, peptide YY, and their receptors (i.e., GHS-R1a, GHS-R1b, and NPY2R) in six different brain regions (frontal cortex, temporal cortex, visual cortex, pons, medulla, and hypothalamus) obtained from three subjects with PWS, two individuals with Angelman syndrome, and six controls to determine if expression of these genes is detectable in different regions of the brain in subjects with and without PWS. In general, expression of these genes using RT-PCR was detected in all subjects and no obvious differences were seen in their pattern of expression between subjects with or without PWS. Additional studies including quantitative gene expression measurements will be required to further evaluate the role of these genes in the eating disorder seen in PWS. PMID:15754036

  14. Determination of growth hormone secretagogue pralmorelin (GHRP-2) and its metabolite in human urine by liquid chromatography/electrospray ionization tandem mass spectrometry.

    PubMed

    Okano, Masato; Sato, Mitsuhiko; Ikekita, Ayako; Kageyama, Shinji

    2010-07-30

    GHRP-2 (pralmorelin, D-Ala-D-(beta-naphthyl)-Ala-Ala-Trp-D-Phe-Lys-NH(2)), which belongs to a class of growth hormone secretagogue (GHS), is intravenously used to diagnose growth hormone (GH) deficiency. Because it may be misused in expectation of a growth-promoting effect by athletes, the illicit use of GHS by athletes has been prohibited by the World Anti-Doping Agency (WADA). Therefore, the mass spectrometric identification of urinary GHRP-2 and its metabolite D-Ala-D-(beta-naphthyl)-Ala-Ala-OH (AA-3) was studied using liquid chromatography/electrospray ionization tandem mass spectrometry for doping control purposes. The method consists of solid-phase extraction using stable-isotope-labeled GHRP-2 as an internal standard and subsequent ultra-performance liquid chromatography/tandem mass spectrometry, and the two target peptides were determined at urinary concentrations of 0.5-10 ng/mL. The recoveries ranged from 84 to 101%, and the assay precisions were calculated as 1.6-3.8% (intra-day) and 1.9-4.3% (inter-day). Intravenous administration of GHRP-2 in ten male volunteers was studied to demonstrate the applicability of the method. In all ten cases, unchanged GHRP-2 and its specific metabolite AA-3 were detected in urine. PMID:20552695

  15. Protective effects of ginseng leaf extract using enzymatic extraction against oxidative damage of UVA-irradiated human keratinocytes.

    PubMed

    Kim, Mi-Ryung; Lee, Hyun-Sun; Choi, Hyeon-Son; Kim, Sun Young; Park, Yooheon; Suh, Hyung Joo

    2014-06-01

    UVA is responsible for numerous biological effects on the skin, including premature aging characterized by wrinkles, leathery texture, and mottled pigmentation. The objective of this study was evaluating the protective effect of ginseng leaf extract prepared by Ultraflo L on skin from photodamage. Anti-wrinkle effect of ginseng leaf extract with or without Ultraflo L treatment were tested on human keratinocyte cells (HaCaT) irradiated with ultraviolet (UV) A. Ginseng leaves inhibited ROS generation, GHS depletion, and expression of MMP-2 and MMP-9 induced by UVA irradiation. The glutathione (GSH) content of the cells was significantly increased by over 25?gmL(-1) of Ultraflo-treated extract (UTGL) as well as by over 100?gmL(-1) of nonenzyme-treated extract (NEGL) compared to control. UTGL and NEGL treatments significantly decreased expression of metalloproteinase (MMP)-2 and 9 compared with control, but inhibitory effects of two groups on expression of MMPs were not significantly different. Overall, ULtraflo L-treated ginseng leaves inhibited ROS generation, GHS depletion, and expression of MMP-2 and MMP-9 in UVA photodamaged HaCat cells. From these results, enzyme-treated ginseng leaf extract has advantages over untreated ginseng leaves and have potential as a skin protective ingredient against UVA-induced photodamage. PMID:24736942

  16. Recombinant protein production facility for fungal biomass-degrading enzymes using the yeast Pichia pastoris.

    PubMed

    Haon, Mireille; Grisel, Sacha; Navarro, David; Gruet, Antoine; Berrin, Jean-Guy; Bignon, Christophe

    2015-01-01

    Filamentous fungi are the predominant source of lignocellulolytic enzymes used in industry for the transformation of plant biomass into high-value molecules and biofuels. The rapidity with which new fungal genomic and post-genomic data are being produced is vastly outpacing functional studies. This underscores the critical need for developing platforms dedicated to the recombinant expression of enzymes lacking confident functional annotation, a prerequisite to their functional and structural study. In the last decade, the yeast Pichia pastoris has become increasingly popular as a host for the production of fungal biomass-degrading enzymes, and particularly carbohydrate-active enzymes (CAZymes). This study aimed at setting-up a platform to easily and quickly screen the extracellular expression of biomass-degrading enzymes in P. pastoris. We first used three fungal glycoside hydrolases (GHs) that we previously expressed using the protocol devised by Invitrogen to try different modifications of the original protocol. Considering the gain in time and convenience provided by the new protocol, we used it as basis to set-up the facility and produce a suite of fungal CAZymes (GHs, carbohydrate esterases and auxiliary activity enzyme families) out of which more than 70% were successfully expressed. The platform tasks range from gene cloning to automated protein purifications and activity tests, and is open to the CAZyme users' community. PMID:26441929

  17. Effects of subacute hypothyroidism on metabolism and growth-related molecules.

    PubMed

    Chang, Yen-Jui; Hwu, Chii-Min; Yeh, Chii-Chang; Wang, Paulus S; Wang, Shyi-Wu

    2014-01-01

    Thyroid hormones are crucial hormones that primarily regulate the metabolism of entire body cells. In this study, Sprague-Dawley rats were grouped into sham thyroidectomy (Sham Tx), thyroidectomy (Tx), Tx with thyroxine replacement (Tx + T4), and PTU injection (PTU) groups. Metabolic parameters were measured by means of metabolic cages for 14 days. After 14 days, the rats were sacrificed while the levels of plasma or serum TSH and growth-related molecules, such as active and total ghrelin, GH, and IGF-1, were assayed. The results revealed that hypothyroid rats tended to eat less food and experienced substantial body weight gain, whereas the rats with T4 replacement tended to eat more food while continuing to lose weight. In hypothyroid rats, the growth-related molecules, such as active ghrelin and total ghrelin secretion, were enhanced, and the ghrelin receptors were also up-regulated. However, circulating GH levels were not elevated and IGF-1 secretion was inhibited in hypothyroid rats. In the Tx + T4 group, the changes of active ghrelin, total ghrelin, GHS-R expression, and IGF-1 were reversed, whereas the GH secretion was higher than that of the Sham Tx group and hypothyroid groups. This study resulted in the novel finding that the ghrelin/GHS-R axis and GH/IGF-1 axis are interrupted in hypothyroid rats. PMID:25079659

  18. Catestatin and GABAAR related feeding habits rely on dopamine, ghrelin plus leptin neuroreceptor expression variations.

    PubMed

    Mele, Maria; Iachetta, Giuseppina; Alò, Raffaella; Avolio, Ennio; Fazzari, Gilda; Carelli, Antonio; Laforgia, Vincenza; Canonaco, Marcello

    2016-04-01

    Catestatin (CST), an endogenously small sympathoinhibitory peptide is capable of interfering with the major cerebral neuroreceptor-blocking site, i.e. γ-aminobutyric acidA receptor (GABAAR) system especially in limbic brain areas that are involved with feeding behaviors. The GABAARergic-related effects seem to derive from its interaction with other molecular neuroreceptors such as dopaminergic, ghrelin and leptinergic. In this context, the present study aimed to investigate probable feeding responses (eating and drinking) induced by treatment with CST and the GABAAR antagonist bicucullin (BIC) alone or simultaneously (CST+BIC) in the Syrian hibernating hamster (Mesocricetus auratus) model. Hamsters that received these compounds via intracerebroventricular infusions displayed notable variations of feeding and drinking bouts. In particular, an anorexigenic response was evident following treatment with CST while BIC evoked a significant increase of eating and drinking behaviors. Surprisingly when both agents were given simultaneously, a predominating anorexigenic response was detected as shown by evident CST-dependent reduction of feeding bouts. Contextually such behaviors, especially those following the combined treatment were tightly correlated with the significantly increased cerebral dopamine receptor 1 (D1) plus reduced ghrelin receptor (GhsR) and leptin receptor (LepR) transcript levels. Overall, the anorexigenic effect of CST deriving from its tight interaction with GABAARs activity plus D1 and GhsR transcripts tends to propose these neuronal elements as pivotal factors responsible for feeding disorders. PMID:26875516

  19. Evidence that the growth hormone receptor mediates differentiation and development of the mammary gland.

    PubMed

    Feldman, M; Ruan, W; Cunningham, B C; Wells, J A; Kleinberg, D L

    1993-10-01

    We have shown that nonlactogenic rat (r) GH is far more potent than rPRL in inducing rat mammary development. To determine the relative roles of GH and PRL in mammary development and their mechanisms of action, we have compared the abilities of a group of native and mutant GHs, PRLs, and placental lactogens (PLs) to induce mammary development, bind to GH receptors, and activate lactogenic receptors. Mammary development was assessed histologically by counting terminal end buds and alveolar structures in glands from sexually immature, hypophysectomized, castrated, estradiol-treated rats. Hormones were implanted, in Elvax pellets, into the lumbar mammary gland. Significant increases in terminal end buds (P < 0.03) over internal control values were obtained with rGH, recombinant human GH (rhGH), rbGH, and one of two mutant rhGHs. These four hormones were also found to bind to GH receptors with high affinity. In contrast, little development occurred with hPRL, rPRL, rhPL, ovine PRL, mutant forms of rhPRL and rhPL, and a mutant of rhGH altered to reduce binding to GH and PRL receptors. All of these substances are more than 50-fold reduced in binding to the GH receptor, yet can bind and activate lactogenic receptors. Thus, only those natural or mutant pituitary or placental hormones with high binding affinity to GH receptors induce mammary development, suggesting that GH receptors play a central role in this process. PMID:8404600

  20. SWeRF—A Method for Estimating the Relevant Fine Particle Fraction in Bulk Materials for Classification and Labelling Purposes

    PubMed Central

    2014-01-01

    In accordance with the European regulation for classification, labelling and packaging of substances and mixtures (CLP) as well as the criteria as set out in the Globally Harmonized System (GHS), fine fraction of crystalline silica (CS) has been classified as a specific target organ toxicity, the specific organ in this case being the lung. Generic cut-off values for products containing a fine fraction of CS trigger the need for a method for the quantification of the fine fraction of CS in bulk materials. This article describes the so-called SWeRF method, the size-weighted relevant fine fraction. The SWeRF method combines the particle size distribution of a powder with probability factors from the EN 481 standard and allows the relevant fine fraction of a material to be calculated. The SWeRF method has been validated with a number of industrial minerals. This will enable manufacturers and blenders to apply the CLP and GHS criteria for the classification of mineral products containing RCS a fine fraction of CS. PMID:24389081

  1. StratBAM: A Discrete-Event Simulation Model to Support Strategic Hospital Bed Capacity Decisions.

    PubMed

    Devapriya, Priyantha; Strömblad, Christopher T B; Bailey, Matthew D; Frazier, Seth; Bulger, John; Kemberling, Sharon T; Wood, Kenneth E

    2015-10-01

    The ability to accurately measure and assess current and potential health care system capacities is an issue of local and national significance. Recent joint statements by the Institute of Medicine and the Agency for Healthcare Research and Quality have emphasized the need to apply industrial and systems engineering principles to improving health care quality and patient safety outcomes. To address this need, a decision support tool was developed for planning and budgeting of current and future bed capacity, and evaluating potential process improvement efforts. The Strategic Bed Analysis Model (StratBAM) is a discrete-event simulation model created after a thorough analysis of patient flow and data from Geisinger Health System's (GHS) electronic health records. Key inputs include: timing, quantity and category of patient arrivals and discharges; unit-level length of care; patient paths; and projected patient volume and length of stay. Key outputs include: admission wait time by arrival source and receiving unit, and occupancy rates. Electronic health records were used to estimate parameters for probability distributions and to build empirical distributions for unit-level length of care and for patient paths. Validation of the simulation model against GHS operational data confirmed its ability to model real-world data consistently and accurately. StratBAM was successfully used to evaluate the system impact of forecasted patient volumes and length of stay in terms of patient wait times, occupancy rates, and cost. The model is generalizable and can be appropriately scaled for larger and smaller health care settings. PMID:26310949

  2. Epigenetic regulation of microRNAs controlling CLDN14 expression as a mechanism for renal calcium handling.

    PubMed

    Gong, Yongfeng; Himmerkus, Nina; Plain, Allein; Bleich, Markus; Hou, Jianghui

    2015-03-01

    The kidney has a major role in extracellular calcium homeostasis. Multiple genetic linkage and association studies identified three tight junction genes from the kidney--claudin-14, -16, and -19--as critical for calcium imbalance diseases. Despite the compelling biologic evidence that the claudin-14/16/19 proteins form a regulated paracellular pathway for calcium reabsorption, approaches to regulate this transport pathway are largely unavailable, hindering the development of therapies to correct calcium transport abnormalities. Here, we report that treatment with histone deacetylase (HDAC) inhibitors downregulates renal CLDN14 mRNA and dramatically reduces urinary calcium excretion in mice. Furthermore, treatment of mice with HDAC inhibitors stimulated the transcription of renal microRNA-9 (miR-9) and miR-374 genes, which have been shown to repress the expression of claudin-14, the negative regulator of the paracellular pathway. With renal clearance and tubule perfusion techniques, we showed that HDAC inhibitors transiently increase the paracellular cation conductance in the thick ascending limb. Genetic ablation of claudin-14 or the use of a loop diuretic in mice abrogated HDAC inhibitor-induced hypocalciuria. The genetic mutations in the calcium-sensing receptor from patients with autosomal dominant hypocalcemia (ADH) repressed the transcription of miR-9 and miR-374 genes, and treatment with an HDAC inhibitor rescued the phenotypes of cell and animal models of ADH. Furthermore, systemic treatment of mice with antagomiRs against these miRs relieved claudin-14 gene silencing and caused an ADH-like phenotype. Together, our findings provide proof of concept for a novel therapeutic principle on the basis of epigenetic regulation of renal miRs to treat hypercalciuric diseases. PMID:25071082

  3. Epigenetic Regulation of MicroRNAs Controlling CLDN14 Expression as a Mechanism for Renal Calcium Handling

    PubMed Central

    Gong, Yongfeng; Himmerkus, Nina; Plain, Allein; Bleich, Markus

    2015-01-01

    The kidney has a major role in extracellular calcium homeostasis. Multiple genetic linkage and association studies identified three tight junction genes from the kidney—claudin-14, -16, and -19—as critical for calcium imbalance diseases. Despite the compelling biologic evidence that the claudin-14/16/19 proteins form a regulated paracellular pathway for calcium reabsorption, approaches to regulate this transport pathway are largely unavailable, hindering the development of therapies to correct calcium transport abnormalities. Here, we report that treatment with histone deacetylase (HDAC) inhibitors downregulates renal CLDN14 mRNA and dramatically reduces urinary calcium excretion in mice. Furthermore, treatment of mice with HDAC inhibitors stimulated the transcription of renal microRNA-9 (miR-9) and miR-374 genes, which have been shown to repress the expression of claudin-14, the negative regulator of the paracellular pathway. With renal clearance and tubule perfusion techniques, we showed that HDAC inhibitors transiently increase the paracellular cation conductance in the thick ascending limb. Genetic ablation of claudin-14 or the use of a loop diuretic in mice abrogated HDAC inhibitor-induced hypocalciuria. The genetic mutations in the calcium-sensing receptor from patients with autosomal dominant hypocalcemia (ADH) repressed the transcription of miR-9 and miR-374 genes, and treatment with an HDAC inhibitor rescued the phenotypes of cell and animal models of ADH. Furthermore, systemic treatment of mice with antagomiRs against these miRs relieved claudin-14 gene silencing and caused an ADH-like phenotype. Together, our findings provide proof of concept for a novel therapeutic principle on the basis of epigenetic regulation of renal miRs to treat hypercalciuric diseases. PMID:25071082

  4. Ultrastrucural Investigation of Crystal deposits in Npt2a knockout mice: Are they similar to Human Randall's plaques?

    PubMed Central

    Khan, Saeed R.; Canales, Benjamin K.

    2013-01-01

    Purpose Idiopathic calcium oxalate (CaOx) stones are suggested to develop attached to renal interstitial calcium phosphate (CaP) deposits, the Randall's plaques (RP), Sodium phosphate co-transporter (Npt2a) null mice are hypercalciuric, hyperphosphaturic, and produce tubular and interstitial CaP deposits. To determine if this mouse is suitable for RP investigations, we chronologically studied their location, structure, and composition. Materials and Methods Kidneys of Npt2a null mice of two days to a year old were examined by light, scanning (SEM) and transmission electron microscopy (TEM). Electron diffraction and energy dispersive x-ray microanalyses were performed to determine the mineral composition. Results Poorly crystalline biological apatite deposits were seen in lumens of collecting ducts. Deposits consisted of aggregates of approx 5μm diameter microspheres of concentrically organized needle or plate-like matrix rich crystals. Epithelium/ crystal interfaces were filled with membrane bound vesicles. Some tubules were completely occluded by crystals, occasionally lost their epithelium and crystals moved into the interstitium. Conclusions CaP crystals formed in tubular lumen and organized as microspheres. The aggregation of CaP crystals produced nuclei, which grew by the addition of crystals on periphery, eventually becoming large enough to occlude tubular lumen and obliterate tubular epithelium, leading to the relocation of microliths into interstitium. The pathogenesis of interstitial deposits of the Npt2a null mice appears different from that proposed for RP's. Since Npt2a null mice purge their renal crystal deposits, these mice may serve as a model to investigate elimination of crystal deposits seen in children and adults with nephrocalcinosis PMID:21784483

  5. Did the Karakoram fault interrupt mid-crustal channel flow in the western Himalaya?

    NASA Astrophysics Data System (ADS)

    Leech, M. L.

    2007-12-01

    There is a marked change in the volume and age of granitoids from west to east across the Himalaya; that change occurs at the southeastern termination of the Karakoram fault where it merges with the Indus-Yarlung suture zone, near the Gurla Mandhata gneiss dome. These granitoids are derived from a ductile mid-crustal channel formed when anatectic melts from the mid-crust beneath the Tibetan plateau were driven south by erosion at the Himalayan topographic front. The "channel flow" model predicts upwellings of these granites within the Tethyan Himalaya Sequence as part of a chain of gneiss domes and exposure of the channel at its southern termination in the Greater Himalaya Sequence (GHS) as evidenced by widespread migmatites and leucogranite bodies at the top of the GHS in the footwall of the South Tibetan Detachment. Leo Pargil is the westernmost gneiss dome in a chain of domes formed within the Tethyan Himalaya Sequence that extends eastward 1600 km through the North Himalayan gneiss domes (that includes the better known Kangmar dome). New U-Pb SHRIMP dating of zircons show leucogranite bodies from the Leo Pargil gneiss dome are Early Miocene (22-20 Ma) corresponding to some of the older granites dated from across the Himalaya. Transects through the GHS along the Beas and Sutlej River valleys in the western Himalaya near Leo Pargil reveal rare to minimal amounts of migmatites and leucogranite, whereas there are abundant migmatites and large leucogranite bodies in a transect along the Friendship Highway from Lhasa to Kathmandu in the area of the North Himalayan gneiss domes. The timing of the initiation of slip on the Karakoram fault is dated from syn- kinematic rocks in the shear zone at Tangste/Pangong Tso at c. 25-21 Ma. If the Karakoram fault acted as a barrier the flow of granitoid melts in a mid-crustal channel, one would expect more abundant and younger granites east of the Karakoram fault as the channel continued to flow south after c. 20 Ma; the youngest granites reported from the eastern Himalaya are 7 Ma from the Renbu dome and there are also abundant leucogranite bodies from 20-12 Ma. This model also predicts that granitoids would leak up the Karakoram fault and this is demonstrated by 20-16 Ma leucogranites along the Karakoram fault in the Tangste/Pangong Tso area. If the Karakoram fault is indeed a barrier to ductile flow and melt migration, then future tectonic models for the Himalaya should recognize the differences between the western and eastern segments of the orogen, rather than emphasizing along-strike uniformity.

  6. Ages, Trace-Element and Hf Isotopic Compositions of the Detrital Zircons from the Metamorphic Basements in the Eastern Himalayan Syntaxis: Implications for Tectonics and Paleogeography

    NASA Astrophysics Data System (ADS)

    Guo, L.; Zhang, H. F.; Harris, N.

    2014-12-01

    The origin of the Greater Himalayan Sequence (GHS) of the Himalaya and the paleogeographic position of the Lhasa terrane within Gondwanaland remain controversial. In the Eastern Himalayan syntaxis, the metamorphic basements of the northern Indian plate (Namche Barwa Group) and the South Lhasa terrane (Nyingchi Complex) can be studied to explore these issues. The youngest ages of detrital zircons in the metasedimentary rocks from the Pai Formation of the Namche Barwa Group (NBG) and the Nyingchi Complex suggest their maximum depositional ages are no older than 942 Ma and 1006 Ma, respectively. A granitic gneiss intruding the Pai Formation and a metarhyolite overlying the Nyingchi Complex have protolith ages of 477 ± 3 Ma and 507 ± 4 Ma, respectively, providing upper age limits for their deposition. The detrital zircons in the Pai Formation and Nyingchi Complex define four major age peaks at ~1170 Ma, ~1350 Ma, ~1565 Ma, and ~1750 Ma. Both the ~1170 Ma and ~1350 Ma zircons have large variation of eHf(t) values (-19.4 to +5.6); most ~1565 Ma zircons have positive eHf(t) values (+1.2 - +9.0), and most ~1750 Ma zircons have negative eHf(t) values (-7.1 to -1.9), which are consistent with those of the Mesoproterozoic orthogneiss in the Duoxiongla migmatite of NBG. The trace-element signatures of ~1.5-1.3 Ga detrital zircons indicate they were derived from sources characterized by bimodal magmatism. The potential sources for the metasediments in the Pai Formation and Nyingchi Complex include the Rayner-Eastern Ghats Orogen and its contact zone with the Archaean Indian cratons, the Central Indian Tectonic Zone, the northeastern India craton and Dharwar craton, South Lhasa terrane and probably Eastern Antarctic. Comparisons of detrital zircon age spectra of the coeval metasedimentary rocks from the Nyingchi Complex, the Pai Formation, the GHS and upper Lesser Himalayan Sequence in Arunachal Himalayan, and the Indian cratonic successions suggest that: (1) the NBG is the northeastern extension of the GHS in Arunachal Himalaya; (2) their protolithes were deposited along the northern passive margin of the Indian craton; (3) prior to the Cambrian, the South Lhasa terrane was tectonically linked to northern India rather than northwest Australia.

  7. Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

    PubMed Central

    Cruz, Maureen T; Herman, Melissa A; Cote, Dawn M; Ryabinin, Andrey E; Roberto, Marisa

    2013-01-01

    The neural circuitry that processes natural rewards converges with that engaged by addictive drugs. Because of this common neurocircuitry, drugs of abuse have been able to engage the hedonic mechanisms normally associated with the processing of natural rewards. Ghrelin is an orexigenic peptide that stimulates food intake by activating GHS-R1A receptors in the hypothalamus. However, ghrelin also activates GHS-R1A receptors on extrahypothalamic targets that mediate alcohol reward. The central nucleus of the amygdala (CeA) has a critical role in regulating ethanol consumption and the response to ethanol withdrawal. We previously demonstrated that rat CeA GABAergic transmission is enhanced by acute and chronic ethanol treatment. Here, we used quantitative RT-PCR (qRT-PCR) to detect Ghsr mRNA in the CeA and performed electrophysiological recordings to measure ghrelin effects on GABA transmission in this brain region. Furthermore, we examined whether acute or chronic ethanol treatment would alter these electrophysiological effects. Our qRT-PCR studies show the presence of Ghsr mRNA in the CeA. In naive animals, superfusion of ghrelin increased the amplitude of evoked inhibitory postsynaptic potentials (IPSPs) and the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Coapplication of ethanol further increased the ghrelin-induced enhancement of IPSP amplitude, but to a lesser extent than ethanol alone. When applied alone, ethanol significantly increased IPSP amplitude, but this effect was attenuated by the application of ghrelin. In neurons from chronic ethanol-treated (CET) animals, the magnitude of ghrelin-induced increases in IPSP amplitude was not significantly different from that in naive animals, but the ethanol-induced increase in amplitude was abolished. Superfusion of the GHS-R1A antagonists 𝒟-Lys3-GHRP-6 and JMV 3002 decreased evoked IPSP and mIPSC frequency, revealing tonic ghrelin activity in the CeA. 𝒟-Lys3-GHRP-6 and JMV 3002 also blocked ghrelin-induced increases in GABAergic responses. Furthermore, 𝒟-Lys3-GHRP-6 did not affect ethanol-induced increases in IPSP amplitude. These studies implicate a potential role for the ghrelin system in regulating GABAergic transmission and a complex interaction with ethanol at CeA GABAergic synapses. PMID:22968812

  8. USING RADIO HALOS AND MINIHALOS TO MEASURE THE DISTRIBUTIONS OF MAGNETIC FIELDS AND COSMIC RAYS IN GALAXY CLUSTERS

    SciTech Connect

    Keshet, Uri; Loeb, Abraham

    2010-10-10

    Some galaxy clusters show diffuse radio emission in the form of giant halos (GHs) on Mpc scales or minihalos (MHs) on smaller scales. Comparing Very Large Array and XMM-Newton radial profiles of several such clusters, we find a universal linear correlation between radio and X-ray surface brightness, valid in both types of halos. It implies a halo central emissivity {nu}j{sub {nu}} = 10{sup -31.4{+-}0.2}(n/10{sup -2}cm{sup -3}){sup 2}(T/T{sub 0}){sup 0.2{+-}0.5}ergs{sup -1}cm{sup -3}, where T and T{sub 0} are the local and central temperatures, respectively, and n is the electron number density. We argue that the tight correlation and the scaling of j{sub {nu}}, combined with morphological and spectral evidence, indicate that both GHs and MHs arise from secondary electrons and positrons, produced in cosmic-ray ion (CRI) collisions with a strongly magnetized B {approx}> 3{mu}G intracluster gas. When the magnetic energy density drops below that of the microwave background, the radio emission weakens considerably, producing halos with a clumpy morphology (e.g., RXC J2003.5 - 2323 and A2255) or a distinct radial break. We thus measure a magnetic field B = 3{mu}G at a radius r {approx_equal} 110kpc in A2029 and r {approx_equal} 50kpc in Perseus. The spectrum of secondaries, produced from hadronic collisions of {approx}20GeV CRIs, reflects the energy dependence of the collision cross section. We use the observed spectra of halos, in particular where they steepen with increasing radius or frequency, to (1) measure B {approx_equal} 10({nu}/700MHz){mu}G with {nu} the spectral break frequency, (2) identify a correlation between the average spectrum and the central magnetic field, and (3) infer a CRI spectral index s {approx}< -2.7 and energy fraction {xi}{sub p} {approx} 10{sup -3.6{+-}0.2} at particle energies above 10 GeV. Our results favor a model where CRIs diffuse away from their sources (which are probably supernovae, according to a preliminary correlation with star formation), whereas the magnetic fields are generated by mergers in GHs and by core sloshing in MHs.

  9. Biographical disruption associated with multiple sclerosis: using propensity scoring to assess the impact.

    PubMed

    Green, Gill; Todd, Jennifer; Pevalin, David

    2007-08-01

    Chronic illness such as multiple sclerosis (MS) is often associated with 'biographical disruption', a concept that is derived from qualitative narrative analyses examining how people make sense of their illness in the context of their lives [Bury, M. (1982). Chronic illness as biographical disruption. Sociology of Health and Illness, 4, 167-182]. This paper attempts to operationalise the idea of disruption to one's life trajectory in quantitative analysis by examining the social, economic and emotional disruption associated with MS. A number of studies have suggested that it impacts negatively on employment, income and sexual relationships; however previous research has been based upon samples of people with MS (pwMS), with a dearth of studies comparing pwMS with the general population. This study reports a systematic comparison of MS and non-MS households to enable the impact of MS to be quantified in terms of household composition and marital status; household income; economic activity; and to determine whether biographical disruptions such as relationship breakdown or unemployment are more or less prevalent among those affected by MS compared to the general population. The MS sample came from randomly selected members of the UK MS Society (n=783) and those accessing the MS Society website (n=133). Data for the general population came from the 2001/02 British General Household Survey (GHS). Cases from the MS Society sample were matched using propensity scoring with cases from the GHS. The results of the matched analysis show that both men and women with MS are significantly less likely to be employed than those in the general population and are significantly more likely to have a 'below average' household income, despite the fact that they are in a higher social class and have higher educational levels than people in the general population. Differences between the MS and GHS samples in terms of marital status become non-significant when socio-demographic variables are controlled for using propensity scoring. This study provides robust evidence on how MS impacts on and disrupts the life of the person with MS and their household in terms of income and employment. PMID:17481791

  10. P-T-t-d History of the Greater Himalaya Sequence metapelites in the Zanskar Shear Zone, NW India

    NASA Astrophysics Data System (ADS)

    Beck, E.; Leech, M. L.; Basta, S.

    2013-12-01

    Greater Himalaya Sequence (GHS) metapelites deformed in the Zanskar Shear Zone (ZSZ) record geochemical and structural evidence of a complex history. This study applies a multi-component approach to understanding the metamorphic and deformational evolution of the high-grade metapelites in western Himalaya. Samples collected from NE to SW from the ZSZ, along Malung Takpo, record increasing metamorphic grade and decreasing mylonitization with increased distance from the shear zone. Microscopic evidence for variable degrees of deformation includes: change in crystal size, foliation development, pressure shadows, and kink bands. The dominant mineralogy is Qz+Kfs+Pl+Bt+Ms+Grt+Ky×Sil×St+opaques. Advanced isochemical phase diagrams (pseudosections) are calculated in Perple_X using whole-rock geochemical (XRF) data for six samples. The pseudosection conditions range 3-15 kbar and 300-800°C and use the solution models Bio(TCC), Chl(HP), St(HP), hCrd, feldspar, Mica(CHA), and Gt(HP) with modifications made to increase the models' accuracy. The generated phase equilibria diagrams, in conjunction with observed mineral growth relationships, are used to determine the P-T paths and illustrate peak and retrograde metamorphic events. Three dating techniques [U-Pb, 40Ar/39Ar, and (U-Th)/He] are incorporated to constrain timing along the P-T paths. U-Pb SHRIMP dating of monazite constrains the timing of regional metamorphism to ~27 Ma. 40Ar/39Ar dating of muscovite and biotite yields ages of ~20-19 Ma and 15 Ma, respectively, for cooling and exhumation through the middle crust. Dates acquired from (U-Th)/He analyses of monazite and zircon will indicate the timing of the end of movement along the ZSZ. Electron backscatter diffraction (EBSD) maps crystallographic orientation of minerals and is used to determine their responses to deformation. Crystallographic responses in quartz and feldspar are used to constrain the conditions during deformation. This will be supplemented by further investigation into the responses to deformation in alluminosilicates. Preliminary results from each of these components (P-T paths, timing, and deformation signature) suggest a progressive change in how the samples evolved (i.e., metamorphosed, exhumed, and sheared) and that this change is correlated to their relative distance from the ZSZ. The culmination of these elements in a P-T-t-d history results in a holistic understanding of the GHS metapelites deformed in the ZSZ. Having a comprehensive data set to compare to, or build from, provides a solid foundation for modeling the broader evolution of the GHS.

  11. The nutrition consult for recurrent stone formers.

    PubMed

    Penniston, Kristina L

    2015-07-01

    Diet is implicated in stone formation and growth. Whether alone or in concert with pharmacologics, dietary changes may be useful in reducing recurrence but only when they correct dietary stone-forming risks. Patients benefit from recommendations individualized to their food preferences as well as to lifestyle, age, food knowledge and access, preparation skills, and cultural and ethnic identities. Urologists can provide general dietary recommendations but often lack the time to provide the full complement of individualized nutrition care offered by a registered dietitian nutritionist (RDN). Urologists can partner with and refer patients to a RDN for any component of the nutrition care process: assessment of diet, diagnosis of dietary factors that contribute to stone risk factors, intervention formulation and implementation, and monitoring the effectiveness of the intervention and modifying it as needed to maintain suitably low dietary risk for stone recurrence. PMID:26025494

  12. A simple method for quantitating the propensity for calcium oxalate crystallization in urine

    NASA Technical Reports Server (NTRS)

    Wabner, C. L.; Pak, C. Y.

    1991-01-01

    To assess the propensity for spontaneous crystallization of calcium oxalate in urine, the permissible increment in oxalate is calculated. The previous method required visual observation of crystallization with the addition of oxalate, this warranted the need for a large volume of urine and a sacrifice in accuracy in defining differences between small incremental changes of added oxalate. Therefore, this method has been miniaturized and spontaneous crystallization is detected from the depletion of radioactive oxalate. The new "micro" method demonstrated a marked decrease (p < 0.001) in the permissible increment in oxalate in urine of stone formers versus normal subjects. Moreover, crystallization inhibitors added to urine, in vitro (heparin or diphosphonate) or in vivo (potassium citrate administration), substantially increased the permissible increment in oxalate. Thus, the "micro" method has proven reliable and accurate in discriminating stone forming from control urine and in distinguishing changes of inhibitory activity.

  13. Kidney stone risk following Roux-en-Y gastric bypass surgery

    PubMed Central

    Gonzalez, Ricardo D.

    2014-01-01

    Since the first report in 2005, Roux-en-Y gastric bypass (RYGB) surgery has been linked to a variety of metabolic changes that alter kidney stone risk. The studies with the highest level of evidence, performed in non-stone forming patients before and after RYGB, cite a number of kidney stone risk factors, including a 25% increase in urinary oxalate, a 30% decrease in urinary citrate, and reduction in urine volume by half a liter. In addition to these, recent clinical and experimental studies have contributed to our understanding of the pathophysiology of stone disease in this unique population. This review summarizes the current RYGB urinary chemistry profiles and epidemiological studies, outlines known and theoretical mechanisms of hyperoxaluria and hypocitrituria, and provides some standard recommendations for reducing stone risk in RYGB stone formers as well as some novel ones, including correction of metabolic acidosis and use of probiotics. PMID:25473624

  14. Effects of microgravity on renal stone risk assessment

    NASA Technical Reports Server (NTRS)

    Pietrzyk, R. A.; Pak, C. Y. C.; Cintron, N. M.; Whitson, P. A.

    1992-01-01

    Physiologic changes induced during human exposure to the microgravity environment of space may contribute to an increased potential for renal stone formation. Renal stone risk factors obtained 10 days before flight and immediately after return to earth indicated that calcium oxalate and uric acid stone-forming potential was increased after space flights of 4-10 days. These data describe the need for examining renal stone risk during in-flight phases of space missions. Because of limited availability of space and refrigerated storage on spacecraft, effective methods must be developed for collecting urine samples in-flight and for preserving (or storing) them at temperatures and under conditions commensurate with mission constraints.

  15. Recent finding and new technologies in nephrolitiasis: a review of the recent literature

    PubMed Central

    2013-01-01

    This review summarizes recent literature on advances regarding renal and ureteral calculi, with particular focus in areas of recent advances in the overall field of urolithiasis. Clinical management in everyday practice requires a complete understanding of the issues regarding metabolic evaluation and subgrouping of stone-forming patients, diagnostic procedures, effective treatment regime in acute stone colic, medical expulsive therapy, and active stone removal. In this review we focus on new perspectives in managing nephrolitihiasis and discuss recentadvances, including medical expulsive therapy, new technologies, and refinements of classical therapy such as shock wave lithotripsy, give a fundamental modification of nephrolithiasis management. Overall, this field appears to be the most promising, capable of new developments in ureterorenoscopy and percutaneous approaches. Further improvements are expected from robotic-assisted procedures, such as flexible robotics in ureterorenoscopy. PMID:23413950

  16. Gender Distribution of Pediatric Stone Formers

    NASA Astrophysics Data System (ADS)

    Novak, Thomas E.; Trock, Bruce J.; Lakshmanan, Yegappan; Gearhart, John P.; Matlaga, Brian R.

    2008-09-01

    Recent epidemiologic evidence suggests that the gender prevalence among adult stone-formers is changing, with an increasing incidence of stone disease among women. No similar data have ever been reported for the pediatric stone-forming population. We performed a study to define the gender distribution among pediatric stone-formers using a large-scale national pediatric database. Our findings suggest that gender distribution among stone formers varies by age with male predominance in the first decade of life shifting to female predominance in the second decade. In contrast to adults, females in the pediatric population are more commonly affected by stones than are males. The incidence of pediatric stone disease appears to be increasing at a great rate in both sexes. Further studies should build on this hypothesis-generating work and define the effects of metabolic and environmental risk factors that may influence stone risk in the pediatric patient population

  17. Serum paraoxonase-1 gene polymorphism and enzyme activity in patients with urolithiasis.

    PubMed

    Atar, Arda; Gedikbasi, Asuman; Sonmezay, Erkan; Kiraz, Zeynep Kusku; Abbasoglu, Semra; Tasci, Ali Ihsan; Tugcu, Volkan

    2016-04-01

    Objectives Paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme implicated in the pathogenesis of atherosclerosis by protecting lipoproteins against peroxidation. PON1 has two genetic polymorphisms both due to amino acid substitution, one involving glutamine and arginine at position 192 and the other leucine and methionine at position 55. Recent reports suggest that nephrolithiasis and atherosclerosis share a number of risk factors. Our study aimed to compare the effects of PON1 192, PON1 55 polymorphisms, and PON1 activity in patients with urolithiasis and controls. Materials and methods PON1's arylesterase/paraoxonase activities and phenotype were determined in 158 stone forming cases (Group 1) and 138 non-stone forming controls (Group 2). The PON1 192 and PON1 55 polymorphisms were studied by polymerase chain reaction/restriction fragment length polymorphism. Results Paraoxonase activity was significantly lower in Group 1 than Group 2 (112 ± 31.8 vs. 208 ± 53.1 IU/L) (p < 0.001). The PON1 L55M polymorphism was significantly higher in Group 1. The "M" allele coding for PON1 was higher in Group 1 (p < 0.001). PON1 192 RR homozygotes had significantly higher PON1 activity than QR and QQ genotypes among all the patients (p < 0.001). Conclusion The results of our study demonstrate that the PON1 55 gene "M" allele is associated with renal stone disease. Individuals possessing the "M" allele have a higher incidence of urolithiasis. The results of this study provide genetic evidence that the PON1 gene may play a role in stone formation. PON1 genotype determination may provide a tool to identify individuals who are at risk of urolithiasis. PMID:26795139

  18. The potential role of salt abuse on the risk for kidney stone formation.

    PubMed

    Sakhaee, K; Harvey, J A; Padalino, P K; Whitson, P; Pak, C Y

    1993-08-01

    The kidney stone-forming risk of a high sodium diet was evaluated by assessing the effect of such a diet on the crystallization of stone-forming salts in urine. Fourteen normal subjects participated in 2 phases of study of 10 days duration each, comprising a low sodium phase (basal metabolic diet containing 50 mmol. sodium per day) and a high sodium phase (basal diet plus 250 mmol. sodium chloride per day). The high sodium intake significantly increased urinary sodium (34 +/- 12 to 267 +/- 56 mmol. per day), calcium (2.73 +/- 1.03 to 3.93 +/- 1.51 mmol. per day) and pH (5.79 +/- 0.44 to 6.15 +/- 0.25), and significantly decreased urinary citrate (3.14 +/- 1.19 to 2.52 +/- 0.83 mmol. per day). Arterialized venous blood bicarbonate and total serum carbon dioxide concentrations decreased significantly during the high sodium diet, whereas serum chloride concentration increased. However, no change in arterialized venous pH was detected. Thus, a high sodium intake not only increased calcium excretion, but also increased urinary pH and decreased citrate excretion. The latter effects are probably due to sodium-induced bicarbonaturia and a significant decrease in serum bicarbonate concentration, respectively. Commensurate with these changes, the urinary saturation of calcium phosphate (brushite) and monosodium urate increased, and the inhibitor activity against calcium oxalate crystallization (formation product) decreased. The net effect of a high sodium diet was an increased propensity for the crystallization of calcium salts in urine. PMID:8326549

  19. Alkali absorption and citrate excretion in calcium nephrolithiasis

    NASA Technical Reports Server (NTRS)

    Sakhaee, K.; Williams, R. H.; Oh, M. S.; Padalino, P.; Adams-Huet, B.; Whitson, P.; Pak, C. Y.

    1993-01-01

    The role of net gastrointestinal (GI) alkali absorption in the development of hypocitraturia was investigated. The net GI absorption of alkali was estimated from the difference between simple urinary cations (Ca, Mg, Na, and K) and anions (Cl and P). In 131 normal subjects, the 24 h urinary citrate was positively correlated with the net GI absorption of alkali (r = 0.49, p < 0.001). In 11 patients with distal renal tubular acidosis (RTA), urinary citrate excretion was subnormal relative to net GI alkali absorption, with data from most patients residing outside the 95% confidence ellipse described for normal subjects. However, the normal relationship between urinary citrate and net absorbed alkali was maintained in 11 patients with chronic diarrheal syndrome (CDS) and in 124 stone-forming patients devoid of RTA or CDS, half of whom had "idiopathic" hypocitraturia. The 18 stone-forming patients without RTA or CDS received potassium citrate (30-60 mEq/day). Both urinary citrate and net GI alkali absorption increased, yielding a significantly positive correlation (r = 0.62, p < 0.0001), with the slope indistinguishable from that of normal subjects. Thus, urinary citrate was normally dependent on the net GI absorption of alkali. This dependence was less marked in RTA, confirming the renal origin of hypocitraturia. However, the normal dependence was maintained in CDS and in idiopathic hypocitraturia, suggesting that reduced citrate excretion was largely dietary in origin as a result of low net alkali absorption (from a probable relative deficiency of vegetables and fruits or a relative excess of animal proteins).

  20. The potential role of salt abuse on the risk for kidney stone formation

    NASA Technical Reports Server (NTRS)

    Sakhaee, K.; Harvey, J. A.; Padalino, P. K.; Whitson, P.; Pak, C. Y.

    1993-01-01

    The kidney stone-forming risk of a high sodium diet was evaluated by assessing the effect of such a diet on the crystallization of stone-forming salts in urine. Fourteen normal subjects participated in 2 phases of study of 10 days duration each, comprising a low sodium phase (basal metabolic diet containing 50 mmol. sodium per day) and a high sodium phase (basal diet plus 250 mmol. sodium chloride per day). The high sodium intake significantly increased urinary sodium (34 +/- 12 to 267 +/- 56 mmol. per day), calcium (2.73 +/- 1.03 to 3.93 +/- 1.51 mmol. per day) and pH (5.79 +/- 0.44 to 6.15 +/- 0.25), and significantly decreased urinary citrate (3.14 +/- 1.19 to 2.52 +/- 0.83 mmol. per day). Arterialized venous blood bicarbonate and total serum carbon dioxide concentrations decreased significantly during the high sodium diet, whereas serum chloride concentration increased. However, no change in arterialized venous pH was detected. Thus, a high sodium intake not only increased calcium excretion, but also increased urinary pH and decreased citrate excretion. The latter effects are probably due to sodium-induced bicarbonaturia and a significant decrease in serum bicarbonate concentration, respectively. Commensurate with these changes, the urinary saturation of calcium phosphate (brushite) and monosodium urate increased, and the inhibitor activity against calcium oxalate crystallization (formation product) decreased. The net effect of a high sodium diet was an increased propensity for the crystallization of calcium salts in urine.

  1. [Epidemiology of nephrolithiasis in France].

    PubMed

    Daudon, M

    2005-12-01

    Nephrolithiasis is a frequent disease that affects about 10% of people in western countries. The prevalence of calcium oxalate stones has been constantly increasing during the past fifty years in France as well as in other industrialized countries. Stone composition varies depending to gender and age of patients and also underlines the role of other risk factors and associated pathologies such as body mass index and diabetes mellitus. The decrease in struvite frequency in female patients is the result of a significantly improved diagnostic and treatment of urinary tract infections by urea-splitting bacteria. In contrast, the increasing occurrence of weddellite calculi in stone forming women aged more than 50 years could be the consequence of post-menopausal therapy. A high prevalence of uric acid was found in overweight and obese stone formers and in diabetic ones as well. Another important finding was the increased occurrence with time of calcium oxalate stones formed from papillary Randall's plaques, especially in young patients. Nutritional risk factors for stone disease are well known: they include excessive consumption of animal proteins, sodium chloride and rapidly absorbed glucides, and insufficient dietary intake of fruits and potassium-rich vegetables, which provide an alkaline load. As a consequence, an excessive production of hydrogen ions may induce several urinary disorders including low urine pH, high urine calcium and uric acid excretion and low urine citrate excretion. Excess in calorie intake, high chocolate consumption inducing hyperoxaluria and low water intake are other factors, which favour excessive urine concentration of solutes. Restoring the dietary balance is the first advice to prevent stone recurrence. However, the striking increase of some types of calculi, such as calcium oxalate stones developed from Randall's plaque, should alert to peculiar lithogenetic risk factors and suggests that specific advices should be given to prevent stone formation. PMID:16425740

  2. LAHS: A novel harmony search algorithm based on learning automata

    NASA Astrophysics Data System (ADS)

    Enayatifar, Rasul; Yousefi, Moslem; Abdullah, Abdul Hanan; Darus, Amer Nordin

    2013-12-01

    This study presents a learning automata-based harmony search (LAHS) for unconstrained optimization of continuous problems. The harmony search (HS) algorithm performance strongly depends on the fine tuning of its parameters, including the harmony consideration rate (HMCR), pitch adjustment rate (PAR) and bandwidth (bw). Inspired by the spur-in-time responses in the musical improvisation process, learning capabilities are employed in the HS to select these parameters based on spontaneous reactions. An extensive numerical investigation is conducted on several well-known test functions, and the results are compared with the HS algorithm and its prominent variants, including the improved harmony search (IHS), global-best harmony search (GHS) and self-adaptive global-best harmony search (SGHS). The numerical results indicate that the LAHS is more efficient in finding optimum solutions and outperforms the existing HS algorithm variants.

  3. “Newton’s cradle” proton relay with amide–imidic acid tautomerization in inverting cellulase visualized by neutron crystallography

    PubMed Central

    Nakamura, Akihiko; Ishida, Takuya; Kusaka, Katsuhiro; Yamada, Taro; Fushinobu, Shinya; Tanaka, Ichiro; Kaneko, Satoshi; Ohta, Kazunori; Tanaka, Hiroaki; Inaka, Koji; Higuchi, Yoshiki; Niimura, Nobuo; Samejima, Masahiro; Igarashi, Kiyohiko

    2015-01-01

    Hydrolysis of carbohydrates is a major bioreaction in nature, catalyzed by glycoside hydrolases (GHs). We used neutron diffraction and high-resolution x-ray diffraction analyses to investigate the hydrogen bond network in inverting cellulase PcCel45A, which is an endoglucanase belonging to subfamily C of GH family 45, isolated from the basidiomycete Phanerochaete chrysosporium. Examination of the enzyme and enzyme-ligand structures indicates a key role of multiple tautomerizations of asparagine residues and peptide bonds, which are finally connected to the other catalytic residue via typical side-chain hydrogen bonds, in forming the “Newton’s cradle”–like proton relay pathway of the catalytic cycle. Amide–imidic acid tautomerization of asparagine has not been taken into account in recent molecular dynamics simulations of not only cellulases but also general enzyme catalysis, and it may be necessary to reconsider our interpretation of many enzymatic reactions. PMID:26601228

  4. Measurement-induced-nonlocality for Dirac particles in Garfinkle-Horowitz-Strominger dilation space-time

    NASA Astrophysics Data System (ADS)

    He, Juan; Xu, Shuai; Ye, Liu

    2016-05-01

    We investigate the quantum correlation via measurement-induced-nonlocality (MIN) for Dirac particles in Garfinkle-Horowitz-Strominger (GHS) dilation space-time. It is shown that the physical accessible quantum correlation decreases as the dilation parameter increases monotonically. Unlike the case of scalar fields, the physical accessible correlation is not zero when the Hawking temperature is infinite owing to the Pauli exclusion principle and the differences between Fermi-Dirac and Bose-Einstein statistics. Meanwhile, the boundary of MIN related to Bell-violation is derived, which indicates that MIN is more general than quantum nonlocality captured by the violation of Bell-inequality. As a by-product, a tenable quantitative relation about MIN redistribution is obtained whatever the dilation parameter is. In addition, it is worth emphasizing that the underlying reason why the physical accessible correlation and mutual information decrease is that they are redistributed to the physical inaccessible regions.

  5. Multiple rewards from a treasure trove of novel glycoside hydrolase and polysaccharide lyase structures: new folds, mechanistic details, and evolutionary relationships.

    PubMed

    Fushinobu, Shinya; Alves, Victor D; Coutinho, Pedro M

    2013-10-01

    Recent progress in three-dimensional structure analyses of glycoside hydrolases (GHs) and polysaccharide lyases (PLs), the historically relevant enzyme classes involved in the cleavage of glycosidic bonds of carbohydrates and glycoconjugates, is reviewed. To date, about 80% and 95% of the GH and PL families, respectively, have a representative crystal structure. New structures have been determined for enzymes acting on plant cell wall polysaccharides, sphingolipids, blood group antigens, milk oligosaccharides, N-glycans, oral biofilms and dietary seaweeds. Some GH enzymes have very unique catalytic residues such as the Asp-His dyad. New methods such as high-speed atomic force microscopy and computational simulation have opened up a path to investigate both the dynamics and the detailed molecular interactions displayed by these enzymes. PMID:23816329

  6. Who Cares? Pre and Post Abortion Experiences among Young Females in Cape Coast Metropolis, Ghana.

    PubMed

    Esia-Donkoh, Kobina; Darteh, Eugene K M; Blemano, Harriet; Asare, Hagar

    2015-06-01

    Issues of abortion are critical in Ghana largely due to its consequences on sexual and reproductive health. The negative perception society attaches to it makes it difficult for young females to access services and share their experiences. This paper examines the pre and post abortion experiences of young females; a subject scarcely researched in the country. Twenty-one clients of Planned Parenthood Association of Ghana (PPAG) clinic at Cape Coast were interviewed. Guided by the biopsychosocial model, the study revealed that fear of societal stigma, shame, and rejection by partners, as well as self-imposed stigma constituted some of the pre and post abortion experiences the respondents. Other experiences reported were bleeding, severe abdominal pain and psychological pain. The Ghana Health Services (GHS) and other service providers should partner the PPAG clinic to integrate psychosocial treatment in its abortion services while intensifying behaviour change communication and community-based stigma-reduction education in the Metropolis. PMID:26506657

  7. [Evaluation of prescription practices for drugs charged in addition to DRG-based fees in Alsace].

    PubMed

    Kuss, Géraldine; Drogue, Nicole; Michel, Bruno

    2012-01-01

    Two studies led in parallel from May till June, 2009, were proposed in Alsace in order to analyze the hospital practices of prescription relative to 6 drugs charged in addition to the GHS: bevacizumab, gemcitabine, trastuzumab, etanercept, adalimumab and infliximab. The first study, led within 9 hospitals, allowed the collection of 343 situations of prescription. The second approach, based on the extraction of the PMSI data from the same hospitals, allowed the exploitation of 771 situations of prescription. The data collected on sites and from the PMSI respectively put in evidence 86.3% and 73.0% of prescriptions corresponding to guidelines. No unacceptable situation was revealed. The differences between approaches can be explained by the important proportion of unclassifiable situations extracted from the PMSI. These approaches bring complementary lightings and allow the OMEDIT of Alsace to take position in its missions of expertise and follow-up of therapeutic innovations. PMID:22874486

  8. Strengthening of Graphene Aerogels with Tunable Density and High Adsorption Capacity towards Pb2+

    PubMed Central

    Han, Zhuo; Tang, Zhihong; Shen, Shuling; Zhao, Bin; Zheng, Guangping; Yang, Junhe

    2014-01-01

    Graphene aerogels (GAs) with high mechanical strength, tunable density and volume have been prepared only via soaking graphene hydrogels (GHs) in ammonia solution. The density and volume of the obtained GAs are controlled by adjusting the concentration of ammonia solution. Although volume of the GAs decreases with increasing the concentration of ammonia solution, its specific surface area maintains at about 350 m2 g−1, and the inner structure changes to radial after ammonia solution treatment. Thus, GAs are particularly suitable for the adsorption and energy storage applications owing to their high specific surface area and unique porous structure. The adsorption capacity of GAs for Pb2+ from aqueous solution maintains at about 80 mg g−1, which could reach as high as 5000 g m−3 per unit volume and they can be separated easily from water after adsorption. PMID:24848100

  9. Cubit Adaptive Meshing Algorithm Library

    Energy Science and Technology Software Center (ESTSC)

    2004-09-01

    CAMAL (Cubit adaptive meshing algorithm library) is a software component library for mesh generation. CAMAL 2.0 includes components for triangle, quad and tetrahedral meshing. A simple Application Programmers Interface (API) takes a discrete boundary definition and CAMAL computes a quality interior unstructured grid. The triangle and quad algorithms may also import a geometric definition of a surface on which to define the grid. CAMAL’s triangle meshing uses a 3D space advancing front method, the quadmore » meshing algorithm is based upon Sandia’s patented paving algorithm and the tetrahedral meshing algorithm employs the GHS3D-Tetmesh component developed by INRIA, France.« less

  10. Detection of the greenhouse gas signal from space - A progress report

    NASA Technical Reports Server (NTRS)

    Barnett, T. P.; Haskins, R.; Chahine, M.

    1991-01-01

    The spatial distribution of the expected changes in the atmospheric water vapor content and cloud cover, as predicted by the transient greenhouse gas (GHG) simulation of Hansen et al. (1988), are examined to determine whether the signals would be large enough and unique enough to be useful in a GHG detection study. The nature of the predicted GHG signal was first examined using the transient CO2 run from the GISS ocean/atmosphere general circulation model. Next, the remotely sensed irradiance characteristics data (as the measure of water vapor content) supplied by the HIRS/MSU sensors for the area of the equatorial cold tongue region (the region in which there are no measurement stations). It is shown that HIRS/MSU signals can provide data necessary for detecting GHS signals in atmospheric moisture for regions where ground observations are not possible.

  11. Line-of-sight millimeter wave propagation characteristics

    NASA Astrophysics Data System (ADS)

    Clifford, S. F.; Hill, R. J.; Fritz, R. B.; Bohlander, R. A.; McMillan, R. W.

    1988-03-01

    From 1983 to 1985 a team of scientists from NOAA's Wave Propagation Laboratory and Georgia Institute of Technology conducted an extensive set of millimeter wave propagation measurements. In five, thirty-day sessions, chosen for the widest variety of weather conditions, millimeter wave frequencies from 116 to 230 GHs were propagated over a 1.4 km horizontal path in Flatville, Illinois. Simultaneous, extensive measurements of the meteorology allowed a detailed comparison of the propagation characteristics with the current state of the atmosphere. The observations of millimeter wave propagation characteristics during clear air and sever weather are reported. Amplitude and phase spectra for propagation in clear air are compared with theory derived using the weak refractive turbulence approximation. Excellant agreement is found. Further, probability density functions appear to be; respectively, lognormal (amplitude) and Gaussian (phase difference), as expected from application of the central limit theorem. Interesting meteorological observations and their millimeter wave signatures will also be presented.

  12. Aquatic hazard, bioaccumulation and screening risk assessment for 6:2 fluorotelomer sulfonate.

    PubMed

    Hoke, Robert A; Ferrell, Barbra D; Ryan, Tim; Sloman, Terry L; Green, John W; Nabb, Diane L; Mingoia, Robert; Buck, Robert C; Korzeniowski, Stephen H

    2015-06-01

    This study assessed the aquatic toxicity and bioaccumulation potential of 6:2 fluorotelomer sulfonate (6:2 FTSA). Acute and chronic aquatic hazard endpoints indicate 6:2 FTSA is not classified for aquatic hazard according to GHS or European CLP legislation. The aqueous bioconcentration factors for 6:2 FTSA were <40 and the dietary assimilation efficiency, growth corrected half-life and dietary biomagnification factor (BMF) were 0.435, 23.1d and 0.295, respectively. These data indicate that 6:2 FTSA is not bioaccumulative in aquatic organisms. Comparison of PNECs with the reported surface water concentrations (non-spill situations) suggests low risk to aquatic organisms from 6:2 FTSA. Future studies are needed to elucidate the biotic and abiotic fate of commercial AFFF surfactants in the environment. PMID:25725394

  13. Testing the channel flow model in the eastern Himalaya, eastern Bhutan: insights from preliminary thermobarometric data

    NASA Astrophysics Data System (ADS)

    Agustsson, K. S.; Gordon, S. M.; Long, S. P.; Seward, G. G.; Zeiger, K. J.; Penfold, M. L.

    2013-12-01

    The study of modern continent-continent collision provides insight into the links between the upper and lower crust, including the processes involved in the deep burial and exhumation of crustal rocks. Rocks of the Greater Himalayan Sequence (GHS), which were buried to mid- to lower-crustal levels, are exposed throughout the Himalayan orogenic belt, between the top-to-the-south Main Central Thrust and the top-to-the-north South Tibetan Detachment. The GHS consists of orthogneiss, metasedimentary rocks, and large-scale (>100 km2) leucogranite bodies. Within the Bhutan Himalaya, the top-to-the south Kakhtang Thrust (KT) separates the GHS into upper (GHSu) and lower (GHSl) structural levels. Previous studies have mapped the location of the KT by the crossing of the second sillimanite isograd and by a significant increase in the volume of crystallized melt. Previous work in Bhutan has mainly focused on the GHSl, whereas the extrusion of the higher-temperature GHSu has not been well studied, and there is little quantitative data describing the P-T history of these rocks. In order to test between different end-member models for the exhumation of the GHSu, including channel flow and critical taper, new thermobarometry data was collected from a transect of samples across the KT. The channel-flow model predicts that the GHSu would have achieved peak upper-amphibolite facies P-T conditions followed by retrograde, near-isothermal decompression. In contrast, the critical-taper model predicts near-isobaric cooling of the GHSu. The electron microprobe at UC-Santa Barbara was used to measure the composition of and test for zoning within garnet, plagioclase, and biotite. Garnets in all four samples are typically subhedral to euhedral and show relatively weak zonation and flat Mg, Fe, and Ca profiles. A few garnets do exhibit bell-shaped Mn and Ca profiles. In addition, a ca. 100 μm rim high in Mg, Ca and Mn but low in Fe is present on all garnets and is indicative of diffusional processes. Using the compositions from zoned garnet, biotite, and plagioclase, THERMOCALC P-T calculations, the garnet-biotite exchange thermometer and GASP barometer, we have obtained preliminary P-T conditions. Two kyanite schists below the KT yield similar P-T estimates of ~5.0-8.5 kbar and ~550-800°C for core and rim components. A sillimanite schist above the KT reveals potentially much higher pressures (up to ~23 kbar) at ~550-850°C for cores and ~700-800°C for rims. However, the plagioclase appears heterogeneous, and more analyses are needed to verify the pressures attained by this sample. In contrast, orthogneiss above the KT reveals lower temperature estimates of ~500-650°C for cores and rims. These preliminary P-T estimates constrain the peak P-T conditions across the KT and possibly reveal much higher pressures for the GHSu. Additional thermobarometry data and analyses of possible cordierite replacing garnet will be used to further constrain the P-T history of GHS rocks in Bhutan.

  14. Eye Irritation Test (EIT) for Hazard Identification of Eye Irritating Chemicals using Reconstructed Human Cornea-like Epithelial (RhCE) Tissue Model.

    PubMed

    Kaluzhny, Yulia; Kandárová, Helena; d'Argembeau-Thornton, Laurence; Kearney, Paul; Klausner, Mitchell

    2015-01-01

    To comply with the Seventh Amendment to the EU Cosmetics Directive and EU REACH legislation, validated non-animal alternative methods for reliable and accurate assessment of ocular toxicity in man are needed. To address this need, we have developed an eye irritation test (EIT) which utilizes a three dimensional reconstructed human cornea-like epithelial (RhCE) tissue model that is based on normal human cells. The EIT is able to separate ocular irritants and corrosives (GHS Categories 1 and 2 combined) and those that do not require labeling (GHS No Category). The test utilizes two separate protocols, one designed for liquid chemicals and a second, similar protocol for solid test articles. The EIT prediction model uses a single exposure period (30 min for liquids, 6 hr for solids) and a single tissue viability cut-off (60.0% as determined by the MTT assay). Based on the results for 83 chemicals (44 liquids and 39 solids) EIT achieved 95.5/68.2/ and 81.8% sensitivity/specificity and accuracy (SS&A) for liquids, 100.0/68.4/ and 84.6% SS&A for solids, and 97.6/68.3/ and 83.1% for overall SS&A. The EIT will contribute significantly to classifying the ocular irritation potential of a wide range of liquid and solid chemicals without the use of animals to meet regulatory testing requirements. The EpiOcular EIT method was implemented in 2015 into the OECD Test Guidelines as TG 492. PMID:26325674

  15. Early life overfeeding decreases acylated ghrelin circulating levels and upregulates GHSR1a signaling pathway in white adipose tissue of obese young mice.

    PubMed

    Soares, Vivian M; Garcia-Souza, Erica P; Lacerda-Miranda, Glauciane; Moura, Anibal S

    2012-02-10

    Ghrelin is a hormone synthesized by the stomach that acts in different tissues via a specific receptor (GHS-R1a), including hypothalamus and adipose tissue. For instance, recent reports have shown that ghrelin has a direct action on hypothalamic regulation of food intake mainly inducing an orexigenic effect. On the other hand, ghrelin also modulates energy stores and expenditure in the adipocytes. This dual action has suggested that this hormone may act as a link between the central nervous system and peripheral mechanisms. Furthermore, concerning nutritional disorders, it has been suggested that obesity may be considered an impairment of the above cited link. Therefore, considering that neonatal overfeeding induces obesity in adulthood by unknown mechanisms, in this study we examined the effects of early life overnutrition on the development of obesity and in particular on adipose tissue ghrelin signaling in young mice. Our data demonstrated that overnutrition during early life induces a significant increase in body weight of young mice, starting at 10 days, and this increase in weight persisted until adulthood (90 days of age). In these animals, blood glucose, liver weight and visceral fat weight were found higher at 21 days when compared to the control group. Acylated ghrelin circulating levels were found lower in the young obese pups. In addition, in white adipose tissue ghrelin receptor (GHS-R1a) expression increased and was associated to positive modulation of content and phosphorylation of proteins involved in cell energy store and use as AKT, PI3K, AMPK, GLUT-4, and CPT1. However, PPARγ content decreased in obese group. Basically, we showed that adipose tissue metabolism is altered in early life acquired obesity and probably due to such modification a new pattern of ghrelin signaling pathway takes place. PMID:22119755

  16. Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF-1.

    PubMed

    Dobie, Ross; Ahmed, Syed F; Staines, Katherine A; Pass, Chloe; Jasim, Seema; MacRae, Vicky E; Farquharson, Colin

    2015-11-01

    Growth hormone (GH) signaling is essential for postnatal linear bone growth, but the relative importance of GHs actions on the liver and/or growth plate cartilage remains unclear. The importance of liver derived insulin like-growth factor-1 (IGF-1) for endochondral growth has recently been challenged. Here, we investigate linear growth in Suppressor of Cytokine Signaling-2 (SOCS2) knockout mice, which have enhanced growth despite normal systemic GH/IGF-1 levels. Wild-type embryonic ex vivo metatarsals failed to exhibit increased linear growth in response to GH, but displayed increased Socs2 transcript levels (P < 0.01). In the absence of SOCS2, GH treatment enhanced metatarsal linear growth over a 12 day period. Despite this increase, IGF-1 transcript and protein levels were not increased in response to GH. In accordance with these data, IGF-1 levels were unchanged in GH-challenged postnatal Socs2(-/-) conditioned medium despite metatarsals showing enhanced linear growth. Growth-plate Igf1 mRNA levels were not elevated in juvenile Socs2(-/-) mice. GH did however elevate IGF-binding protein 3 levels in conditioned medium from GH challenged metatarsals and this was more apparent in Socs2(-/-) metatarsals. GH did not enhance the growth of Socs2(-/-) metatarsals when the IGF receptor was inhibited, suggesting that IGF receptor mediated mechanisms are required. IGF-2 may be responsible as IGF-2 promoted metatarsal growth and Igf2 expression was elevated in Socs2(-/-) (but not WT) metatarsals in response to GH. These studies emphasise the critical importance of SOCS2 in regulating GHs ability to promote bone growth. Also, GH appears to act directly on the metatarsals of Socs2(-/-) mice, promoting growth via a mechanism that is independent of IGF-1. PMID:25833299

  17. Potassium Current Is Not Affected by Long-Term Exposure to Ghrelin or GHRP-6 in Somatotropes GC Cells.

    PubMed

    Domínguez Mancera, Belisario; Monjaraz Guzman, Eduardo; Flores-Hernández, Jorge L V; Barrientos Morales, Manuel; Martínez Hernandez, José M; Hernández Beltran, Antonio; Cervantes Acosta, Patricia

    2013-01-01

    Ghrelin is a growth hormone (GH) secretagogue (GHS) and GHRP-6 is a synthetic peptide analogue; both act through the GHS receptor. GH secretion depends directly on the intracellular concentration of Ca(2+); this is determined from the intracellular reserves and by the entrance of Ca(2+) through the voltage-dependent calcium channels, which are activated by the membrane depolarization. Membrane potential is mainly determined by K(+) channels. In the present work, we investigated the effect of ghrelin (10 nM) or GHRP-6 (100 nM) for 96 h on functional expression of voltage-dependent K(+) channels in rat somatotropes: GC cell line. Physiological patch-clamp whole-cell recording was used to register the K(+) currents. With Cd(2+) (1 mM) and tetrodotoxin (1  μ m) in the bath solution recording, three types of currents were characterized on the basis of their biophysical and pharmacological properties. GC cells showed a K(+) current with a transitory component (I A) sensitive to 4-aminopyridine, which represents ~40% of the total outgoing current; a sustained component named delayed rectifier (I K), sensitive to tetraethylammonium; and a third type of K(+) current was recorded at potentials more negative than -80 mV, permitting the entrance of K(+) named inward rectifier (KIR). Chronic treatment with ghrelin or GHRP-6 did not modify the functional expression of K(+) channels, without significant changes (P < 0.05) in the amplitudes of the three currents observed; in addition, there were no modifications in their biophysical properties and kinetic activation or inactivation. PMID:23533398

  18. Potassium Current Is Not Affected by Long-Term Exposure to Ghrelin or GHRP-6 in Somatotropes GC Cells

    PubMed Central

    Domínguez Mancera, Belisario; Monjaraz Guzman, Eduardo; Flores-Hernández, Jorge L. V.; Barrientos Morales, Manuel; Martínez Hernandez, José M.; Hernández Beltran, Antonio; Cervantes Acosta, Patricia

    2013-01-01

    Ghrelin is a growth hormone (GH) secretagogue (GHS) and GHRP-6 is a synthetic peptide analogue; both act through the GHS receptor. GH secretion depends directly on the intracellular concentration of Ca2+; this is determined from the intracellular reserves and by the entrance of Ca2+ through the voltage-dependent calcium channels, which are activated by the membrane depolarization. Membrane potential is mainly determined by K+ channels. In the present work, we investigated the effect of ghrelin (10 nM) or GHRP-6 (100 nM) for 96 h on functional expression of voltage-dependent K+ channels in rat somatotropes: GC cell line. Physiological patch-clamp whole-cell recording was used to register the K+ currents. With Cd2+ (1 mM) and tetrodotoxin (1 μm) in the bath solution recording, three types of currents were characterized on the basis of their biophysical and pharmacological properties. GC cells showed a K+ current with a transitory component (IA) sensitive to 4-aminopyridine, which represents ~40% of the total outgoing current; a sustained component named delayed rectifier (IK), sensitive to tetraethylammonium; and a third type of K+ current was recorded at potentials more negative than −80 mV, permitting the entrance of K+ named inward rectifier (KIR). Chronic treatment with ghrelin or GHRP-6 did not modify the functional expression of K+ channels, without significant changes (P < 0.05) in the amplitudes of the three currents observed; in addition, there were no modifications in their biophysical properties and kinetic activation or inactivation. PMID:23533398

  19. Ghrelin signaling in heart remodeling of adult obese mice.

    PubMed

    Lacerda-Miranda, Glauciane; Soares, Vivian M; Vieira, Anatalia K G; Lessa, Juliana G; Rodrigues-Cunha, Alessandra C S; Cortez, Erika; Garcia-Souza, Erica P; Moura, Anibal S

    2012-05-01

    Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), has been suggested to be associated to obesity, insulin secretion, cardiovascular growth and homeostasis. GHS-R has been found in most of the tissues, and among the hormone action it is included the regulation of heart energy metabolism. Therefore, hypernutrition during early life leads to obesity, induces cardiac hypertrophy, compromises myocardial function, inducing heart failure in adulthood. We examined ghrelin signaling process in cardiac remodeling in these obese adult mice. The cardiomyocytes (cmy) of left ventricle were analyzed by light microscopy and stereology, content and phosphorilation of cardiac proteins: ghrelin receptor (growth hormone secretagogue receptor 1a, GHSR-1a), protein kinase B (AKT and pAKT), phosphatidil inositol 3 kinase (PI3K), AMP-activated protein kinase (AMPK and pAMPK) and actin were achieved by Western blotting. GHSR-1a gene expression was analyzed by Real Time-PCR. We observed hyperglycemia and higher liver and visceral fat weight in obese when compared to control group. Obese mice presented a marked increase in heart weight/tibia length, indicating an enlarged heart size or a remodeling process. Obese mice had increased GHSR-1a content and expression in the heart associated to PI3K content and increased AKT content and phosphorylation. In contrast, AMPK content and phosphorylation in heart was not different between experimental groups. Ghrelin plasma levels in obese group were decreased when compared to control group. Our data suggest that remodeled myocardial in adult obese mice overnourished in early life are associated with higher phosphorylation of GHSR-1a, PI3K and AKT but not with AMPK. PMID:22407166

  20. Regulation of pituitary cell function by adiponectin.

    PubMed

    Rodriguez-Pacheco, Francisca; Martinez-Fuentes, Antonio J; Tovar, Sulay; Pinilla, Leonor; Tena-Sempere, Manuel; Dieguez, Carlos; Castaño, Justo P; Malagon, María M

    2007-01-01

    Adiponectin is a member of the family of adipose tissue-related hormones known as adipokines, which exerts antidiabetic, antiatherogenic, antiinflammatory, and antiangiogenic properties. Adiponectin actions are primarily mediated through binding to two receptors expressed in several tissues, AdipoR1 and AdipoR2. Likewise, adiponectin expression has been detected in adipocytes as well as in a variety of extra-adipose tissues, including the chicken pituitary. Interestingly, adiponectin secretion and adiponectin receptor expression in adipocytes have been shown to be regulated by pituitary hormones. These observations led us to investigate whether adiponectin, like the adipokine leptin, regulates pituitary hormone production. Specifically, we focused our analysis on somatotrophs and gonadotrophs because of the relationship between the control of energy metabolism, growth and reproduction. To this end, the effects of adiponectin on both GH and LH secretion as well as its interaction with major stimulatory regulators of somatotrophs (ghrelin and GHRH) and gonadotrophs (GnRH) and with their corresponding receptors (GHS-R, GHRH-R, and GnRH-R), were evaluated in rat pituitary cell cultures. Results show that adiponectin inhibits GH and LH release as well as both ghrelin-induced GH release and GnRH-stimulated LH secretion in short-term (4 h) treated cell cultures, wherein the adipokine also increases GHRH-R and GHS-R mRNA content while decreasing that of GnRH-R. Additionally, we demonstrate that the pituitary expresses both adiponectin and adiponectin receptors under the regulation of the adipokine. In sum, our data indicate that adiponectin, either locally produced or from other sources, may play a neuroendocrine role in the control of both somatotrophs and gonadotrophs. PMID:17038552

  1. Development Characteristics of PMMA in alternative alcohol:water mixtures

    NASA Astrophysics Data System (ADS)

    Ocola, Leonidas E.

    2015-03-01

    The most widely used resist in electron beam lithography is polymethylmethacrylate (PMMA). The standard developers used are solution mixtures of isopropanol (IPA) and methyl isobutyl ketone (MIBK) in a ratio of 3:1 and mixtures of IPA and water (H2O) in a ratio of 7:3. The Globally Harmonized System (GHS) classification entry for IPA includes: Specific target organ toxicity - single exposure (Category 3). MIBK is much more hazardous than IPA. The only GHS classification entry for Ethanol is: Flammable liquids (Category 2), i.e. more environmentally safe. Using Ethanol/H2O as a developer will therefore enable lower hazardous waste disposal costs to cleanrooms. We find Ethanol/H2O at 85% volume (2:1 molar) exhibits excellent lithography results as good as with IPA/H2O, and better contrast and sensitivity than IPA/H2O and MIBK/IPA developers. Lithographic data shows trends similar to published cosolvency data, but differ too much to be explained by it. In addition, unusual development at 50% volume concentrations for both IPA and Ethanol in H2O show dramatic pothole formation instead of uniform thickness loss found in standard contrast curve exposures. We believe local pockets of concentrated alcohol water molar mixtures are responsible for such behavior. This work was supported by the Department of Energy under Contract No. DE-AC02-06CH11357. Use of the Center for Nanoscale Materials was supported by the U. S. Department of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357.

  2. Eye Irritation Test (EIT) for Hazard Identification of Eye Irritating Chemicals using Reconstructed Human Cornea-like Epithelial (RhCE) Tissue Model

    PubMed Central

    Kaluzhny, Yulia; Kandárová, Helena; d’Argembeau-Thornton, Laurence; Kearney, Paul; Klausner, Mitchell

    2015-01-01

    To comply with the Seventh Amendment to the EU Cosmetics Directive and EU REACH legislation, validated non-animal alternative methods for reliable and accurate assessment of ocular toxicity in man are needed. To address this need, we have developed an eye irritation test (EIT) which utilizes a three dimensional reconstructed human cornea-like epithelial (RhCE) tissue model that is based on normal human cells. The EIT is able to separate ocular irritants and corrosives (GHS Categories 1 and 2 combined) and those that do not require labeling (GHS No Category). The test utilizes two separate protocols, one designed for liquid chemicals and a second, similar protocol for solid test articles. The EIT prediction model uses a single exposure period (30 min for liquids, 6 hr for solids) and a single tissue viability cut-off (60.0% as determined by the MTT assay). Based on the results for 83 chemicals (44 liquids and 39 solids) EIT achieved 95.5/68.2/ and 81.8% sensitivity/specificity and accuracy (SS&A) for liquids, 100.0/68.4/ and 84.6% SS&A for solids, and 97.6/68.3/ and 83.1% for overall SS&A. The EIT will contribute significantly to classifying the ocular irritation potential of a wide range of liquid and solid chemicals without the use of animals to meet regulatory testing requirements. The EpiOcular EIT method was implemented in 2015 into the OECD Test Guidelines as TG 492. PMID:26325674

  3. Histopathological evaluation of the ocular-irritation potential of shampoos, make-up removers and cleansing foams in the bovine corneal opacity and permeability assay

    PubMed Central

    Furukawa, Masatoshi; Sakakibara, Takashi; Itoh, Kouta; Kawamura, Kohtaro; Sasaki, Satoshi; Matsuura, Masao

    2015-01-01

    The bovine corneal opacity and permeability (BCOP) assay is an alternative method to the in vivo Draize eye test in rabbits for evaluating eye irritation in vitro. Here, we compared the numerical results of the BCOP assay with the corresponding histopathology for three different corneas for each test substance, including commercially available shampoos, make-up removers and cleansing foams that contained surfactants and other ingredients. The histopathological score was defined based on the severity of lesions in the corneal epithelium. The histopathological findings and scores of the three sections for each test substance were comparable. The in vitro irritancy score (IVIS) generally corresponds to the corneal irritant potential of the test substances assigned on the basis of the histopathological findings in this study. In the present study, we characterized the histopathology of the corneal epithelium and stroma and especially showed that the corneal epithelial injury caused by test substances might be important in assessment of test substances that are mild eye irritants (category 2B) as classified by the United Nations (UN) Globally Harmonized System of Classification and Labelling of Chemicals (GHS), as corneal lesions suggestive of classification into category 2B were localized on the border between the corneal epithelium and stroma, which contained cell elements related to assessment of prognosis of an in vivo eye injury. Histopathological assessment might be useful in predicting in vivo ocular irritation, particularly for test substances with an IVIS >3.1 but ≤25 that are classified as mild irritants (category 2B) according to the UN GHS. PMID:26538816

  4. Pressure-temperature-time-deformation path of kyanite-bearing migmatitic paragneiss in the Kali Gandaki valley (Central Nepal): Investigation of Late Eocene-Early Oligocene melting processes

    NASA Astrophysics Data System (ADS)

    Iaccarino, Salvatore; Montomoli, Chiara; Carosi, Rodolfo; Massonne, Hans-Joachim; Langone, Antonio; Visonà, Dario

    2015-08-01

    Kyanite-bearing migmatitic paragneiss of the lower Greater Himalayan Sequence (GHS) in the Kali Gandaki transect (Central Himalaya) was investigated. In spite of the intense shearing, it was still possible to obtain many fundamental information for understanding the processes active during orogenesis. Using a multidisciplinary approach, including careful meso- and microstructural observations, pseudosection modelling (with PERPLE_X), trace element thermobarometry and in situ monazite U-Th-Pb geochronology, we constrained the pressure-temperature-time-deformation path of the studied rock, located in a structural key position. The migmatitic gneiss has experienced protracted prograde metamorphism after the India-Asia collision (50-55 Ma) from ~ 43 Ma to 28 Ma. During the late phase (36-28 Ma) of this metamorphism, the gneiss underwent high-pressure melting at "near peak" conditions (710-720 °C/1.0-1.1 GPa) leading to kyanite-bearing leucosome formation. In the time span of 25-18 Ma, the rock experienced decompression and cooling associated with pervasive shearing reaching P-T conditions of 650-670 °C and 0.7-0.8 GPa, near the sillimanite-kyanite transition. This time span is somewhat older than previously reported for this event in the study area. During this stage, additional, but very little melt was produced. Taking the migmatitic gneiss as representative of the GHS, these data demonstrate that this unit underwent crustal melting at about 1 GPa in the Eocene-Early Oligocene, well before the widely accepted Miocene decompressional melting related to its extrusion. In general, kyanite-bearing migmatite, as reported here, could be linked to the production of the high-Ca granitic melts found along the Himalayan belt.

  5. De Novo Analysis of Wolfiporia cocos Transcriptome to Reveal the Differentially Expressed Carbohydrate-Active Enzymes (CAZymes) Genes During the Early Stage of Sclerotial Growth

    PubMed Central

    Zhang, Shaopeng; Hu, Bingxiong; Wei, Wei; Xiong, Ying; Zhu, Wenjun; Peng, Fang; Yu, Yang; Zheng, Yonglian; Chen, Ping

    2016-01-01

    The sclerotium of Wolfiporia cocos has been used as an edible mushroom and/or a traditional herbal medicine for centuries. W. cocos sclerotial formation is dependent on parasitism of the wood of Pinus species. Currently, the sclerotial development mechanisms of W. cocos remain largely unknown and the lack of pine resources limit the commercial production. The CAZymes (carbohydrate-active enzymes) play important roles in degradation of the plant cell wall to provide carbohydrates for fungal growth, development, and reproduction. In this study, the transcript profiles from W. cocos mycelium and 2-months-old sclerotium, the early stage of sclerotial growth, were specially analyzed using de novo sequencing technology. A total of 142,428,180 high-quality reads of mycelium and 70,594,319 high-quality reads of 2-months-old sclerotium were obtained. Additionally, differentially expressed genes from the W. cocos mycelium and 2-months-old sclerotium stages were analyzed, resulting in identification of 69 CAZymes genes which were significantly up-regulated during the early stage of sclerotial growth compared to that of in mycelium stage, and more than half of them belonged to glycosyl hydrolases (GHs) family, indicating the importance of W. cocos GHs family for degrading the pine woods. And qRT-PCR was further used to confirm the expression pattern of these up-regulated CAZymes genes. Our results will provide comprehensive CAZymes genes expression information during W. cocos sclerotial growth at the transcriptional level and will lay a foundation for functional genes studies in this fungus. In addition, our study will also facilitate the efficient use of limited pine resources, which is significant for promoting steady development of Chinese W. cocos industry. PMID:26870032

  6. Association between Resistin Levels and All-Cause and Cardiovascular Mortality: A New Study and a Systematic Review and Meta-Analysis

    PubMed Central

    Fontana, Andrea; Spadaro, Sara; Copetti, Massimiliano; Spoto, Belinda; Salvemini, Lucia; Pizzini, Patrizia; Frittitta, Lucia; Mallamaci, Francesca; Pellegrini, Fabio; Trischitta, Vincenzo; Menzaghi, Claudia

    2015-01-01

    Context Studies concerning the association between circulating resistin and mortality risk have reported, so far, conflicting results. Objective To investigate the association between resistin and both all-cause and cardiovascular (CV) mortality risk by 1) analyzing data from the Gargano Heart Study (GHS) prospective design (n=359 patients; 81 and 58 all-cause and CV deaths, respectively); 2) performing meta-analyses of all published studies addressing the above mentioned associations. Data Source and Study Selection MEDLINE and Web of Science search of studies reporting hazard ratios (HR) of circulating resistin for all-cause or CV mortality. Data Extraction Performed independently by two investigators, using a standardized data extraction sheet. Data Synthesis In GHS, adjusted HRs per one standard deviation (SD) increment in resistin concentration were 1.28 (95% CI: 1.07-1.54) and 1.32 (95% CI: 1.06-1.64) for all-cause and CV mortality, respectively. The meta-analyses included 7 studies (n=4016; 961 events) for all-cause mortality and 6 studies (n=4,187: 412 events) for CV mortality. Pooled HRs per one SD increment in resistin levels were 1.21 (95% CI: 1.03-1.42, Q-test p for heterogeneity<0.001) and 1.05 (95% CI: 1.01-1.10, Q-test p for heterogeneity=0.199) for all-cause and CV mortality, respectively. At meta-regression analyses, study mean age explained 9.9% of all-cause mortality studies heterogeneity. After adjusting for age, HR for all-cause mortality was 1.24 (95% CI: 1.06-1.45). Conclusions Our results provide evidence for an association between circulating resistin and mortality risk among high-risk patients as are those with diabetes and coronary artery disease. PMID:25793385

  7. Comparative analysis of fungal genomes reveals different plant cell wall degrading capacity in fungi

    PubMed Central

    2013-01-01

    Background Fungi produce a variety of carbohydrate activity enzymes (CAZymes) for the degradation of plant polysaccharide materials to facilitate infection and/or gain nutrition. Identifying and comparing CAZymes from fungi with different nutritional modes or infection mechanisms may provide information for better understanding of their life styles and infection models. To date, over hundreds of fungal genomes are publicly available. However, a systematic comparative analysis of fungal CAZymes across the entire fungal kingdom has not been reported. Results In this study, we systemically identified glycoside hydrolases (GHs), polysaccharide lyases (PLs), carbohydrate esterases (CEs), and glycosyltransferases (GTs) as well as carbohydrate-binding modules (CBMs) in the predicted proteomes of 103 representative fungi from Ascomycota, Basidiomycota, Chytridiomycota, and Zygomycota. Comparative analysis of these CAZymes that play major roles in plant polysaccharide degradation revealed that fungi exhibit tremendous diversity in the number and variety of CAZymes. Among them, some families of GHs and CEs are the most prevalent CAZymes that are distributed in all of the fungi analyzed. Importantly, cellulases of some GH families are present in fungi that are not known to have cellulose-degrading ability. In addition, our results also showed that in general, plant pathogenic fungi have the highest number of CAZymes. Biotrophic fungi tend to have fewer CAZymes than necrotrophic and hemibiotrophic fungi. Pathogens of dicots often contain more pectinases than fungi infecting monocots. Interestingly, besides yeasts, many saprophytic fungi that are highly active in degrading plant biomass contain fewer CAZymes than plant pathogenic fungi. Furthermore, analysis of the gene expression profile of the wheat scab fungus Fusarium graminearum revealed that most of the CAZyme genes related to cell wall degradation were up-regulated during plant infection. Phylogenetic analysis also revealed a complex history of lineage-specific expansions and attritions for the PL1 family. Conclusions Our study provides insights into the variety and expansion of fungal CAZyme classes and revealed the relationship of CAZyme size and diversity with their nutritional strategy and host specificity. PMID:23617724

  8. Concomitant Release of Ventral Tegmental Acetylcholine and Accumbal Dopamine by Ghrelin in Rats

    PubMed Central

    Jerlhag, Elisabet; Janson, Anna Carin; Waters, Susanna; Engel, Jörgen A.

    2012-01-01

    Ghrelin, an orexigenic peptide, regulates energy balance specifically via hypothalamic circuits. Growing evidence suggest that ghrelin increases the incentive value of motivated behaviours via activation of the cholinergic-dopaminergic reward link. It encompasses the cholinergic afferent projection from the laterodorsal tegmental area (LDTg) to the dopaminergic cells of the ventral tegmental area (VTA) and the mesolimbic dopamine system projecting from the VTA to nucleus accumbens (N.Acc.). Ghrelin receptors (GHS-R1A) are expressed in these reward nodes and ghrelin administration into the LDTg increases accumbal dopamine, an effect involving nicotinic acetylcholine receptors in the VTA. The present series of experiments were undertaken directly to test this hypothesis. Here we show that ghrelin, administered peripherally or locally into the LDTg concomitantly increases ventral tegmental acetylcholine as well as accumbal dopamine release. A GHS-R1A antagonist blocks this synchronous neurotransmitter release induced by peripheral ghrelin. In addition, local perfusion of the unselective nicotinic antagonist mecamylamine into the VTA blocks the ability of ghrelin (administered into the LDTg) to increase N.Acc.-dopamine, but not VTA-acetylcholine. Collectively our data indicate that ghrelin activates the LDTg causing a release of acetylcholine in the VTA, which in turn activates local nicotinic acetylcholine receptors causing a release of accumbal dopamine. Given that a dysfunction in the cholinergic-dopaminergic reward system is involved in addictive behaviours, including compulsive overeating and alcohol use disorder, and that hyperghrelinemia is associated with such addictive behaviours, ghrelin-responsive circuits may serve as a novel pharmacological target for treatment of alcohol use disorder as well as binge eating. PMID:23166710

  9. Challenges in linking health research to policy: a commentary on developing a multi-stakeholder response to orphans and vulnerable children in Ghana.

    PubMed

    Gyapong, John Owusu; Selby, Richmond Ato; Anakwah, Kwadwo Antwi

    2011-01-01

    The Research and Development Division (RDD) of the Ghana Health Service (GHS) has a remit to build research capacity and conduct policy relevant research. By being situated within the GHS, RDD has good access to directors and programme managers, within and beyond the Ministry of Health. This structure has been facilitating collaboration through research cycles for 20 years, from agenda setting to discussions on policy relevance.This approach has been applied to research activities within the Addressing the Balance of Burden in AIDS (ABBA) Research Programme Consortium to tackle the challenges facing HIV affected orphans and vulnerable children (OVCs). The government strategy on OVCs recommends they should be encouraged to live in their home communities rather than in institutions. We present lessons here on efforts to use research to build a response across different agencies to address the problems that communities and families face in caring for these children in their communities.This approach to building consensus on research priorities points to the value of collaboration and dialogue with multiple stakeholders as a means of fostering ownership of a research process and supporting the relevance of research to different groups. Our experience has shown that if the context within which researchers, policy makers and stakeholders work were better understood, the links between them were improved and research were communicated more effectively, then better policy making which links across different sectors may follow. At the same time, collaboration among these different stakeholders to ensure that research meets social needs, must also satisfy the requirements of scientific rigour. PMID:21679381

  10. The N-Glycan Cluster from Xanthomonas campestris pv. campestris

    PubMed Central

    Dupoiron, Stéphanie; Zischek, Claudine; Ligat, Laetitia; Carbonne, Julien; Boulanger, Alice; Dugé de Bernonville, Thomas; Lautier, Martine; Rival, Pauline; Arlat, Matthieu; Jamet, Elisabeth; Lauber, Emmanuelle; Albenne, Cécile

    2015-01-01

    N-Glycans are widely distributed in living organisms but represent only a small fraction of the carbohydrates found in plants. This probably explains why they have not previously been considered as substrates exploited by phytopathogenic bacteria during plant infection. Xanthomonas campestris pv. campestris, the causal agent of black rot disease of Brassica plants, possesses a specific system for GlcNAc utilization expressed during host plant infection. This system encompasses a cluster of eight genes (nixE to nixL) encoding glycoside hydrolases (GHs). In this paper, we have characterized the enzymatic activities of these GHs and demonstrated their involvement in sequential degradation of a plant N-glycan using a N-glycopeptide containing two GlcNAcs, three mannoses, one fucose, and one xylose (N2M3FX) as a substrate. The removal of the α-1,3-mannose by the α-mannosidase NixK (GH92) is a prerequisite for the subsequent action of the β-xylosidase NixI (GH3), which is involved in the cleavage of the β-1,2-xylose, followed by the α-mannosidase NixJ (GH125), which removes the α-1,6-mannose. These data, combined to the subcellular localization of the enzymes, allowed us to propose a model of N-glycopeptide processing by X. campestris pv. campestris. This study constitutes the first evidence suggesting N-glycan degradation by a plant pathogen, a feature shared with human pathogenic bacteria. Plant N-glycans should therefore be included in the repertoire of molecules putatively metabolized by phytopathogenic bacteria during their life cycle. PMID:25586188

  11. Disability prevalence and disability-related employment gaps in the UK 1998-2012: Different trends in different surveys?

    PubMed

    Baumberg, Ben; Jones, Melanie; Wass, Victoria

    2015-09-01

    The persistently low employment rate among disabled individuals has been an enduring concern of governments across developed countries and has been the subject of a succession of policy initiatives, including labour market activation programmes, equality laws and welfare reform. A key indicator of progress is the trend in the disability-related employment gap, the percentage point difference between the employment rate for disabled and non-disabled individuals. Confusingly for the UK, studies undertaken between 1998 and 2012 have simultaneously reported both a widening and a narrowing of the gap. The source of the discrepancy can be found in the choice of survey, the General Household Survey (GHS) or the Labour Force Survey (LFS), although both use a common conception of disability and collect self-reported information from a random sample of households. The literature has analysed these surveys separately from each other and ignored inter-survey differences in findings. The Health Survey for England (HSE), a third national household survey, replicates the GHS questions on disability but has had limited use in this context. This empirical study compares the trends in disability prevalence and the disability-related employment gap across the three surveys using a three-stage harmonisation process. The negative relationship between the prevalence of disability and the employment gap found in cross-section inter-survey comparisons prompts an initial focus on differences in the definition of disability as an explanation of the discrepancy. This is broadened to include differences in survey methods and sample composition. Differences in the trend in disability prevalence and the employment gap remain following harmonisation for definition, survey method and sample composition. It is the LFS, the main policy-influencing and policy-assessment survey, which generates outlying results. As such, we cannot be confident that the disability-related employment gap has narrowed in the UK since 1998. PMID:26248307

  12. Patterns of preventive health services in rheumatoid arthritis patients compared to a primary care patient population.

    PubMed

    Bili, Androniki; Schroeder, Lisa L; Ledwich, Lindsay J; Kirchner, H Lester; Newman, Eric D; Wasko, Mary Chester M

    2011-09-01

    To determine the proportion of rheumatoid arthritis (RA) patients receiving preventive health care according to US Preventive Services Task Force recommendations compared with a community-based population sample, with emphasis on dyslipidemia testing, given the increased risk of cardiovascular disease (CVD) in RA patients. Patients with RA (ICD-9 code 714.0 at ≥2 office visits with a rheumatologist) and a primary care physician (PCP) at the Geisinger Health System (GHS) were identified through electronic health records. The records were searched back from 3/31/08 for the length of time required to satisfy each outcome measure. Percentages were compared with population testing rates using the Pearson Chi-square test. Eight hundred and thirty-one RA patients were compared to 169,476 subjects with a PCP at GHS, stratified by gender and age. Patients with RA were more likely to have had dyslipidemia and osteoporosis testing compared with the general population (86 vs. 75 and 75 vs. 55%, respectively, P < 0.0001 for both). The proportion of RA patients receiving breast and cervical cancer testing was similar to the general population. The majority (79%) of lipid testing was ordered by PCPs. Those RA patients with recommended lipid testing had more traditional CVD factors (hypertension, diabetes, coronary artery disease). RA patients are screened more than the general population for two RA-related co-morbidities, i.e. dyslipidemia and osteoporosis. The RA patients with traditional cardiovascular risk factors are more likely to be tested for dyslipidemia. Further work is warranted to improve testing for modifiable CVD risk factors in this group with multiple co-morbidities. PMID:20349066

  13. The crystal structure of an inverting glycoside hydrolase family 9 exo-?-D-glucosaminidase and the design of glycosynthase.

    PubMed

    Honda, Yuji; Arai, Sachiko; Suzuki, Kentaro; Kitaoka, Motomitsu; Fushinobu, Shinya

    2016-02-15

    Exo-?-D-glucosaminidase (EC 3.2.1.165) from Photobacterium profundum (PpGlcNase) is an inverting GH (glycoside hydrolase) belonging to family 9. We have determined the three-dimensional structure of PpGlcNase to describe the first structure-function relationship of an exo-type GH9 glycosidase. PpGlcNase has a narrow and straight active-site pocket, in contrast with the long glycan-binding cleft of a GH9 endoglucanase. This is because PpGlcNase has a long loop, which blocks the position corresponding to subsites -4 to -2 of the endoglucanase. The pocket shape of PpGlcNase explains its substrate preference for a ?1,4-linkage at the non-reducing terminus. Asp(139), Asp(143) and Glu(555) in the active site were located near the ?-O1 hydroxy group of GlcN (D-glucosamine), with Asp(139) and Asp(143) holding a nucleophilic water molecule for hydrolysis. The D139A, D143A and E555A mutants significantly decreased hydrolytic activity, indicating their essential role. Of these mutants, D139A exclusively exhibited glycosynthase activity using ?-GlcN-F (?-D-glucosaminyl fluoride) and GlcN as substrates, to produce (GlcN)2. Using saturation mutagenesis at Asp(139), we obtained D139E as the best glycosynthase. Compared with the wild-type, the hydrolytic activity of D139E was significantly suppressed (<0.1%), and the F(-)-release activity also decreased (<3%). Therefore the glycosynthase activity of D139E was lower than that of glycosynthases created previously from other inverting GHs. Mutation at the nucleophilic water holder is a general strategy for creating an effective glycosynthase from inverting GHs. However, for GH9, where two acidic residues seem to share the catalytic base role, mutation of Asp(139) might inevitably reduce F(-)-release activity. PMID:26621872

  14. De Novo Analysis of Wolfiporia cocos Transcriptome to Reveal the Differentially Expressed Carbohydrate-Active Enzymes (CAZymes) Genes During the Early Stage of Sclerotial Growth.

    PubMed

    Zhang, Shaopeng; Hu, Bingxiong; Wei, Wei; Xiong, Ying; Zhu, Wenjun; Peng, Fang; Yu, Yang; Zheng, Yonglian; Chen, Ping

    2016-01-01

    The sclerotium of Wolfiporia cocos has been used as an edible mushroom and/or a traditional herbal medicine for centuries. W. cocos sclerotial formation is dependent on parasitism of the wood of Pinus species. Currently, the sclerotial development mechanisms of W. cocos remain largely unknown and the lack of pine resources limit the commercial production. The CAZymes (carbohydrate-active enzymes) play important roles in degradation of the plant cell wall to provide carbohydrates for fungal growth, development, and reproduction. In this study, the transcript profiles from W. cocos mycelium and 2-months-old sclerotium, the early stage of sclerotial growth, were specially analyzed using de novo sequencing technology. A total of 142,428,180 high-quality reads of mycelium and 70,594,319 high-quality reads of 2-months-old sclerotium were obtained. Additionally, differentially expressed genes from the W. cocos mycelium and 2-months-old sclerotium stages were analyzed, resulting in identification of 69 CAZymes genes which were significantly up-regulated during the early stage of sclerotial growth compared to that of in mycelium stage, and more than half of them belonged to glycosyl hydrolases (GHs) family, indicating the importance of W. cocos GHs family for degrading the pine woods. And qRT-PCR was further used to confirm the expression pattern of these up-regulated CAZymes genes. Our results will provide comprehensive CAZymes genes expression information during W. cocos sclerotial growth at the transcriptional level and will lay a foundation for functional genes studies in this fungus. In addition, our study will also facilitate the efficient use of limited pine resources, which is significant for promoting steady development of Chinese W. cocos industry. PMID:26870032

  15. c-Src Regulates Akt Signaling in Response to Ghrelin via β-Arrestin Signaling-Independent and -Dependent Mechanisms

    PubMed Central

    Lodeiro, Maria; Theodoropoulou, Marily; Pardo, Maria; Casanueva, Felipe F.; Camiña, Jesus P.

    2009-01-01

    The aim of the present study was to identify the signaling mechanisms to ghrelin-stimulated activation of the serine/threonine kinase Akt. In human embryonic kidney 293 (HEK293) cells transfected with GHS-R1a, ghrelin leads to the activation of Akt through the interplay of distinct signaling mechanisms: an early Gi/o protein-dependent pathway and a late pathway mediated by β-arrestins. The starting point is the Gi/o-protein dependent PI3K activation that leads to the membrane recruitment of Akt, which is phosphorylated at Y by c-Src with the subsequent phosphorylation at A-loop (T308) and HM (S473) by PDK1 and mTORC2, respectively. Once the receptor is activated, a second signaling pathway is mediated by β-arrestins 1 and 2, involving the recruitment of at least β-arrestins, c-Src and Akt. This β-arrestin-scaffolded complex leads to full activation of Akt through PDK1 and mTORC2, which are not associated to the complex. In agreement with these results, assays performed in 3T3-L1 preadipocyte cells indicate that β-arrestins and c-Src are implicated in the activation of Akt in response to ghrelin through the GHS-R1a. In summary this work reveals that c-Src is crucially involved in the ghrelin-mediated Akt activation. Furthermore, the results support the view that β-arrestins act as both scaffolding proteins and signal transducers on Akt activation. PMID:19262695

  16. The N-Glycan cluster from Xanthomonas campestris pv. campestris: a toolbox for sequential plant N-glycan processing.

    PubMed

    Dupoiron, Stéphanie; Zischek, Claudine; Ligat, Laetitia; Carbonne, Julien; Boulanger, Alice; Dugé de Bernonville, Thomas; Lautier, Martine; Rival, Pauline; Arlat, Matthieu; Jamet, Elisabeth; Lauber, Emmanuelle; Albenne, Cécile

    2015-03-01

    N-Glycans are widely distributed in living organisms but represent only a small fraction of the carbohydrates found in plants. This probably explains why they have not previously been considered as substrates exploited by phytopathogenic bacteria during plant infection. Xanthomonas campestris pv. campestris, the causal agent of black rot disease of Brassica plants, possesses a specific system for GlcNAc utilization expressed during host plant infection. This system encompasses a cluster of eight genes (nixE to nixL) encoding glycoside hydrolases (GHs). In this paper, we have characterized the enzymatic activities of these GHs and demonstrated their involvement in sequential degradation of a plant N-glycan using a N-glycopeptide containing two GlcNAcs, three mannoses, one fucose, and one xylose (N2M3FX) as a substrate. The removal of the α-1,3-mannose by the α-mannosidase NixK (GH92) is a prerequisite for the subsequent action of the β-xylosidase NixI (GH3), which is involved in the cleavage of the β-1,2-xylose, followed by the α-mannosidase NixJ (GH125), which removes the α-1,6-mannose. These data, combined to the subcellular localization of the enzymes, allowed us to propose a model of N-glycopeptide processing by X. campestris pv. campestris. This study constitutes the first evidence suggesting N-glycan degradation by a plant pathogen, a feature shared with human pathogenic bacteria. Plant N-glycans should therefore be included in the repertoire of molecules putatively metabolized by phytopathogenic bacteria during their life cycle. PMID:25586188

  17. Cortistatin Is Not a Somatostatin Analogue but Stimulates Prolactin Release and Inhibits GH and ACTH in a Gender-Dependent Fashion: Potential Role of Ghrelin

    PubMed Central

    Córdoba-Chacón, José; Gahete, Manuel D.; Pozo-Salas, Ana I.; Martínez-Fuentes, Antonio J.; de Lecea, Luis; Gracia-Navarro, Francisco; Kineman, Rhonda D.

    2011-01-01

    Cortistatin (CST) and somatostatin (SST) evolve from a common ancestral gene and share remarkable structural, pharmacological, and functional homologies. Although CST has been considered as a natural SST-analogue acting through their shared receptors (SST receptors 1–5), emerging evidence indicates that these peptides might in fact exert unique roles via selective receptors [e.g. CST, not SST, binds ghrelin receptor growth hormone secretagogue receptor type 1a (GHS-R1a)]. To determine whether the role of endogenous CST is different from SST, we characterized the endocrine-metabolic phenotype of male/female CST null mice (cort−/−) at hypothalamic-pituitary-systemic (pancreas-stomach-adrenal-liver) levels. Also, CST effects on hormone expression/secretion were evaluated in primary pituitary cell cultures from male/female mice and female primates (baboons). Specifically, CST exerted an unexpected stimulatory role on prolactin (PRL) secretion, because both male/female cort−/− mice had reduced PRL levels, and CST treatment (in vivo and in vitro) increased PRL secretion, which could be blocked by a GHS-R1a antagonist in vitro and likely relates to the decreased success of female cort−/− in first-litter pup care at weaning. In contrast, CST inhibited GH and adrenocorticotropin-hormone axes in a gender-dependent fashion. In addition, a rise in acylated ghrelin levels was observed in female cort−/− mice, which were associated with an increase in stomach ghrelin/ghrelin O-acyl transferase expression. Finally, CST deficit uncovered a gender-dependent role of this peptide in the regulation of glucose-insulin homeostasis, because male, but not female, cort−/− mice developed insulin resistance. The fact that these actions are not mimicked by SST and are strongly gender dependent offers new grounds to investigate the hitherto underestimated physiological relevance of CST in the regulation of physiological/metabolic processes. PMID:21971153

  18. Histopathological evaluation of the ocular-irritation potential of shampoos, make-up removers and cleansing foams in the bovine corneal opacity and permeability assay.

    PubMed

    Furukawa, Masatoshi; Sakakibara, Takashi; Itoh, Kouta; Kawamura, Kohtaro; Sasaki, Satoshi; Matsuura, Masao

    2015-10-01

    The bovine corneal opacity and permeability (BCOP) assay is an alternative method to the in vivo Draize eye test in rabbits for evaluating eye irritation in vitro. Here, we compared the numerical results of the BCOP assay with the corresponding histopathology for three different corneas for each test substance, including commercially available shampoos, make-up removers and cleansing foams that contained surfactants and other ingredients. The histopathological score was defined based on the severity of lesions in the corneal epithelium. The histopathological findings and scores of the three sections for each test substance were comparable. The in vitro irritancy score (IVIS) generally corresponds to the corneal irritant potential of the test substances assigned on the basis of the histopathological findings in this study. In the present study, we characterized the histopathology of the corneal epithelium and stroma and especially showed that the corneal epithelial injury caused by test substances might be important in assessment of test substances that are mild eye irritants (category 2B) as classified by the United Nations (UN) Globally Harmonized System of Classification and Labelling of Chemicals (GHS), as corneal lesions suggestive of classification into category 2B were localized on the border between the corneal epithelium and stroma, which contained cell elements related to assessment of prognosis of an in vivo eye injury. Histopathological assessment might be useful in predicting in vivo ocular irritation, particularly for test substances with an IVIS >3.1 but ?25 that are classified as mild irritants (category 2B) according to the UN GHS. PMID:26538816

  19. Nanoparticulate TiO2 protection of midgut damage in the silkworm (Bombyx mori) following phoxim exposure.

    PubMed

    Wang, Ling; Su, Mingyu; Zhao, Xiaoyang; Hong, Jie; Yu, Xiaohong; Xu, Bingqing; Sheng, Lei; Liu, Dong; Shen, Weide; Li, Bing; Hong, Fashui

    2015-04-01

    Bombyx mori (B. mori) is often subjected to phoxim poisoning in China due to phoxim exposure, which leads to a decrease in silk production. Nanoparticulate (NP) titanium dioxide (nano-TiO2) has been shown to attenuate damages in B. mori caused by phoxim exposure. However, little is known about the molecular mechanisms of midgut injury due to organophosphorus insecticide exposure and its repair by nano-TiO2 pretreatment. In this study, phoxim exposure for 36 h led to significant decreases in body weight and survival and increased oxidative stress and midgut injury. Pretreatment with nano-TiO2 attenuated the phoxim-induced midgut injury, increased body weight and survival, and decreased oxidative stress in the midgut of B. mori. Digital gene-expression data showed that exposure to phoxim results in significant changes in the expression of 254 genes in the phoxim-exposed midgut and 303 genes in phoxim + nano-TiO2-exposed midgut. Specifically, phoxim exposure led to upregulation of Tpx, α-amylase, trypsin, and glycoside hydrolase genes involved in digestion and absorption. Phoxim exposure also led to the downregulation of Cyp450 and Cyp4C1 genes involved in an antioxidant capacity. In contrast, a combination of both phoxim and nano-TiO2 treatment significantly decreased the change in α-amylase, trypsin, and glycoside hydrolases (GHs), which are involved in digestion and absorption. These results indicated that Tpx, α-amylase, trypsin, GHs, Cyp450, and Cyp4C1 may be potential biomarkers of midgut toxicity caused by phoxim exposure and the attenuation of these toxic impacts by nano-TiO2. PMID:25552327

  20. Hepatic receptors for homologous growth hormone in the eel

    SciTech Connect

    Hirano, T. )

    1991-03-01

    The specific binding of 125I-labeled eel growth hormone (eGH) to liver membranes of the eel was examined. The specific binding to the 10,000g pellet was greater than that to the 600g pellet. The specific binding was linear up to about 100 mg fresh tissue, and was saturable with increasing amounts of membrane. The specific binding was pH-, temperature-, and time-dependent, with the optimum pH at 7.4, and greater specific binding was obtained at 15 and 25 degrees than at 35 degrees. Scatchard analysis of liver binding gave an association constant of 1.1 x 10(9) M-1 and a capacity of 105 fmol/mg protein. The receptor preparation was highly specific for GHs. Natural and recombinant eel GHs as well as recombinant salmon GH competed equally with 125I-eGH for the receptor sites of the 10,000g liver membrane. Ovine GH was more potent in displacing the labeled eGH than the homologous eel hormone. Tilapia GH and ovine prolactin (PRL) were needed in greater amounts (40 times) than eGH to displace the labeled eGH. Salmon and tilapia PRLs were still less potent (500 times) than eGH. There was no displacement with eel PRL. No significant change in the specific binding was seen 1 week after hypophysectomy, whereas injection of eGH into the hypophysectomized eel caused a significant reduction after 24 hr. The binding to the membrane fractions from gills, kidney, muscle, intestine, and brain was low and exclusively nonspecific, indicating the presence of specific GH receptors predominantly in the liver.

  1. Ghrelin Modulates the fMRI BOLD Response of Homeostatic and Hedonic Brain Centers Regulating Energy Balance in the Rat

    PubMed Central

    Deli, Levente; Gajári, Dávid; Dávid, Szabolcs; Pozsgay, Zsófia; Hegedűs, Nikolett; Tihanyi, Károly; Liposits, Zsolt

    2014-01-01

    The orexigenic gut-brain peptide, ghrelin and its G-protein coupled receptor, the growth hormone secretagogue receptor 1a (GHS-R1A) are pivotal regulators of hypothalamic feeding centers and reward processing neuronal circuits of the brain. These systems operate in a cooperative manner and receive a wide array of neuronal hormone/transmitter messages and metabolic signals. Functional magnetic resonance imaging was employed in the current study to map BOLD responses to ghrelin in different brain regions with special reference on homeostatic and hedonic regulatory centers of energy balance. Experimental groups involved male, ovariectomized female and ovariectomized estradiol-replaced rats. Putative modulation of ghrelin signaling by endocannabinoids was also studied. Ghrelin-evoked effects were calculated as mean of the BOLD responses 30 minutes after administration. In the male rat, ghrelin evoked a slowly decreasing BOLD response in all studied regions of interest (ROI) within the limbic system. This effect was antagonized by pretreatment with GHS-R1A antagonist JMV2959. The comparison of ghrelin effects in the presence or absence of JMV2959 in individual ROIs revealed significant changes in the prefrontal cortex, nucleus accumbens of the telencephalon, and also within hypothalamic centers like the lateral hypothalamus, ventromedial nucleus, paraventricular nucleus and suprachiasmatic nucleus. In the female rat, the ghrelin effects were almost identical to those observed in males. Ovariectomy and chronic estradiol replacement had no effect on the BOLD response. Inhibition of the endocannabinoid signaling by rimonabant significantly attenuated the response of the nucleus accumbens and septum. In summary, ghrelin can modulate hypothalamic and mesolimbic structures controlling energy balance in both sexes. The endocannabinoid signaling system contributes to the manifestation of ghrelin's BOLD effect in a region specific manner. In females, the estradiol milieu does not influence the BOLD response to ghrelin. PMID:24830778

  2. Integrating optical fabrication and metrology into the optical design process

    NASA Astrophysics Data System (ADS)

    Harvey, James E.

    2014-12-01

    Image degradation due to scattered radiation from residual optical fabrication errors is a serious problem in many short wavelength (X-ray/EUV) imaging systems. Most commercially-available image analysis codes (ZEMAX, Code V, ASAP, FRED, etc.) currently require the scatter behavior (BSDF data) to be provided as input in order to calculate the image quality of such systems. This BSDF data is difficult to measure and rarely available for the operational wavelengths of interest. Since the smooth-surface approximation is often not satisfied at these short wavelengths, the classical Rayleigh-Rice expression that indicates the BRDF is directly proportional to the surface PSD cannot be used to calculate BRDFs from surface metrology data for even slightly rough surfaces. However, an FFTLog numerical Hankel transform algorithm enables the practical use of the computationally intensive Generalized Harvey-Shack (GHS) surface scatter theory [1] to calculate BRDFs from surface PSDs for increasingly short wavelengths that violate the smooth surface approximation implicit in the Rayleigh-Rice surface scatter theory [2-3]. The recent numerical validation [4] of the GHS theory (a generalized linear systems formulation of surface scatter theory), and an analysis of image degradation due to surface scatter in the presence of aberrations [5] has provided credence to the development of a systems engineering analysis of image quality as degraded not only by diffraction effects and geometrical aberrations, but to scattering effects due to residual optical fabrication errors as well. These advances, combined with the continuing increase in computer speed, leave us poised to fully integrate optical metrology and fabrication into the optical design process.

  3. Fertility, birth timing and marital breakdown: a reinterpretation of the evidence.

    PubMed

    Murphy, M J

    1984-10-01

    The conventional view that childlessness was associated with higher than average risk of marital breakdown was questioned on the basis of analysis of divorce records. The General Household Survey (GHS) is a large scale multipurpose continuous household survey in Great Britain. Since 1979, it has contained an expanded family information section addressed to women under 50 which, for ever-married women, collects information about numbers and dates of marriages, births (both inside and outside marriage) and, in the case of marriages which have ended, the reason for ending (death, divorce or separation), the date when cohabitation ceased and the date of absolute decree if available. In 1980, there were 5017 ever-married women aged 16-49 for whom marriage and fertility histories were obtained. Some results are shown for the interval between separation and divorce based on life table methods for women aged 50 and under. The marriage duration data suggest that, apart from very short and very long durations, the proportion of separation not followed by divorce by 10 years is reasonably constant, about 13%. The median interval is around 2.5 years, with short and long duration marriages having above-average intervals, partly due to restictions on divorce in the early years of marriage. The proportion of marriages breaking down at various marriage durations by the fertility status at the start of the year in question is shown. The proportion is calculated as the number of marriages which were intact at various specified marriage durations, but which had broken down in 1, 5 or 10 years and which could have experienced the full period in the absence of breakdown. At short durations, early childbearing (including premarital births) is associated with higher than average probabilities of breakdown. The impression given by these results is different from other studies. Retrospective multipurpose surveys such as the GHS appear to have many advantages over administrative records. PMID:6490686

  4. Processivity, Substrate Positioning, and Binding: The Role of Polar Residues in a Family 18 Glycoside Hydrolase.

    PubMed

    Hamre, Anne Grethe; Jana, Suvamay; Reppert, Nicole K; Payne, Christina M; Sørlie, Morten

    2015-12-15

    The enzymatic degradation of recalcitrant polysaccharides such as cellulose (β-1,4-linked glucose) and chitin (β-1,4-linked N-acetylglucosamine) by glycoside hydrolases (GHs) is of significant biological and economical importance. In nature, depolymerization is primarily accomplished by processive GHs, which remain attached to the substrate between subsequent hydrolytic reactions. Recent computational efforts have suggested that the processive ability of a GH is directly linked to the ligand binding free energy. The contribution of individual aromatic residues in the active site of these enzymes has been extensively studied. In this study, we offer the first experimental evidence confirming correlation of binding free energy and degree of processivity and evidence that polar residues are essential for maintaining processive ability. Exchanging Thr(276) with Ala in substrate binding subsite -2 in the processive ChiA of Serratia marcescens results in a decrease in both the enthalpy (2.6 and 3.8 kcal/mol) and free energy (0.5 and 2.2 kcal/mol) for the binding to the substrate (GlcNAc)6 and the inhibitor allosamidin, respectively, compared to that of the wild type. Moreover, the initial apparent processivity as measured by [(GlcNAc)2]/[GlcNAc] ratios (17.1 ± 0.4) and chitin degradation efficiency (20%) are greatly reduced for ChiA-T276A versus those of the wild type (30.1 ± 1.5 and 75%, respectively). Mutation of Arg(172) to Ala reduces the level of recognition and positioning of the substrate into the active site. Molecular dynamics simulations indicate ChiA-R172A behaves like the wild type, but the dynamics of ChiA-T276A are greatly influenced by mutation, which is reflective of their influence on processivity. PMID:26503416

  5. Diet and renal stone formation.

    PubMed

    Trinchieri, A

    2013-02-01

    The relationship between diet and the formation of renal stones is demonstrated, but restrictive diets do not take into account the complexity of metabolism and the complex mechanisms that regulate the saturation and crystallization processes in the urine. The restriction of dietary calcium can reduce the urinary excretion of calcium but severe dietary restriction of calcium causes hyperoxaluria and a progressive loss of bone mineral component. Furthermore urinary calcium excretion is influenced by other nutrients than calcium as sodium, potassium, protein and refined carbohydrates. Up to 40% of the daily excretion of oxalate in the urine is from dietary source, but oxalate absorption in the intestine depends linearly on the concomitant dietary intake of calcium and is influenced by the bacterial degradation by several bacterial species of intestinal flora. A more rational approach should be based on the cumulative effects of foods and different dietary patterns on urinary saturation rather than on the effect of single nutrients. A diet based on a adequate intake of calcium (1000-1200 mg per day) and containment of animal protein and salt can decrease significantly urinary supersaturation for calcium oxalate and reduce the relative risk of stone recurrence in hypercalciuric renal stone formers. The DASH-style diet that is high in fruits and vegetables, moderate in low-fat dairy products and low in animal proteins and salt is associated with a lower relative supersaturation for calcium oxalate and a marked decrease in risk of incident stone formation. All the diets above mentioned have as a common characteristic the reduction of the potential acid load of the diet that can be correlated with a higher risk of recurrent nephrolithiasis, because the acid load of diet is inversely related to urinary citrate excretion. The restriction of protein and salt with an adequate calcium intake seem to be advisable but should be implemented with the advice to increase the intake of vegetables that can carry a plentiful supply of alkali that counteract the acid load coming from animal protein. New prospective studies to evaluate the effectiveness of the diet for the prevention of renal stones should be oriented to simple dietary advices that should be focused on a few specific goals easily controlled by means of self-evaluation tools, such as the LAKE food screener. PMID:23392537

  6. Renal Stone Risk During Space Flight

    NASA Technical Reports Server (NTRS)

    Whitson, Peggy A.; Pietrzyk, Robert A.; Sams, Clarence F.; Pak, Charles Y. C.; Jones, Jeffrey A.

    1999-01-01

    Space flight produces a number of metabolic and physiological changes in the crewmembers exposed to microgravity. Following launch, body fluid volumes, electrolyte levels, and bone and muscle undergo changes as the human body adapts to the weightless environment. Changes in the urinary chemical composition may lead to the potentially serious consequences of renal stone formation. Previous data collected immediately after space flight indicate changes in the urine chemistry favoring an increased risk of calcium oxalate and uric acid stone formation (n = 323). During short term Shuttle space flights, the changes observed include increased urinary calcium and decreased urine volume, pH and citrate resulting in a greater risk for calcium oxalate and brushite stone formation (n = 6). Results from long duration Shuttle/Mir missions (n = 9) followed a similar trend and demonstrated decreased fluid intake and urine volume and increased urinary calcium resulting in a urinary environment saturated with the calcium stone-forming salts. The increased risk occurs rapidly upon exposure to microgravity, continues throughout the space flight and following landing. Dietary factors, especially fluid intake, or pharmacologic intervention can significantly influence the urinary chemical composition. Increasing fluid intake to produce a daily urine output of 2 liters/day may allow the excess salts in the urine to remain in solution, crystals formation will not occur and a renal stone will not develop. Results from long duration crewmembers (n = 2) who had urine volumes greater than 2.5 L/day minimized their risk of renal stone formation. Also, comparisons of stone-forming risk in short duration crewmembers clearly identified greater risk in those who produced less than 2 liters of urine/day. However, hydration and increased urine output does not correct the underlying calcium excretion due to bone loss and only treats the symptoms and not the cause of the increased urinary salts. Dietary modification and promising pharmacologic treatments may also be used to reduce the potential risk for renal stone formation. Potassium citrate is being used clinically to increase the urinary inhibitor levels to minimize the development of crystals and the growth of renal stones. Bisphosphonates are a class of drugs recently shown to help in patients with osteoporosis by inhibiting the loss of bones in elderly patients. This drug could potentially prevent the bone loss observed in astronauts and thereby minimize the increase in urinary calcium and reduce the risk for renal stone development. Results of NASA's renal stone risk assessment program clearly indicate that exposure to microgravity changes the urinary chemical environment such that there is an increased risk for supersaturation of stone-forming salts, including calcium oxalaie and brushite. These studies have indicated specific avenues for development of countermeasures for the increased renal stone risk observed during and following space flight. Increased hydration and implementation of pharmacologic countermeasures should largely mitigate the in-flight risk of renal stones.

  7. Linking microstructures, petrology and in situ U-(Th)-Pb geochronology to constrain P-T-t-D evolution of the Greather Himalyan Sequences in Western Nepal (Central Himalaya)

    NASA Astrophysics Data System (ADS)

    Iaccarino, Salvatore; Montomoli, Chiara; Carosi, Rodolfo; Langone, Antonio

    2013-04-01

    Last advances in forward modelling of metamorphic rocks and into the understanding of accessories minerals behaviour, suitable for geochronology (e.g. zircon and monazite), during metamorphism, bring new insights for understanding the evolution of metamorphic tectonites during orogenic cycles (Williams and Jercinovic, 2012 and reference therein). One of the best exposure of high- to medium grade- metamorphic rocks, is represented by the Greater Himalayan Sequence (GHS) in the Himalayan Belt, one of the most classic example of collisional orogen. Recent field work in Mugu Karnali valley, Western Nepal (Central Himalaya), identified a compressional top to the South ductile shear zone within the core of the GHS, named Magri Shear Zone (MSZ), developed in a high temperature regime as testified by quartz microstructures and syn-kinematic growth of sillimanite. In order to infer the tectono-metamorphic meaning of MSZ, a microstructural study coupled with pseudosection modelling and in situ U-(Th)-Pb monazite geochronology was performed on selected samples from different structural positions. Footwall sample constituted by (Grt + St Ky) micaschist shows a prograde garnet growth (cores to inner rims zoning), from ~500C, ~0.60GPa (close to garnet-in curve) to ~580C, ~1.2 GPa temporal constrained between 21-18 Ma, by medium Y cores to very low Y mantles monazite micro-chemical/ages domain . In this sample garnet was still growing during decompression and heating at ~640C, ~0.75 GPa (rims), and later starts to be consumed, in conjunction with staurolite growth at 15-13 Ma, as revealed by high Y rims monazite micro-chemical/ages domain. Hanging-wall mylonitic samples have a porphyroclastic texture, with garnet preserve little memory of prograde path. Garnet near rim isoplets and matrix minerals intersect at ~700C and ~0.70 GPa. A previous higher P stage, at ~1.10 GPa ~600C, is testified by cores of larger white mica porhyroclasts. Prograde zoned allanite (Janots et al., 2008) is rarely found within garnet crystal, while monazite found only along mylonitic foliation helps to constrain the age of shearing and hanging-wall rocks exhumation, between 25 Ma (low Y cores interpretd as Aln out product, close to P peak) and 18 Ma (high Y rims interpreted as Grt breakdown/melt crystallization product during decompression). The present results point out the occurence of a high-temperature shear zone, in the core of the GHS, active before the onset of the Main Central Thrust, responsible of at least a part of the exhumation of the metamorphic rocks. References Janots, E., Engi, M., Berger, J., Allaz, J., Schwarz, O., Spandler, C., (2008): Prograde metamorphic sequence of REE minerals in pelitic rocks of the Central Alps: implications for allanite monazite-xenotime phase relations from 250 to 610C. Journal of Metamorphic Geology 26, 509-526. Williams, M.L., Jercinovic, M.J., (2012): Tectonic interpretation of metamorphic tectonites: integrating compositional mapping, microstructrual analyses and in situ monazite dating. Journal of Metamorphic Geology 30, 739-752.

  8. Isotopic analysis of northern Himalayan gneiss domes

    NASA Astrophysics Data System (ADS)

    Hassett, W. C.

    2010-12-01

    The Leo Pargil, Renbu, and Yalashangbo gneiss domes are among the western and eastern most in the chain of north Himalayan gneiss domes. The processes of gneiss dome formation are still debated, but there is a growing consensus that they result from the diapiric rise of pooled melt from a mid-crustal, ductile channel (Whitney et al., 2004). Under the channel flow model, the ductile channel is exhumed towards the southern Himalayan range front and is exposed as the Greater Himalayan Sequence (GHS) (Beaumont et al., 2004). Gneiss domes should have a petrogenetic relationship to the GHS if the channel flow theory is correct. Geochemical investigation of these gneiss domes can therefore help to determine their provenance and mode of origin. Leo Pargil is composed of high-grade metamorphic rocks consisting of schists, phyllites, metasiltstone, metagraywacke, and subordinate quartzites, with numerous cm-m scale two-mica granite, tourmaline granite, and leucogranite dikes that constitute between 10% and 50% of the host rock (Thiede, 2006). The Renbu gneiss dome consists of an undeformed two-mica leucogranite pluton intruded into Triassic shales, and lies on the west side of a northerly trending graben belonging to the Yadong-Gulu rift system (Miller, unpublished). The Yalashangbo gneiss dome consists of muscovite-biotite granite pluton, with common pegmatite dikes and gneisses (Zhang et al., 2007). Leo Pargil has relict U/Pb zircon core ages ranging from Late Archean to Middle Paleozoic (2.8 Ga to 400 Ma) and Middle Eocene to Middle Miocene ages (49 Ma to 15 Ma) for zircon rims. The Renbu dome has relict U/Pb zircon core ages ranging from Late Archean to Late Triassic (2.5 Ga to 200 Ma) and Late Eocene to Late Miocene ages (39 Ma to 7 Ma) for zircon rims. Yalashangbo has relict U/Pb zircon core ages ranging from Late Paleoproterozoic to Middle Cretaceous (1.8 Ga to 115 Ma), but has no zircon rim ages and therefore does not record the timing of most recent magmatism. Statistical analysis between granitic zircon cores and host rock zircon for Leo Pargil show that 9 out of 10 REE are statistically indistinguishable, with only Pr showing significant variation in mean relative abundance. Similar results are found for analysis of host rock zircon compared between gneiss domes, where 8 out of 10 REE are statistically indistinguishable. There is little agreement between granitic zircon rims and cores, suggesting that fractionation occurred during the last magmatic event and zircon rims became enriched in HREE relative to zircon cores. These results indicate that the granitic and host rock zircon share a common source, that leucogranites within gneiss domes are most likely anatectic melts of the host rock, and that gneiss domes across the entire Himalayan orogen share a common source. U/Pb age data from zircon cores indicate that this common source can not be the Lesser Himalayan Sequence as this lithology has no ages younger than 1.5 Ga (Richards et al., 2005), but are consistent with either the GHS or the Tethyan Himalayan Sequence. Pb and Nd isotopic analyses will help to identify the source of the north Himalayan gneiss domes, and may strengthen arguments in favor of channel flow.

  9. Correction: Comparative analysis of fungal genomes reveals different plant cell wall degrading capacity in fungi

    PubMed Central

    2014-01-01

    Abstract The version of this article published in BMC Genomics 2013, 14: 274, contains 9 unpublished genomes (Botryobasidium botryosum, Gymnopus luxurians, Hypholoma sublateritium, Jaapia argillacea, Hebeloma cylindrosporum, Conidiobolus coronatus, Laccaria amethystina, Paxillus involutus, and P. rubicundulus) downloaded from JGI website. In this correction, we removed these genomes after discussion with editors and data producers whom we should have contacted before downloading these genomes. Removing these data did not alter the principle results and conclusions of our original work. The relevant Figures 1, 2, 3, 4 and 6; and Table 1 have been revised. Additional files 1, 3, 4, and 5 were also revised. We would like to apologize for any confusion or inconvenience this may have caused. Background Fungi produce a variety of carbohydrate activity enzymes (CAZymes) for the degradation of plant polysaccharide materials to facilitate infection and/or gain nutrition. Identifying and comparing CAZymes from fungi with different nutritional modes or infection mechanisms may provide information for better understanding of their life styles and infection models. To date, over hundreds of fungal genomes are publicly available. However, a systematic comparative analysis of fungal CAZymes across the entire fungal kingdom has not been reported. Results In this study, we systemically identified glycoside hydrolases (GHs), polysaccharide lyases (PLs), carbohydrate esterases (CEs), and glycosyltransferases (GTs) as well as carbohydrate-binding modules (CBMs) in the predicted proteomes of 94 representative fungi from Ascomycota, Basidiomycota, Chytridiomycota, and Zygomycota. Comparative analysis of these CAZymes that play major roles in plant polysaccharide degradation revealed that fungi exhibit tremendous diversity in the number and variety of CAZymes. Among them, some families of GHs and CEs are the most prevalent CAZymes that are distributed in all of the fungi analyzed. Importantly, cellulases of some GH families are present in fungi that are not known to have cellulose-degrading ability. In addition, our results also showed that in general, plant pathogenic fungi have the highest number of CAZymes. Biotrophic fungi tend to have fewer CAZymes than necrotrophic and hemibiotrophic fungi. Pathogens of dicots often contain more pectinases than fungi infecting monocots. Interestingly, besides yeasts, many saprophytic fungi that are highly active in degrading plant biomass contain fewer CAZymes than plant pathogenic fungi. Furthermore, analysis of the gene expression profile of the wheat scab fungus Fusarium graminearum revealed that most of the CAZyme genes related to cell wall degradation were up-regulated during plant infection. Phylogenetic analysis also revealed a complex history of lineage-specific expansions and attritions for the PL1 family. Conclusions Our study provides insights into the variety and expansion of fungal CAZyme classes and revealed the relationship of CAZyme size and diversity with their nutritional strategy and host specificity. PMID:24422981

  10. Quantifying Relationships Between Mid-Crustal Metamorphism and Exhumation-Erosion. A Case Study From the Greater Himalayan Sequence of the Everest-Makalu Massif, East Nepal

    NASA Astrophysics Data System (ADS)

    Streule, M. J.; Carter, A.; Searle, M. P.; Cottle, J. M.; Horstwood, M. S.; Waters, D. J.

    2008-12-01

    Metapelites and anatectic granites from the upper structural levels of the Greater Himalayan Sequence (GHS) in the Everest-Makalu area of east Nepal record a history of prograde burial metamorphism, decompression melting and exhumation-erosion. This area presents itself as an ideal case study for understanding the links between these processes. Peak sillimanite-grade metamorphism in metapelitic migmatites is associated with crustal anatexis and is quantified at 713±107 °C and >5.9±1.8 kbar. However, a mapped area of the metapelite with a cordierite grade metamorphic overprint is observed along the uppermost levels of the GHS. This secondary overprint is quantified at 618±58 °C with pressures as low as 2.1±0.9 kbar and is associated with additional crustal anatexis producing cordierite leucogranites related to decompression. U-Pb monazite and xenotime geochronology on both metapelites and granites date this decompression part of the P-T path at 18.7±0.7 Ma to 16.1±0.2 Ma despite melting and high-grade metamorphic conditions being prevalent prior to this time. Such rapid decompression is thought to be the result of flow of ductile mid crust from beneath Tibet (see Law et al, 2006, and references therein). This forms a 'channel flow' system between a lower thrust fault (Main Central Thrust) and an upper low-angle normal fault (South Tibetan Detachment). Decompression to 2.1 kbar would have brought rocks to within ~8 km of the surface, yet their temperatures remain relatively elevated at this point. Zircon and Apatite Fission Track data from samples collected at a range of altitudes between 860m and 6500m then reveal a much slower, protracted cooling of these rocks from 16 Ma onwards. We interpret this to represent slower exhumation largely due to erosion. This demonstrates the transition from mid-crustal gravity driven ductile deformation (channel flow) to brittle-ductile exhumation-erosion implying that ductile flow had ceased by then, at least in rocks now along the Himalayan crest. Law, R. D., Searle, M. P. and Godin, L. (Editors) 2006. Channel Flow, Ductile Extrusion and Exhumation in Continental Collision Zones. Geol. Soc. London, Special Publication 268.

  11. 21 Ma Eclogite From the Main Central Thrust Sheet, Eastern Nepal Himalaya

    NASA Astrophysics Data System (ADS)

    Corrie, S. L.; Kohn, M. J.; Vervoort, J. D.; Parkinson, C. D.

    2007-12-01

    Though uncommon throughout the Himalaya, eclogites have been documented in the Kaghan Valley of Pakistan, the Tso Morari dome in India, the Kharta region of Tibet, and the Makalu-Everest region of the Arun River valley in eastern Nepal. The Kaghan and Tso Morari UHP eclogites have been dated at ~50 Ma, and are commonly viewed as reflecting aborted subduction of the leading edge of the Indian plate during the initial stages of Indo- Asian collision. Here we show that the Arun eclogites are significantly younger, only ~21 Ma, so reflect either different origins, or substantial time lags in tectonics along strike. The Arun eclogites are stratigraphically continuous with the surrounding Greater Himalayan Sequence (GHS) felsic gneisses, and have been interpreted as metamorphosed basaltic sills. P-T conditions have been estimated at >14 kbar at 670-710 °C. The GHS in this region overlies Lesser Himalayan rocks along the Main Central Thrust (MCT), which can be traced for over 2000 km along strike. Lu-Hf dates from garnet separates in one relict eclogite indicate an age of 20.7±0.4 Ma (MSWD = 2.2). Five garnet amphibolites from nearby were also dated via Lu-Hf, and their ages range from 14-20 Ma (13.9±2.5, 14.1±0.3, 14.5±2.8, 15.1±0.6, and 19.8±1.1 Ma). The ~21 Ma age obtained from the eclogite postdates eclogite ages from the western Himalaya (Kaghan and Tso Morari) by ~30 Myr, and has important implications for tectonic models of Himalayan orogenesis. One possible model is that (aborted) subduction, slab breakoff, and ascent of India's leading edge occurred diachronously: ~50 Ma in the western Himalaya, ~20 Ma in eastern Nepal, and presumably even younger in the eastern Himalaya. Alternatively, because the Arun eclogites did not reach ultra-high pressure conditions seen by western eclogites (only ≥45, not ≥90 km depth), they may simply reflect deepening or longer transport of the MCT in the Arun area. Regardless, a ~21 Ma age for these eclogites combined with several 14-15 Ma ages for nearby garnet amphibolites implies young initial movement on the MCT at Arun, as late as 14 Ma.

  12. South African farm workers' interpretation of risk assessment data expressed as pictograms on pesticide labels

    SciTech Connect

    Rother, Hanna-Andrea

    2008-11-15

    Pesticide companies and regulators in developing countries use the United Nations Food and Agricultural Organization (FAO) recommended pictograms on pesticide labels to communicate risk information based on toxicological and environmental risk assessment data. The pesticide label not only is often the only access people have to pesticide risk information, but also in many countries is a legally binding document. As a result of the crucial role pesticide labels play in protecting health and the environment and as a legal instrument, pictograms are used to overcome literacy challenges in transmitting pesticide risk information. Yet, this risk communication tool is often prone to misinterpretations of the risk information which results in hazardous exposures to pesticides for farm workers and end-users generally. In this paper, results are presented from a study with 115 farm workers on commercial vineyards in the Western Cape, South Africa, assessing their interpretations of 10 commonly used pictograms. A standardized questionnaire based on four commonly used pesticide labels was administered. Overall, 50% or more of the study farm workers had misleading, incorrect and critically confused interpretations of the label pictograms. Interpretations often reflected farm workers' social and cultural frames of reference rather than the technically intended risk information. For example, the pictogram indicating a pesticide's toxicity requires boots must be worn, evoked interpretations of 'dangerous to pedestrians' and 'don't walk through pesticides'. Furthermore, there was a gender variation in pictogram comprehension whereby males generally had more correct interpretations than females. This is a result both of a lack of training for women who are assumed to not work with pesticides, as well as a lack of pictograms relevant for female exposures. These findings challenge the viability of the United Nations current initiative to globally harmonize pictograms used on all chemical labels under the new Globally Harmonized System for the Classification and Labelling of Chemicals (GHS). Particularly as the GHS pictograms were not piloted prior to adoption of the system and represent complex risk assessment data such as chronic hazards. Public health and pesticide policy, backed by relevant research, need to address developing applicable and effective pesticide risk communication tools, particularly for developing country populations. Merely providing risk assessment derived information in a pictogram does not ensure that an end-user will interpret the message as intended and be able to make risk decisions which mitigate risks from exposures to pesticides or chemicals in general.

  13. Sharing Physician Notes Through an Electronic Portal is Associated With Improved Medication Adherence: Quasi-Experimental Study

    PubMed Central

    Darer, Jonathan; Tang, Xiaoqin; Thompson, Jason; Tusing, Lorraine; Fossa, Alan; Delbanco, Tom

    2015-01-01

    Background In surveys, interviews, and focus groups, patients taking medications and offered Web portal access to their primary care physicians’ (PCPs) notes report improved adherence to their regimens. However, objective confirmation has yet to be reported. Objective To evaluate the association between patient Internet portal access to primary care physician visit notes and medication adherence. Methods This study is a retrospective comparative analysis at one site of the OpenNotes quasi-experimental trial. The setting includes primary care practices at the Geisinger Health System (GHS) in Danville, Pennsylvania. Participants include patients 18 years of age or older with electronic portal access, GHS primary care physicians, and Geisinger health plan insurance, and taking at least one antihypertensive or antihyperlipidemic agent from March 2009 to June 2011. Starting in March 2010, intervention patients were invited and reminded to read their PCPs' notes. Control patients also had Web portal access throughout, but their PCPs' notes were not available. From prescription claims, adherence was assessed by using the proportion of days covered (PDC). Patients with a PDC ≥.80 were considered adherent and were compared across groups using generalized linear models. Results A total of 2147 patients (756 intervention participants, 35.21%; 1391 controls, 64.79%) were included in the analysis. Compared to those without access, patients invited to review notes were more adherent to antihypertensive medications—adherence rate 79.7% for intervention versus 75.3% for control group; adjusted risk ratio, 1.06 (95% CI 1.00-1.12). Adherence was similar among patient groups taking antihyperlipidemic agents—adherence rate 77.6% for intervention versus 77.3% for control group; adjusted risk ratio, 1.01 (95% CI 0.95-1.07). Conclusions Availability of notes following PCP visits was associated with improved adherence by patients prescribed antihypertensive, but not antihyperlipidemic, medications. As the use of fully transparent records spreads, patients invited to read their clinicians’ notes may modify their behaviors in clinically valuable ways. PMID:26449757

  14. Two strands of the South Tibetan Fault System in NW Bhutan: Insights from field mapping, ASTER imagery, and U-Pb geochronology

    NASA Astrophysics Data System (ADS)

    Cooper, F. J.; Hodges, K.; Parrish, R. R.; Adams, B. A.

    2010-12-01

    The Jomolhari region of NW Bhutan contains one of the largest and most accessible continuous exposures of the South Tibetan Fault System in the Himalaya. Lying immediately southeast of the Yadong Graben (Mount Jomolhari is part of the eastern rift flank uplift), the geology of this area is dominated by banded orthogneiss and paragneiss of the Greater Himalayan Sequence (GHS), Chekha Group pelitic schist and quartzite and carbonate units of the Tibetan Sedimentary Sequence (TSS). All contain abundant leucogranite sills and dikes. New mapping of the Jomolhari region combined with decorrelation stretched, multispectral ASTER (Advanced Spaceborne Thermal Emission and Reflection Radiometer) imagery has revealed two fault contacts that we interpret as two strands of the South Tibetan Fault System. The structurally lower of the two faults has been recognized by other research groups previously, although published maps of its trace differ from what we have established through field mapping and satellite data interpretation. The lower contact places Chekha Group quartzite over Greater Himalayan Sequence paragneiss. One extremely good exposure of the contact in the Paro Chhu valley expresses as a normal-sense, brittle-ductile shear zone marked by calcareous mylonite overlain by a chloritic breccia. This shear zone locally trends WSW-ENE and dips 35° to the SSE, before changing to a N-dip farther north as it disappears beneath the Chung La leucogranite pluton. The upper contact is marked by a major structural discontinuity between recumbently-folded TSS carbonate above and folded Chekha Group units below. TSS carbonate rock outcrops at Jomolhari base camp and farther west towards Mount Jomolhari suggest that the geology of this area may be more complex than previously described. Since outcrop in the region is generally poor, the Chekha-TSS Carbonate contact is inferred from changes in landslide material and a distinct change in weathering style. A suite of deformed granites that intrude all units have been dated by zircon U-Pb geochronology to ca. 21 Ma. This suggests that: (1) motion on the lower structure began prior to 21 Ma; and (2) folding of the carbonate unit is younger than 21 Ma. Rim ages of multiple zircons from a deformed leucogranite intrusion within the GHS-Chekha shear zone have more complex U-Pb systematics with ages as young as ca. 14 Ma, suggesting a prolonged history of fault motion. This study reinforces work done by other researchers across the Himalaya, demonstrating multiple strands of the South Tibetan Fault System, rather than a single detachment.

  15. The Gutenberg Health Study: measuring psychosocial factors at work and predicting health and work-related outcomes with the ERI and the COPSOQ questionnaire

    PubMed Central

    2013-01-01

    Background Several instruments have been developed to assess psychosocial workload. We compared two of these instruments, the Effort-Reward Imbalance (ERI) model and the Copenhagen Psychosocial Questionnaire (COPSOQ) with regard to congruent validity and internal validity. Methods This analysis is based on a population-based sample of the baseline examination of 2,783 employees from the Gutenberg Health Study (GHS). About half of the participants completed the ERI questionnaire (n = 1,342), the other half completed the COPSOQ (n = 1,441). First, the two samples were compared and descriptive analyses were carried out calculating mean values for both instruments in general, then separately for age, gender and main occupational groups. Second, we analyzed the relationship between ERI and COPSOQ scales on the workplace situation and on the workplace outcomes: job satisfaction, general health, burnout, satisfaction with life, by applying stepwise logistic regression analysis. Results and discussion For the majority of occupations, high effort as reflected by the ERI corresponded with high demands as reflected by the COPSOQ. Comparably, high reward (according to ERI) yielded a good agreement with high “influence and development” (according to COPSOQ). However, we could also find differences between ERI and COPSOQ concerning the intensity of psychosocial workload in some occupations (e.g., physicians/pharmacists or warehouse managers/warehousemen/transport workers). These differences point to differing theoretical concepts of ERI and COPSOQ. When the ability of ERI and COPSOQ was examined to determine the associations with health and work outcomes, burnout could be better predicted by the COPSOQ; this might be due to the fact that COPSOQ comprises the constructs “work-privacy conflict” and “emotional demand”, which are closely related to burnout. However, methodological differences between these instruments limit their direct comparability. Conclusions The ERI and COPSOQ instrument yielded similar results for most occupational groups. The slightly stronger association between psychosocial workload as assessed by COPSOQ and burnout might be explained by its broader approach. The ability of the ERI and COPSOQ instrument to reflect relevant risk factors for clinically manifest disorders (e.g., coronary heart disease) will be derived from subsequent prospective analyses of the GHS with the follow-up data. PMID:23734632

  16. Effect of Deletion of Ghrelin-O-Acyltransferase on the Pulsatile Release of Growth Hormone in Mice.

    PubMed

    Xie, T Y; Ngo, S T; Veldhuis, J D; Jeffery, P L; Chopin, L K; Tschöp, M; Waters, M J; Tolle, V; Epelbaum, J; Chen, C; Steyn, F J

    2015-12-01

    Ghrelin, a gut hormone originating from the post-translational cleavage of preproghrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of ghrelin requires octanoylation by ghrelin-O-acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated ghrelin. Complete loss of preproghrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release; however, the selective contribution of endogenous acyl-ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat(-/-) mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat(-/-) mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat(-/-) mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat(-/-) mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of altered GH secretory patterning remains unclear, we propose that this may contribute to sustained IGF-1 release and growth in goat(-/-) mice. PMID:26442444

  17. Petrochronologic study of granites in the eastern Nepal Himalaya

    NASA Astrophysics Data System (ADS)

    Lederer, G. W.; Cottle, J. M.; Larson, K.; McAtamney, J.; Moulton, K.; Kellett, D.

    2013-12-01

    Anatexis strongly influences the chemical, thermal, and rheological evolution of continental crust. Partial melting causes compositional differentiation by redistribution of incompatible elements, upward advection of heat during magma transport, and reduction of viscosity in migmatite zones. The orogenic core of the Himalaya consists of a continuous belt of schists and gneisses pervasively intruded by leucogranites derived from partial melting of crustal sources. This study employs high-temperature petrochronology of granites to reveal the spatial and temporal relationships between metamorphism, melting, deformation, and exhumation of the Himalayan middle crust. In eastern Nepal the Greater Himalayan Series (GHS) extends southward from the Everest region to the Mahabharat range forming a broad thrust sheet above the Main Central thrust (MCT). High-grade upper GHS rocks occur along the main orographic front to the north and the Mahabharat range to the south, whereas lower-grade rocks of the MCT zone occur beyween them near Okhaldhunga. Three types of granites were distinguished along a ~100-km-long north-south transect across the area, including 1) weakly to highly deformed granites and orthogneisses of the MCT zone, 2) deformed tourmaline-bearing leucogranite dikes intruding kyanite-bearing gneisses of the Mahabharat, and 3) undeformed to moderately deformed two-mica and tourmaline-bearing leucogranite dikes and sills intruding migmatites of the High Himalaya. U-Th/Pb dating of zircon and monazite by LA-ICPMS reveal the magmatic ages of each of the three types of granites. Granites and orthogneisses of the MCT zone yield dates of c.1800 Ma with evidence for Archean inheritance and recent Pb-loss. Magmatic ages are consistent with those of the Phaplu orthogneiss and Pb-loss may have resulted from Tertiary deformation. The Mahabharat leucogranites dominantly yield ages of c. 480 Ma overprinted by Oligo-Miocene metamorphism and deformation. However, one leucogranite specimen from the Mahabharat yields magmatic zircon crystallization ages ranging from 28.5 to 21 Ma, providing evidence for Oligo-Miocene melting farther toward the foreland than previously recognized. By contrast, granites from the High Himalaya yield monazite ages ranging from 23-18 Ma near Namche Bazaar, and 17-13 Ma near Dudh Kund. These new age constraints build upon previous work, and help form the basis for kinematic interpretations of the MCT.

  18. Progression from South-Directed to Orogen-Parallel Mid-Crustal Flow on the Southern Margin of the Tibetan Plateau, Ama Drime Massif, Tibet

    NASA Astrophysics Data System (ADS)

    Jessup, M. J.; Cottle, J. M.; Newell, D. L.; Berger, A. L.; Spotila, J. A.

    2008-12-01

    In the South Tibetan Himalaya, two major detachment systems are exposed in the Ama Drime and Mount Everest Massifs. These structures represent a fundamental shift in the dynamics of the Himalayan orogen, recording a progression from south-directed to orogen-parallel mid-crustal flow and exhumation. The South Tibetan detachment system (STDS) accommodated exhumation of the Greater Himalayan series (GHS) until the Middle Miocene. A relatively narrow mylonite zone that progressed into a brittle detachment accommodated exhumation of the GHS. Northward, in the down-dip direction (Dzakaa Chu and Doya La), a 1-km-wide distributed zone of deformation that lacks a foliation-parallel brittle detachment characterizes the STDS. Leucogranites in the footwall of the STDS range between 17-18 Ma. Previously published 40Ar/39Ar ages suggest that movement on the STDS ended by ~ 16 Ma in Rongbuk Valley and ~ 13 Ma near Dinggye. This once continuous section of the STDS is displaced by the trans- Himalayan Ama Drime Massif and Xainza-Dinggye graben. Two oppositely dipping normal faults and shear zones that bound the Ama Drime Massif record orogen-parallel extension. During exhumation, deformation was partitioned into relatively narrow (100-300-m-thick) mylonite zones that progressed into brittle faults/detachments, which offset Quaternary deposits. U(-Th-)Pb geochronology of mafic lenses suggests that the core of the ADM reached granulite facies at ~ 15 Ma. Leucogranites in the footwall of the detachment faults range between 12-11 Ma: significantly younger than those related to movement on the STDS. Previously published 40Ar/39Ar ages from the eastern limb of the Ama Drime Massif suggest that exhumation progressed into the footwall of the Nyüonno detachment between ~ 13-10 Ma. (U-Th)/He apatite ages record a minimum exhumation rate of ~ 1mm/yr between 1.5-3.0 Ma that was enhanced by focused denudation in the trans-Himalayan Arun River gorge. Together these bracket the timing (~ 12 Ma) of a transition from south-directed to orogen-parallel mid-crustal flow and associated graben formation and exhumation along the southern margin of the Tibetan Plateau.

  19. GUESS-ing Polygenic Associations with Multiple Phenotypes Using a GPU-Based Evolutionary Stochastic Search Algorithm

    PubMed Central

    Hastie, David I.; Zeller, Tanja; Liquet, Benoit; Newcombe, Paul; Yengo, Loic; Wild, Philipp S.; Schillert, Arne; Ziegler, Andreas; Nielsen, Sune F.; Butterworth, Adam S.; Ho, Weang Kee; Castagné, Raphaële; Munzel, Thomas; Tregouet, David; Falchi, Mario; Cambien, François; Nordestgaard, Børge G.; Fumeron, Fredéric; Tybjærg-Hansen, Anne; Froguel, Philippe; Danesh, John; Petretto, Enrico; Blankenberg, Stefan; Tiret, Laurence; Richardson, Sylvia

    2013-01-01

    Genome-wide association studies (GWAS) yielded significant advances in defining the genetic architecture of complex traits and disease. Still, a major hurdle of GWAS is narrowing down multiple genetic associations to a few causal variants for functional studies. This becomes critical in multi-phenotype GWAS where detection and interpretability of complex SNP(s)-trait(s) associations are complicated by complex Linkage Disequilibrium patterns between SNPs and correlation between traits. Here we propose a computationally efficient algorithm (GUESS) to explore complex genetic-association models and maximize genetic variant detection. We integrated our algorithm with a new Bayesian strategy for multi-phenotype analysis to identify the specific contribution of each SNP to different trait combinations and study genetic regulation of lipid metabolism in the Gutenberg Health Study (GHS). Despite the relatively small size of GHS (n = 3,175), when compared with the largest published meta-GWAS (n>100,000), GUESS recovered most of the major associations and was better at refining multi-trait associations than alternative methods. Amongst the new findings provided by GUESS, we revealed a strong association of SORT1 with TG-APOB and LIPC with TG-HDL phenotypic groups, which were overlooked in the larger meta-GWAS and not revealed by competing approaches, associations that we replicated in two independent cohorts. Moreover, we demonstrated the increased power of GUESS over alternative multi-phenotype approaches, both Bayesian and non-Bayesian, in a simulation study that mimics real-case scenarios. We showed that our parallel implementation based on Graphics Processing Units outperforms alternative multi-phenotype methods. Beyond multivariate modelling of multi-phenotypes, our Bayesian model employs a flexible hierarchical prior structure for genetic effects that adapts to any correlation structure of the predictors and increases the power to identify associated variants. This provides a powerful tool for the analysis of diverse genomic features, for instance including gene expression and exome sequencing data, where complex dependencies are present in the predictor space. PMID:23950726

  20. Crystal aggregation in kidney stones; a polymer aggregation problem?

    NASA Astrophysics Data System (ADS)

    Wesson, J.; Beshensky, A.; Viswanathan, P.; Zachowicz, W.; Kleinman, J.

    2008-03-01

    Kidney stones most frequently form as aggregates of calcium oxalate monohydrate (COM) crystals with organic layers between them, and the organic layers contain principally proteins. The pathway leading to the formation of these crystal aggregates in affected people has not been identified, but stone forming patients are thought to have a defect in the structure or distribution of urinary proteins, which normally protect against stone formation. We have developed two polyelectrolyte models that will induce COM crystal aggregation in vitro, and both are consistent with possible urinary protein compositions. The first model was based on mixing polyanionic and polycationic proteins, in portions such that the combined protein charge is near zero. The second model was based on reducing the charge density on partially charged polyanionic proteins, specifically Tamm-Horsfall protein, the second most abundant protein in urine. Both models demonstrated polymer phase separation at solution conditions where COM crystal aggregation was observed. Correlation with data from other bulk crystallization measurements suggest that the anionic side chains form critical binding interactions with COM surfaces that are necessary along with the phase separation process to induce COM crystal aggregation.

  1. Artificial tektites: an experimental technique for capturing the shapes of spinning drops

    PubMed Central

    Baldwin, Kyle A.; Butler, Samuel L.; Hill, Richard J. A.

    2015-01-01

    Determining the shapes of a rotating liquid droplet bound by surface tension is an archetypal problem in the study of the equilibrium shapes of a spinning and charged droplet, a problem that unites models of the stability of the atomic nucleus with the shapes of astronomical-scale, gravitationally-bound masses. The shapes of highly deformed droplets and their stability must be calculated numerically. Although the accuracy of such models has increased with the use of progressively more sophisticated computational techniques and increases in computing power, direct experimental verification is still lacking. Here we present an experimental technique for making wax models of these shapes using diamagnetic levitation. The wax models resemble splash-form tektites, glassy stones formed from molten rock ejected from asteroid impacts. Many tektites have elongated or ‘dumb-bell' shapes due to their rotation mid-flight before solidification, just as we observe here. Measurements of the dimensions of our wax ‘artificial tektites' show good agreement with equilibrium shapes calculated by our numerical model, and with previous models. These wax models provide the first direct experimental validation for numerical models of the equilibrium shapes of spinning droplets, of importance to fundamental physics and also to studies of tektite formation. PMID:25564381

  2. Nutrition and renal stone disease in space

    NASA Technical Reports Server (NTRS)

    Zerwekh, Joseph E.

    2002-01-01

    There is a growing body of evidence from the National Aeronautics and Space Administration and the Russian space program showing that humans exposed to the microgravity environment of space have a greater risk for developing renal stones. Increased bone resorption and the attendant hypercalciuria and hyperphosphaturia contribute significantly to raising the urinary state of saturation with respect to the calcium salts, namely calcium oxalate and calcium phosphate. In addition, other environmental and dietary factors may adversely affect urine composition and increase stone formation risk during space flight. For example, reductions in urinary volume, pH, and citrate contribute to raising stone formation risk. In addition to raising the risk for calcium stone formation, this metabolic profile is conducive to the formation of uric acid stones. Although observations to date have suggested that there may actually be a reduced food intake during the early phase of flight, crew members on longer-duration flights may increase food intake and be at increased risk for stone formation. Taken together, these findings support the use of nutritional recommendations for crew members that would serve to reduce the stone-forming propensity of the urinary environment. Pharmacologic intervention should be directed at raising urinary volumes, diminishing bone losses, and preventing reductions in urinary pH and citrate. Success in reducing the risk for stone formation in astronauts would also be of potential major benefit to the estimated 20 million Americans with nephrolithiasis.

  3. Artificial tektites: an experimental technique for capturing the shapes of spinning drops

    NASA Astrophysics Data System (ADS)

    Baldwin, Kyle A.; Butler, Samuel L.; Hill, Richard J. A.

    2015-01-01

    Determining the shapes of a rotating liquid droplet bound by surface tension is an archetypal problem in the study of the equilibrium shapes of a spinning and charged droplet, a problem that unites models of the stability of the atomic nucleus with the shapes of astronomical-scale, gravitationally-bound masses. The shapes of highly deformed droplets and their stability must be calculated numerically. Although the accuracy of such models has increased with the use of progressively more sophisticated computational techniques and increases in computing power, direct experimental verification is still lacking. Here we present an experimental technique for making wax models of these shapes using diamagnetic levitation. The wax models resemble splash-form tektites, glassy stones formed from molten rock ejected from asteroid impacts. Many tektites have elongated or `dumb-bell' shapes due to their rotation mid-flight before solidification, just as we observe here. Measurements of the dimensions of our wax `artificial tektites' show good agreement with equilibrium shapes calculated by our numerical model, and with previous models. These wax models provide the first direct experimental validation for numerical models of the equilibrium shapes of spinning droplets, of importance to fundamental physics and also to studies of tektite formation.

  4. Mechanisms of human kidney stone formation.

    PubMed

    Evan, Andrew P; Worcester, Elaine M; Coe, Fredric L; Williams, James; Lingeman, James E

    2015-01-01

    The precise mechanisms of kidney stone formation and growth are not completely known, even though human stone disease appears to be one of the oldest diseases known to medicine. With the advent of the new digital endoscope and detailed renal physiological studies performed on well phenotyped stone formers, substantial advances have been made in our knowledge of the pathogenesis of the most common type of stone former, the idiopathic calcium oxalate stone former as well as nine other stone forming groups. The observations from our group on human stone formers and those of others on model systems have suggested four entirely different pathways for kidney stone formation. Calcium oxalate stone growth over sites of Randall's plaque appear to be the primary mode of stone formation for those patients with hypercalciuria. Overgrowths off the ends of Bellini duct plugs have been noted in most stone phenotypes, do they result in a clinical stone? Micro-lith formation does occur within the lumens of dilated inner medullary collecting ducts of cystinuric stone formers and appear to be confined to this space. Lastly, cystinuric stone formers also have numerous small, oval, smooth yellow appearing calyceal stones suggestive of formation in free solution. The scientific basis for each of these four modes of stone formation are reviewed and used to explore novel research opportunities. PMID:25108546

  5. Inhibition of calcium oxalate crystal deposition on kidneys of urolithiatic rats by Hibiscus sabdariffa L. extract.

    PubMed

    Laikangbam, Reena; Damayanti Devi, M

    2012-06-01

    The present study aims at systematic evaluation of the calyces of Hibiscus sabdariffa to establish its scientific validity for anti-urolithiatic property using ethylene glycol-induced hyperoxaluria model in male albino rats. Administration of a mixture of 0.75% ethylene glycol and 2% ammonium chloride resulted in hyperoxaluria as well as increased renal excretion of calcium and phosphate. The decrease in the serum calcium concentration indicates an increased calcium oxalate formation. Supplementation of aqueous extract of H. sabdariffa at different doses (250, 500 and 750 mg/kg body weight) significantly lowered the deposition of stone-forming constituents in the kidneys and serum of urolithiatic rats. These findings have been confirmed through histological investigations. Results of in vivo genotoxicity testing showed no significant chromosomal aberrations in the bone marrow cells of ethylene glycol-induced rats. The plant extracts at the doses investigated induced neither toxic nor lethal effects and are safe. It can be concluded that the calyces of H. sabdariffa are endowed with anti-urolithiatic activity and do not have genotoxic effects. Thus, it can be introduced in clinical practices and medicine in the form of orally administered syrup after further investigations and clinical trials. PMID:22057204

  6. Uric Acid Nephrolithiasis: A Systemic Metabolic Disorder

    PubMed Central

    Moe, Orson W.

    2014-01-01

    Uric acid nephrolithiasis is characteristically a manifestation of a systemic metabolic disorder. It has a prevalence of about 10% among all stone formers, the third most common type of kidney stone in the industrialized world. Uric acid stones form primarily due to an unduly acid urine; less deciding factors are hyperuricosuria and a low urine volume. The vast majority of uric acid stone formers have the metabolic syndrome, and not infrequently, clinical gout is present as well. A universal finding is a low baseline urine pH plus insufficient production of urinary ammonium buffer. Persons with gastrointestinal disorders, in particular chronic diarrhea or ostomies, and patients with malignancies with a large tumor mass and high cell turnover comprise a less common but nevertheless important subset. Pure uric acid stones are radiolucent but well visualized on renal ultrasound. A 24 h urine collection for stone risk analysis provides essential insight into the pathophysiology of stone formation and may guide therapy. Management includes a liberal fluid intake and dietary modification. Potassium citrate to alkalinize the urine to a goal pH between 6 and 6.5 is essential, as undissociated uric acid deprotonates into its much more soluble urate form. PMID:25045326

  7. Elemental Content of Calcium Oxalate Stones from a Canine Model of Urinary Stone Disease

    PubMed Central

    Killilea, David W.; Westropp, Jodi L.; Shiraki, Ryoji; Mellema, Matthew; Larsen, Jennifer; Kahn, Arnold J.; Kapahi, Pankaj; Chi, Thomas; Stoller, Marshall L.

    2015-01-01

    One of the most common types of urinary stones formed in humans and some other mammals is composed of calcium oxalate in ordered hydrated crystals. Many studies have reported a range of metals other than calcium in human stones, but few have looked at stones from animal models such as the dog. Therefore, we determined the elemental profile of canine calcium oxalate urinary stones and compared it to reported values from human stones. The content of 19 elements spanning 7-orders of magnitude was quantified in calcium oxalate stones from 53 dogs. The elemental profile of the canine stones was highly overlapping with human stones, indicating similar inorganic composition. Correlation and cluster analysis was then performed on the elemental profile from canine stones to evaluate associations between the elements and test for potential subgrouping based on elemental content. No correlations were observed with the most abundant metal calcium. However, magnesium and sulfur content correlated with the mineral hydration form, while phosphorous and zinc content correlated with the neuter status of the dog. Inter-elemental correlation analysis indicated strong associations between barium, phosphorous, and zinc content. Additionally, cluster analysis revealed subgroups within the stones that were also based primarily on barium, phosphorous, and zinc. These data support the use of the dog as a model to study the effects of trace metal homeostasis in urinary stone disease. PMID:26066810

  8. Antiurolithiatic effect of lithocare against ethylene glycol-induced urolithiasis in Wistar rats

    PubMed Central

    Lulat, Sumaiya I.; Yadav, Yogesh Chand; Balaraman, R.; Maheshwari, Rajesh

    2016-01-01

    Aim: This study is aimed to investigate the protective effect of Lithocare (LC) (a polyherbal formulation) against ethylene glycol (EG) induced urolithiasis in Wistar rats. Materials and Methods: The protective effect of LC (400 and 800 mg/kg) was evaluated using EG-induced urolithiasis in rats. Results: Administration of EG in drinking water resulted in hyperoxaluria, hypocalcemia as well as an increased renal excretion of phosphate. Supplementation with LC significantly reduced the urinary calcium, oxalate, and phosphate excretion dose-dependently. There was a significant reduction in the levels of calcium, oxalate as well as a number of calcium oxalate crystals deposits in the kidney tissue of rats administered with LC in EG-treated rats. There was a significant reduction in creatinine, urea, uric acid, and blood urea nitrogen when LC was administered in EG-treated rats. Conclusions: From this study, it was concluded that the supplementation of LC protected EG-induced urolithiasis as it reduced the growth of urinary stones. The mechanism underlying this effect might be due to its antioxidant, diuretic, and reduction in stone-forming constituents. PMID:26997728

  9. Alterations in some risk factors and urinary enzymes in urolithiatic rats treated with sodium pentosan polysulphate.

    PubMed

    Subha, K; Varalakshmi, P

    1993-02-01

    The effect of sodium pentosan polysulphate (SPP) was investigated in calcium oxalate stone forming rats with respect to the urinary excretion of certain risk factors and enzymes. Calcium oxalate stones were induced by feeding 3% w/w sodium glycollate to the rats. Urinary calcium, oxalate, phosphorus and uric acid levels were increased in stone formers. In contrast magnesium excretion was low in this group. SPP treatment lowered oxalate and calcium levels in both controls and experimental animals. Magnesium levels were increased moderately. Increased excretion of urinary enzymes--LDH, alkaline phosphatase, gamma-GT and beta glucuronidase--in calculogenic rats indicates membranuria and damage to proximal tubules during stone formation. Decreased pyrophosphatase activity was observed in glycollate fed rats. SPP treatment decreased the excretion of the above enzymes in the treated groups. Stone formers exhibited decreased LAP and fibrinolytic (urokinase) activities. SPP being associated with fibrinolytic properties, increased the activities of the above two enzymes to that of control levels in calculogenic rats. PMID:7684293

  10. Chemistry and Materials Science Directorate 2002 Postdoctoral Symposium

    SciTech Connect

    Wirth, B D

    2002-08-14

    The understanding of the physical mechanisms by which important biological inhibitors control the nucleation, growth, aggregation, and phase transformation of calcium oxalate crystals at fundamental level is of importance not only to the advances in biomineralization but also to the development of stone disease therapy. Of the three phases of calcium oxalate crystalline, calcium oxalate monohydrate (COM) and dehydrate (COD) are found in the majority of stones formed in the urinary system. Only COM, a major inorganic component of kidney stones, produces adverse physiological effects to human, however. Although a great deal of research has been carried out on the modulation of nucleation, growth, aggregation, and phase transformation of calcium oxalates by biological molecules, the basic mechanism has not yet been determined due to inherent limitations of those techniques that have been utilized The invention of atomic force microscopy (AFM) has opened a new avenue for the study of the crystal growth in general. One can now probe the growth kinetics and dynamics, and morphology of crystal surfaces down to molecular levels as a typical AFM has a lateral resolution of nanometers. In this study, in situ AFM was used to monitor the COM surface under controlled growth conditions. The growth on both (-101) and (010) faces was investigated. The effect of the macromolecules such as citrate and uropontin to the growth of surfaces was also explored. In this presentation, the structural basis for the observed results will be discussed and the implications of the findings to the field of medicine will also be addressed.

  11. Prevention and treatment of nephrolithiasis: a review on the role of spa therapy.

    PubMed

    Mennuni, G; Serio, A; Fontana, M; Nocchi, S; Costantino, C; Tanzi, G; Stornelli, G; Fraioli, A

    2015-01-01

    The prevalence and incidence of nephrolithiasis is reported to be increasing across the world. It is a disease of increased urinary concentration of stone-forming salts. The physicochemical mechanism of stone formation includes precipitation, homogenous/heterogeneous nucleation, growth, aggregation and concretion of various modulators in urine. Necessary condition to develop stones is urinary supersaturation, due to reduced urinary volume or to an excesses solutes. Fluid intake is the main determinant of urine volume. Urine dilution can significantly decrease both the crystallization rate of the urinary salts and the aggregation of the crystals. A correct fluid intake can act on different effects: urinary tract washing, urinary volume increasing and dilution of solutes. In addition mineral waters have other particular features: greater diuretic effect, more important urinary dilution with solutes and microbial concentration reduction, urinary pH changes, superior washout effect due to mechanical effects and ureteral contractions. Adequate water intake is the most important conservative strategy in urolithiasis prevention; particularly hydropinotherapy with oligomineral water should be considered as an important instrument to prevent stones in subjects predisposed to the disease (family members of people suffering from kidney stones), to reduce relapses, and can help to eliminate residual fragments also after extracorporeal shock wave lithotripsy. It is recommended a management with increased mineral water intake to promote urine volume of at least 2.5L each day to prevent stone formation. Obviously water intake shall be varied in relation to the presence of contraindications or any diseases. PMID:26550821

  12. Do Kidney Stone Formers Have A Kidney Disease?

    PubMed Central

    Zisman, Anna L.; Evan, Andrew P.; Coe, Fredric L.; Worcester, Elaine M.

    2015-01-01

    Nephrolithiasis is a highly prevalent disorder affecting approximately one in eleven people and is associated with multiple complications including hypertension, cardiovascular disease, and chronic kidney disease. Significant epidemiologic associations with chronic kidney disease and ESRD have been noted and are reviewed herein, but debate persists in the literature as to whether kidney stone formation is a pathogenic process contributing to kidney disease. Corroborating evidence supporting the presence of kidney disease in stone formers includes the variability of renal function by stone type, the positive association of stone size with renal dysfunction, the presence of markers of renal injury in the urine of even asymptomatic stone formers, and direct evidence of renal tissue injury on histopathology. Proposed pathogenic mechanisms include recurrent obstruction and comorbid conditions such as recurrent urinary tract infections and structural abnormalities. Recent work evaluating the renal histopathology of different groups of stone formers adds further granularity, suggesting variability in mechanisms of renal injury by stone type and confirming the pathogenic effects of crystal formation. Genetic abnormalities leading to stone formation including cystinuria and primary hyperoxaluria, among others, contribute to the burden of disease in the stone-forming population. PMID:26376133

  13. Factors governing urinary tract stone disease.

    PubMed

    Watts, R W

    1989-07-01

    Urinary stone formation depends on the degree of saturation of the urine with respect to potential stone-forming substances. Urine contains a range of electrolytes which ionise to different and variable degrees and which interact with one another in ways which influence their solubilities. These ionisations are themselves influenced by the pH of the urine which is another variable factor. Urinary organic molecules, which may or may not ionise and which may bear surface charges, also influence the solubility of the low molecular weight stone-constituents. Some other substances in the urine, such as glycosaminoglycans, can modify the ability of inorganic micro-crystals to aggregate and form stones. Environmental factors, other urinary tract pathology and genetic influences all predispose to urolithiasis, but many cases lack either an identifiable specific cause or the presence of recognisable risk factors. In the risk factor model of calcium stone formation there are pre-renal risk factors which lead to urinary risk factors and hence to the chemical risk factors of supersaturation and decreased ability to inhibit crystallisation. There are, in addition to these general factors which may act synergistically to produce urinary stones, several specific single enzyme defects which alter the urinary composition in such a way as to produce stones of a highly characteristic composition. PMID:2702116

  14. Effect of Hygrophila spinosa in ethylene glycol induced nephrolithiasis in rats

    PubMed Central

    Ingale, Kundan G.; Thakurdesai, Prasad A.; Vyawahare, Neeraj S.

    2012-01-01

    Objective: Hygrophila spinosa (Acanthaceae) is traditionally used to treat urinary calculi. The present study aimed to evaluate the antiurolithiatic activity of methanolic extract of Hygrophila spinosa (Acanthaceae) in ethylene glycol induced nephrolithiasic rats. Materials and Methods: Methanolic extract of Hygrophila spinosa (HSME) (250 and 500 mg/ kg body weight) was administered orally to male Wistar albino rats. Ethylene glycol (EG) was used to induce nephrolithiasis. The parameters studied included water intake, urinary volume, urinary pH, urinary and kidney oxalate and calcium, urinary magnesium and serum uric acid. Results: Ethylene glycol feeding resulted in hyperoxaluria as well as increased renal excretion of calcium and serum uric acid along with decreased excretion of urinary magnesium. Treatment with HSME significantly reduced the elevated urinary oxalate, urinary calcium and serum uric acid with increase in reduced urinary magnesium. Ethylene glycol feeding also resulted in increased levels of calcium and oxalate in kidney which was decreased after the treatment with HSME. The increased deposition of stone forming constituents in the kidneys of ethylene glycol treated rats was significantly lowered by treatment with HSME. Conclusion: The results indicate that the aerial parts of Hygrophila spinosa are endowed with antiurolithiatic activity, thereby justifying its traditional claim. PMID:23112429

  15. Citrate and renal calculi: an update

    NASA Technical Reports Server (NTRS)

    Pak, C. Y.

    1994-01-01

    Citrate is an inhibitor of the crystallization of stone-forming calcium salts. Hypocitraturia, frequently encountered in patients with nephrolithiasis, is therefore an important risk factor for stone formation. Potassium citrate provides physiological and physicochemical correction and inhibits new stone formation, not only in hypocitraturic calcium nephrolithiasis but also in uric acid nephrolithiasis. Inhibition of stone recurrence has now been validated by a randomized trial. Ongoing research has disclosed additional causes of hypocitraturia (sodium excess, low intestinal alkali absorption, but not primary citrate malabsorption). Moreover, new insights on potassium citrate action have been shown, notably that some of absorbed citrate escapes oxidation and contributes to the citraturic response, that ingestion with a meal does not sacrifice physiological or physicochemical action, that orange juice mimics but does not completely duplicate its actions, that potassium citrate may have a beneficial bone-sparing effect, that it may reduce stone fragments following ESWL, and that danger of aluminum toxicity is not great in subjects with functioning kidneys. Finally, the research on potassium citrate has led to two promising products, calcium citrate as an optimum calcium supplement and potassium-magnesium citrate which may be superior to potassium citrate in the management of stone disease.

  16. Application of SERS spectroscopy for detection of trace components in urinary deposits

    NASA Astrophysics Data System (ADS)

    Pucetaite, Milda; Velicka, Martynas; Tamosaityte, Sandra; Sablinskas, Valdas

    2014-03-01

    Surface-enhanced Raman scattering (SERS) spectroscopy can be a useful tool in regard to disease diagnosis and prevention. Advantage of SERS over conventional Raman spectroscopy is its significantly increased signal (up to factor of 106-108) which allows detection of trace amounts of substances in the sample. So far, this technique is successfully used for analysis of food, pieces of art and various biochemical/biomedical samples. In this work, we survey the possibility of applying SERS spectroscopy for detection of trace components in urinary deposits. Early discovery together with the identification of the exact chemical composition of urinary sediments could be crucial for taking appropriate preventive measures that inhibit kidney stone formation or growth processes. In this initial study, SERS spectra (excitation wavelength - 1064 nm) of main components of urinary deposits (calcium oxalate, uric acid, cystine, etc.) were recorded by using silver (Ag) colloid. Spectra of 10-3-10-5 M solutions were obtained. While no/small Raman signal was detected without the Ag colloid, characteristic peaks of the substances could be clearly separated in the SERS spectra. This suggests that even small amounts of the components could be detected and taken into account while determining the type of kidney stone forming in the urinary system. We found for the first time that trace amounts of components constituting urinary deposits could be detected by SERS spectroscopy. In the future study, the analysis of centrifuged urine samples will be carried out.

  17. Micovascular integration into porous polyHEMA scaffold

    NASA Astrophysics Data System (ADS)

    Cho, Eugenia H.; Boico, Alina; Wisniewski, Natalie A.; Gant, Rebecca; Helton, Kristen L.; Brown, Nga L.; Register, Janna K.; Vo-Dinh, Tuan; Schroeder, Thies; Klitzman, Bruce

    2014-03-01

    Surface-enhanced Raman scattering (SERS) spectroscopy can be a useful tool in regard to disease diagnosis and prevention. Advantage of SERS over conventional Raman spectroscopy is its significantly increased signal (up to factor of 106-108) which allows detection of trace amounts of substances in the sample. So far, this technique is successfully used for analysis of food, pieces of art and various biochemical/biomedical samples. In this work, we survey the possibility of applying SERS spectroscopy for detection of trace components in urinary deposits. Early discovery together with the identification of the exact chemical composition of urinary sediments could be crucial for taking appropriate preventive measures that inhibit kidney stone formation or growth processes. In this initial study, SERS spectra (excitation wavelength - 1064 nm) of main components of urinary deposits (calcium oxalate, uric acid, cystine, etc.) were recorded by using silver (Ag) colloid. Spectra of 10-3-10-5 M solutions were obtained. While no/small Raman signal was detected without the Ag colloid, characteristic peaks of the substances could be clearly separated in the SERS spectra. This suggests that even small amounts of the components could be detected and taken into account while determining the type of kidney stone forming in the urinary system. We found for the first time that trace amounts of components constituting urinary deposits could be detected by SERS spectroscopy. In the future study, the analysis of centrifuged urine samples will be carried out.

  18. The risk of renal stone formation during and after long duration space flight

    NASA Technical Reports Server (NTRS)

    Whitson, P. A.; Pietrzyk, R. A.; Morukov, B. V.; Sams, C. F.

    2001-01-01

    BACKGROUND: The formation of a renal stone during space flight may have serious negative effects on the health of the crewmember and the success of the mission. Urinary biochemical factors and the influence of dietary factors associated with renal stone development were assessed during long duration Mir Space Station missions. METHODS: Twenty-four-hour urine samples were collected prior to, during and following long duration space flight. The relative urinary supersaturation of calcium oxalate, calcium phosphate (brushite), sodium urate, struvite and uric acid were determined. RESULTS: Changes in the urinary biochemistry of crewmembers during long duration spaceflight demonstrated increases in the supersaturation of the stone-forming salts. In-flight hypercalciuria was evident in a number of individual crewmembers and 24-hour dietary fluid intake and urine volume were significantly lower. During flight, there was a significant increase in brushite supersaturation. CONCLUSIONS: These data suggest acute effects of space flight and postflight changes in the urinary biochemistry favoring increased crystallization in the urine. The effects of dietary intake, especially fluid intake, may have a significant impact on the potential for renal stone formation. Efforts are now underway to assess the efficacy of a countermeasure to mitigate the increased risk. Copyright 2001 S. Karger AG, Basel.

  19. Histopathology Predicts the Mechanism of Stone Formation

    NASA Astrophysics Data System (ADS)

    Evan, Andrew P.

    2007-04-01

    About 5% of American women and 12% of men will develop a kidney stone at some time in their life and these numbers appear to be on the rise. Despite years of scientific research into the mechanisms of stone formation and growth, limited advances have been made until recently. Randall's original observations and thoughts on the mechanisms for kidney stone formation have been validated for idiopathic calcium oxalate stone formers (ICSF) but not for most other stone forming groups. Our current studies on selected groups of human stone formers using intraoperative papillary biopsies has shown overwhelming evidence for the presence of Randall's plaque in ICSF and that stone formation and growth are exclusively linked to its availability to urinary ions and proteins. Intense investigation of the plaque-stone junction is needed if we are to understand the factors leading to the overgrowth process on exposed regions of plaque. Such information should allow the development of treatment strategies to block stone formation in ICSF patients. Patients who form brushite stones, or who form apatite stones because of distal renal tubular acidosis (dRTA), or patients with calcium oxalate stones due to obesity bypass procedures, or patients with cystinuria, get plugged inner medullary collecting ducts (IMCD) which leads to total destruction of the lining cells and focal sites of interstitial fibrosis. These stone formers have plaque but at levels equal to or below non-stone formers, which would suggest that they form stones by a different mechanism than do ICSF patients.

  20. Protective effects of the aqueous extract of Crocus sativus against ethylene glycol induced nephrolithiasis in rats

    PubMed Central

    Amin, Bahareh; Feriz, Hanieh Moghri; Hariri, Alireza Timcheh; Meybodi, Naser Tayyebi; Hosseinzadeh, Hossein

    2015-01-01

    This study evaluated the possible protective effect of Crocus sativus L. (saffron) in the treatment of renal calculi. Aqueous extract of saffron (25, 50 and 100 mg/kg, daily) was administered intraperitoneally in two regimens of protective or curative, using male Wistar rats. Urolithiasis was induced by ethylene glycol (% 0.75) in drinking water. Urine was collected for biochemical analysis and the kidneys were prepared for total lipid peroxide and histological evaluation. Ethylene glycol feeding resulted in an increased urine output, renal excretion of oxalate and decreased excretion of citrate and magnesium. Saffron did not show diuretic effect; however, it significantly reduced the elevated urinary oxalate in prophylactic (50 and 100 mg/kg) and curative (100 mg/kg) studies. Only the high dose of prophylactic regimen restored citrate concentration of urine. Increased number of calcium oxalate crystals deposits in the kidney tissue of calculogenic rats was significantly reverted by the prophylactic and high dose of curative saffron treatment. Malondialdehyde (MDA, a lipid peroxidation product) in the kidneys was increased following the lithogenic treatment; however, prophylactic (50, 100 mg/kg) and curative (100 mg/kg) regimens with saffron reduced the elevated levels of MDA. Results in the current study indicate that saffron can protect against ethylene glycol induced calcium oxalate (CaOx) nephrolithiasis. The mechanisms underlying this effect are mediated possibly through effect on the urinary concentration of stone-forming constituents and an antioxidant effect. PMID:26535035

  1. Kidney Stones

    PubMed Central

    Kleeman, Charles R.; Coburn, Jack W.; Brickman, Arnold S.; Lee, David B. N.; Narins, Robert G.; Ehrlich, Richard M.

    1980-01-01

    The prevalence of kidney stones has steadily risen during this century; passage of a calculus and a positive family history increase the probability of recurrence. Findings from recent studies on the cause of renal calculi have stressed crystallization and crystal aggregation of stone minerals from supersaturated urine, rather than excessive organic matrix. Absence of normal urine inhibitors of calcium salts is also stressed. Formation of calcium oxalate stones is the major problem. Therapy with decreased calcium and oxalate intake, thiazides, phosphate salts and allopurinol in various combinations has substantially decreased the prevalence of recurrent stones. The rationale for the use of allopurinol is that uric acid salts enhance the tendency for calcium oxalate to crystallize from supersaturated urine. The hypercalciuria seen in 30 percent to 40 percent of patients with oxalate stones is usually caused by intestinal hyperabsorption of calcium. Although patients with uric acid calculi constitute only a small fraction of those in whom stones form, they represent a group in whom good medical therapy, based on sound physiologic principles, has proved extremely successful. Renal tubular syndromes lead to nephrocalcinosis and lithiasis through hypercalciuria, alkaline urine and hypocitraturia, the latter an inhibitor of calcium salt precipitation. Recent advances in surgical techniques are discussed, including the rationale for removing staghorn calculi. The ileal ureter and coagulum pyelolithotomy deserve special emphasis. ImagesFigure 2.Figure 4.Figure 5.Figure 7. PMID:7385835

  2. Studying inhibition of calcium oxalate stone formation: an in vitro approach for screening hydrogen sulfide and its metabolites

    PubMed Central

    Vaitheeswari, S.; Sriram, R.; Brindha, P.; Kurian, Gino A.

    2015-01-01

    ABSTRACT Purpose: Calcium oxalate urolithiasis is one of the most common urinary tract diseases and is of high prevalence. The present study proposes to evaluate the antilithiatic property of hydrogen sulfide and its metabolites like thiosulfate & sulfate in an in vitro model. Materials and Methods: The antilithiatic activity of sodium hydrogen sulfide (NaSH), sodium thiosulfate (Na2S2O3) and sodium sulfate (Na2SO4) on the kinetics of calcium oxalate crystal formation was investigated both in physiological buffer and in urine from normal and recurrent stone forming volunteers. The stones were characterized by optical and spectroscopic techniques. Results: The stones were characterized to be monoclinic, prismatic and bipyramidal habit which is of calcium monohydrate and dihydrate nature. The FTIR displayed fingerprint corresponding to calcium oxalate in the control while in NaSH treated, S=O vibrations were visible in the spectrum. The order of percentage inhibition was NaSH>Na2S2O3>Na2SO4. Conclusion: Our study indicates that sodium hydrogen sulfide and its metabolite thiosulfate are inhibitors of calcium oxalate stone agglomeration which makes them unstable both in physiological buffer and in urine. This effect is attributed to pH changes and complexing of calcium by S2O3 2-and SO4 2- moiety produced by the test compounds. PMID:26200543

  3. Sedimentary rocks in our mouth: dental pulp stones made by nanobacteria

    NASA Astrophysics Data System (ADS)

    Ciftcioglu, Neva; Ciftcioglu, Vefa; Vali, Hojatollah; Turcott, Eduardo; Kajander, E. Olavi

    1998-07-01

    The mechanisms of dental pulp stone formation are still largely unknown. Pulp stones are mainly composed of carbonate apatite. Only few experimental reports have elucidated the potential of some selected bacteria to produce apatite under in vitro conditions using special calcification media. The tested stone forming bacteria were, in fact, often better known for their cariogenic potential. Our preliminary work with 18 dental pulp stones from Turkey, selected only by severity of the stone formation, indicated the presence of nanobacterial antigens in the demineralized stones. Furthermore, high incidence of kidney stones and gall stones in the patient group and in their parents was found. This raises the implication that nanobacteria may enter the body also via oral route, in addition to the parenteral and transplacental routes. The role of nanobacteria in dental pulp stone formation was further studied by following nanobacterial colonization and mineral formation on human tooth in vitro. Two molar teeth, one having pulp stone and one without, were vertically cut into two pieces, sterilized by autoclaving and incubated with or without nanobacteria in DMEM. Electron microscopic observations indicate that nanobacteria can cause apatite stone formation on tooth surface. The sever from of dental pulp stone formation might be associated with nanobacteria. This form of dental disease results in loss of teeth due to osteolytic processes. This addresses the necessity for a study on unconventional mineral-forming bacteria as a cause for human diseases.

  4. Artificial tektites: an experimental technique for capturing the shapes of spinning drops.

    PubMed

    Baldwin, Kyle A; Butler, Samuel L; Hill, Richard J A

    2015-01-01

    Determining the shapes of a rotating liquid droplet bound by surface tension is an archetypal problem in the study of the equilibrium shapes of a spinning and charged droplet, a problem that unites models of the stability of the atomic nucleus with the shapes of astronomical-scale, gravitationally-bound masses. The shapes of highly deformed droplets and their stability must be calculated numerically. Although the accuracy of such models has increased with the use of progressively more sophisticated computational techniques and increases in computing power, direct experimental verification is still lacking. Here we present an experimental technique for making wax models of these shapes using diamagnetic levitation. The wax models resemble splash-form tektites, glassy stones formed from molten rock ejected from asteroid impacts. Many tektites have elongated or 'dumb-bell' shapes due to their rotation mid-flight before solidification, just as we observe here. Measurements of the dimensions of our wax 'artificial tektites' show good agreement with equilibrium shapes calculated by our numerical model, and with previous models. These wax models provide the first direct experimental validation for numerical models of the equilibrium shapes of spinning droplets, of importance to fundamental physics and also to studies of tektite formation. PMID:25564381

  5. The influence of bacteria on struvite crystal habit and its importance in urinary stone formation

    NASA Astrophysics Data System (ADS)

    Clapham, L.; McLean, R. J. C.; Nickel, J. C.; Downey, J.; Costerton, J. W.

    1990-07-01

    Infection-induced urinary stones form as a result of a urinary tract infection by urease-producing bacteria. These stones are not totally crystalline in nature but rather consist of an agglomeration of bacteria, organic matrix, and crystal of struvite (MgNH 4PO 4· 6H 2O). Crystal formation is related to the ability of the bacteria to effect an increase in the urine pH. Another equally important bacterial role lies in their formation of a 'biofilm' which later becomes the organic matrix constituent of the stone. Results of the present in vitro study indicate that crystals are formed more readily if produced within the bacterial biofilm than in the surrounding urine. It is proposed that supersaturation, due in part to a bacterial-induced pH increase and in part to the metal binding tendency of the biofilm, leads to crystal formation via a gel growth mechanism within the biofilm itself. In time further bacterial cell division, microcolony.

  6. Modification by food of the calcium absorbability and physicochemical effects of calcium citrate

    NASA Technical Reports Server (NTRS)

    Wabner, C. L.; Pak, C. Y.

    1992-01-01

    The food-calcium (Ca) interaction was examined in 12 healthy women (mean age 38 years) maintained on a constant metabolic diet. They underwent three phases of study, comprised of control (no Ca), Ca citrate (1 g Ca/day) during meals, and Ca citrate separately from meals. Each phase was 7 days in length and two 24-hour urine samples were collected on days 6 and 7. The rise from the control phase in urinary Ca was slightly more prominent when Ca citrate was given with meals than without (68 and 62%, respectively). The fall in urinary phosphorus was equivalent at about 25% between Ca citrate phases. The rise in urinary citrate and pH and the decline in urinary ammonium were more prominent when Ca citrate was given with meals; however, the changes were small or nonsignificant. The urinary saturation of Ca oxalate, brushite or monosodium urate did not differ between the two Ca citrate phases. There was a nonsignificant rise in serum iron during Ca citrate phases. The results suggest that: 1) dissolution and absorption of Ca citrate might be slightly greater when given with food than without; 2) that the ability of Ca citrate to attenuate crystallization of stone-forming Ca salts in urine is not modified by food; and 3) that Ca citrate may not impair iron absorption from food.

  7. Antiurolithiatic Activity of Whole-Plant Hydroalcoholic Extract of Pergularia daemia in Rats

    PubMed Central

    Vyas, BA; Vyas, RB; Joshi, SV; Santani, DD

    2011-01-01

    The whole-plant, Pergularia daemia (Family: Asclepediaceae), extract (50% alcohol) was investigated for its antiurolithiatic and diuretic activity. Ethylene glycol (0.75% in water) feeding resulted in hyperoxaluria as well as increased renal excretion of calcium and phosphate. Alcoholic extract (400 mg/kg) of P. daemia was given orally in curative and preventive regimens over a period of 28 days. Supplementation with extract significantly (P < 0.001) lowered the urinary excretion and kidney retention levels of oxalate, calcium and phosphate. Furthermore, high serum levels of urea nitrogen, creatinine and uric acid were significantly (P < 0.001) reduced by the extract. The results were comparable with the standard drug, cystone (750 mg/kg). The reduction of stone-forming constituents in urine and their decreased kidney retention reduces the solubility product of crystallizing salts such as calcium oxalate and calcium phosphate, which could contribute to the antiurolithiatic property of the extract. The extract exhibited significant diuretic activity at dose of 400 mg/kg body weight as evidenced by increased total urine volume and the urine concentration of Na+, and K+. These findings affirm assertions made regarding the effectiveness of the extract of this plant against urinary pathologies in the Indian folk medicine. PMID:21607052

  8. GENETIC BASIS OF RENAL CELLULAR DYSFUNCTION AND THE FORMATION OF KIDNEY STONES

    PubMed Central

    Khan, Saeed R.; Canales, Benjamin K.

    2013-01-01

    Nephrolithiasis is a result of formation and retention of crystals within the kidneys. The driving force behind crystal formation is urinary supersaturation with respect to the stone forming salts, which means that crystals form when the concentrations of participating ions are higher than the thermodynamic solubility for that salt. Levels of supersaturation are kept low and under control by proper functioning of a variety of cells including those that line the renal tubules. It is our hypothesis that crystal deposition i.e. formation and retention in the kidneys, is a result of impaired cellular function, which may be intrinsic and inherent or triggered by external stimuli and challenges. Cellular impairment or dysfunction affects the supersaturation, by influencing the excretion of participating ions such as calcium, oxalate and citrate and causing hypercalciuria, hyperoxaluria or hypocitraturia. The production and excretion of macromolecular promoters and inhibitors of crystallization is also dependent upon proper functioning of the renal epithelial cells. Insufficient or ineffective crystallization modulators such as osteopontin (OPN), Tamm Horsfall protein (THP), bikunin (BK) etc are most likely produced by the impaired cells. PMID:19517103

  9. Prospects for laser-induced breakdown spectroscopy for biomedical applications: a review.

    PubMed

    Singh, Vivek Kumar; Rai, Awadhesh Kumar

    2011-09-01

    We review the different spectroscopic techniques including the most recent laser-induced breakdown spectroscopy (LIBS) for the characterization of materials in any phase (solid, liquid or gas) including biological materials. A brief history of the laser and its application in bioscience is presented. The development of LIBS, its working principle and its instrumentation (different parts of the experimental set up) are briefly summarized. The generation of laser-induced plasma and detection of light emitted from this plasma are also discussed. The merit and demerits of LIBS are discussed in comparison with other conventional analytical techniques. The work done using the laser in the biomedical field is also summarized. The analysis of different tissues, mineral analysis in different organs of the human body, characterization of different types of stone formed in the human body, analysis of biological aerosols using the LIBS technique are also summarized. The unique abilities of LIBS including detection of molecular species and calibration-free LIBS are compared with those of other conventional techniques including atomic absorption spectroscopy, inductively coupled plasma atomic emission spectroscopy and mass spectroscopy, and X-ray fluorescence. PMID:21533560

  10. Patients with recurrent renal stones have a physico-chemically altered urinary Tamm-Horsfall glycoprotein profile.

    PubMed

    Jefferson, A; Reynolds, T M; Elves, A; Wierzbicki, A S

    1996-11-01

    We describe an immunoblotting method for examining the electrophoretic properties of urinary Tamm-Horsfall protein. Using this method we tested frozen urine samples from a group of 37 thoroughly investigated recurrent idiopathic renal calcium stone formers and compared this with fresh urine from 19 non-stone forming laboratory staff. We found that there was a statistically significant different pattern of Tamm-Horsfall protein bands in the two sets of urines, with stone formers tending to have two bands and non-stone formers tending to have three bands. This could have been due to storage artefact and therefore a further group of 13 fresh urines from unselected renal stone formers was tested. A smaller proportion of these cases showed the two-band pattern, possibly because not all of this group were idiopathic calcium stone formers. This suggests that but does not prove that there is no significant storage artefact and that there may be an in vivo effect causing stone formation. PMID:8937586

  11. Computational fluid dynamics analysis of salivary flow and its effect on sialolithogenesis

    PubMed Central

    Zhu, P; Lin, Y; Lin, H; Xu, Y; Zheng, QY; Han, Y

    2014-01-01

    OBJECTIVE Sialolithiasis is a common disease caused by intraductal stones, formed by reduction in salivary flow, salivary stagnation, and metabolic events. We used computational fluid dynamics to investigate changes in salivary flow field around parotid stones of different shapes. MATERIALS AND METHODS Three-dimensional configurations of the Stensen’s duct were reconstructed from computed tomography sialographic images. Fluid dynamics modeling was used to analyze the salivary flow field around stones under unstimulated and stimulated conditions. RESULTS The majority of sialoliths were oval-shaped (59/98), followed by irregular (24/98) and round (15/98). Salivary velocity was significantly higher around streamlined stones, compared with round (P = 0.013) and oval (P = 0.025) types. Changes in salivary flow field around sialoliths were found to affect the pattern of mineral deposition in saliva. The area of low velocity around the round stone was double the size observed around the streamlined stone during the unstimulated state, whereas in the stimulated state, local vortexes were formed on the downstream side of round and oval stones. CONCLUSIONS Salivary flow field around sialoliths plays an important role in the progression of multicentric stones, and analysis of the salivary dynamics during sialolithiasis may provide deeper understandings of the condition and aid in developing successful treatment strategies. PMID:24164693

  12. The Role of Semantics in Open-World, Integrative, Collaborative Science Data Platforms

    NASA Astrophysics Data System (ADS)

    Fox, Peter; Chen, Yanning; Wang, Han; West, Patrick; Erickson, John; Ma, Marshall

    2014-05-01

    As collaborative science spreads into more and more Earth and space science fields, both participants and funders are expressing stronger needs for highly functional data and information capabilities. Characteristics include a) easy to use, b) highly integrated, c) leverage investments, d) accommodate rapid technical change, and e) do not incur undue expense or time to build or maintain - these are not a small set of requirements. Based on our accumulated experience over the last ~ decade and several key technical approaches, we adapt, extend, and integrate several open source applications and frameworks to handle major portions of functionality for these platforms. This includes: an object-type repository, collaboration tools, identity management, all within a portal managing diverse content and applications. In this contribution, we present our methods and results of information models, adaptation, integration and evolution of a networked data science architecture based on several open source technologies (Drupal, VIVO, the Comprehensive Knowledge Archive Network; CKAN, and the Global Handle System; GHS). In particular we present the Deep Carbon Observatory - a platform for international science collaboration. We present and discuss key functional and non-functional attributes, and discuss the general applicability of the platform.

  13. Predictability of in vitro dermal assays when evaluating fatty amine derivatives.

    PubMed

    Houthoff, Erik; Rugen, Pamela; Hart, David

    2015-09-01

    It is widely accepted that skin assays based on reconstructed human epidermis (RhE) models can be used in place of in vivo testing to accurately predict corrosivity and/or irritancy of commodity chemicals. Due to REACH legislation, substances from various categories of fatty amines derivatives have been evaluated for dermal corrosion applying either the EpiDerm™ (EPI-200) or EpiSkin™ assay. Available data and practical experience indicated that these substances are corrosive to the skin. The substances tested are cationic surfactants which dermal effects are characterized by a delayed severe inflammatory reaction. The mechanism is thought to be related to disruption of the cellular membrane following diffusion of the long apolar tails of the molecules into the lipid bilayers. However, unexpectedly almost all obtained study results indicated that these substances are NOT corrosive in these in vitro RhE test systems. Since these results did not align with the experiences on such substances, limited in vivo rabbit studies were employed additionally. These studies confirmed that after some delay full skin tissue destruction occurs, requiring classification as Corrosive Cat.1B or 1C for GHS. The results obtained for various fatty amine derivatives shows that RhE assays do not always predict corrosivity correctly. PMID:25458482

  14. G protein-coupled receptors in regulation of body weight.

    PubMed

    Schiöth, Helgi B

    2006-06-01

    In this issue of CNS & Neurological Disorders-Drug Targets, we focus on G protein-coupled receptors (GPCRs) that are involved in regulating body weight. In six reviews, the melanocortins system (including MC4 and MC3 receptors, Agrp, MSH), the NPY receptors (including NPY-Y1, NPY-Y2, and NPY-Y5, PYY3-36), the cannabinoid system (including the development of rimonabant), the ghrelin (GHS, growth hormone secretagogue) system, the monoamine GPCRs (including serotonin, adrenergic and histamine receptors), orexin (hypocretin) system and the galanin receptors are covered. In this overview, an introduction to the GPCRs and the field of central regulation of food intake is provided together with brief mentioning of some other GPCRs that are also implicated in regulation of body weight, such as the melanin-concentrating hormone (MCH), neuromedin U, prolactin-releasing peptide (PrRP), bombesin, cholecystokinin (CCK), Glucagon-like peptide-1 (GLP-1) (and oxyntomodulin), neuropeptide B (NPB) and neuropeptide W (NPW), opioids peptides, free fatty acid (FFA) receptors (GPR40, GPR41). In total over 40 GPCRs are listed that have been implicated to affect regulation of body weight. PMID:16787226

  15. Extracellular Glycoside Hydrolase Activities in the Human Oral Cavity

    PubMed Central

    Walker, Lauren C.; Dodds, Michael W. J.; Hanley, A. Bryan

    2015-01-01

    Carbohydrate availability shifts when bacteria attach to a surface and form biofilm. When salivary planktonic bacteria form an oral biofilm, a variety of polysaccharides and glycoproteins are the primary carbon sources; however, simple sugar availabilities are limited due to low diffusion from saliva to biofilm. We hypothesized that bacterial glycoside hydrolase (GH) activities would be higher in a biofilm than in saliva in order to maintain metabolism in a low-sugar, high-glycoprotein environment. Salivary bacteria from 13 healthy individuals were used to grow in vitro biofilm using two separate media, one with sucrose and the other limiting carbon sources to a complex carbohydrate. All six GHs measured were higher in vitro when grown in the medium with complex carbohydrate as the sole carbon source. We then collected saliva and overnight dental plaque samples from the same individuals and measured ex vivo activities for the same six enzymes to determine how oral microbial utilization of glycoconjugates shifts between the planktonic phase in saliva and the biofilm phase in overnight dental plaque. Overall higher GH activities were observed in plaque samples, in agreement with in vitro observation. A similar pattern was observed in GH activity profiles between in vitro and ex vivo data. 16S rRNA gene analysis showed that plaque samples had a higher abundance of microorganisms with larger number of GH gene sequences. These results suggest differences in sugar catabolism between the oral bacteria located in the biofilm and those in saliva. PMID:26048943

  16. Classification of dermal sensitizers in pharmaceutical manufacturing.

    PubMed

    Winkler, Gian C; Perino, Christopher; Araya, Selene H; Bechter, Rudolf; Kuster, Martin; Lovsin Barle, Ester

    2015-08-01

    Workers in development and manufacturing of pharmaceuticals are at risk for occupational contact dermatitis (OCD) of irritative (ICD) or allergic (ACD) origin, due to contacts with reactive intermediates (IM) and drug substances (DS). We examined, if alternative methods could replace presently used animal tests for identification of ACD in pharmaceutical development and manufacturing, without apparent loss of worker health, in line with regulations. The status of alternative methods for regulatory toxicology for consumer products has recently been reviewed by the Organisation for Economic Co-operation and Development (OECD) and the European Commission's Joint Research Center (JRC) for the European Chemicals Agency (ECHA). They concluded that prediction of skin sensitization potential, extent and quality by in vitro methods, for regulatory assessments, will depend on the regulatory purpose and level of confidence required. Some alternative methods are currently in validation. Current Globally Harmonized System (GHS) regulations on classification, labeling and packaging of substances and mixtures depend on human and animal data, whereas alternative methods may provide supportive evidence. Since the levels of workplace skin exposure to DS and IM in manufacturing of pharmaceuticals are usually not known, it is not possible to conduct quantitative risk assessments based on threshold calculations for contact sensitizers. PMID:26028366

  17. Role of ghrelin system in neuroprotection and cognitive functions: implications in Alzheimer’s disease

    PubMed Central

    Gahete, Manuel D.; Córdoba-Chacón, José; Kineman, Rhonda D.; Luque, Raúl M.; Castaño, Justo P.

    2011-01-01

    Alzheimer’s disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by loss of memory and cognitive deficits, strongly influenced by the metabolic status, in which the impairment of neuropeptides/neurotransmitters systems has been previously observed. Ghrelin is a multifunctional hormone produced in a wide variety of tissues, which has been associated with the progression of obesity and metabolic syndrome, but has been also linked to neuromodulation, neuroprotection and memory and learning processes. In addition, ghrelin system also acts in an autocrine/paracrine fashion where the majority of its components [ghrelin variants (native ghrelin, In2-ghrelin), acylation enzymes (GOAT) and receptors (GHS-Rs)] are expressed in the different regions of central nervous system. In spite of all these pieces of information strongly suggesting a close association between ghrelin system and AD, which could be of pathophysiological relevance, few studies have been addressed to clarify this relationship. In this work, the role of ghrelin system in neuroprotection, memory consolidation and learning is reviewed, and its influence in AD, as well as the regulation of its expression in AD patients, is discussed. PMID:21983104

  18. Characterization of antifungal activity of the GH-46 subclass III chitosanase from Bacillus circulans MH-K1.

    PubMed

    Tomita, Masayo; Kikuchi, Ayami; Kobayashi, Mariko; Yamaguchi, Masashi; Ifuku, Shinsuke; Yamashoji, Shiro; Ando, Akikazu; Saito, Akihiro

    2013-11-01

    We characterized the antifungal activity of the Bacillus circulans subclass III MH-K1 chitosanase (MH-K1 chitosanase), which is one of the most intensively studied glycoside hydrolases (GHs) that belong to GH family 46. MH-K1 chitosanase inhibited the growth of zygomycetes fungi, Rhizopus and Mucor, even at 10 pmol (0.3 μg)/ml culture probably via its fungistatic effect. The amino acid substitution E37Q abolished the antifungal activity of MH-K1 chitosanase, but retained binding to chitotriose. The E37Q mutant was fused with green fluorescent protein (GFP) at its N-terminus and proved to act as a chitosan probe in combination with wheat-germ agglutinin (WGA), which is a chitin-specific binding lectin. The GFP-fused MH-K1 chitosanase mutant E37Q (GFP-E37Q) bound clearly to the hyphae of the Rhizopus and Mucor strains, indicating the presence of chitosan. In contrast, Cy5-labelled WGA (Cy5-WGA), but not GFP-E37Q, stained the hyphae of non-zygomycetes species, i.e. Fusarium oxysporum, Penicillium expansum, and Aspergillus awamori. When the mycelia of Rhizopus oryzae were treated with wild type MH-K1 chitosanase, they could not bind to GFP-E37Q but were stained instead by Cy5-WGA. We conclude that chitin is covered by chitosan in the cell walls of R. oryzae. PMID:23892828

  19. Effects of ghrelin and motilin on smooth muscle contractility of the isolated gastrointestinal tract from the bullfrog and Japanese fire belly newt.

    PubMed

    Kitazawa, Takio; Shimazaki, Misato; Kikuta, Ayumi; Yaosaka, Noriko; Teraoka, Hiroki; Kaiya, Hiroyuki

    2016-06-01

    Ghrelin has been identified in some amphibians and is known to stimulate growth hormone release and food intake as seen in mammals. Ghrelin regulates gastrointestinal motility in mammals and birds. The aim of this study was to determine whether ghrelin affects gastrointestinal smooth muscle contractility in bullfrogs (anuran) and Japanese fire belly newts (urodelian) in vitro. Neither bullfrog ghrelin nor rat ghrelin affected longitudinal smooth muscle contractility of gastrointestinal strips from the bullfrog. Expression of growth hormone secretagogue receptor 1a (GHS-R1a) mRNA was confirmed in the bullfrog gastrointestinal tract, and the expression level in the gastric mucosa was lower than that in the intestinal mucosa. In contrast, some gastrointestinal peptides, including substance P, neurotensin and motilin, and the muscarinic receptor agonist carbachol showed marked contraction, indicating normality of the smooth muscle preparations. Similar results were obtained in another amphibian, the Japanese fire belly newt. Newt ghrelin and rat ghrelin did not cause any contraction in gastrointestinal longitudinal muscle, whereas substance P and carbachol were effective causing contraction. In conclusion, ghrelin does not affect contractility of the gastrointestinal smooth muscle in anuran and urodelian amphibians, similar to results for rainbow trout and goldfish (fish) but different from results for rats and chickens. The results suggest diversity of ghrelin actions on the gastrointestinal tract across animals. This study also showed for the first time that motilin induces gastrointestinal contraction in amphibians. PMID:26704852

  20. Relamorelin: A Novel Gastrocolokinetic Synthetic Ghrelin Agonist

    PubMed Central

    Camilleri, Michael; Acosta, Andres

    2015-01-01

    Synthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM-131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)-1a (also called the ghrelin) receptor with approximately 6-fold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin. In this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a pre-specified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders. PMID:25545036

  1. Ghrelin-like peptide with fatty acid modification and O-glycosylation in the red stingray, Dasyatis akajei

    PubMed Central

    2009-01-01

    Background Ghrelin (GRLN) is now known to be an appetite-stimulating and growth hormone (GH)-releasing peptide that is predominantly synthesized and secreted from the stomachs of various vertebrate species from fish to mammals. Here, we report a GRLN-like peptide (GRLN-LP) in a cartilaginous fish, the red stingray, Dasyatis akajei. Results The purified peptide contains 16 amino acids (GVSFHPQPRS10TSKPSA), and the serine residue at position 3 is modified by n-octanoic acid. The modification is the characteristic of GRLN. The six N-terminal amino acid residues (GVSFHP) were identical to another elasmobranch shark GRLN-LP that was recently identified although it had low identity with other GRLN peptides. Therefore, we designated this peptide stingray GRLN-LP. Uniquely, stingray GRLN-LP was O-glycosylated with mucin-type glycan chains [N-acetyl hexosamine (HexNAc)3 hexose(Hex)2] at threonine at position 11 (Thr-11) or both serine at position 10 (Ser-10) and Thr-11. Removal of the glycan structure by O-glycanase made the in vitro activity of stingray GRLN-LP decreased when it was evaluated by the increase in intracellular Ca2+ concentrations using a rat GHS-R1a-expressing cell line, suggesting that the glycan structure plays an important role for maintaining the activity of stingray GRLN-LP. Conclusions This study reveals the structural diversity of GRLN and GRLN-LP in vertebrates. PMID:20003394

  2. Utilisation of Mucin Glycans by the Human Gut Symbiont Ruminococcus gnavus Is Strain-Dependent

    PubMed Central

    Crost, Emmanuelle H.; Tailford, Louise E.; Le Gall, Gwenaelle; Fons, Michel; Henrissat, Bernard; Juge, Nathalie

    2013-01-01

    Commensal bacteria often have an especially rich source of glycan-degrading enzymes which allow them to utilize undigested carbohydrates from the food or the host. The species Ruminococcus gnavus is present in the digestive tract of ≥90% of humans and has been implicated in gut-related diseases such as inflammatory bowel diseases (IBD). Here we analysed the ability of two R. gnavus human strains, E1 and ATCC 29149, to utilize host glycans. We showed that although both strains could assimilate mucin monosaccharides, only R. gnavus ATCC 29149 was able to grow on mucin as a sole carbon source. Comparative genomic analysis of the two R. gnavus strains highlighted potential clusters and glycoside hydrolases (GHs) responsible for the breakdown and utilization of mucin-derived glycans. Transcriptomic and functional activity assays confirmed the importance of specific GH33 sialidase, and GH29 and GH95 fucosidases in the mucin utilisation pathway. Notably, we uncovered a novel pathway by which R. gnavus ATCC 29149 utilises sialic acid from sialylated substrates. Our results also demonstrated the ability of R. gnavus ATCC 29149 to produce propanol and propionate as the end products of metabolism when grown on mucin and fucosylated glycans. These new findings provide molecular insights into the strain-specificity of R. gnavus adaptation to the gut environment advancing our understanding of the role of gut commensals in health and disease. PMID:24204617

  3. Associations between depression and different measures of obesity (BMI, WC, WHtR, WHR)

    PubMed Central

    2013-01-01

    Background Growing evidence suggests that abdominal obesity is a more important risk factor for the prognosis of cardiovascular and metabolic diseases than BMI. Somatic-affective symptoms of depression have also been linked to cardiovascular risk. The relationship between obesity and depression, however, has remained contradictory. Our aim was therefore to relate body mass index (BMI) and different measures for abdominal obesity (waist circumference, WC, waist-to-hip ratio, WHR, waist-to-height ratio, WHtR) to somatic vs. cognitive-affective symptoms of depression. Methods In a cross-sectional population based study, data on the first N = 5000 participants enrolled in the Gutenberg Health Study (GHS) are reported. To analyze the relationship between depression and obesity, we computed linear regression models with the anthropometric measure (BMI, WC, WHR, WHtR) as the dependent variable and life style factors, cardiovascular risk factors and psychotropic medications as potential confounders of obesity/depression. Results We found that only the somatic, but not the cognitive-affective symptoms of depression are consistently positively associated with anthropometric measures of obesity. Conclusions We could demonstrate that the somatic-affective symptoms of depression rather than the cognitive-affective symptoms are strongly related to anthropometric measures. This is also true for younger obese starting at the age of 35 years. Our results are in line with previous studies indicating that visceral adipose tissue plays a key role in the relationship between obesity, depression and cardiovascular disease. PMID:24028572

  4. Molecular characterization of a family 5 glycoside hydrolase suggests an induced-fit enzymatic mechanism

    PubMed Central

    Liberato, Marcelo V.; Silveira, Rodrigo L.; Prates, Érica T.; de Araujo, Evandro A.; Pellegrini, Vanessa O. A.; Camilo, Cesar M.; Kadowaki, Marco A.; Neto, Mario de O.; Popov, Alexander; Skaf, Munir S.; Polikarpov, Igor

    2016-01-01

    Glycoside hydrolases (GHs) play fundamental roles in the decomposition of lignocellulosic biomaterials. Here, we report the full-length structure of a cellulase from Bacillus licheniformis (BlCel5B), a member of the GH5 subfamily 4 that is entirely dependent on its two ancillary modules (Ig-like module and CBM46) for catalytic activity. Using X-ray crystallography, small-angle X-ray scattering and molecular dynamics simulations, we propose that the C-terminal CBM46 caps the distal N-terminal catalytic domain (CD) to establish a fully functional active site via a combination of large-scale multidomain conformational selection and induced-fit mechanisms. The Ig-like module is pivoting the packing and unpacking motions of CBM46 relative to CD in the assembly of the binding subsite. This is the first example of a multidomain GH relying on large amplitude motions of the CBM46 for assembly of the catalytically competent form of the enzyme. PMID:27032335

  5. Isolation and characterization of growth hormone from a marine fish, bonito (Katsuwonus pelamis).

    PubMed

    Noso, T; Yasuda, A; Kawazoe, I; Takehara, H; Takahasi, A; Sakai, K; Kawauchi, H

    1988-12-01

    Growth hormone (GH) was extracted under alkaline conditions (pH 10) from pituitary glands (6.3 g) of bonito (Katsuwonus pelamis), and subsequently purified by gel filtration, ion exchange chromatography, and reversed-phase HPLC. The GH was monitored by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and by immunoblotting with yellowtail GH antiserum at each step of purification. GH activity was determined by an in vivo bioassay. The yield of this hormone was 4.8 mg/g wet tissue. Intraperitoneal injection of bonito GH at doses of 0.1 and 1 micrograms/g body wt at 7-day intervals resulted in a significant increase in body weight and length of juvenile rainbow trout. Bonito GH antiserum exhibited both species and hormone specificity in radioimmunoassay. However, the bonito GH antiserum as well as yellowtail GH antiserum exhibited hormone specificity but not species specificity in immunoblotting. A molecular weight of 21,000 and an isoelectric point of 7.0 for bonito GH were estimated by SDS-PAGE and gel electrofocusing, respectively. The complete amino acid sequence of 185 residues was determined by sequencing fragment peptides prepared by chemical and enzymatic cleavages. Sequence comparison of bonito GH with other GHs revealed that there is a significant deletion in the middle of the molecule. PMID:3246482

  6. Aquatic Toxicity Comparison of Silver Nanoparticles and Silver Nanowires

    PubMed Central

    Kim, Tae Gyu; Kim, Jin Kwon; Kim, Ellen; Lee, Ji Hyun; Chung, Young Shin

    2015-01-01

    To better understand the potential ecotoxicological impact of silver nanoparticles (AgNPs) and silver nanowires (AgNWs) released into freshwater environments, the toxicities of these nanomaterials were assessed and compared using Organization for Economic Cooperation and Development (OECD) test guidelines, including a “Daphnia sp., acute immobilization test,” “Fish, acute toxicity test,” and “freshwater alga and cyanobacteria, growth inhibition test.” Based on the estimated median lethal/effective concentrations of AgNPs and AgNWs, the susceptibility to the nanomaterials was different among test organisms (daphnia > algae > fish), suggesting that the AgNPs are classified as “category acute 1” for Daphnia magna, “category acute 2” for Oryzias latipes, and “category acute 1” for Raphidocelis subcapitata, while the AgNWs are classified as “category acute 1” for Daphnia magna, “category acute 2” for Oryzias latipes, and “category acute 2” for Raphidocelis subcapitata, according to the GHS (Globally Harmonized System of Classification and Labelling of Chemicals). In conclusion, the present results suggest that more attention should be paid to prevent the accidental or intentional release of silver nanomaterials into freshwater aquatic environments. PMID:26125025

  7. Sequence and Bioinformatic Analysis of Family 1 Glycoside Hydrolase (GH) 1 Gene from the Oomycete Pythium myriotylum Drechsler.

    PubMed

    Nair, R Aswati; Geethu, C; Sangwan, Amit; Pillai, P Padmesh

    2015-06-01

    The oomycetous phytopathogen Pythium myriotylum secretes cellulases for growth/nutrition of the necrotroph. Cellulases are multi-enzyme system classified into different glycoside hydrolase (GH) families. The present study deals with identification and characterization of GH gene sequence from P. myriotylum by a PCR strategy using consensus primers. Cloning of the full-length gene sequence using genome walker strategy resulted in identification of 1230-bp P. myriotylum GH gene sequence, designated as PmGH1. Analysis revealed that PmGH1 encodes a predicted cytoplasmic 421 amino acid protein with an apparent molecular weight of 46.77 kDa and a theoretical pI of 8.11. Tertiary structure of the deduced amino acid sequence showed typical (α/β)8 barrel folding of family 1 GHs. Sequence characterization of PmGH1 identified the conserved active site residues, viz., Glu 181 and Glu 399, that function as acid-base catalyst and catalytically active nucleophile, respectively. Binding sites for N-acetyl-D-glucosamine (NAG) were revealed in the PmGH1 3D structure with Glu181 and Glu399 positioned on either side to form a catalytic pair. Phylogenetic analysis indicated a closer affiliation of PmGH1 with sequences of GH1 family. Results presented are first attempts providing novel insights into the evolutionary and functional perspectives of the identified P. myriotylum GH. PMID:25877398

  8. Effect of zink oxyde nanoparticles on the test function of water organisms of different trophic levels

    NASA Astrophysics Data System (ADS)

    Morgalev, Yu; Morgaleva, T.; Gosteva, I.; Morgalev, S.; Kulizhskiy, S.; Astafurova, T.

    2015-11-01

    The toxicity of zinc oxide nanoparticles (nZnO) with particle size Δ50 = 20 nm was evaluated according to the degree of toxicity of the aqueous disperse system (DS) with biological testing methods using a set of test organisms representing the major trophic levels.We observed the influence of the concentration degree of nZnO on toxic effects level on the fluorescence of the bacterial biosensor "Ekolyum-13", the chemotactic response of ciliates Paramecium caudatum, the rate of growth of unicellular algae Chlorella vulgaris Bayer, mortality of entomostracans Daphnia magna Straus and fish Danio rerio. The detected values of L(E)C50 are: for biosensor "Ekolyum-13" - 0.30 mg/L, for ciliates Paramecium caudatum - 0.14 mg/L, for Chlorella vulgaris Bayer - 0.17 mg/L and for Daphnia magna Straus - 0.52 mg/L. No toxicity of nZnO was detected in relation to fish Danio rerio, L(E)C50 > 100 mg/L. In assessing the maximum effect of nZnO according to GHS and EU Directive 93/67/ EEC, it is assigned to dangerous substances with a high degree of toxicity "Acute toxicity 1".

  9. Vegetarian diet and mental disorders: results from a representative community survey

    PubMed Central

    2012-01-01

    Background The present study investigated associations between vegetarian diet and mental disorders. Methods Participants were drawn from the representative sample of the German Health Interview and Examination Survey and its Mental Health Supplement (GHS-MHS). Completely vegetarian (N = 54) and predominantly vegetarian (N = 190) participants were compared with non-vegetarian participants (N = 3872) and with a non-vegetarian socio-demographically matched subsample (N = 242). Results Vegetarians displayed elevated prevalence rates for depressive disorders, anxiety disorders and somatoform disorders. Due to the matching procedure, the findings cannot be explained by socio-demographic characteristics of vegetarians (e.g. higher rates of females, predominant residency in urban areas, high proportion of singles). The analysis of the respective ages at adoption of a vegetarian diet and onset of a mental disorder showed that the adoption of the vegetarian diet tends to follow the onset of mental disorders. Conclusions In Western cultures vegetarian diet is associated with an elevated risk of mental disorders. However, there was no evidence for a causal role of vegetarian diet in the etiology of mental disorders. PMID:22676203

  10. Production of a biologically active novel goldfish growth hormone in Escherichia coli.

    PubMed

    Mahmoud, S S; Wang, S; Moloney, M M; Habibi, H R

    1998-08-01

    Goldfish pituitary contains two types of growth hormones. One with five cysteine residues (type-I) similar to other Cyprinid GHs, and the other with four Cys residues (type-II) similar to those of other fish and tertapod species. Recombinant goldfish type II GH (gfGH-II) was produced in Escherichia coli using the pRSETB expression vector. The gfGH-II was produced fused to a leader sequence, which sequestered into inclusion bodies after expression. The inclusion bodies were solubilized using sodium hydroxide and the fusion protein purified by chelating affinity chromatography. Subsequently, gfGH-II was cleaved and analyzed by Western blotting, using a specific antiserum. For comparison we also produced recombinant common carp GH (cGH) which has 95% similarity to gfGH-II, and tested their growth promoting activity in goldfish. Both forms of GH significantly increased the growth rate of goldfish (P < 0.05), although cGH was found to have a somewhat higher potency than gfGH-II. PMID:9854813

  11. Subsite-specific contributions of different aromatic residues in the active site architecture of glycoside hydrolase family 12

    PubMed Central

    Zhang, Xiaomei; Wang, Shuai; Wu, Xiuyun; Liu, Shijia; Li, Dandan; Xu, Hao; Gao, Peiji; Chen, Guanjun; Wang, Lushan

    2015-01-01

    The active site architecture of glycoside hydrolase (GH) is a contiguous subregion of the enzyme constituted by residues clustered in the three-dimensional space, recognizing the monomeric unit of ligand through hydrogen bonds and hydrophobic interactions. Mutations of the key residues in the active site architecture of the GH12 family exerted different impacts on catalytic efficiency. Binding affinities between the aromatic amino acids and carbohydrate rings were quantitatively determined by isothermal titration calorimetry (ITC) and the quantum mechanical (QM) method, showing that the binding capacity order of Tyr>Trp>His (and Phe) was determined by their side-chain properties. The results also revealed that the binding constant of a certain residue remained unchanged when altering its location, while the catalytic efficiency changed dramatically. Increased binding affinity at a relatively distant subsite, such as the mutant of W7Y at the −4 subsite, resulted in a marked increase in the intermediate product of cellotetraose and enhanced the reactivity of endoglucanase by 144%; while tighter binding near the catalytic center, i.e. W22Y at the −2 subsite, enabled the enzyme to bind and hydrolyze smaller oligosaccharides. Clarification of the specific roles of the aromatics at different subsites may pave the way for a more rational design of GHs. PMID:26670009

  12. Comparison between bioconcentration factor (BCF) data provided by industry to the European Chemicals Agency (ECHA) and data derived from QSAR models.

    PubMed

    Petoumenou, Maria I; Pizzo, Fabiola; Cester, Josep; Fernández, Alberto; Benfenati, Emilio

    2015-10-01

    The bioconcentration factor (BCF) is the ratio of the concentration of a chemical in an organism to the concentration in the surrounding environment at steady state. It is a valuable indicator of the bioaccumulation potential of a substance. BCF is an essential environmental property required for regulatory purposes within the Registration, Evaluation, Authorization and restriction of Chemicals (REACH) and Globally Harmonized System (GHS) regulations. In silico models for predicting BCF can facilitate the risk assessment for aquatic toxicology and reduce the cost and number of animals used. The aim of the present study was to examine the correlation of BCF data derived from the dossiers of registered chemicals submitted to the European Chemical Agency (ECHA) with the results of a battery of Quantitative Structure-Activity Relationship (QSAR). After data pruning, statistical analysis was performed using the predictions of the selected models. Results in terms of R(2) had low rating around 0.5 for the pruned dataset. The use of the model applicability domain index (ADI) led to an improvement of the performance for compounds falling within it. The variability of the experimental data and the use of different parameters to define the applicability domain can influence the performance of each model. All available information should be adapted to the requirements of the regulation to obtain a safe decision. PMID:26282223

  13. Molecular characterization of a family 5 glycoside hydrolase suggests an induced-fit enzymatic mechanism

    NASA Astrophysics Data System (ADS)

    Liberato, Marcelo V.; Silveira, Rodrigo L.; Prates, Érica T.; de Araujo, Evandro A.; Pellegrini, Vanessa O. A.; Camilo, Cesar M.; Kadowaki, Marco A.; Neto, Mario De O.; Popov, Alexander; Skaf, Munir S.; Polikarpov, Igor

    2016-04-01

    Glycoside hydrolases (GHs) play fundamental roles in the decomposition of lignocellulosic biomaterials. Here, we report the full-length structure of a cellulase from Bacillus licheniformis (BlCel5B), a member of the GH5 subfamily 4 that is entirely dependent on its two ancillary modules (Ig-like module and CBM46) for catalytic activity. Using X-ray crystallography, small-angle X-ray scattering and molecular dynamics simulations, we propose that the C-terminal CBM46 caps the distal N-terminal catalytic domain (CD) to establish a fully functional active site via a combination of large-scale multidomain conformational selection and induced-fit mechanisms. The Ig-like module is pivoting the packing and unpacking motions of CBM46 relative to CD in the assembly of the binding subsite. This is the first example of a multidomain GH relying on large amplitude motions of the CBM46 for assembly of the catalytically competent form of the enzyme.

  14. The use of human adipose-derived stem cells based cytotoxicity assay for acute toxicity test.

    PubMed

    Abud, Ana Paula Ressetti; Zych, Jaiesa; Reus, Thamile Luciane; Kuligovski, Crisciele; de Moraes, Elizabeth; Dallagiovanna, Bruno; de Aguiar, Alessandra Melo

    2015-12-01

    Human adipose-derived stem cells (ADSC) were evaluated as cell culture model for cytotoxicity assay and toxicity prediction by using the neutral red uptake assay (NRU). In this study, we compared ADSC and the murine cell line BALB/c 3T3 clone A31 to predict the toxicity of 12 reference substances as recommended by the Interagency Coordinating Committee on the Validation of Alternative Methods. We predicted the LD50 for RC-rat-only weight and RC-rat-only millimole regressions for both cell culture models. For RC rat-only weight regression, both cells had the same accordance (50%), while for RC rat-only millimole regression, the accordance was 50% for ADSC and 42% for 3T3s. Thus, ADSC have similar capability for GHS class prediction as the 3T3 cell line for the evaluated reference substances. Therefore, ADSCs showed the potential to be considered a novel model for use in evaluating cytotoxicity in drug development and industry as well as for regulatory purposes to reduce or replace the use of laboratory animals with acceptable sensitivity for toxicity prediction in humans. These cells can be used to complete the results from other models, mainly because of its human origin. Moreover, it is less expensive in comparison with other existing models. PMID:26382612

  15. Clinical application of ghrelin in the field of surgery.

    PubMed

    Takiguchi, Shuji; Murakami, Kohei; Yanagimoto, Yoshitomo; Takata, Akihiro; Miyazaki, Yasuhiro; Mori, Masaki; Doki, Yuichiro

    2015-07-01

    Ghrelin was discovered as an intrinsic ligand for the growth hormone (GH)-secretagogue receptor (GHS-R) in 1999. The endogenous production of ghrelin occurs mainly in the stomach. Ghrelin has multiple functions; it has orexigenic action, stimulates GH secretion, has anti-inflammatory activities, stimulates gastrointestinal activity, stabilizes heart function and has other metabolic roles. Moreover, ghrelin is the only gastrointestinal hormone known to stimulate appetite. In the past decade, clinical applications of ghrelin have been attempted for various pathologies, based on its anabolic function, including applications for patients with anorexia nervosa and cachexia due to chronic heart, renal or pulmonary diseases. In the field of surgery, we have conducted several clinical trials using exogenous ghrelin in patients undergoing total gastrectomy, esophagectomy and neoadjuvant chemotherapy, including cisplatin treatment, and consistently obtained unique and striking benefits in these patients. Ghrelin comprehensively improves the patients' general conditions and quality of life via its pleiotropic physiological functions. This characteristic is unique and different from the existing drugs; therefore, ghrelin may be an indispensable supplement to prevent surgical stress and postoperative sequelae. This review summarizes the recent advances toward the clinical application of ghrelin. PMID:25366350

  16. Carbohydrate-active enzymes from pigmented Bacilli: a genomic approach to assess carbohydrate utilization and degradation

    PubMed Central

    2011-01-01

    Background Spore-forming Bacilli are Gram-positive bacteria commonly found in a variety of natural habitats, including soil, water and the gastro-intestinal (GI)-tract of animals. Isolates of various Bacillus species produce pigments, mostly carotenoids, with a putative protective role against UV irradiation and oxygen-reactive forms. Results We report the annotation of carbohydrate active enzymes (CAZymes) of two pigmented Bacilli isolated from the human GI-tract and belonging to the Bacillus indicus and B. firmus species. A high number of glycoside hydrolases (GHs) and carbohydrate binding modules (CBMs) were found in both isolates. A detailed analysis of CAZyme families, was performed and supported by growth data. Carbohydrates able to support growth as the sole carbon source negatively effected carotenoid formation in rich medium, suggesting that a catabolite repression-like mechanism controls carotenoid biosynthesis in both Bacilli. Experimental results on biofilm formation confirmed genomic data on the potentials of B. indicus HU36 to produce a levan-based biofilm, while mucin-binding and -degradation experiments supported genomic data suggesting the ability of both Bacilli to degrade mammalian glycans. Conclusions CAZy analyses of the genomes of the two pigmented Bacilli, compared to other Bacillus species and validated by experimental data on carbohydrate utilization, biofilm formation and mucin degradation, suggests that the two pigmented Bacilli are adapted to the intestinal environment and are suited to grow in and colonize the human gut. PMID:21892951

  17. Studies on the thyroid in transgenic mice expressing the genes for human and bovine growth hormone.

    PubMed

    Mayerhofer, A; Easterly, S; Amador, A G; Gher, J; Bartke, A; Yun, J; Wagner, T E

    1990-10-15

    The thyroid glands of transgenic mice (TM) expressing the genes for human (h) and bovine (b) growth hormone (GH) were studied. The percentages of larger follicles in hGH TM of either sex were significantly greater than in the corresponding normal littermates, and follicles ranging up to 350 microns in diameter were present in male hGH TM. In contrast, thyroid follicles were only slightly enlarged in male bGH TM, and were unchanged in female bGH TM. The serum concentrations of T4 were significantly decreased in male bGH TM and not altered in the other groups. Serum concentrations of T3 were slightly, but significantly increased in female hGH TM and female bGH TM, but were unaffected in male TM of either type. Since the principal difference between these foreign GHs in rodents is the additional lactogenic activity of human GH, these results may indicate that the effects of prolactin can influence the development of the thyroid. PMID:2226720

  18. A Noncellulosomal Mannanase26E Contains a CBM59 in Clostridium cellulovorans

    PubMed Central

    Yamamoto, Kosuke; Tamaru, Yutaka

    2014-01-01

    A multicomponent enzyme-complex prevents efficient degradation of the plant cell wall for biorefinery. In this study, the method of identifying glycoside hydrolases (GHs) to degrade hemicelluloses was demonstrated. The competence of C. cellulovorans, which changes to be suitable for degradation of each carbon source, was used for the method. C. cellulovorans was cultivated into locust bean gum (LBG) that is composed of galactomannan. The proteins produced by C. cellulovorans were separated into either fractions binding to crystalline cellulose or not. Proteins obtained from each fraction were further separated by SDS-PAGE and were stained with Coomassie Brilliant Blue and were detected for mannanase activity. The proteins having the enzymatic activity for LBG were cut out and were identified by mass spectrometry. As a result, four protein bands were classified into glycosyl hydrolase family 26 (GH26) mannanases. One of the identified mannanases, Man26E, contains a carbohydrate-binding module (CBM) family 59, which binds to xylan, mannan, and Avicel. Although mannose and galactose are the same as a hexose, the expression patterns of the proteins from C. cellulovorans were quite different. More interestingly, zymogram for mannanase activity showed that Man26E was detected in only LBG medium. PMID:24795881

  19. Extracellular Glycoside Hydrolase Activities in the Human Oral Cavity.

    PubMed

    Inui, Taichi; Walker, Lauren C; Dodds, Michael W J; Hanley, A Bryan

    2015-08-15

    Carbohydrate availability shifts when bacteria attach to a surface and form biofilm. When salivary planktonic bacteria form an oral biofilm, a variety of polysaccharides and glycoproteins are the primary carbon sources; however, simple sugar availabilities are limited due to low diffusion from saliva to biofilm. We hypothesized that bacterial glycoside hydrolase (GH) activities would be higher in a biofilm than in saliva in order to maintain metabolism in a low-sugar, high-glycoprotein environment. Salivary bacteria from 13 healthy individuals were used to grow in vitro biofilm using two separate media, one with sucrose and the other limiting carbon sources to a complex carbohydrate. All six GHs measured were higher in vitro when grown in the medium with complex carbohydrate as the sole carbon source. We then collected saliva and overnight dental plaque samples from the same individuals and measured ex vivo activities for the same six enzymes to determine how oral microbial utilization of glycoconjugates shifts between the planktonic phase in saliva and the biofilm phase in overnight dental plaque. Overall higher GH activities were observed in plaque samples, in agreement with in vitro observation. A similar pattern was observed in GH activity profiles between in vitro and ex vivo data. 16S rRNA gene analysis showed that plaque samples had a higher abundance of microorganisms with larger number of GH gene sequences. These results suggest differences in sugar catabolism between the oral bacteria located in the biofilm and those in saliva. PMID:26048943

  20. Glutathione (GSH) production is increased in copper deficient isolated hepatocytes and inhibition of GSH synthesis decreases intracellular cholesterol

    SciTech Connect

    Pi Yu Chao; Allen, K.G.D )

    1991-03-15

    Thirty male weanling Sprague Dawley rats were assigned to three groups of 10 animals each and fed AIN based copper deficient ad libitum, copper control meal fed and copper deficient meal fed diets. 12h meals were provided. Beginning on day 54 animals were used to prepare isolated hepatocytes, following a 4h meal, by portal vein collagenase infusion. Washed isolated hepatocytes were incubated in Krebs Henseleit bicarbonate buffer pH 7.4 under 95/5 O{sub 2}/CO{sub 2} at 37{degree} with 2.5 mM Ca, 0.75% gelatin and 10 mM glucose, either with or without 1 mM buthionine sulfoximine (BSO) a specific inhibitor of GSH synthesis. Hepatocyte viability was assessed by trypan blue exclusion. Copper deficiency significantly increased GSH production by 30-50% at 1.5 and 3 h, with no changes in GSSG. GSH production was inhibited by BSO which also significantly inhibited intracellular cholesterol appearance at 3 h. The intracellular (GHS){sup 2}/GSSG at 3 hr showed a significant correlation with cholesterol appearance rate at 3 h. Copper deficiency increases hepatocyte GSH production. Inhibition of GSH production is correlated with decreased cholesterol appearance.

  1. Intraportal Infusion of Ghrelin Could Inhibit Glucose-Stimulated GLP-1 Secretion by Enteric Neural Net in Wistar Rat

    PubMed Central

    Zhang, Xiyao; Li, Wensong; Li, Ping; Chang, Manli; Huang, Xu; Li, Qiang; Cui, Can

    2014-01-01

    As a regulator of food intake and energy metabolism, the role of ghrelin in glucose metabolism is still not fully understood. In this study, we determined the in vivo effect of ghrelin on incretin effect. We demonstrated that ghrelin inhibited the glucose-stimulated release of glucagon-like peptide-1 (GLP-1) when infused into the portal vein of Wistar rat. Hepatic vagotomy diminished the inhibitory effect of ghrelin on glucose-stimulated GLP-1 secretion. In addition, phentolamine, a nonselective α receptor antagonist, could recover the decrease of GLP-1 release induced by ghrelin infusion. Pralmorelin (an artificial growth hormone release peptide) infusion into the portal vein could also inhibit the glucose-stimulated release of GLP-1. And growth hormone secretagogue receptor antagonist, [D-lys3]-GHRP-6, infusion showed comparable increases of glucose stimulated GLP-1 release compared to ghrelin infusion into the portal vein. The data showed that intraportal infusion of ghrelin exerted an inhibitory effect on GLP-1 secretion through growth hormone secretagogue receptor 1α (GHS1α receptor), which indicated that the downregulation of ghrelin secretion after food intake was necessary for incretin effect. Furthermore, our results suggested that the enteric neural net involved hepatic vagal nerve and sympathetic nerve mediated inhibition effect of ghrelin on incretin effect. PMID:25247193

  2. Missense mutations in the growth hormone receptor dimerization region in Laron syndrome

    SciTech Connect

    Berg, M.A.; Francke, U. |; Geffner, M.E.; Bersch, N.

    1994-09-01

    Laron syndrome (LS) is an autosomal recessively inherited condition characterized by insensitivity to endogenous and exogenous GH. Affected individuals have severe episodes and other characteristic features. GH receptor gene mutations are present in all affected individuals in whom molecular studies have been reported. The GH receptor is a plasma membrane-spanning protein in which the extracellular domain binds circulating GH and the intracellular domain interacts with the JAK-2 kinase and possibly other intracellular signaling molecules. GH receptor dimerization occurs on GH binding and is thought to be required for normal signal transduction. We have studied the GH receptor genes of four unrelated individuals affected with LS from the United States, Italy, Saudi Arabia, and India. We have identified four different missense mutations that alter consecutive amino acids 152 to 155 in or near the dimerization domain of the GH receptor. One of these mutations, D152H, has been reported previously in Asian LS patients and, in in vitro studies, the mutant receptor was unable to dimerize. This report increases to over 20 the number of different GH receptor gene mutations that have been reported in LS patients and defines the first apparent mutational {open_quotes}hotspot{close_quotes} region in this gene. This cluster of mutations in patients with classic LS phenotype provides additional in vivo evidence that receptor dimerization plays an important role in signaling GH`s growth promoting and metabolic effects. Further in vitro studies of the mutations in this region are in progress.

  3. Ghrelin protects MES23.5 cells against rotenone via inhibiting mitochondrial dysfunction and apoptosis.

    PubMed

    Yu, Jianhan; Xu, Huamin; Shen, Xiaoli; Jiang, Hong

    2016-04-01

    Ghrelin is an endogenous ligand for the growth hormone secretagogue (GHS) receptor and has several important physiological functions. Recently, particular attention has been paid to its neuroprotective effect. Rotenone is used to investigate the pathogenesis of Parkinson's disease (PD) for its ability to inhibit mitochondrial complex I. The current study was carried out to investigate the neuroprotective effects of ghrelin against rotenone in MES 23.5 dopaminergic cells and explored the possible mechanisms underlying this protection. Our results showed that rotenone induced significant decrease in cell viability which was counteracted by ghrelin treatment. In addition, rotenone challenge reduced mitochondrial membrane potential, inhibited the activity of mitochondrial complex I and depressed cytochrome C release from mitochondria. This mitochondrial dysfunction was reversed by ghrelin treatment. Furthermore, our results demonstrated that ghrelin protected MES23.5 cells against rotenone-induced apoptosis by inhibiting activation of caspase-3. Overall, our findings showed ghrelin provided protective effects on MES23.5 dopaminergic cells against rotenone via restoring mitochondrial dysfunction and inhibiting mitochondrial dependent apoptosis. PMID:26459609

  4. Ghrelin protects human umbilical vein endothelial cells against advanced glycation end products-induced apoptosis via NO/cGMP signaling

    PubMed Central

    Li, Pengjie; Liu, Ying; Xiang, Ying; Lin, Miao; Gao, Jinling

    2015-01-01

    Objectives: The aim of this study was to investigate the intracellular mechanism involved in the anti-apoptotic effect of ghrelin on human umbilical vein endothelial cells (HUVECs). Methods: HUVECs were pretreated with ghrelin before exposure to 200 μg/ml advanced glycation end products (AGEs)-BSA for 48 h. Cell viability and apoptosis were determined by MTT assay and Annexin V/PI staining. Intracellular cGMP levels evaluation and cGMP analogs were employed to explore possible mechanisms. Results: The inhibitory effect on AGEs induced HUVECs apoptosis could be exerted by ghrelin and co-incubation with growth hormone secretagogue receptor (GHSR)-1a antagonist [D-Lys3]-GHRP-6 abolished this inhibition. Decreased cGMP level in AGEs induced HUVECs apoptosis was restored by ghrelin pretreatment and abolished by [D-Lys3]-GHRP-6 co-incubation. cGMP analogs (8 Br-cGMP and DB-cGMP) pretreatment also exhibited inhibitory effect on AGEs induced HUVECs apoptosis. Conclusions: Our results demonstrated that ghrelin produces a protective effect on HUVECs through GHS-R1a and cGMP/NO signaling pathway mediates the effect of ghrelin. These observations suggest a novel intracellular mechanism in the process of AGEs induced HUVECs apoptosis. PMID:26629013

  5. Ghrelin Protects against Dexamethasone-Induced INS-1 Cell Apoptosis via ERK and p38MAPK Signaling

    PubMed Central

    2016-01-01

    Glucocorticoid excess induces apoptosis of islet cells, which may result in diabetes. In this study, we investigated the protective effect of ghrelin on dexamethasone-induced INS-1 cell apoptosis. Our data showed that ghrelin (0.1 μM) inhibited dexamethasone-induced (0.1 μM) apoptosis of INS-1 cells and facilitated cell proliferation. Moreover, ghrelin upregulated Bcl-2 expression, downregulated Bax expression, and decreased caspase-3 activity. The protective effect of ghrelin against dexamethasone-induced INS-1 cell apoptosis was mediated via growth hormone secretagogue receptor 1a. Further studies revealed that ghrelin increased ERK activation and decreased p38MAPK expression after dexamethasone treatment. Ghrelin-mediated protection of dexamethasone-induced apoptosis of INS-1 cells was attenuated using the ERK inhibitor U0126 (10 μM), and cell viability increased using the p38MAPK inhibitor SB203580 (10 μM). In conclusion, ghrelin could protect against dexamethasone-induced INS-1 cell apoptosis, at least partially via GHS-R1a and the signaling pathway of ERK and p38MAPK. PMID:27190513

  6. Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage.

    PubMed

    Page, Melissa M; Withers, Dominic J; Selman, Colin

    2013-06-01

    Insulin receptor substrate-1 null (Irs1 (-/-)) mice are long lived and importantly they also demonstrate increased resistance to several age-related pathologies compared to wild type (WT) controls. Currently, the molecular mechanisms that underlie lifespan extension in long-lived mice are unclear although protection against oxidative damage may be important. Here, we determined both the activities of several intracellular antioxidants and levels of oxidative damage in brain, skeletal muscle, and liver of Irs1 (-/-) and WT mice at 80, 450, and 700 days of age, predicting that long-lived Irs1 (-/-) mice would be protected against oxidative damage. We measured activities of both intracellular superoxide dismutases (SOD); cytosolic (CuZnSOD) and mitochondrial (MnSOD), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT), and reduced glutathione (GHS). Of these, only hepatic CAT was significantly altered (increased) in Irs1 (-/-) mice. In addition, the levels of protein oxidation (protein carbonyl content) and lipid peroxidation (4-hydroxynonenal) were unaltered in Irs1 (-/-) mice, although the hepatic GSH/GSSG ratio, indicating an oxidized environment, was significantly lower in long-lived Irs1 (-/-) mice. Overall, our results do not support the premise that lifespan extension in Irs1 (-/-) mice is associated with greater tissue antioxidant protection or reduced oxidative damage. PMID:22371226

  7. Two-dimensional distributions of activation enthalpy and entropy from kinetics by the maximum entropy method.

    PubMed Central

    Steinbach, P J

    1996-01-01

    The maximum entropy method (MEM) is used to numerically invert the kinetics of ligand rebinding at low temperatures to obtain the underlying two-dimensional distribution of activation enthalpies and entropies, g(H,S). A global analysis of the rebinding of carbon monoxide (CO) to myoglobin (Mb), monitored in the Soret band at temperatures from 60 to 150 K, is performed using a Newton-Raphson optimization algorithm. The MEM approach describes the data much better than traditional least-squares analyses, reducing chi 2 by an order of magnitude. The MEM resolves two barrier distributions suggestive of rebinding to different bound conformations of MbCO, the so-called A1 and A3 substates, whose activation barriers have been independently estimated from kinetics monitored in the infrared. The distribution corresponding to A3 possesses higher activation entropies, also consistent with infrared measurements. Within an A substate, correlations of S and H are recovered qualitatively from simulated data but can be difficult to obtain from experimental data. When the rebinding measured at 60 K is excluded from the inversion, two peaks are no longer clearly resolved. Thus, data of very high quality are required to unambiguously determine the kinetic resolvability of subpopulations and the shape of the barrier distribution for a single A substate. Images FIGURE 2 FIGURE 4 PMID:8785309

  8. [Obstructive airway disorders representing occupational diseases].

    PubMed

    Baur, X

    2011-11-01

    Obstructive airway diseases, i. e., bronchial asthma and COPD, have a prevalence of about 5 % each in our population. 5 to 25 % of the cases are caused by the impact of hazardous substances in workplace atmospheres. Pathophysiologically and according to legal definitions on occupational diseases, allergic disorders (occupational disease no 4301) have to be differentiated from those of chemically irritative genesis (occupational disease no 4302 and predominantly also no 1315) and from afflictions in coal miners induced by inorganic dust (occupational disease no 4111). At present, hard coal mine dust is still the prevailing noxious agent followed by flour/baking additives, fumes occurring during welding, casting and cutting procedures, and isocyanates. In the majority of cases, the prognosis is not good and depends on the duration of exposure to the causative impact. This emphasises the urgency of early diagnosis and targetted individual prevention. The new international labelling of working materials hazardous to health (GHS; EU: CLP) also refers to inhalative noxae. It replaces the hitherto valid R und S notes by hazard statements (H) and precautionary statements (P) as well as by new hazard pictograms. PMID:22083291

  9. Operationalizing the Learning Health Care System in an Integrated Delivery System

    PubMed Central

    Psek, Wayne A.; Stametz, Rebecca A.; Bailey-Davis, Lisa D.; Davis, Daniel; Darer, Jonathan; Faucett, William A.; Henninger, Debra L.; Sellers, Dorothy C.; Gerrity, Gloria

    2015-01-01

    Introduction: The Learning Health Care System (LHCS) model seeks to utilize sophisticated technologies and competencies to integrate clinical operations, research and patient participation in order to continuously generate knowledge, improve care, and deliver value. Transitioning from concept to practical application of an LHCS presents many challenges but can yield opportunities for continuous improvement. There is limited literature and practical experience available in operationalizing the LHCS in the context of an integrated health system. At Geisinger Health System (GHS) a multi-stakeholder group is undertaking to enhance organizational learning and develop a plan for operationalizing the LHCS system-wide. We present a framework for operationalizing continuous learning across an integrated delivery system and lessons learned through the ongoing planning process. Framework: The framework focuses attention on nine key LHCS operational components: Data and Analytics; People and Partnerships; Patient and Family Engagement; Ethics and Oversight; Evaluation and Methodology; Funding; Organization; Prioritization; and Deliverables. Definitions, key elements and examples for each are presented. The framework is purposefully broad for application across different organizational contexts. Conclusion: A realistic assessment of the culture, resources and capabilities of the organization related to learning is critical to defining the scope of operationalization. Engaging patients in clinical care and discovery, including quality improvement and comparative effectiveness research, requires a defensible ethical framework that undergirds a system of strong but flexible oversight. Leadership support is imperative for advancement of the LHCS model. Findings from our ongoing work within the proposed framework may inform other organizations considering a transition to an LHCS. PMID:25992388

  10. Prediction of skin sensitization potency of chemicals by human Cell Line Activation Test (h-CLAT) and an attempt at classifying skin sensitization potency.

    PubMed

    Nukada, Yuko; Ashikaga, Takao; Miyazawa, Masaaki; Hirota, Morihiko; Sakaguchi, Hitoshi; Sasa, Hitoshi; Nishiyama, Naohiro

    2012-10-01

    The human Cell Line Activation Test (h-CLAT), an in vitro skin sensitization test, is based on the augmentation of CD86 and CD54 expression in THP-1 cells following exposure to chemicals. The h-CLAT was found to be capable of determining the hazard of skin sensitization. In contrast, the local lymph node assay (LLNA), widely used as a stand-alone method in Europe and US, identifies the same hazard, but also classifies the potency by using the estimated concentration of SI=3 (EC3). In this study, several values calculated from the h-CLAT data were evaluated for its correlation to the LLNA EC3 determination. A statistically significant correlation was observed between h-CLAT concentration providing a cell viability of 75% (CV75), h-CLAT estimated concentration of RFI=150 for CD86 (EC150), and for CD54 (EC200) with LLNA's EC3. From EC150 and EC200, a minimum induction threshold (MIT) was determined as the smaller of either EC150 or EC200. MIT showed a correlation with EC3 (R=0.638). Also, MIT had an approximate 80% accuracy for sub-categories of the globally harmonized system (GHS) when a tentative threshold of 13 ?g/mL was used. From these data, the h-CLAT values may be one of the useful tools to predict the allergic potency of chemicals. PMID:22796097

  11. Nutritional state-dependent ghrelin activation of vasopressin neurons via retrograde trans-neuronal-glial stimulation of excitatory GABA circuits.

    TOXLINE Toxicology Bibliographic Information

    Haam J; Halmos KC; Di S; Tasker JG

    2014-04-30

    Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal-glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal-glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal-glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis.

  12. Nutritional state-dependent ghrelin activation of vasopressin neurons via retrograde trans-neuronal-glial stimulation of excitatory GABA circuits.

    PubMed

    Haam, Juhee; Halmos, Katalin C; Di, Shi; Tasker, Jeffrey G

    2014-04-30

    Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal-glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal-glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal-glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis. PMID:24790191

  13. Nutritional State-Dependent Ghrelin Activation of Vasopressin Neurons via Retrograde Trans-NeuronalGlial Stimulation of Excitatory GABA Circuits

    PubMed Central

    Haam, Juhee; Halmos, Katalin C.; Di, Shi

    2014-01-01

    Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronalglial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronalglial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronalglial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis. PMID:24790191

  14. Moraxella catarrhalis Expresses a Cardiolipin Synthase That Impacts Adherence to Human Epithelial Cells

    PubMed Central

    Buskirk, Sean W.

    2014-01-01

    The major phospholipid constituents of Moraxella catarrhalis membranes are phosphatidylglycerol, phosphatidylethanolamine, and cardiolipin (CL). However, very little is known regarding the synthesis and function of these phospholipids in M. catarrhalis. In this study, we discovered that M. catarrhalis expresses a cardiolipin synthase (CLS), termed MclS, that is responsible for the synthesis of CL within the bacterium. The nucleotide sequence of mclS is highly conserved among M. catarrhalis isolates and is predicted to encode a protein with significant amino acid similarity to the recently characterized YmdC/ClsC protein of Escherichia coli. Isogenic mclS mutant strains were generated in M. catarrhalis isolates O35E, O12E, and McGHS1 and contained no observable levels of CL. Site-directed mutagenesis of a highly conserved HKD motif of MclS also resulted in a CL-deficient strain. Moraxella catarrhalis, which depends on adherence to epithelial cells for colonization of the human host, displays significantly reduced levels of adherence to HEp-2 and A549 cell lines in the mclS mutant strains compared to wild-type bacteria. The reduction in adherence appears to be attributed to the absence of CL. These findings mark the first instance in which a CLS has been related to a virulence-associated trait. PMID:24142255

  15. Mechanistic insights into a Ca2+-dependent family of α-mannosidases in a human gut symbiont

    PubMed Central

    Zhu, Yanping; Suits, Michael D. L.; Thompson, Andrew J.; Chavan, Sambhaji; Dinev, Zoran; Dumon, Claire; Smith, Nicola; Moremen, Kelley W.; Xiang, Yong; Siriwardena, Aloysius; Williams, Spencer J.; Gilbert, Harry J.; Davies, Gideon J.

    2014-01-01

    Colonic bacteria, exemplified by Bacteroides thetaiotaomicron, play a key role in maintaining human health by harnessing large families of glycoside hydrolases (GHs) to exploit dietary polysaccharides and host glycans as nutrients. Such GH family expansion is exemplified by the 23 family GH92 glycosidases encoded by the B. thetaiotaomicron genome. Here we show that these are α-mannosidases that act via a single displacement mechanism to utilize host N-glycans. The three-dimensional structure of two GH92 mannosidases defines a family of two-domain proteins in which the catalytic center is located at the domain interface, providing acid (glutamate) and base (aspartate) assistance to hydrolysis in a Ca2+-dependent manner. The three-dimensional structures of the GH92s in complex with inhibitors provide insight into the specificity, mechanism and conformational itinerary of catalysis. Ca2+ plays a key catalytic role in helping distort the mannoside away from its ground-state 4C1 chair conformation toward the transition state. PMID:20081828

  16. Structure of Bacteroides thetaiotaomicron BT2081 at 2.05 Å resolution: the first structural representative of a new protein family that may play a role in carbohydrate metabolism.

    PubMed

    Yeh, Andrew P; Abdubek, Polat; Astakhova, Tamara; Axelrod, Herbert L; Bakolitsa, Constantina; Cai, Xiaohui; Carlton, Dennis; Chen, Connie; Chiu, Hsiu Ju; Chiu, Michelle; Clayton, Thomas; Das, Debanu; Deller, Marc C; Duan, Lian; Ellrott, Kyle; Farr, Carol L; Feuerhelm, Julie; Grant, Joanna C; Grzechnik, Anna; Han, Gye Won; Jaroszewski, Lukasz; Jin, Kevin K; Klock, Heath E; Knuth, Mark W; Kozbial, Piotr; Krishna, S Sri; Kumar, Abhinav; Lam, Winnie W; Marciano, David; McMullan, Daniel; Miller, Mitchell D; Morse, Andrew T; Nigoghossian, Edward; Nopakun, Amanda; Okach, Linda; Puckett, Christina; Reyes, Ron; Tien, Henry J; Trame, Christine B; van den Bedem, Henry; Weekes, Dana; Wooten, Tiffany; Xu, Qingping; Hodgson, Keith O; Wooley, John; Elsliger, Marc André; Deacon, Ashley M; Godzik, Adam; Lesley, Scott A; Wilson, Ian A

    2010-10-01

    BT2081 from Bacteroides thetaiotaomicron (GenBank accession code NP_810994.1) is a member of a novel protein family consisting of over 160 members, most of which are found in the different classes of Bacteroidetes. Genome-context analysis lends support to the involvement of this family in carbohydrate metabolism, which plays a key role in B. thetaiotaomicron as a predominant bacterial symbiont in the human distal gut microbiome. The crystal structure of BT2081 at 2.05 Å resolution represents the first structure from this new protein family. BT2081 consists of an N-terminal domain, which adopts a β-sandwich immunoglobulin-like fold, and a larger C-terminal domain with a β-sandwich jelly-roll fold. Structural analyses reveal that both domains are similar to those found in various carbohydrate-active enzymes. The C-terminal β-jelly-roll domain contains a potential carbohydrate-binding site that is highly conserved among BT2081 homologs and is situated in the same location as the carbohydrate-binding sites that are found in structurally similar glycoside hydrolases (GHs). However, in BT2081 this site is partially occluded by surrounding loops, which results in a deep solvent-accessible pocket rather than a shallower solvent-exposed cleft. PMID:20944224

  17. Zinc mediation of the binding of human growth hormone to the human prolactin receptor

    SciTech Connect

    Cunningham, B.C.; Bass, S.; Fuh, G.; Wells, J.A. )

    1990-12-21

    Human growth hormone (hGH) elicits a diverse set of biological activities including lactation that derives from binding to the prolactin (PRL) receptor. The binding affinity of hGH for the extracellular binding domain of the hPRL receptor (hPRLbp) was increased about 8,000-fold by addition of 50 micromolar ZnCl{sub 2}. Zinc was not required for binding of hGH to the hGH binding protein (hGHbp) or for binding of hPRL to the hPRLbp. Other divalent metal ions (Ca{sup 2+}, Mg{sup 2+}, Cu{sup 2+}, Mn{sup 2+}, and Co{sup 2+}) at physiological concentrations did not support such strong binding. Scatchard analysis indicated a stoichiometry of one Zn{sup 2+} per hGH{center dot}hPRLbp complex. Mutational analysis showed that a cluster of three residues (His{sup 18}, His{sup 21}, and Glu{sup 174}) in hGH and His{sup 188} from the hPRLbp (conserved in all PRL receptors but not GH receptors) are probable Zn{sup 2+} ligands. This polypeptide hormone{center dot}receptor zinc sandwich provides a molecular mechanism to explain why nonprimate GHs are not lactogenic and offers a molecular link between zinc deficiency and its association with altered functions of hGH.

  18. Multi-laboratory validation of SkinEthic HCE test method for testing serious eye damage/eye irritation using liquid chemicals.

    PubMed

    Alépée, N; Leblanc, V; Adriaens, E; Grandidier, M H; Lelièvre, D; Meloni, M; Nardelli, L; Roper, C S; Santirocco, E; Toner, F; Van Rompay, A; Vinall, J; Cotovio, J

    2016-03-01

    A prospective multicentric study of the reconstructed human corneal epithelial tissue-based in vitro test method (SkinEthic™ HCE) was conducted to evaluate its usefulness to identify chemicals as either not classified for serious eye damage/eye irritation (No Cat.) or as classified (Cat. 1/Cat. 2) within UN GHS. The aim of this study was to demonstrate the transferability and reproducibility of the SkinEthic™ HCE EITL protocol for liquids and define its predictive capacity. Briefly, 60 chemicals were three times tested (double blinded) in 3 laboratories and 45 additional chemicals were tested three times in one laboratory. Good within laboratory reproducibility was achieved of at least 88.3% (53/60) and 92.4% (97/105) for the extended data set. Furthermore, the overall concordance between the laboratories was 93.3% (56/60). The accuracy of the SkinEthic™ HCE EITL for the extended dataset, based on bootstrap resampling, was 84.4% (95% CI: 81.9% to 87.6%) with a sensitivity of 99.0% (95% CI: 96.4% to 100%) and specificity of 68.5% (95% CI: 64.0% to 74.0%), thereby meeting all acceptance criteria for predictive capacity. This efficient transferable and reproducible assay is a promising tool to be integrated within a battery of assays to perform an eye irritation risk assessment. PMID:26612353

  19. Role of SST, CORT and ghrelin and its receptors at the endocrine pancreas

    PubMed Central

    Beléen, Chanclón; Martínez-Fuentes, Antonio J.; Gracia-Navarro, Francisco

    2012-01-01

    Somatostatin (SST), cortistatin (CORT), and its receptors (sst1–5), and ghrelin and its receptors (GHS-R) are two highly interrelated neuropeptide systems with a broad range of overlapping biological actions at central, cardiovascular, and immune levels among others. Besides their potent regulatory role on GH release, its endocrine actions are highlighted by SST/CORT and ghrelin influence on insulin secretion, glucose homeostasis, and insulin resistance. Interestingly, most components of these systems are expressed at the endocrine pancreas and are actively involved in the modulation of pancreatic islet function and, consequently influence glucose homeostasis. In addition, some of them also participate in islet survival and regeneration. Furthermore, under severe metabolic condition as well as in endocrine pathologies, their expression profile is severely deregulated. These findings suggest that SST/CORT and ghrelin systems could play a relevant role in pancreatic function under metabolic and endocrine pathologies. Accordingly, these systems have been therapeutically targeted for the prevention or amelioration of certain metabolic conditions (obesity) as well as for tumor growth inhibition and/or hormonal regulation in endocrine pathologies (neuroendocrine tumors). This review focuses on the interrelationship between SST/CORT and ghrelin systems and their role in severe metabolic conditions and some endocrine disorders. PMID:23162532

  20. Kidney Stones in Primary Hyperoxaluria: New Lessons Learnt

    PubMed Central

    Jacob, Dorrit E.; Grohe, Bernd; Gener, Michaela; Beck, Bodo B.; Hoppe, Bernd

    2013-01-01

    To investigate potential differences in stone composition with regard to the type of Primary Hyperoxaluria (PH), and in relation to the patients medical therapy (treatment nave patients versus those on preventive medication) we examined twelve kidney stones from ten PH I and six stones from four PH III patients. Unfortunately, no PH II stones were available for analysis. The study on this set of stones indicates a more diverse composition of PH stones than previously reported and a potential dynamic response of morphology and composition of calculi to treatment with crystallization inhibitors (citrate, magnesium) in PH I. Stones formed by PH I patients under treatment are more compact and consist predominantly of calcium-oxalate monohydrate (COM, whewellite), while calcium-oxalate dihydrate (COD, weddellite) is only rarely present. In contrast, the single stone available from a treatment nave PH I patient as well as stones from PH III patients prior to and under treatment with alkali citrate contained a wide size range of aggregated COD crystals. No significant effects of the treatment were noted in PH III stones. In disagreement with findings from previous studies, stones from patients with primary hyperoxaluria did not exclusively consist of COM. Progressive replacement of COD by small COM crystals could be caused by prolonged stone growth and residence times in the urinary tract, eventually resulting in complete replacement of calcium-oxalate dihydrate by the monohydrate form. The noted difference to the nave PH I stone may reflect a reduced growth rate in response to treatment. This pilot study highlights the importance of detailed stone diagnostics and could be of therapeutic relevance in calcium-oxalates urolithiasis, provided that the effects of treatment can be reproduced in subsequent larger studies. PMID:23940605

  1. KIDNEY STONE INCIDENCE AND METABOLIC URINARY CHANGES AFTER MODERN BARIATRIC SURGERY: REVIEW OF CLINICAL STUDIES, EXPERIMENTAL MODELS, AND PREVENTION STRATEGIES

    PubMed Central

    Canales, Benjamin K.; Hatch, Marguerite

    2014-01-01

    Bariatric surgery has been associated with increased metabolic kidney stone risk and post-operative stone formation. A MEDLINE search, performed for articles published between January 2005 and November 2013, identified 24 pertinent studies containing 683 bariatric patients with 24-hour urine profiles, 6,777 bariatric patients with kidney stone incidence, and 7,089 non-stone forming controls. Of all procedures reviewed, only Roux-en-Y gastric bypass (RYGB) was linked to post-operative kidney stone development, increasing stone incidence two-fold in non-stone formers (8.5%) and four-fold in patients with previous stone history (16.7%). High quality evidence from 7 studies (n=277 patients) before and after RYGB identified the following post-RYGB urinary lithogenic risk factors: 30% reduction in urine volume (the main driver of urinary crystal saturation), 40% reduction in urinary citrate (a potent stone inhibitor), and 50% increase in urinary oxalate (a stone promotor). Based on this, a summary of strategies to reduce calcium oxalate stone risk following RYGB is provided. Furthermore, recent experimental RYGB studies are assessed for insights into the pathophysiology of oxalate handling, and the literature in gut anion (oxalate) transport is reviewed. Finally, as a potential probiotic therapy for hyperoxaluria, primary data from our laboratory is presented, demonstrating a 70% reduction in urinary oxalate levels in four experimental RYGB animals after colonization with Oxalobacter formigines, a non-pathogenic gut commensal that uses oxalate as an energy source. Overall, urine profiles and kidney stone risk following bariatric surgery appear modifiable by dietary adjustments, appropriate supplementation, and lifestyle changes. For hyperoxaluria resistant to dietary oxalate restriction and calcium binding, well-designed human investigations are needed to identify additional means of lowering urinary oxalate, such as Oxalobacter colonization or empiric pyridoxine therapy. Further investigations are also needed to determine tolerability and compliance of stone prevention strategies, such as citrate supplementation and hydration, in this population. PMID:24969092

  2. Noncitrus alkaline fruit: a dietary alternative for the treatment of hypocitraturic stone formers.

    TOXLINE Toxicology Bibliographic Information

    Baia Lda C; Baxmann AC; Moreira SR; Holmes RP; Heilberg IP

    2012-09-01

    BACKGROUND AND PURPOSE: Fruits and vegetables are natural suppliers of potassium, bicarbonate, or bicarbonate precursors such as citrate, malate and others-hence, possessing potential effects on citraturia. We aimed to compare the acute effects of a noncitrus (melon) fruit vs citric ones (orange and lime) on citraturia and other lithogenic parameters.PATIENTS AND METHODS: Two-hour urine samples were collected from 30 hypocitraturic stone-forming patients after an overnight fast and 2, 4, and 6 hours after the consumption of 385 mL (13 oz) of either freshly squeezed orange juice (n=10), freshly blended melon juice (n=10), or freshly squeezed lime juice (n=10). Urinary citrate, potassium, pH, and other lithogenic parameters were determined and net gastrointestinal alkali absorption (NGIA) was calculated. Potential renal acid load (PRAL) and pH from juices were determined.RESULTS: Significant and comparable increases of mean urinary citrate were observed in all groups, whereas mean urinary potassium, pH, and NGIA were significantly increased only after consumption of melon and orange juices. The pH of melon juice was higher and the PRAL value was more negative compared with orange juice, indicating a higher alkalinity.CONCLUSIONS: These findings suggested that melon, a noncitrus source of potassium, citrate, and malate, yielded an increase in urinary citrate excretion equivalent to that provided by orange, and hence represents another dietary alternative for the treatment of hypocitraturic stone-formers. Despite its low potassium content, lime also produced comparable increases in citraturia possibly because of its high citric acid content.

  3. Inhibitory effect of rutin and curcumin on experimentally-induced calcium oxalate urolithiasis in rats

    PubMed Central

    Ghodasara, Jaydip; Pawar, Anil; Deshmukh, Chinmay; Kuchekar, Bhanudas

    2010-01-01

    Background: Renal epithelial cell injury by reactive oxygen species is pre-requisite step in the pathogenesis of urolithiasis. Rutin and curcumin are polyphenolic compounds known to have antioxidant and anti-inflammatory activities, but their effect on urolithiasis is yet to be elucidated. In the present study, we have investigated the inhibitory effect of rutin and curcumin on calcium oxalate urolithiasis in Wistar albino rats. Methods: Calcium oxalate urolithiasis was induced experimentally by administration of 0.75% v/v ethylene glycol with 1% w/v ammonium chloride in drinking water for three days followed by only 0.75% v/v ethylene glycol for 25 days. Rutin (20 mg/kg body weight) and curcumin (60 mg/kg body weight) were given once daily for 28 days by oral route. After treatment period, calcium and oxalate levels in urine and kidney tissue homogenate were measured. Kidney was also used for histopathological examination. Results: Stone-induction with ethylene glycol and ammonium chloride resulted in elevated levels of calcium and oxalate in the urine and kidney sample, whereas supplementation of rutin and curcumin restored it near to normal. Histopathological study revealed minimum tissue damage and less number of calcium oxalate deposits in kidney of animal treated with rutin and curcumin as compared to calculi-induced animal. Conclusion: The data suggest that the rutin and curcumin inhibits calcium oxalate urolithiasis. This effect is mediated possibly through a lowering of urinary concentration of stone forming constituents, anti-inflammatory and antioxidant effects. PMID:21713144

  4. Protecting Space Travelers from Kidney Stones: Renal Stone Risk During Space Flight

    NASA Technical Reports Server (NTRS)

    Whitson, Peggy; Bloomberg, Jacob; Lee, Angie (Technical Monitor)

    2002-01-01

    Renal stones, popularly known as kidney or bladder stones, are small rock-like objects formed in the kidneys or urinary tract by deposits of calcium and other minerals. The problem arises when the stones block the drainage of the kidney, resulting in urinary obstruction and pain. Passing these stones can be one of the most painful experiences a person will endure so doctors often prescribe pain relievers to ease the experience. Drinking plenty of fluids, which help flush waste out of the body, and eating a well-balanced diet are the first steps to preventing stones. For individuals at risk, this may not be enough, and a doctor may recommend a special diet and medications. Unfortunately, approximately 60 percent of people who have had a renal stone will experience a recurrence. This is particularly true of men, who are four to five times more likely to develop stones than women. Renal stones do not discriminate based on age; even children are at risk. Astronauts are particularly at risk of developing renal stones because they lose bone and muscle mass; calcium, other minerals, and protein normally used for bone and muscle end up in the bloodstream and then in the kidneys. Without plenty of fluid to wash them away, crystals can form and then grow into stones. This factor compounds the risk for astronauts, since they also perceive that they are less thirsty in space and will drink less than normal during the mission. To minimize all of these factors, doctors must instead treat the stone-forming compounds with medication. This study will use potassium citrate to reduce the risk of stone formation. Renal stones are never convenient, but they are a particular concern for astronauts who have limited access to treatment during flight. Researchers are examining how earthbound preventions for renal stone formation work in flight, ensuring missions are not ended prematurely due to this medical condition. During STS-107, earthbound preventions and treatments become astronauts' gain.

  5. Physicochemical action of potassium-magnesium citrate in nephrolithiasis

    NASA Technical Reports Server (NTRS)

    Pak, C. Y.; Koenig, K.; Khan, R.; Haynes, S.; Padalino, P.

    1992-01-01

    Effect of potassium-magnesium citrate on urinary biochemistry and crystallization of stone-forming salts was compared with that of potassium citrate at same dose of potassium in five normal subjects and five patients with calcium nephrolithiasis. Compared to the placebo phase, urinary pH rose significantly from 6.06 +/- 0.27 to 6.48 +/- 0.36 (mean +/- SD, p less than 0.0167) during treatment with potassium citrate (50 mEq/day for 7 days) and to 6.68 +/- 0.31 during therapy with potassium-magnesium citrate (containing 49 mEq K, 24.5 mEq Mg, and 73.5 mEq citrate per day). Urinary pH was significantly higher during potassium-magnesium citrate than during potassium citrate therapy. Thus, the amount of undissociated uric acid declined from 118 +/- 61 mg/day during the placebo phase to 68 +/- 54 mg/day during potassium citrate treatment and, more prominently, to 41 +/- 46 mg/day during potassium-magnesium citrate therapy. Urinary magnesium rose significantly from 102 +/- 25 to 146 +/- 37 mg/day during potassium-magnesium citrate therapy but not during potassium citrate therapy. Urinary citrate rose more prominently during potassium-magnesium citrate therapy (to 1027 +/- 478 mg/day from 638 +/- 252 mg/day) than during potassium citrate treatment (to 932 +/- 297 mg/day). Consequently, urinary saturation (activity product) of calcium oxalate declined significantly (from 1.49 x 10(-8) to 1.03 x 10(-8) M2) during potassium-magnesium citrate therapy and marginally (to 1.14 x 10(-8) M2) during potassium citrate therapy.(ABSTRACT TRUNCATED AT 250 WORDS).

  6. Recent advances in managing and understanding nephrolithiasis/nephrocalcinosis

    PubMed Central

    Gambaro, Giovanni; Trinchieri, Alberto

    2016-01-01

    Urinary stone disease is a very common disease whose prevalence is still increasing. Stone formation is frequently associated with other diseases of affluence such as hypertension, osteoporosis, cardiovascular disease, metabolic syndrome, and insulin resistance. The increasing concentration of lithogenic solutes along the different segments of the nephron involves supersaturation conditions leading to the formation, growth, and aggregation of crystals. Crystalline aggregates can grow free in the tubular lumen or coated on the wall of the renal tubule. Plugs of crystalline material have been highlighted in the tubular lumen in some patients, but crystalline growth starting from plaques of calcium phosphate within the renal papillae has been demonstrated in others. Urinary supersaturation is the result of a complex interaction between predisposing genetic features and environmental factors. Dietary intake is certainly the most important environmental risk factor. In particular, an insufficient intake of dietary calcium (<600 mg/day) can increase the intestinal absorption of oxalate and the risk of calcium oxalate stone formation. Other possible risk factors that have been identified include excessive intake of salt and proteins. The potential role of dietary acid load seems to play an important role in causing a state of subclinical chronic acidosis; therefore, the intake of vegetables is encouraged in stone-forming patients. Consumption of sugar-sweetened soda and punch is associated with a higher risk of stone formation, whereas consumption of coffee, tea, beer, wine, and orange juice is associated with a lower risk. A high fluid intake is widely recognized as the cornerstone of prevention of all forms of stones. The effectiveness of protein and salt restriction has been evaluated in some studies that still do not allow definitive conclusions to be made. Calcium stone formation can be prevented by the use of different drugs with different mechanisms of action (thiazide diuretics, allopurinol, and potassium citrate), but there is no ideal drug that is both risk free and well tolerated. PMID:27134735

  7. Stone Composition as a Function of Age and Sex

    PubMed Central

    Rule, Andrew D.; Krambeck, Amy E.; Williams, James C.; Bergstralh, Eric J.; Mehta, Ramila A.; Moyer, Thomas P.

    2014-01-01

    Background and objectives Kidney stones are heterogeneous but often grouped together. The potential effects of patient demographics and calendar month (season) on stone composition are not widely appreciated. Design, setting, participants, & measurements The first stone submitted by patients for analysis to the Mayo Clinic Metals Laboratory during 2010 was studied (n=43,545). Stones were classified in the following order: any struvite, any cystine, any uric acid, any brushite, majority (?50%) calcium oxalate, or majority (?50%) hydroxyapatite. Results Calcium oxalate (67%) was the most common followed by hydroxyapatite (16%), uric acid (8%), struvite (3%), brushite (0.9%), and cystine (0.35%). Men accounted for more stone submissions (58%) than women. However, women submitted more stones than men between the ages of 1019 (63%) and 2029 (62%) years. Women submitted the majority of hydroxyapatite (65%) and struvite (65%) stones, whereas men submitted the majority of calcium oxalate (64%) and uric acid (72%) stones (P<0.001). Although calcium oxalate stones were the most common type of stone overall, hydroxyapatite stones were the second most common before age 55 years, whereas uric acid stones were the second most common after age 55 years. More calcium oxalate and uric acid stones were submitted in the summer months (July and August; P<0.001), whereas the season did not influence other stone types. Conclusions It is well known that calcium oxalate stones are the most common stone type. However, age and sex have a marked influence on the type of stone formed. The higher number of stones submitted by women compared with men between the ages of 10 and 29 years old and the change in composition among the elderly favoring uric acid have not been widely appreciated. These data also suggest increases in stone risk during the summer, although this is restricted to calcium oxalate and uric acid stones. PMID:25278549

  8. Antiurolithiatic and antioxidant activity of Mimusops elengi on ethylene glycol-induced urolithiasis in rats

    PubMed Central

    Ashok, Purnima; Koti, Basavaraj C.; Vishwanathswamy, A.H.M.

    2010-01-01

    Objective: To evaluate the potential of Mimusops elengi in the treatment of renal calculi. Materials and Methods: Petroleum ether, chloroform, and alcohol extracts of Mimusops elengi bark were evaluated for antiurolithiatic and antioxidant activity in male albino Wistar rats. Ethylene glycol (0.75%) in drinking water was fed to all the groups (Groups II–IX) except normal control (Group I) for 28 days to induce urolithiasis for curative (CR) and preventive (PR) regimen. Groups IV, V, and VI served as CR, and groups VII, VIII, and IX as PR were treated with different extracts of M. elengi bark. Groups I, II, and III served as normal control, positive control (hyperurolithiatic), and standard (cystone 750 mg/kg), respectively. Oxalate, calcium, and phosphate were monitored in the urine and kidney. Serum BUN, creatinine, and uric acid were also recorded. In vivo antioxidant parameters such as lipid peroxidation (MDA), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were also monitored. Results: All the extracts of M. elengi were safe orally and exhibited no gross behavioral changes in the rats. In hypercalculi animals, the oxalate, calcium, and phosphate excretion grossly increased. However, the increased deposition of stone forming constituents in the kidneys of calculogenic rats were significantly (P < 0.001) lowered by curative and preventive treatment with alcohol extract (AlE) of M. elengi. It was also observed that alcoholic extract of M. elengi produced significant (P < 0.001) decrease in MDA, and increased GSH, SOD, and CAT. These results confirm that AlE of M. elengi possess potent antiurolithiatic activity. Conclusion: The results obtained suggest potential usefulness of the AlE of M. elengi bark as an antiurolithiatic agent. PMID:21189910

  9. Recent advances in managing and understanding nephrolithiasis/nephrocalcinosis.

    PubMed

    Gambaro, Giovanni; Trinchieri, Alberto

    2016-01-01

    Urinary stone disease is a very common disease whose prevalence is still increasing. Stone formation is frequently associated with other diseases of affluence such as hypertension, osteoporosis, cardiovascular disease, metabolic syndrome, and insulin resistance. The increasing concentration of lithogenic solutes along the different segments of the nephron involves supersaturation conditions leading to the formation, growth, and aggregation of crystals. Crystalline aggregates can grow free in the tubular lumen or coated on the wall of the renal tubule. Plugs of crystalline material have been highlighted in the tubular lumen in some patients, but crystalline growth starting from plaques of calcium phosphate within the renal papillae has been demonstrated in others. Urinary supersaturation is the result of a complex interaction between predisposing genetic features and environmental factors. Dietary intake is certainly the most important environmental risk factor. In particular, an insufficient intake of dietary calcium (<600 mg/day) can increase the intestinal absorption of oxalate and the risk of calcium oxalate stone formation. Other possible risk factors that have been identified include excessive intake of salt and proteins. The potential role of dietary acid load seems to play an important role in causing a state of subclinical chronic acidosis; therefore, the intake of vegetables is encouraged in stone-forming patients. Consumption of sugar-sweetened soda and punch is associated with a higher risk of stone formation, whereas consumption of coffee, tea, beer, wine, and orange juice is associated with a lower risk. A high fluid intake is widely recognized as the cornerstone of prevention of all forms of stones. The effectiveness of protein and salt restriction has been evaluated in some studies that still do not allow definitive conclusions to be made. Calcium stone formation can be prevented by the use of different drugs with different mechanisms of action (thiazide diuretics, allopurinol, and potassium citrate), but there is no ideal drug that is both risk free and well tolerated. PMID:27134735

  10. Difference in 24-Hour Urine Composition between Diabetic and Non-Diabetic Adults without Nephrolithiasis

    PubMed Central

    Qin, Jing; Duan, Xiaolu; Liu, Yang; Zhao, Zhijian; Yuan, Jian; Wan, Shaw P.; Zeng, Guohua

    2016-01-01

    Background Diabetic patients are more likely to develop kidney stones than the general population. The underlying mechanisms for this disparity remain to be elucidated. Little is known about the relationship between urine composition and diabetes mellitus in non-stone-forming individuals. We sought to examine the differences in the 24-hour (24-h) urine composition between diabetic and non-diabetic adults who were not stone formers. Methods A convenience sample of 538 individuals without a history of nephrolithiasis, gout, hyperparathyroidism, or gastroenteric diseases participated in this study. The 24-h urine profiles of 115 diabetic adults were compared with those of 423 non-diabetic adults. Diabetes was defined by self-reported physician diagnosis or medication use. All participants were non-stone formers confirmed by urinary tract ultrasonography. Participants provided a fasting blood sample and a single 24-h urine collection for stone risk analysis. Student’s t-test was used to compare mean urinary values. Linear regression models were adjusted for age, gender, body mass index, hypertension, fasting serum glucose, serum total cholesterol, estimated creatinine clearance rate and urinary factors. Results Univariable analysis showed that the diabetic participants had significantly higher 24-h urine volumes and lower urine calcium and magnesium excretions than non-diabetic participants (all P < 0.05). After multivariate adjustment, no significant differences in 24-h urine composition were observed between diabetic and non-diabetic participants except for a slightly increased 24-h urine volume in diabetic participants (all P > 0.05). The main limitation of this study is that the convenience samples and self-reported data may have been sources of bias. Conclusion Our data showed that there were no differences in 24-h urine composition between diabetic and non-diabetic adults who are not stone formers. The reason for it might be the improved glycemic control in diabetic individuals in our study. Therefore, a tighter glycemic control might reduce stone formation in diabetic adults. PMID:26906900

  11. Deformation and exhumation of the Bhutan Himalaya derived from the inversion of thermochronologic and thermometric data

    NASA Astrophysics Data System (ADS)

    Coutand, I.; Grujic, D.; Whipp, D. M., Jr.; Bernet, M.; Fellin, M. G.; Landry, K.; McQuarrie, N.

    2012-04-01

    The kinematics of late Tertiary crustal deformation across the Himalaya has seen passionate debate over the past decade. Data acquisition and modelling studies have focused primarily on the western and central Himalaya, where findings about crustal deformation and exhumation, and the resulting thermal structure, have been extrapolated to elsewhere in the orogen. Although the major lithotectonic units and their bounding structures are remarkably continuous along strike, significant differences in other features limit the applicability of individual study conclusions to the greater orogen. In particular, the Eastern Himalaya of Bhutan are difficult to link to existing kinematic models, due to unique documented features including: (1) Preservation of Tethyan metasediments atop the Greater Himalayan Sequence (GHS) indicating a lower exhumation magnitude, (2) apatite fission-track (FT) ages markedly older than further west (3) a steep, convex topographic front spatially restricting modern orographic precipitation to foothill elevations of <2000 m, (4) preservation of low-relief landscape remnants at 2000-3000 m elevation and (5) uplift of a foreland plateau producing tectono-climatic perturbations along the range front since the Late Miocene. We quantify the kinematic history of the Bhutanese Himalaya using low-temperature thermochronology, thermometric data and thermokinematic numerical modelling. We complement published data with 75 apatite FT, 27 zircon FT, 60 apatite (U-Th-Sm)/He (AHe) and 40 zircon (U-Th-Sm)/He (ZHe) ages from bedrock samples along two North-South and one East-West transect across Bhutan. Thermochronometric analysis for up to five systems in selected GHS bedrock samples indicates dissimilar cooling patterns from temperatures of ~375 °C to the near surface (i.e., muscovite 39Ar/40Ar to AHe). Specifically, all the samples from the landscape remnants in central and eastern Bhutan show a marked decrease in cooling rate from 50-100 °C/Ma between 5-8 Ma to 7-20 °C after 5 Ma. In contrast, samples from outside these geomorphic features, in northern and western Bhutan, show near steady cooling at ~25 °C/Ma. This disparity and the age data sets are further considered in new kinematic models for North-South transects across eastern and western Bhutan. These models honour existing geophysical, metamorphic and structural data, including balanced cross-sections, and are evaluated by inversion of observed age/temperature data to clarify key tectonic and thermal parameters using the 3D thermokinematic model Pecube. Models consider the last 12 Ma, with the geometry of the Main Himalayan Thrust (MHT), the India-southern Tibet convergence rate, its partitioning into over- and underthrusting of the Indian plate, radiogenic heat production and model basal temperature treated as free parameters. Preliminary model results suggest the MHT geometry varies from West to East and that the age distribution is particularly sensitive to the convergence rate partitioning; with respect to Nepal, we find slightly higher overthrusting values (~30% of the total convergence). Ongoing work will define the permissible range of other free parameters.

  12. Orogen-scale along-strike continuity in quartz recrystallization microstructures adjacent to the Main Central Thrust: implications for deformation temperatures, strain rates and flow stresses

    NASA Astrophysics Data System (ADS)

    Law, Richard

    2015-04-01

    Traced for ~ 1500 km along the foreland edge of the Himalaya from NW India to Bhutan published reports indicate a remarkable along-strike continuity of quartz recrystallization microstructures in the footwall and hanging wall to the Main Central Thrust (MCT). Recrystallization in Lesser Himalayan Series (LHS) rocks in the footwall to the MCT is dominated by grain boundary bulging (BLG) microstructures, while recrystallization in Greater Himalayan Series (GHS) rocks in the hanging wall is dominated by grain boundary migration microstructures that traced structurally upwards transition in to the anatectic core of the GHS. In foreland-positioned high-strain rocks adjacent to the MCT recrystallization is dominated by subgrain rotation (SGR) with transitional BLG-SGR and SGR-GBM microstructures being recorded at structural distances of up to a few hundred meters below and above the MCT, respectively. Correlation with available information on temperatures of metamorphism indicated by mineral phase equilibria and RSCM data suggests that recrystallization in the structural zones dominated by BLG, SGR and GBM occurred at temperatures of ~ 350-450, 450-550 and 550- > 650 °C, respectively. It should be kept in mind, however, that these temperatures are likely to be 'close-to-peak' temperatures of metamorphism, whereas penetrative shearing and recrystallization may have continued during cooling. The dominance of SGR along the more foreland-positioned exposures of the MCT intuitively suggests that shearing occurred under a relatively restricted range of deformation temperatures and strain rates. Plotting the 'close-to-peak' 450-500 °C temperatures of metamorphism indicated for SGR-dominated rocks located at up to a few hundred meters below/above the MCT on the quartz recrystallization map developed by Stipp et al. (2002) indicates 'ball-park' strain rates of ~ 10-13 to 10-10 sec-1. However, only strain rates slower than 10-12 sec-1 on the MCT are likely to be compatible with know convergence rates between the Indian and Asian plates. If shearing continued during retrograde cooling while remaining in the SGR field, then the recrystallization map suggests that a significant drop in deformation temperature (> ~75-100 °C) would result in a decrease in strain rate. In general, however, the presence of a single recrystallization microstructure traced over a large (regional scale) distance does not necessarily mean that deformation temperature (or strain rate) remains constant but could, for example, indicate that spatial variations in deformation temperature are compensated for by changes in strain rate, with grain-scale deformation remaining within a particular recrystallization regime. Constant stress conditions plot along a straight line in the 1/T versus log strain rate space used in the quartz recrystallization mechanism map. This suggests that the observed along-strike consistency of SGR-dominated recrystallization microstructures may indicate near to constant stress boundary conditions (albeit with varying temperatures and strain rates) prevailing along what are now the more foreland-positioned exposures of the MCT. Extrapolation of the Hirth et al. (2001) flow law suggests a flow stress of ~ 30-50 MPa based on the deformation temperatures and strain rates inferred for foreland-positioned exposures of the MCT, in agreement with flow stresses estimated from recrystallized quartz grain size data.

  13. P-T data from central Bhutan imply distributed extensional shear at the Black Mountain "klippe"

    NASA Astrophysics Data System (ADS)

    Corrie, S. L.; Kohn, M. J.; Long, S. P.; McQuarrie, N.; Tobgay, T.

    2011-12-01

    The Southern Tibetan Detachment system (STDS) occurs along the entire length of the Himalayan orogen, and extensionally emplaces low-grade to unmetamorphosed Tethyan Himalayan (TH) rocks over highly metamorphosed Greater Himalayan sequence (GH) rocks. The base of TH remnants preserved in northern Bhutan all have top-to-the-north shear sense indicators (C'-type shear bands, asymmetric folds, and boudinaged leucogranite dikes) that are interpreted to reflect a discrete shear zone. In contrast, the GH-TH contact in the southernmost TH remnant (the Black Mountain region, central Bhutan) has been interpreted as depositional. A depositional contact limits the magnitude of displacement along the early STDS to 10's of km. If the GH-TH contact in the Black Mountain region is instead a discrete shear zone, as observed farther north, displacement on the STDS could be as high as 100's of km. To discriminate between these two interpretations, we determined peak metamorphic P-T conditions through the GH and TH sections, reasoning that a discrete shear zone would produce a distinct jump in metamorphic temperature, pressure or both. Thin section-scale kinematic indicators reveal pervasive top-to-the-north shear from 2-3 km structurally above the Main Central thrust (MCT) through the rest of the 11 km thick GH and TH sections. P-T conditions were determined from immediately above the MCT to 4 km above the GH-TH contact, with 19 samples from the GH, 6 from the overlying Chekha Fm (TH), and 9 from the overlying Maneting Fm (TH). We applied standard Fe-Mg exchange thermometers and Ca net-transfer barometers involving garnet. P-T conditions range from 700 °C and 11 kbar in migmatitic GHS to 600 °C and 8 kbar at the GH-Chekha contact, and 500 °C and 5 kbar at the top of the Maneting. We found no jumps in either temperature or pressure at any level, but a steeper than lithostatic pressure gradient, which we interpret to result from distributed extensional shear. The average thermal field gradient is surprisingly cool - only 20-25 °C/km. The baric field gradient is approximately 2 times steeper than lithostatic - 0.6 to 0.7 kbar/km, rather than 0.3 - so approximately 10 km of section has been excised. We argue that instead of a discrete structure, the Black Mountain "klippe," is part of a broad (≥8 km thick), low displacement shear zone and that the relationship between the GH and TH rocks in this region is depositional. These results support relatively minor displacement (a few tens of km) on the STDS remnants in northern Bhutan. Thus while channel- like behavior is present within the GHS and TH sections, its role in controlling Himalayan architecture is minor.

  14. Functional Metagenomics Unveils a Multifunctional Glycosyl Hydrolase from the Family 43 Catalysing the Breakdown of Plant Polymers in the Calf Rumen

    PubMed Central

    Vieites, José María; López-Cortés, Nieves; Marín-Navarro, Julia; Nechitaylo, Taras Y.; Guazzaroni, María-Eugenia; Polaina, Julio; Waliczek, Agnes; Chernikova, Tatyana N.; Reva, Oleg N.; Golyshina, Olga V.; Golyshin, Peter N.

    2012-01-01

    Microbial communities from cow rumen are known for their ability to degrade diverse plant polymers at high rates. In this work, we identified 15 hydrolases through an activity-centred metagenome analysis of a fibre-adherent microbial community from dairy cow rumen. Among them, 7 glycosyl hydrolases (GHs) and 1 feruloyl esterase were successfully cloned, expressed, purified and characterised. The most striking result was a protein of GH family 43 (GHF43), hereinafter designated as R_09-02, which had characteristics very distinct from the other proteins in this family with mono-functional β-xylosidase, α-xylanase, α-L-arabinase and α-L-arabinofuranosidase activities. R_09-02 is the first multifunctional enzyme to exhibit β-1,4 xylosidase, α-1,5 arabinofur(pyr)anosidase, β-1,4 lactase, α-1,6 raffinase, α-1,6 stachyase, β-galactosidase and α-1,4 glucosidase activities. The R_09-02 protein appears to originate from the chromosome of a member of Clostridia, a class of phylum Firmicutes, members of which are highly abundant in ruminal environment. The evolution of R_09-02 is suggested to be driven from the xylose- and arabinose-specific activities, typical for GHF43 members, toward a broader specificity to the glucose- and galactose-containing components of lignocellulose. The apparent capability of enzymes from the GHF43 family to utilise xylose-, arabinose-, glucose- and galactose-containing oligosaccharides has thus far been neglected by, or could not be predicted from, genome and metagenome sequencing data analyses. Taking into account the abundance of GHF43-encoding gene sequences in the rumen (up to 7% of all GH-genes) and the multifunctional phenotype herein described, our findings suggest that the ecological role of this GH family in the digestion of ligno-cellulosic matter should be significantly reconsidered. PMID:22761666

  15. Structural Basis for Inhibition of Xyloglucan-specific Endo-?-1,4-glucanase (XEG) by XEG-Protein Inhibitor*

    PubMed Central

    Yoshizawa, Takuya; Shimizu, Toshiyuki; Hirano, Hisashi; Sato, Mamoru; Hashimoto, Hiroshi

    2012-01-01

    Microorganisms such as plant pathogens secrete glycoside hydrolases (GHs) to digest the polysaccharide chains of plant cell walls. The degradation of cell walls by these enzymes is a crucial step for nutrition and invasion. To protect the cell wall from these enzymes, plants secrete glycoside hydrolase inhibitor proteins (GHIPs). Xyloglucan-specific endo-?-1,4-glucanase (XEG), a member of GH family 12 (GH12), could be a great threat to many plants because xyloglucan is a major component of the cell wall in most plants. Understanding the inhibition mechanism of XEG by GHIP is therefore of great importance in the field of plant defense, but to date the mechanism and specificity of GHIPs remain unclear. We have determined the crystal structure of XEG in complex with extracellular dermal glycoprotein (EDGP), a carrot GHIP that inhibits XEG. The structure reveals that the conserved arginines of EDGP intrude into the active site of XEG and interact with the catalytic glutamates of the enzyme. We have also determined the crystal structure of the XEG-xyloglucan complex. These structures show that EDGP closely mimics the XEG-xyloglucan interaction. Although EDGP shares structural similarity to a wheat GHIP (Triticum aestivum xylanase inhibitor-IA (TAXI-IA)) that inhibits GH11 family xylanases, the arrangement of GH and GHIP in the XEG-EDGP complex is distinct from that in the xylanase-TAXI-IA complex. Our findings imply that plants have evolved structures of GHIPs to inhibit different GH family members that attack their cell walls. PMID:22496365

  16. De Novo Transcriptome Sequencing and Analysis of the Cereal Cyst Nematode, Heterodera avenae

    PubMed Central

    Kumar, Mukesh; Gantasala, Nagavara Prasad; Roychowdhury, Tanmoy; Thakur, Prasoon Kumar; Banakar, Prakash; Shukla, Rohit N.; Jones, Michael G. K.; Rao, Uma

    2014-01-01

    The cereal cyst nematode (CCN, Heterodera avenae) is a major pest of wheat (Triticum spp) that reduces crop yields in many countries. Cyst nematodes are obligate sedentary endoparasites that reproduce by amphimixis. Here, we report the first transcriptome analysis of two stages of H. avenae. After sequencing extracted RNA from pre parasitic infective juvenile and adult stages of the life cycle, 131 million Illumina high quality paired end reads were obtained which generated 27,765 contigs with N50 of 1,028 base pairs, of which 10,452 were annotated. Comparative analyses were undertaken to evaluate H. avenae sequences with those of other plant, animal and free living nematodes to identify differences in expressed genes. There were 4,431 transcripts common to H. avenae and the free living nematode Caenorhabditis elegans, and 9,462 in common with more closely related potato cyst nematode, Globodera pallida. Annotation of H. avenae carbohydrate active enzymes (CAZy) revealed fewer glycoside hydrolases (GHs) but more glycosyl transferases (GTs) and carbohydrate esterases (CEs) when compared to M. incognita. 1,280 transcripts were found to have secretory signature, presence of signal peptide and absence of transmembrane. In a comparison of genes expressed in the pre-parasitic juvenile and feeding female stages, expression levels of 30 genes with high RPKM (reads per base per kilo million) value, were analysed by qRT-PCR which confirmed the observed differences in their levels of expression levels. In addition, we have also developed a user-friendly resource, Heterodera transcriptome database (HATdb) for public access of the data generated in this study. The new data provided on the transcriptome of H. avenae adds to the genetic resources available to study plant parasitic nematodes and provides an opportunity to seek new effectors that are specifically involved in the H. avenae-cereal host interaction. PMID:24802510

  17. Differential Associations of Depressive Symptom Dimensions with Cardio-Vascular Disease in the Community: Results from the Gutenberg Health Study

    PubMed Central

    Michal, Matthias; Wiltink, Jörg; Kirschner, Yvonne; Wild, Philipp S.; Münzel, Thomas; Ojeda, Francisco M.; Zeller, Tanja; Schnabel, Renate B.; Lackner, Karl; Blettner, Maria; Zwiener, Isabella; Beutel, Manfred E.

    2013-01-01

    A current model suggested that the somatic symptom dimension accounts for the adverse effect of depression in patients with coronary heart disease (CHD). In order to test this model we sought to determine in a large population-based sample how symptom dimensions of depression are associated with CHD, biomarkers and traditional risk factors. The associations of cognitive and somatic symptom dimensions of depression with CHD, risk factors, endothelial function, and biomarkers of inflammation and myocardial stress were analyzed cross-sectionally in a sample of n = 5000 Mid-Europeans aged 35–74 years from the Gutenberg Health Study (GHS). Only the somatic symptom dimension of depression was associated with CHD, biomarkers (inflammation, vascular function) and cardio-vascular risk factors. When multivariable adjustment was applied by demographic and cardiovascular risk factors, the weak associations of the somatic symptom dimension with the biomarkers disappeared. However, the associations of the somatic symptom dimension with CHD, myocardial infarction, obesity, dyslipidemia and family history of myocardial infarction remained. Both dimensions of depression were independently associated with a previous diagnosis of depression and distressed personality (type D). Thus, our results partly confirm current models: Somatic, but not cognitive-affective symptom dimensions are responsible for the association between depression and CHD, inflammation, vascular function and cardiovascular risk factors in the general population. However, our findings challenge the assumptions that somatic depression might be due to inflammation or vascular dysfunction as consequence of progressed atherosclerotic disease. They rather emphasize a close interplay with life-style factors and with a family history of MI. PMID:23967272

  18. Intergenerational class mobility in contemporary Britain: political concerns and empirical findings.

    PubMed

    Goldthorpe, John H; Jackson, Michelle

    2007-12-01

    In Britain in recent years social mobility has become a topic of central political concern, primarily as a result of the effort made by New Labour to make equality of opportunity rather than equality of condition a focus of policy. Questions of the level, pattern and trend of mobility thus bear directly on the relevance of New Labour's policy analysis, and in turn are likely be crucial to the evaluation of its performance in government. However, politically motivated discussion of social mobility often reveals an inadequate grasp of both empirical and analytical issues. We provide new evidence relevant to the assessment of social mobility - in particular, intergenerational class mobility - in contemporary Britain through cross-cohort analyses based on the NCDS and BCS datasets which we can relate to earlier cross-sectional analyses based on the GHS. We find that, contrary to what seems now widely supposed, there is no evidence that absolute mobility rates are falling; but, for men, the balance of upward and downward movement is becoming less favourable. This is overwhelmingly the result of class structural change. Relative mobility rates, for both men and women, remain essentially constant, although there are possible indications of a declining propensity for long-range mobility. We conclude that under present day structural conditions there can be no return to the generally rising rates of upward mobility that characterized the middle decades of the twentieth century - unless this is achieved through changing relative rates in the direction of greater equality or, that is, of greater fluidity. But this would then produce rising rates of downward mobility to exactly the same extent - an outcome apparently unappreciated by, and unlikely to be congenial to, politicians preoccupied with winning the electoral 'middle ground'. PMID:18076385

  19. Changes in the ghrelin hormone pathway maybe part of an unusual gastric system in monotremes.

    PubMed

    He, Chuan; Tsend-Ayush, Enkhjargal; Myers, Mark A; Forbes, Briony E; Grützner, Frank

    2013-09-15

    Ghrelin is a growth hormone (GH)-releasing and appetite-regulating peptide predominately released from the stomach. Ghrelin is evolutionarily highly conserved and known to have a wide range of functions including the regulation of metabolism by maintaining an insulin-glucose balance. The peptide is produced as a single proprotein, which is later proteolytically cleaved. Ghrelin exerts its biological function after O-n-octanoylation at residue serine 3, which is catalyzed by ghrelin O-acyl transferase (GOAT) and allows binding to the growth hormone secretagogue receptor (GHS-R 1a). Genes involved in the ghrelin pathway have been identified in a broad range of vertebrate species, however, little is known about this pathway in the basal mammalian lineage of monotremes (platypus and echidna). Monotremes are particularly interesting in this context, as they have undergone massive changes in stomach anatomy and physiology, accompanied by a striking loss of genes involved in gastric function. In this study, we investigated genes in the ghrelin pathway in monotremes. Using degenerate PCR, database searches and synteny analysis we found that genes encoding ghrelin and GOAT are missing in the platypus genome, whilst, as has been reported in other species, the GHSR is present and expressed in brain, pancreas, kidney, intestine, heart and stomach. This is the first report suggesting the loss of ghrelin in a mammal. The loss of this gene may be related to changes to the platypus digestive system and raises questions about the control of blood glucose levels and insulin response in monotreme mammals. In addition, the conservation of the ghrelin receptor gene in platypus indicates that another ligand(s) maybe acting via this receptor in monotremes. PMID:23770219

  20. A catch-up validation study of an in vitro skin irritation test method using reconstructed human epidermis LabCyte EPI-MODEL24.

    PubMed

    Kojima, Hajime; Katoh, Masakazu; Shinoda, Shinsuke; Hagiwara, Saori; Suzuki, Tamie; Izumi, Runa; Yamaguchi, Yoshihiro; Nakamura, Maki; Kasahawa, Toshihiko; Shibai, Aya

    2014-07-01

    Three validation studies were conducted by the Japanese Society for Alternatives to Animal Experiments in order to assess the performance of a skin irritation assay using reconstructed human epidermis (RhE) LabCyte EPI-MODEL24 (LabCyte EPI-MODEL24 SIT) developed by the Japan Tissue Engineering Co., Ltd. (J-TEC), and the results of these studies were submitted to the Organisation for Economic Co-operation and Development (OECD) for the creation of a Test Guideline (TG). In the summary review report from the OECD, the peer review panel indicated the need to resolve an issue regarding the misclassification of 1-bromohexane. To this end, a rinsing operation intended to remove exposed chemicals was reviewed and the standard operating procedure (SOP) revised by J-TEC. Thereafter, in order to confirm general versatility of the revised SOP, a new validation management team was organized by the Japanese Center for the Validation of Alternative Methods (JaCVAM) to undertake a catch-up validation study that would compare the revised assay with similar in vitro skin irritation assays, per OECD TG No. 439 (2010). The catch-up validation and supplementary studies for LabCyte EPI-MODEL24 SIT using the revised SOPs were conducted at three laboratories. These results showed that the revised SOP of LabCyte EPI-MODEL24 SIT conformed more accurately to the classifications for skin irritation under the United Nations Globally Harmonised System of Classification and Labelling of Chemicals (UN GHS), thereby highlighting the importance of an optimized rinsing operation for the removal of exposed chemicals in obtaining consistent results from in vitro skin irritation assays. PMID:24122860

  1. Hallmarks of Processivity in Glycoside Hydrolases from Crystallographic and Computational Studies of the Serratia marcescens Chitinases

    PubMed Central

    Payne, Christina M.; Baban, Jamil; Horn, Svein J.; Backe, Paul H.; Arvai, Andrew S.; Dalhus, Bjørn; Bjørås, Magnar; Eijsink, Vincent G. H.; Sørlie, Morten; Beckham, Gregg T.; Vaaje-Kolstad, Gustav

    2012-01-01

    Degradation of recalcitrant polysaccharides in nature is typically accomplished by mixtures of processive and nonprocessive glycoside hydrolases (GHs), which exhibit synergistic activity wherein nonprocessive enzymes provide new sites for productive attachment of processive enzymes. GH processivity is typically attributed to active site geometry, but previous work has demonstrated that processivity can be tuned by point mutations or removal of single loops. To gain additional insights into the differences between processive and nonprocessive enzymes that give rise to their synergistic activities, this study reports the crystal structure of the catalytic domain of the GH family 18 nonprocessive endochitinase, ChiC, from Serratia marcescens. This completes the structural characterization of the co-evolved chitinolytic enzymes from this bacterium and enables structural analysis of their complementary functions. The ChiC catalytic module reveals a shallow substrate-binding cleft that lacks aromatic residues vital for processivity, a calcium-binding site not previously seen in GH18 chitinases, and, importantly, a displaced catalytic acid (Glu-141), suggesting flexibility in the catalytic center. Molecular dynamics simulations of two processive chitinases (ChiA and ChiB), the ChiC catalytic module, and an endochitinase from Lactococcus lactis show that the nonprocessive enzymes have more flexible catalytic machineries and that their bound ligands are more solvated and flexible. These three features, which relate to the more dynamic on-off ligand binding processes associated with nonprocessive action, correlate to experimentally measured differences in processivity of the S. marcescens chitinases. These newly defined hallmarks thus appear to be key dynamic metrics in determining processivity in GH enzymes complementing structural insights. PMID:22952223

  2. Identification of cornifelin and early growth response-1 gene as novel biomarkers for in vitro eye irritation using a 3D reconstructed human cornea model MCTT HCE™.

    PubMed

    Choi, Seunghye; Lee, Miri; Lee, Su-Hyon; Jung, Haeng-Sun; Kim, Seol-Yeong; Chung, Tae-Young; Choe, Tae-boo; Chun, Young-Jin; Lim, Kyung-Min

    2015-09-01

    Evaluation of the eye irritation is essential in the development of new cosmetic products. Draize rabbit eye irritation test has been widely used in which chemicals are directly applied to rabbit eye, and the symptoms and signs of eyes are scored. However, due to the invasive procedure, it causes substantial pain and discomfort to animals. Recently, we reported in vitro eye irritation test method using a 3D human corneal epithelial model (MCTT HCE™) which is reconstructed from remaining human tissues after a corneal transplantation. This model exhibited an excellent predictive capacity for 25 reference chemicals (sensitivity 100%, specificity 77% and accuracy 88% vs. GHS). To improve the test performance, we explored new biomarkers for the eye irritation through transcriptomic approach. Three surfactants were selected as model eye irritants that include sodium lauryl sulfate, benzalkonium chloride and triton X-100. After test chemicals were treated, we investigated differentially expressed genes through a whole-gene microarray (Affymetrix GeneChip(®) Human Gene 2.0 ST Array, 48,000 probes). As a result, we identified that mRNAs of cornifelin (CNFN), a constituent of the insoluble cornified cell envelope of stratified squamous epithelia, and early growth response-1 (EGR1), a nuclear transcriptional regulator, were significantly up-regulated by all three irritants. Up-regulation of CNFN and EGR1 was further confirmed by Q-RT-PCR, and immunohistochemistry revealed increased level of CNFN in irritant-treated tissues, supporting the relevance of CNFN and EGR1 as new biomarkers for eye irritation. PMID:25377654

  3. Reduced toxicity polyester resins and microvascular pre-preg tapes for advanced composites manufacturing

    NASA Astrophysics Data System (ADS)

    Poillucci, Richard

    Advanced composites manufacturing broadly encapsulates topics ranging from matrix chemistries to automated machines that lay-up fiber-reinforced materials. Environmental regulations are stimulating research to reduce matrix resin formulation toxicity. At present, composites fabricated with polyester resins expose workers to the risk of contact with and inhalation of styrene monomer, which is a potential carcinogen, neurotoxin, and respiratory irritant. The first primary goal of this thesis is to reduce the toxicity associated with polyester resins by: (1) identification of potential monomers to replace styrene, (2) determination of monomer solubility within the polyester, and (3) investigation of approaches to rapidly screen a large resin composition parameter space. Monomers are identified based on their ability to react with polyester and their toxicity as determined by the Globally Harmonized System (GHS) and a green screen method. Solubilities were determined by the Hoftyzer -- Van Krevelen method, Hansen solubility parameter database, and experimental mixing of monomers. A combinatorial microfluidic mixing device is designed and tested to obtain distinct resin compositions from two input chemistries. The push for safer materials is complemented by a thrust for multifunctional composites. The second primary goal of this thesis is to design and implement the manufacture of sacrificial fiber materials suitable for use in automated fiber placement of microvascaular multifunctional composites. Two key advancements are required to achieve this goal: (1) development of a roll-to-roll method to place sacrificial fibers onto carbon fiber pre-preg tape; and (2) demonstration of feasible manufacture of microvascular carbon fiber plates with automated fiber placement. An automated method for placing sacrificial fibers onto carbon fiber tapes is designed and a prototype implemented. Carbon fiber tows with manual placement of sacrificial fibers is implemented within an automated fiber placement machine and the successful fabrication of a carbon fiber plate with an integrated microvascular channel is demonstrated.

  4. Not So Giants: Mice Lacking Both Somatostatin and Cortistatin Have High GH Levels but Show No Changes in Growth Rate or IGF-1 Levels.

    PubMed

    Pedraza-Arévalo, S; Córdoba-Chacón, J; Pozo-Salas, A I; L-López, F; de Lecea, L; Gahete, M D; Castaño, J P; Luque, R M

    2015-06-01

    Somatostatin (SST) and cortistatin (CORT) are two highly related neuropeptides involved in the regulation of various endocrine secretions. In particular, SST and CORT are two primary negative regulators of GH secretion. Consequently, single SST or CORT knockout mice exhibit elevated GH levels; however, this does not lead to increased IGF-1 levels or somatic growth. This apparent lack of correspondence has been suggested to result from compensatory mechanisms between both peptides. To test this hypothesis, in this study we explored, for the first time, the consequences of simultaneously deleting endogenous SST and CORT by generating a double SST/CORT knockout mouse model and exploring its endocrine and metabolic phenotype. Our results demonstrate that simultaneous deletion of SST and CORT induced a drastic elevation of endogenous GH levels, which, surprisingly, did not lead to changes in growth rate or IGF-1 levels, suggesting the existence of additional factors/systems that, in the absence of endogenous SST and CORT, could counteract GH actions. Notably, elevation in circulating GH levels were not accompanied by changes in pituitary GH expression or by alterations in the expression of its main regulators (GHRH and ghrelin) or their receptors (GHRH receptor, GHS receptor, or SST/CORT receptors) at the hypothalamic or pituitary level. However, although double-SST/CORT knockout male mice exhibited normal glucose and insulin levels, they had improved insulin sensitivity compared with the control mice. Therefore, these results suggest the existence of an intricate interplay among the known (SST/CORT), and likely unknown, inhibitory components of the GH/IGF-1 axis to regulate somatic growth and glucose/insulin homeostasis. PMID:25830706

  5. Degradation of lambda-carrageenan by Pseudoalteromonas carrageenovora lambda-carrageenase: a new family of glycoside hydrolases unrelated to kappa- and iota-carrageenases.

    PubMed

    Guibet, Marion; Colin, Sébastien; Barbeyron, Tristan; Genicot, Sabine; Kloareg, Bernard; Michel, Gurvan; Helbert, William

    2007-05-15

    Carrageenans are sulfated galactans found in the cell walls of red seaweeds. They are classified according to the number and the position of sulfate ester groups. lambda-Carrageenan is the most sulfated carrageenan and carries at least three sulfates per disaccharide unit. The sole known depolymerizing enzyme of lambda-carrageenan, the lambda-carrageenase from Pseudoalteromonas carrageenovora, has been purified, cloned and sequenced. Sequence analyses have revealed that the lambda-carrageenase, referred to as CglA, is the first member of a new family of GHs (glycoside hydrolases), which is unrelated to families GH16, that contains kappa-carrageenases, and GH82, that contains iota-carrageenases. This large enzyme (105 kDa) features a low-complexity region, suggesting the presence of a linker connecting at least two independent modules. The N-terminal region is predicted to fold as a beta-propeller. The main degradation products have been purified and characterized as neo-lambda-carratetraose [DP (degree of polymerization) 4] and neo-lambda-carrahexaose (DP6), indicating that CglA hydrolyses the beta-(1-->4) linkage of lambda-carrageenan. LC-MALLS (liquid chromatography-multi-angle laser light scattering) and (1)H-NMR monitoring of the enzymatic degradation of lambda-carrageenan indicate that CglA proceeds according to an endolytic mode of action and a mechanism of inversion of the anomeric configuration. Using 2-aminoacridone-labelled neo-lambda-carrabiose oligosaccharides, in the present study we demonstrate that the active site of CglA comprises at least 8 subsites (-4 to +4) and that a DP6 oligosaccharide binds in the subsites -4 to +2 and can be hydrolysed into DP4 and DP2. PMID:17269933

  6. Genetic Variation of the Ghrelin Signalling System in Individuals with Amphetamine Dependence

    PubMed Central

    Jayaram-Lindström, Nitya; Nilsson, Staffan; Toren, Kjell; Rosengren, Annika; Engel, Jörgen A.; Franck, Johan

    2013-01-01

    The development of amphetamine dependence largely depends on the effects of amphetamine in the brain reward systems. Ghrelin, an orexigenic peptide, activates the reward systems and is required for reward induced by alcohol, nicotine, cocaine and amphetamine in mice. Human genetic studies have shown that polymorphisms in the pre-proghrelin (GHRL) as well as GHS-R1A (GHSR) genes are associated with high alcohol consumption, increased weight and smoking in males. Since the heritability factor underlying drug dependence is shared between different drugs of abuse, we here examine the association between single nucleotide polymorphisms (SNPs) and haplotypes in the GHRL and GHSR, and amphetamine dependence. GHRL and GHSR SNPs were genotyped in Swedish amphetamine dependent individuals (n = 104) and controls from the general population (n = 310). A case-control analysis was performed and SNPs and haplotypes were additionally tested for association against Addiction Severity Interview (ASI) composite score of drug use. The minor G-allele of the GHSR SNP rs2948694, was more common among amphetamine dependent individuals when compared to controls (pc = 0.02). A significant association between the GHRL SNP rs4684677 and ASI composite score of drug use was also reported (pc = 0.03). The haplotype analysis did not add to the information given by the individual polymorphisms. Although genetic variability of the ghrelin signalling system is not a diagnostic marker for amphetamine dependence and problem severity of drug use, the present results strengthen the notion that ghrelin and its receptor may be involved in the development of addictive behaviours and may thus serve as suitable targets for new treatments of such disorders. PMID:23579732

  7. De novo transcriptome sequencing and analysis of the cereal cyst nematode, Heterodera avenae.

    PubMed

    Kumar, Mukesh; Gantasala, Nagavara Prasad; Roychowdhury, Tanmoy; Thakur, Prasoon Kumar; Banakar, Prakash; Shukla, Rohit N; Jones, Michael G K; Rao, Uma

    2014-01-01

    The cereal cyst nematode (CCN, Heterodera avenae) is a major pest of wheat (Triticum spp) that reduces crop yields in many countries. Cyst nematodes are obligate sedentary endoparasites that reproduce by amphimixis. Here, we report the first transcriptome analysis of two stages of H. avenae. After sequencing extracted RNA from pre parasitic infective juvenile and adult stages of the life cycle, 131 million Illumina high quality paired end reads were obtained which generated 27,765 contigs with N50 of 1,028 base pairs, of which 10,452 were annotated. Comparative analyses were undertaken to evaluate H. avenae sequences with those of other plant, animal and free living nematodes to identify differences in expressed genes. There were 4,431 transcripts common to H. avenae and the free living nematode Caenorhabditis elegans, and 9,462 in common with more closely related potato cyst nematode, Globodera pallida. Annotation of H. avenae carbohydrate active enzymes (CAZy) revealed fewer glycoside hydrolases (GHs) but more glycosyl transferases (GTs) and carbohydrate esterases (CEs) when compared to M. incognita. 1,280 transcripts were found to have secretory signature, presence of signal peptide and absence of transmembrane. In a comparison of genes expressed in the pre-parasitic juvenile and feeding female stages, expression levels of 30 genes with high RPKM (reads per base per kilo million) value, were analysed by qRT-PCR which confirmed the observed differences in their levels of expression levels. In addition, we have also developed a user-friendly resource, Heterodera transcriptome database (HATdb) for public access of the data generated in this study. The new data provided on the transcriptome of H. avenae adds to the genetic resources available to study plant parasitic nematodes and provides an opportunity to seek new effectors that are specifically involved in the H. avenae-cereal host interaction. PMID:24802510

  8. Analysis of AtGUS1 and AtGUS2 in Arabidopsis root apex by a highly sensitive TSA-MISH method.

    PubMed

    Bruno, Leonardo; Ronchini, Matteo; Gagliardi, Olimpia; Corinti, Tamara; Chiappetta, Adriana; Gerola, Paolo; Bitonti, Maria B

    2015-01-01

    A new highly sensitive whole-mount in situ hybridization method, based on tyramide signal amplification (TSA-MISH) was developed and a combined GFP detection and TSA-MISH procedure was applied for the first time in plants, to precisely define the spatial pattern of AtGUS1 and AtGUS2 expression in the root apex. β-glucuronidases (GUSs) belonging to the glycosyl hydrolases (GHs) 79 family, are widely distributed in plants, but their functional role has not yet been fully investigated. In the model system Arabidopsis Thaliana, three different AtGUS genes have been identified which encode proteins with putative different fates. Endogenous GUS expression has been detected in different organs and tissues, but the cyto-histological domains of gene expression remain unclear. The results here reported show co-expression of AtGUS1 and AtGUS2 in different functional zones of the root apex (the cap central zone, the root cap meristem, the staminal cell niche and the cortical cell layers of the proximal meristem), while AtGUS2 is exclusively expressed in the cap peripheral layer and in the epidermis in the elongation zone. Interestingly, both genes are not expressed in the stelar portion of the proximal meristem. A spatial (cortex vs. stele) and temporal (proximal meristem vs. transition zone) regulation of AtGUS1 and AtGUS2 expression is therefore active in the root apex. This expression pattern, although globally consistent with the involvement of GUS activity in both cell proliferation and elongation, clearly indicates that AtGUS1 and AtGUS2 could control distinct downstream process depending on the developmental context and the interaction with other players of root growth control. In the future, the newly developed approaches may well be very useful to dissect such interactions. PMID:26505256

  9. Secretion and assembly of functional mini-cellulosomes from synthetic chromosomal operons in Clostridium acetobutylicum ATCC 824

    PubMed Central

    2013-01-01

    Background Consolidated bioprocessing (CBP) is reliant on the simultaneous enzyme production, saccharification of biomass, and fermentation of released sugars into valuable products such as butanol. Clostridial species that produce butanol are, however, unable to grow on crystalline cellulose. In contrast, those saccharolytic species that produce predominantly ethanol, such as Clostridium thermocellum and Clostridium cellulolyticum, degrade crystalline cellulose with high efficiency due to their possession of a multienzyme complex termed the cellulosome. This has led to studies directed at endowing butanol-producing species with the genetic potential to produce a cellulosome, albeit by localising the necessary transgenes to unstable autonomous plasmids. Here we have explored the potential of our previously described Allele-Coupled Exchange (ACE) technology for creating strains of the butanol producing species Clostridium acetobutylicum in which the genes encoding the various cellulosome components are stably integrated into the genome. Results We used BioBrick2 (BB2) standardised parts to assemble a range of synthetic genes encoding C. thermocellum cellulosomal scaffoldin proteins (CipA variants) and glycoside hydrolases (GHs, Cel8A, Cel9B, Cel48S and Cel9K) as well as synthetic cellulosomal operons that direct the synthesis of Cel8A, Cel9B and a truncated form of CipA. All synthetic genes and operons were integrated into the C. acetobutylicum genome using the recently developed ACE technology. Heterologous protein expression levels and mini-cellulosome self-assembly were assayed by western blot and native PAGE analysis. Conclusions We demonstrate the successful expression, secretion and self-assembly of cellulosomal subunits by the recombinant C. acetobutylicum strains, providing a platform for the construction of novel cellulosomes. PMID:23962085

  10. Functional characterization of cellulases identified from the cow rumen fungus Neocallimastix patriciarum W5 by transcriptomic and secretomic analyses

    PubMed Central

    2011-01-01

    Background Neocallimastix patriciarum is one of the common anaerobic fungi in the digestive tracts of ruminants that can actively digest cellulosic materials, and its cellulases have great potential for hydrolyzing cellulosic feedstocks. Due to the difficulty in culture and lack of a genome database, it is not easy to gain a global understanding of the glycosyl hydrolases (GHs) produced by this anaerobic fungus. Results We have developed an efficient platform that uses a combination of transcriptomic and proteomic approaches to N. patriciarum to accelerate gene identification, enzyme classification and application in rice straw degradation. By conducting complementary studies of transcriptome (Roche 454 GS and Illumina GA IIx) and secretome (ESI-Trap LC-MS/MS), we identified 219 putative GH contigs and classified them into 25 GH families. The secretome analysis identified four major enzymes involved in rice straw degradation: β-glucosidase, endo-1,4-β-xylanase, xylanase B and Cel48A exoglucanase. From the sequences of assembled contigs, we cloned 19 putative cellulase genes, including the GH1, GH3, GH5, GH6, GH9, GH18, GH43 and GH48 gene families, which were highly expressed in N. patriciarum cultures grown on different feedstocks. Conclusions These GH genes were expressed in Pichia pastoris and/or Saccharomyces cerevisiae for functional characterization. At least five novel cellulases displayed cellulytic activity for glucose production. One β-glucosidase (W5-16143) and one exocellulase (W5-CAT26) showed strong activities and could potentially be developed into commercial enzymes. PMID:21849025

  11. Rapid syn-convergent Exhumation of Miocene-aged Lower Orogenic Crust in the Eastern Himalaya

    NASA Astrophysics Data System (ADS)

    Grujic, D.; Warren, C. J.; Wooden, J. L.

    2011-12-01

    Rare granulitized eclogites exposed in the eastern Himalaya provide an insight into conditions and processes deep within the orogen. SHRIMP U-Pb, Ti and REE data from zircons in mafic granulitized eclogites located in the upper structural levels of the GHS in Bhutan show that zircon crystallized under eclogite facies metamorphic conditions, between 15.3 ± 0.3 and 14.4 ± 0.3 Ma, within a couple of million years of the later granulite-facies overprint. In conjunction with pressure estimates of the eclogite and granulite facies stages of metamorphism, the age data suggest that initial exhumation occurred at plate tectonic rates (cm yr-1). These extremely rapid syn-convergence exhumation rates during the later stages of the India-Asia collision require a revision of theories about how crustal materials are transported and exhumed during continental collisions. In contrast to western Himalayan examples, the eastern Himalayan eclogites cannot be tectonically related to steep subduction of India beneath Asia. Instead, they more likely represent fragments from the base of the over-thickened Tibetan crust. Based on the zircon age and trace element data we hypothesize that the protolith of the mafic granulites are Middle Miocene mafic intrusions into the lower crust of southern Tibet, linked to the Miocene volcanism in the Lhasa block. We suggest that a transient tectonic event, possibly the indenting of a strong Indian crustal ramp into crust under southern Tibet weakened by partial melting, may have promoted exhumation of the eclogitized lower crust under Tibet. Mafic magmatism and volcanism themselves may be related to the convective thinning of the lithospheric mantle triggered by the reduction in India-Eurasia convergence rate during the Middle Miocene, which in turn could have helped the rapid extrusion of the lower crust over the earlier exhumed middle crust.

  12. Purification of a recombinant human growth hormone by an integrated IMAC procedure.

    PubMed

    Mooney, Jane T; Fredericks, Dale P; Zhang, Chunfang; Christensen, Thorkild; Jespergaard, Christina; Schidt, Christine Bruun; Hearn, Milton T W

    2014-02-01

    In this study, integration of three discrete process aspects of the IMAC purification of Escherichia coli expressed recombinant proteins has been investigated. To this end, novel N-terminally tagged human growth hormone variants (tagged-vhGHs) have been expressed in E. coli by tank fermentation and captured directly from the cell lysate by a new IMAC approach. The chelating ligands used were 1,4,7-triaza-cyclononane (tacn) and bis(1,4,7-triazacyclononyl)-propane (dtnp) with copper(II) as the immobilised metal ion. The N-terminal tags were specifically selected for their potential to bind to these immobilised complexes and also for their ease of removal from the tagged protein by the dipeptidyl peptidase, DAP-1. Low levels of detergents in the binding buffer did not dramatically affect the purification, but increased concentrations of NaCl in the loading buffer improved the binding performance. The same IMAC systems, operated in the 'negative' adsorption chromatographic mode, could be used to obtain the purified mature human growth hormone variant, as assessed by MALDI-TOF and N-terminal sequencing studies, following removal of the affinity tag by the dipeptidyl peptidase 1. Western immunoblot analysis of the eluted fractions of both the tagged and de-tagged vhGH demonstrated significant clearance of E. coli host cell proteins (HCPs). Further, these IMAC resins can be used multiple times without the need for metal ion re-charging between runs. This study thus documents an integrated approach for the purification of specifically tagged recombinant proteins expressed in genetically modified E. coli. PMID:24275639

  13. Toward production from gas hydrates: Current status, assessment of resources, and simulation-based evaluation of technology and potential

    USGS Publications Warehouse

    Moridis, G.J.; Collett, T.S.; Boswell, R.; Kurihara, M.; Reagan, M.T.; Koh, C.; Sloan, E.D.

    2009-01-01

    Gas hydrates (GHs) are a vast energy resource with global distribution in the permafrost and in the oceans. Even if conservative estimates are considered and only a small fraction is recoverable, the sheer size of the resource is so large that it demands evaluation as a potential energy source. In this review paper, we discuss the distribution of natural GH accumulations, the status of the primary international research and development (R&D) programs, and the remaining science and technological challenges facing the commercialization of production. After a brief examination of GH accumulations that are well characterized and appear to be models for future development and gas production, we analyze the role of numerical simulation in the assessment of the hydrate-production potential, identify the data needs for reliable predictions, evaluate the status of knowledge with regard to these needs, discuss knowledge gaps and their impact, and reach the conclusion that the numerical-simulation capabilities are quite advanced and that the related gaps either are not significant or are being addressed. We review the current body of literature relevant to potential productivity from different types of GH deposits and determine that there are consistent indications of a large production potential at high rates across long periods from a wide variety of hydrate deposits. Finally, we identify (a) features, conditions, geology and techniques that are desirable in potential production targets; (b) methods to maximize production; and (c) some of the conditions and characteristics that render certain GH deposits undesirable for production. Copyright ?? 2009 Society of Petroleum Engineers.

  14. International harmonization of models for selecting less toxic chemical alternatives: Effect of regulatory disparities in the United States and Europe.

    PubMed

    Lam, Carl W; Aguirre, Muskilda P; Schischke, Karsten; Nissen, Nils F; Ogunseitan, Oladele A; Schoenung, Julie M

    2012-10-01

    The desire to reduce human exposure to toxic chemicals associated with consumer products that are marketed globally demands the creation of comparative toxicity assessment tools that are based on uniform thresholds of acceptable risks and guidelines for materials use across international boundaries. The Toxic Potential Indicator (TPI) is a quantitative model based on European Union (EU) regulatory standards for toxicity and environmental quality. Here, we describe a version of TPI that we developed with US regulatory thresholds for environmental and human health impacts of toxic materials. The customized US-based TPI (USTPI) model integrates occupational permissible exposure limits (PELs), carcinogen categories based on the scheme of the International Agency for Research on Cancer (IARC), and median effect concentration for acute aquatic toxicity (EC50s). As a case study, we compare calculated scores for EU-based TPI (EUTPI) and USTPI for a large group of chemicals including 578 substances listed in the US Toxics Release Inventory (TRI). Statistical analyses show that the median difference between USTPI and EUTPI scores do not approximate to zero, implying a general discrepancy in TPI score results. Comparison of chemical ranking with Spearman's correlation coefficient suggests a positive but imperfect rank correlation. Although some discrepancies between EUTPI and USTPI may be explained by missing toxicity information in some regulatory categories, disparities between the 2 models are associated mostly with different input parameters, i.e., different regulatory thresholds and guidelines. These results demonstrate that regional differences in regulatory thresholds for material toxicity may compromise the ideals of international agreements, such as the Globally Harmonized System (GHS) of Classification and Labeling of Chemicals, and emphasis needs to be placed on eliminating inconsistencies in hazard assessment frameworks for substances. PMID:22492719

  15. Functional Analyses of Multiple Lichenin-Degrading Enzymes from the Rumen Bacterium Ruminococcus albus 8▿†

    PubMed Central

    Iakiviak, Michael; Mackie, Roderick I.; Cann, Isaac K. O.

    2011-01-01

    Ruminococcus albus 8 is a fibrolytic ruminal bacterium capable of utilization of various plant cell wall polysaccharides. A bioinformatic analysis of a partial genome sequence of R. albus revealed several putative enzymes likely to hydrolyze glucans, including lichenin, a mixed-linkage polysaccharide of glucose linked together in β-1,3 and β-1,4 glycosidic bonds. In the present study, we demonstrate the capacity of four glycoside hydrolases (GHs), derived from R. albus, to hydrolyze lichenin. Two of the genes encoded GH family 5 enzymes (Ra0453 and Ra2830), one gene encoded a GH family 16 enzyme (Ra0505), and the last gene encoded a GH family 3 enzyme (Ra1595). Each gene was expressed in Escherichia coli, and the recombinant protein was purified to near homogeneity. Upon screening on a wide range of substrates, Ra0453, Ra2830, and Ra0505 displayed different hydrolytic properties, as they released unique product profiles. The Ra1595 protein, predicted to function as a β-glucosidase, preferred cleavage of a nonreducing end glucose when linked by a β-1,3 glycosidic bond to the next glucose residue. The major product of Ra0505 hydrolysis of lichenin was predicted to be a glucotriose that was degraded only by Ra0453 to glucose and cellobiose. Most importantly, the four enzymes functioned synergistically to hydrolyze lichenin to glucose, cellobiose, and cellotriose. This lichenin-degrading enzyme mix should be of utility as an additive to feeds administered to monogastric animals, especially those high in fiber. PMID:21890664

  16. Metatranscriptomic Analyses of Plant Cell Wall Polysaccharide Degradation by Microorganisms in the Cow Rumen

    PubMed Central

    Dai, Xin; Tian, Yan; Li, Jinting; Su, Xiaoyun; Wang, Xuewei; Zhao, Shengguo; Liu, Li; Luo, Yingfeng; Liu, Di; Zheng, Huajun; Wang, Jiaqi; Dong, Zhiyang

    2014-01-01

    The bovine rumen represents a highly specialized bioreactor where plant cell wall polysaccharides (PCWPs) are efficiently deconstructed via numerous enzymes produced by resident microorganisms. Although a large number of fibrolytic genes from rumen microorganisms have been identified, it remains unclear how they are expressed in a coordinated manner to efficiently degrade PCWPs. In this study, we performed a metatranscriptomic analysis of the rumen microbiomes of adult Holstein cows fed a fiber diet and obtained a total of 1,107,083 high-quality non-rRNA reads with an average length of 483 nucleotides. Transcripts encoding glycoside hydrolases (GHs) and carbohydrate binding modules (CBMs) accounted for ∼1% and ∼0.1% of the total non-rRNAs, respectively. The majority (∼98%) of the putative cellulases belonged to four GH families (i.e., GH5, GH9, GH45, and GH48) and were primarily synthesized by Ruminococcus and Fibrobacter. Notably, transcripts for GH48 cellobiohydrolases were relatively abundant compared to the abundance of transcripts for other cellulases. Two-thirds of the putative hemicellulases were of the GH10, GH11, and GH26 types and were produced by members of the genera Ruminococcus, Prevotella, and Fibrobacter. Most (∼82%) predicted oligosaccharide-degrading enzymes were GH1, GH2, GH3, and GH43 proteins and were from a diverse group of microorganisms. Transcripts for CBM10 and dockerin, key components of the cellulosome, were also relatively abundant. Our results provide metatranscriptomic evidence in support of the notion that members of the genera Ruminococcus, Fibrobacter, and Prevotella are predominant PCWP degraders and point to the significant contribution of GH48 cellobiohydrolases and cellulosome-like structures to efficient PCWP degradation in the cow rumen. PMID:25501482

  17. Genomewide analysis of polysaccharides degrading enzymes in 11 white- and brown-rot Polyporales provides insight into mechanisms of wood decay.

    PubMed

    Hori, Chiaki; Gaskell, Jill; Igarashi, Kiyohiko; Samejima, Masahiro; Hibbett, David; Henrissat, Bernard; Cullen, Dan

    2013-01-01

    To degrade the polysaccharides, wood-decay fungi secrete a variety of glycoside hydrolases (GHs) and carbohydrate esterases (CEs) classified into various sequence-based families of carbohydrate-active enzymes (CAZys) and their appended carbohydrate-binding modules (CBM). Oxidative enzymes, such as cellobiose dehydrogenase (CDH) and lytic polysaccharide monooxygenase (LPMO, formerly GH61), also have been implicated in cellulose degradation. To examine polysaccharide-degrading potential between white- and brown-rot fungi, we performed genomewide analysis of CAZys and these oxidative enzymes in 11 Polyporales, including recently sequenced monokaryotic strains of Bjerkandera adusta, Ganoderma sp. and Phlebia brevispora. Furthermore, we conducted comparative secretome analysis of seven Polyporales grown on wood culture. As a result, it was found that genes encoding cellulases belonging to families GH6, GH7, GH9 and carbohydrate-binding module family CBM1 are lacking in genomes of brown-rot polyporales. In addition, the presence of CDH and the expansion of LPMO were observed only in white-rot genomes. Indeed, GH6, GH7, CDH and LPMO peptides were identified only in white-rot polypores. Genes encoding aldose 1-epimerase (ALE), previously detected with CDH and cellulases in the culture filtrates, also were identified in white-rot genomes, suggesting a physiological connection between ALE, CDH, cellulase and possibly LPMO. For hemicellulose degradation, genes and peptides corresponding to GH74 xyloglucanase, GH10 endo-xylanase, GH79 β-glucuronidase, CE1 acetyl xylan esterase and CE15 glucuronoyl methylesterase were significantly increased in white-rot genomes compared to brown-rot genomes. Overall, relative to brown-rot Polyporales, white-rot Polyporales maintain greater enzymatic diversity supporting lignocellulose attack. PMID:23935027

  18. Potential ghrelin-mediated benefits and risks of hydrogen water.

    PubMed

    McCarty, Mark F

    2015-04-01

    Molecular hydrogen (H2) can scavenge hydroxyl radical and diminish the toxicity of peroxynitrite; hence, it has interesting potential for antioxidant protection. Recently, a number of studies have explored the utility of inhaled hydrogen gas, or of hydrogen-saturated water, administered parenterally or orally, in rodent models of pathology and in clinical trials, oftentimes with very positive outcomes. The efficacy of orally ingested hydrogen-rich water (HW) has been particularly surprising, given that only transient and rather small increments in plasma hydrogen can be achieved by this method. A recent study in mice has discovered that orally administered HW provokes increased gastric production of the orexic hormone ghrelin, and that this ghrelin mediates the favorable impact of HW on a mouse model of Parkinson's disease. The possibility that most of the benefits observed with HW in experimental studies are mediated by ghrelin merits consideration. Ghrelin is well known to function as an appetite stimulant and secretagogue for growth hormone, but it influences physiological function throughout the body via interaction with the widely express GHS-R1a receptor. Rodent and, to a more limited extent, clinical studies establish that ghrelin has versatile neuroprotective and cognitive enhancing activity, favorably impacts vascular health, exerts anti-inflammatory activity useful in autoimmune disorders, and is markedly hepatoprotective. The stimulatory impact of ghrelin on GH-IGF-I activity, while potentially beneficial in sarcopenia or cachectic disorders, does raise concerns regarding the long-term impact of ghrelin up-regulation on cancer risk. The impact of ingesting HW water on ghrelin production in humans needs to be evaluated; if HW does up-regulate ghrelin in humans, it may have versatile potential for prevention and control of a number of health disorders. PMID:25649854

  19. Mammalian genome projects reveal new growth hormone (GH) sequences. Characterization of the GH-encoding genes of armadillo (Dasypus novemcinctus), hedgehog (Erinaceus europaeus), bat (Myotis lucifugus), hyrax (Procavia capensis), shrew (Sorex araneus), ground squirrel (Spermophilus tridecemlineatus), elephant (Loxodonta africana), cat (Felis catus) and opossum (Monodelphis domestica).

    PubMed

    Wallis, Michael

    2008-01-15

    Mammalian growth hormone (GH) sequences have been shown previously to display episodic evolution: the sequence is generally strongly conserved but on at least two occasions during mammalian evolution (on lineages leading to higher primates and ruminants) bursts of rapid evolution occurred. However, the number of mammalian orders studied previously has been relatively limited, and the availability of sequence data via mammalian genome projects provides the potential for extending the range of GH gene sequences examined. Complete or nearly complete GH gene sequences for six mammalian species for which no data were previously available have been extracted from the genome databases-Dasypus novemcinctus (nine-banded armadillo), Erinaceus europaeus (western European hedgehog), Myotis lucifugus (little brown bat), Procavia capensis (cape rock hyrax), Sorex araneus (European shrew), Spermophilus tridecemlineatus (13-lined ground squirrel). In addition incomplete data for several other species have been extended. Examination of the data in detail and comparison with previously available sequences has allowed assessment of the reliability of deduced sequences. Several of the new sequences differ substantially from the consensus sequence previously determined for eutherian GHs, indicating greater variability than previously recognised, and confirming the episodic pattern of evolution. The episodic pattern is not seen for signal sequences, 5' upstream sequence or synonymous substitutions-it is specific to the mature protein sequence, suggesting that it relates to the hormonal function. The substitutions accumulated during the course of GH evolution have occurred mainly on the side of the hormone facing away from the receptor, in a non-random fashion, and it is suggested that this may reflect interaction of the receptor-bound hormone with other proteins or small ligands. PMID:17574247

  20. Transcriptomic Analysis of the Rice White Tip Nematode, Aphelenchoides besseyi (Nematoda: Aphelenchoididae)

    PubMed Central

    Li, Danlei; Wang, Zhiying; Dong, Airong; Chen, Qiaoli; Liu, Xiaohan

    2014-01-01

    Background The rice white tip nematode Aphelenchoides besseyi, a devastating nematode whose genome has not been sequenced, is distributed widely throughout almost all the rice-growing regions of the world. The aims of the present study were to define the transcriptome of A. besseyi and to identify parasite-related, mortality-related or host resistance-overcoming genes in this nematode. Methodology and Principal Findings Using Solexa/Illumina sequencing, we profiled the transcriptome of mixed-stage populations of A. besseyi. A total of 51,270 transcripts without gaps were produced based on high-quality clean reads. Of all the A. besseyi transcripts, 9,132 KEGG Orthology assignments were annotated. Carbohydrate-active enzymes of glycoside hydrolases (GHs), glycosyltransferases (GTs), carbohydrate esterases (CEs) and carbohydrate-binding modules (CBMs) were identified. The presence of the A. besseyi GH45 cellulase gene was verified by in situ hybridization. Given that 13 unique A. besseyi potential effector genes were identified from 41 candidate effector homologs, further studies of these homologs are merited. Finally, comparative analyses were conducted between A. besseyi contigs and Caenorhabditis elegans genes to look for orthologs of RNAi phenotypes, neuropeptides and peptidases. Conclusions and Significance The present results provide comprehensive insight into the genetic makeup of A. besseyi. Many of this species' genes are parasite related, nematode mortality-related or necessary to overcome host resistance. The generated transcriptome dataset of A. besseyi reported here lays the foundation for further studies of the molecular mechanisms related to parasitism and facilitates the development of new control strategies for this species. PMID:24637831

  1. High Level Expression of a Novel Family 3 Neutral β-Xylosidase from Humicola insolens Y1 with High Tolerance to D-Xylose

    PubMed Central

    Xia, Wei; Shi, Pengjun; Xu, Xinxin; Qian, Lichun; Cui, Ying; Xia, Mengjuan; Yao, Bin

    2015-01-01

    A novel β-xylosidase gene of glycosyl hydrolase (GH) family 3, xyl3A, was identified from the thermophilic fungus Humicola insolens Y1, which is an innocuous and non-toxic fungus that produces a wide variety of GHs. The cDNA of xyl3A, 2334 bp in length, encodes a 777-residue polypeptide containing a putative signal peptide of 19 residues. The gene fragment without the signal peptide-coding sequence was cloned and overexpressed in Pichia pastoris GS115 at a high level of 100 mg/L in 1-L Erlenmeyer flasks without fermentation optimization. Recombinant Xyl3A showed both β-xylosidase and α-arabinfuranosidase activities, but had no hydrolysis capacity towards polysaccharides. It was optimally active at pH 6.0 and 60°C with a specific activity of 11.6 U/mg. It exhibited good stability over pH 4.0–9.0 (incubated at 37°C for 1 h) and at temperatures of 60°C and below, retaining over 80% maximum activity. The enzyme had stronger tolerance to xylose than most fungal GH3 β-xylosidases with a high Ki value of 29 mM, which makes Xyl3A more efficient to produce xylose in fermentation process. Sequential combination of Xyl3A following endoxylanase Xyn11A of the same microbial source showed significant synergistic effects on the degradation of various xylans and deconstructed xylo-oligosaccharides to xylose with high efficiency. Moreover, using pNPX as both the donor and acceptor, Xyl3A exhibited a transxylosylation activity to synthesize pNPX2. All these favorable properties suggest that Xyl3A has good potential applications in the bioconversion of hemicelluloses to biofuels. PMID:25658646

  2. Genome-Wide Association Study of L-Arginine and Dimethylarginines Reveals Novel Metabolic Pathway for Symmetric Dimethylarginine

    PubMed Central

    Lüneburg, Nicole; Lieb, Wolfgang; Zeller, Tanja; Chen, Ming-Huei; Maas, Renke; Carter, Angela M.; Xanthakis, Vanessa; Glazer, Nicole L; Schwedhelm, Edzard; Seshadri, Sudha; Ikram, M. Arfan; Longstreth, W.T.; Fornage, Myriam; König, Inke R.; Loley, Christina; Ojeda, Francisco M.; Schillert, Arne; Wang, Thomas J.; Sticht, Heinrich; Kittel, Anja; König, Jörg; Benjamin, Emelia J.; Sullivan, Lisa M.; Bernges, Isabel; Anderssohn, Maike; Ziegler, Andreas; Gieger, Christian; Illig, Thomas; Meisinger, Christa; Wichmann, H.-Erich; Wild, Philipp S.; Schunkert, Heribert; Psaty, Bruce M.; Wiggins, Kerri L.; Heckbert, Susan R.; Smith, Nicholas; Lackner, Karl; Lunetta, Kathryn L.; Blankenberg, Stefan; Erdmann, Jeanette; Munzel, Thomas; Grant, Peter J.; Vasan, Ramachandran S.; Böger, Rainer H.

    2016-01-01

    Background Dimethylarginines (DMA) interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA) and L-arginine uptake into the cell (ADMA and symmetric dimethylarginine, SDMA). In prospective clinical studies ADMA has been characterized as a cardiovascular risk marker whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterise the environmental and genetic contributions to inter-individual variability of these biomarkers. Methods and Results This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (FHS (n=2992), GHS (n=4354) and MONICA/KORA F3 (n=581)) and identified replicated loci (DDAH1, MED23, Arg1 and AGXT2) associated with the inter-individual variability in ADMA, L-arginine and SDMA. Experimental in-silico and in-vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants and various cardiometabolic risk factors. AGXT2 variants were not associated with post-stroke survival in the Leeds study, nor were they associated with incident stroke in the CHARGE consortium. Conclusion These GWAS support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and L-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation. PMID:25245031

  3. Isolation and Complete Genome Sequence of Algibacter alginolytica sp. nov., a Novel Seaweed-Degrading Bacteroidetes Bacterium with Diverse Putative Polysaccharide Utilization Loci.

    PubMed

    Sun, Cong; Fu, Ge-Yi; Zhang, Chong-Ya; Hu, Jing; Xu, Lin; Wang, Rui-Jun; Su, Yue; Han, Shuai-Bo; Yu, Xiao-Yun; Cheng, Hong; Zhang, Xin-Qi; Huo, Ying-Yi; Xu, Xue-Wei; Wu, Min

    2016-05-15

    The members of the phylum Bacteroidetes are recognized as some of the most important specialists for the degradation of polysaccharides. However, in contrast to research on Bacteroidetes in the human gut, research on polysaccharide degradation by marine Bacteroidetes is still rare. The genus Algibacter belongs to the Flavobacteriaceae family of the Bacteroidetes, and most species in this genus are isolated from or near the habitat of algae, indicating a preference for the complex polysaccharides of algae. In this work, a novel brown-seaweed-degrading strain designated HZ22 was isolated from the surface of a brown seaweed (Laminaria japonica). On the basis of its physiological, chemotaxonomic, and genotypic characteristics, it is proposed that strain HZ22 represents a novel species in the genus Algibacter with the proposed name Algibacter alginolytica sp. nov. The genome of strain HZ22, the type strain of this species, harbors 3,371 coding sequences (CDSs) and 255 carbohydrate-active enzymes (CAZymes), including 104 glycoside hydrolases (GHs) and 18 polysaccharide lyases (PLs); this appears to be the highest proportion of CAZymes (∼7.5%) among the reported strains in the class Flavobacteria Seventeen polysaccharide utilization loci (PUL) are predicted to be specific for marine polysaccharides, especially algal polysaccharides from red, green, and brown seaweeds. In particular, PUL N is predicted to be specific for alginate. Taking these findings together with the results of assays of crude alginate lyases, we prove that strain HZ22(T) can completely degrade alginate. This work reveals that strain HZ22(T) has good potential for the degradation of algal polysaccharides and that the structure and related mechanism of PUL in strain HZ22(T) are worth further research. PMID:26969704

  4. Brain Mapping of Ghrelin O-Acyltransferase in Goldfish (Carassius Auratus): Novel Roles for the Ghrelinergic System in Fish?

    PubMed

    Blanco, Ayelén M; Sánchez-Bretaño, Aída; Delgado, María J; Valenciano, Ana I

    2016-06-01

    Ghrelin O-acyltransferase (GOAT) is the enzyme responsible for acylation of ghrelin, a gut-brain hormone with important roles in many physiological functions in vertebrates. Many aspects of GOAT remain to be elucidated, especially in fish, and particularly its anatomical distribution within the different brain areas has never been reported to date. The present study aimed to characterize the brain mapping of GOAT using RT-qPCR and immunohistochemistry in a teleost, the goldfish (Carassius auratus). Results show that goat transcripts are expressed in different brain areas of the goldfish, with the highest levels in the vagal lobe. Using immunohistochemistry, we also report the presence of GOAT immunoreactive cells in different encephalic areas, including the telencephalon, some hypothalamic nuclei, pineal gland, optic tectum and cerebellum, although they are especially abundant in the hindbrain. Particularly, an important signal is observed in the vagal lobe and some fiber tracts of the brainstem, such as the medial longitudinal fasciculus, Mauthneri fasciculus, secondary gustatory tract and spinothalamic tract. Most of the forebrain areas where GOAT is detected, particularly the hypothalamic nuclei, also express the ghs-r1a ghrelin receptor and other appetite-regulating hormones (e.g., orexin and NPY), supporting the role of ghrelin as a modulator of food intake and energy balance in fish. Present results are the first report on the presence of GOAT in the brain using imaging techniques. The high presence of GOAT in the hindbrain is a novelty, and point to possible new functions for the ghrelinergic system in fish. Anat Rec, 299:748-758, 2016. © 2016 Wiley Periodicals, Inc. PMID:27064922

  5. Inter-state variations in integration of leprosy services into general health system in low/ moderately endemic states of India.

    PubMed

    Pandey, A; Patel, R; Rathod, H

    2006-01-01

    The objective of the study was to analyse inter-state variations in integration of leprosy services into the general health system, covering broad categories of structure integration, training of health functionaries, availability of MDT services and record maintenance, in 24 low/moderately endemic states. Multi-stage random sampling technique was used to select 9 states, 86 health facilities (including district hospitals, community health centres, primary health centres) and 108 sub-centres. Information from each level was collected on a pre-tested form by officers of three leprosy institutions of the Government of India. The results showed wide inter-state variations on each aspect. Redeployment of vertical staff was complete (100%) in Tamil Nadu and Tripura. Assam reported a higher level of training (97%) of medical officers in leprosy. Training of health supervisors and multipurpose workers was better than that of medical officers in most of the states. Tripura reported negligible training of all the health functionaries because of specific local problems. In Assam, Maharashtra and Sikkim, all the urban and rural health facilities were providing MDT. Three months' stock of all types of MDT blister packs was available only in one health facility in Andhra Pradesh and in Goa. Assam and Haryana had lower availability of MDT stocks. In Assam and Maharashtra, medical officers in all health facilities were diagnosing and treating leprosy cases, as compared with Himachal Pradesh where the value was 30%. Involvement of sub-centres in MDT delivery was more at 92% and 100% in Tamil Nadu and Maharashtra respectively in comparison to none in Himachal Pradesh and Tripura. Use of the Simplified Information System (SIS) 2002 guidelines and formats was universal. However, lower involvement of GHS staff in recording and reporting was noted in Assam (0%), Andhra Pradesh (10% and 30%). The study emphasized the need for further tailor-made follow-up studies to suit local problems. PMID:17120508

  6. Characterization of the toxicological hazards of hydrocarbon solvents.

    PubMed

    Mckee, Richard H; Adenuga, M David; Carrillo, Juan-Carlos

    2015-04-01

    Hydrocarbon solvents are liquid hydrocarbon fractions derived from petroleum processing streams, containing only carbon and hydrogen atoms, with carbon numbers ranging from approximately C5-C20 and boiling between approximately 35-370C. Many of the hydrocarbon solvents have complex and variable compositions with constituents of 4 types, alkanes (normal paraffins, isoparaffins, and cycloparaffins) and aromatics (primarily alkylated one- and two-ring species). Because of the compositional complexity, hydrocarbon solvents are now identified by a nomenclature ("the naming convention") that describes them in terms of physical/chemical properties and compositional elements. Despite the compositional complexity, most hydrocarbon solvent constituents have similar toxicological properties, and the overall toxicological hazards can be characterized in generic terms. To facilitate hazard characterization, the solvents were divided into 9 groups (categories) of substances with similar physical and chemical properties. Hydrocarbon solvents can cause chemical pneumonitis if aspirated into the lung, and those that are volatile can cause acute CNS effects and/or ocular and respiratory irritation at exposure levels exceeding occupational recommendations. Otherwise, there are few toxicologically important effects. The exceptions, n-hexane and naphthalene, have unique toxicological properties, and those solvents containing constituents for which classification is required under the Globally Harmonized System (GHS) are differentiated by the substance names. Toxicological information from studies of representative substances was used to fulfill REACH registration requirements and to satisfy the needs of the OECD High Production Volume (HPV) initiative. As shown in the examples provided, the hazard characterization data can be used for hazard classification and for occupational exposure limit recommendations. PMID:25868376

  7. Bayesian integrated testing strategy (ITS) for skin sensitization potency assessment: a decision support system for quantitative weight of evidence and adaptive testing strategy.

    PubMed

    Jaworska, Joanna S; Natsch, Andreas; Ryan, Cindy; Strickland, Judy; Ashikaga, Takao; Miyazawa, Masaaki

    2015-12-01

    The presented Bayesian network Integrated Testing Strategy (ITS-3) for skin sensitization potency assessment is a decision support system for a risk assessor that provides quantitative weight of evidence, leading to a mechanistically interpretable potency hypothesis, and formulates adaptive testing strategy for a chemical. The system was constructed with an aim to improve precision and accuracy for predicting LLNA potency beyond ITS-2 (Jaworska et al., J Appl Toxicol 33(11):1353-1364, 2013) by improving representation of chemistry and biology. Among novel elements are corrections for bioavailability both in vivo and in vitro as well as consideration of the individual assays' applicability domains in the prediction process. In ITS-3 structure, three validated alternative assays, DPRA, KeratinoSens and h-CLAT, represent first three key events of the adverse outcome pathway for skin sensitization. The skin sensitization potency prediction is provided as a probability distribution over four potency classes. The probability distribution is converted to Bayes factors to: 1) remove prediction bias introduced by the training set potency distribution and 2) express uncertainty in a quantitative manner, allowing transparent and consistent criteria to accept a prediction. The novel ITS-3 database includes 207 chemicals with a full set of in vivo and in vitro data. The accuracy for predicting LLNA outcomes on the external test set (n=60) was as follows: hazard (two classes)-100%, GHS potency classification (three classes)-96%, potency (four classes)-89%. This work demonstrates that skin sensitization potency prediction based on data from three key events, and often less, is possible, reliable over broad chemical classes and ready for practical applications. PMID:26612363

  8. Children's misunderstandings of hazard warning signs in the new globally harmonized system for classification and labeling.

    PubMed

    Latham, Garry; Long, Tony; Devitt, Patric

    2013-12-01

    Accidental chemical poisoning causes more than 35 000 child deaths every year across the world, and it leads to disease, disability, and suffering for many more children. Children's ignorance of dangers and their failure to interpret hazard warning signs as intended contribute significantly to this problem. A new Globally Harmonized System for Classification and Labeling is being implemented internationally with a view to unifying the current multiple and disparate national systems. This study was designed to establish a productive, effective means of teaching the new GHS warning signs to primary school children (aged 7-11 years). A pre-test, post-test, follow-up test design was employed, with a teaching intervention informed by a Delphi survey of expert opinion. Children from one school formed the experimental group (n = 49) and a second school provided a control group (n = 23). Both groups showed a gain in knowledge from pre-test to post-test, the experimental group with a larger gain but which was not statistically significant. However, longer-term retention of knowledge, as shown by the follow-up test, was statistically significantly greater in the experimental group (p = 0.001). The employment of teaching to match children's preferred learning styles, and the use of active learning were found to be related to improved retention of knowledge. Part of the study involved eliciting children's interpretation of standard hazard warning symbols, and this provoked considerable concern over the potential for dangerous misinterpretation with disastrous consequences. This article focuses on the reasons for such misconception and the action required to address this successfully in testing the intervention. PMID:23964825

  9. Construction of a rice glycoside hydrolase phylogenomic database and identification of targets for biofuel research

    PubMed Central

    Sharma, Rita; Cao, Peijian; Jung, Ki-Hong; Sharma, Manoj K.; Ronald, Pamela C.

    2013-01-01

    Glycoside hydrolases (GH) catalyze the hydrolysis of glycosidic bonds in cell wall polymers and can have major effects on cell wall architecture. Taking advantage of the massive datasets available in public databases, we have constructed a rice phylogenomic database of GHs (http://ricephylogenomics.ucdavis.edu/cellwalls/gh/). This database integrates multiple data types including the structural features, orthologous relationships, mutant availability, and gene expression patterns for each GH family in a phylogenomic context. The rice genome encodes 437 GH genes classified into 34 families. Based on pairwise comparison with eight dicot and four monocot genomes, we identified 138 GH genes that are highly diverged between monocots and dicots, 57 of which have diverged further in rice as compared with four monocot genomes scanned in this study. Chromosomal localization and expression analysis suggest a role for both whole-genome and localized gene duplications in expansion and diversification of GH families in rice. We examined the meta-profiles of expression patterns of GH genes in twenty different anatomical tissues of rice. Transcripts of 51 genes exhibit tissue or developmental stage-preferential expression, whereas, seventeen other genes preferentially accumulate in actively growing tissues. When queried in RiceNet, a probabilistic functional gene network that facilitates functional gene predictions, nine out of seventeen genes form a regulatory network with the well-characterized genes involved in biosynthesis of cell wall polymers including cellulose synthase and cellulose synthase-like genes of rice. Two-thirds of the GH genes in rice are up regulated in response to biotic and abiotic stress treatments indicating a role in stress adaptation. Our analyses identify potential GH targets for cell wall modification. PMID:23986771

  10. Insight into Dominant Cellulolytic Bacteria from Two Biogas Digesters and Their Glycoside Hydrolase Genes

    PubMed Central

    Zhang, Jun; Zhang, Lei; Geng, Alei; Liu, Fanghua; Zhao, Guoping; Wang, Shengyue; Zhou, Zhihua; Yan, Xing

    2015-01-01

    Diverse cellulolytic bacteria are essential for maintaining high lignocellulose degradation ability in biogas digesters. However, little was known about functional genes and gene clusters of dominant cellulolytic bacteria in biogas digesters. This is the foundation to understand lignocellulose degradation mechanisms of biogas digesters and apply these gene resource for optimizing biofuel production. A combination of metagenomic and 16S rRNA gene clone library methods was used to investigate the dominant cellulolytic bacteria and their glycoside hydrolase (GH) genes in two biogas digesters. The 16S rRNA gene analysis revealed that the dominant cellulolytic bacteria were strains closely related to Clostridium straminisolvens and an uncultured cellulolytic bacterium designated BG-1. To recover GH genes from cellulolytic bacteria in general, and BG-1 in particular, a refined assembly approach developed in this study was used to assemble GH genes from metagenomic reads; 163 GH-containing contigs ≥ 1 kb in length were obtained. Six recovered GH5 genes that were expressed in E. coli demonstrated multiple lignocellulase activities and one had high mannanase activity (1255 U/mg). Eleven fosmid clones harboring the recovered GH-containing contigs were sequenced and assembled into 10 fosmid contigs. The composition of GH genes in the 163 assembled metagenomic contigs and 10 fosmid contigs indicated that diverse GHs and lignocellulose degradation mechanisms were present in the biogas digesters. In particular, a small portion of BG-1 genome information was recovered by PhyloPythiaS analysis. The lignocellulase gene clusters in BG-1 suggested that it might use a possible novel lignocellulose degradation mechanism to efficiently degrade lignocellulose. Dominant cellulolytic bacteria of biogas digester possess diverse GH genes, not only in sequences but also in their functions, which may be applied for production of biofuel in the future. PMID:26070087

  11. Socioeconomic differentials and availability of domestic water in South Africa

    NASA Astrophysics Data System (ADS)

    Dungumaro, Esther W.

    The past few decades has seen massive efforts to increasing provision of domestic water. However, water is still unavailable to many people most of them located in sub-Saharan Africa, South Asia and East Asia. Furthermore, availability of water varies greatly both spatially and temporary. While other people pay so dearly for domestic water others have an easy access to adequate clean water and sanitation. Accessibility and affordability of domestic water and sanitation is determined by a great variety of factors including socioeconomic status of households. The main objective of the paper is to inform on factors which need to be taken into account when coming up with projects to provide domestic water. It is more critical when the issue of water pricing comes into the equation. Water pricing has many facets, including equity, willingness to pay and affordability. In this premise, it is deemed important to understand the socioeconomic characteristics of the people before deciding on the amount of money they will have to pay for water consumption. It is argued that understanding people’s socioeconomic situation will greatly help to ensure that principles of sustainability and equity in water allocation and pricing are achieved. To do so, the paper utilized 2002 South Africa General Household Survey (GHS), to analyze socioeconomic variables and availability of domestic water. Analysis was mainly descriptive. However, logistic regression analysis was also utilized to determine the likelihood of living in a household that obtain water from a safe source. The study found that there is a strong relationship between availability of domestic water and socioeconomic conditions. Economic status, household size and to a lesser extent gender of head of household were found to be strong predictors of living in a household which obtained water from a safe source. The paper recommends that needs and priorities for interventions in water provision should take into account socioeconomic status of households.

  12. Computational investigation of the pH dependence of loop flexibility and catalytic function in glycoside hydrolases.

    PubMed

    Bu, Lintao; Crowley, Michael F; Himmel, Michael E; Beckham, Gregg T

    2013-04-26

    Cellulase enzymes cleave glycosidic bonds in cellulose to produce cellobiose via either retaining or inverting hydrolysis mechanisms, which are significantly pH-dependent. Many fungal cellulases function optimally at pH ~5, and their activities decrease dramatically at higher or lower pH. To understand the molecular-level implications of pH in cellulase structure, we use a hybrid, solvent-based, constant pH molecular dynamics method combined with pH-based replica exchange to determine the pK(a) values of titratable residues of a glycoside hydrolase (GH) family 6 cellobiohydrolase (Cel6A) and a GH family 7 cellobiohydrolase (Cel7A) from the fungus Hypocrea jecorina. For both enzymes, we demonstrate that a bound substrate significantly affects the pKa values of the acid residues at the catalytic center. The calculated pK(a) values of catalytic residues confirm their proposed roles from structural studies and are consistent with the experimentally measured apparent pKa values. Additionally, GHs are known to impart a strained pucker conformation in carbohydrate substrates in active sites for catalysis, and results from free energy calculations combined with constant pH molecular dynamics suggest that the correct ring pucker is stable near the optimal pH for both Cel6A and Cel7A. Much longer molecular dynamics simulations of Cel6A and Cel7A with fixed protonation states based on the calculated pK(a) values suggest that pH affects the flexibility of tunnel loops, which likely affects processivity and substrate complexation. Taken together, this work demonstrates several molecular-level effects of pH on GH enzymes important for cellulose turnover in the biosphere and relevant to biomass conversion processes. PMID:23504310

  13. The endogenous growth hormone secretagogue (ghrelin) is synthesized and secreted by chondrocytes.

    PubMed

    Caminos, J E; Gualillo, O; Lago, F; Otero, M; Blanco, M; Gallego, R; Garcia-Caballero, T; Goldring, M B; Casanueva, F F; Gomez-Reino, J J; Dieguez, C

    2005-03-01

    Ghrelin, the endogenous ligand for the GH secretagogue receptor (GHS-R), is a recently isolated hormone, prevalently expressed in stomach but also in other tissues such as hypothalamus and placenta. This novel acylated peptide acts at a central level to stimulate GH secretion and, notably, to regulate food intake. However, the existence of further, as yet unknown, effects or presence of ghrelin in peripheral tissues cannot be ruled out. In this report, we provide clear evidence for the expression of ghrelin peptide and mRNA in human, mouse, and rat chondrocytes. Immunoreactive ghrelin was identified by immunohistochemistry in rat cartilage, being localized prevalently in proliferative and maturative zone of the epiphyseal growth plate, and in mouse and human chondrocytic cell lines. Moreover, ghrelin mRNA was detected by RT-PCR and confirmed by Southern analysis in rat cartilage as well as in mouse and human chondrocytes cell lines. Ghrelin mRNA expression has been studied in rat along early life development showing a stable profile of expression throughout. Although ghrelin expression in chondrocytes suggests the presence of an unexpected autocrine/paracrine pathway, we failed to identify the functional GH secretagogue receptor type 1A by RT-PCR. On the other hand, binding analysis with 125I ghrelin suggests the presence of specific receptors different from the 1A isotype. Scatchard analysis revealed the presence of two receptors with respectively high and low affinity. Finally, ghrelin, in vitro, was able to significantly stimulate cAMP production and inhibits chondrocytes metabolic activity both in human and murine chondrocytes. In addition, ghrelin is able to actively decrease both spontaneous or insulin-induced long chain fatty acid uptake in human and mouse chondrocytes. This study is the first to provide evidence for the presence of this novel peptide in chondrocytes and suggests novel potential roles for this newly recognized component of the GH axis in cartilage metabolism. PMID:15576457

  14. Association of gas hydrate formation in fluid discharges with anomalous hydrochemical profiles

    NASA Astrophysics Data System (ADS)

    Matveeva, T.

    2009-04-01

    Numerous investigations worldwide have shown that active underwater fluid discharge produces specific structures on the seafloor such as submarine seepages, vents, pockmarks, and collapse depressions. Intensive fluxes of fluids, especially of those containing hydrocarbon gases, result in specific geochemical and physical conditions favorable for gas hydrate (GH) formation. GH accumulations associated with fluid discharge are usually controlled by fluid conduits such as mud volcanoes, diapirs or faults. During last decade, subaqueous GHs become the subject of the fuel in the nearest future. However, the expediency of their commercial development can be proved solely by revealing conditions and mechanisms of GH formation. Kinetic of GH growth (although it is incompletely understood) is one of the important parameters controlling their formation among with gas solubility, pressure, temperature, gas quantity and others. Original large dataset on hydrate-related interstitial fluids obtained from different fluid discharge areas at the Sea of Okhotsk, Black Sea, Gulf of Cadiz, Lake Baikal (Eastern Siberia) allow to suggest close relation of the subaqueous GH formation process to anomalous hydrochemical profiles. We have studied the chemical and isotopic composition of interstitial fluids from GH-bearing and GH-free sediments obtained at different GH accumulations. Most attention was paid to possible influence of the interstitial fluid chemistry on the kinetic of GH formation in a porous media. The influence of salts on methane solubility within hydrate stability zones was considered by Handa (1990), Zatsepina & Buffet (1998), and later by Davie et al. (2004) from a theoretical point of view. Our idea is based on the experimentally proved fact that fugacity coefficient of methane dissolved in saline gas-saturated water which is in equilibrium with hydrates, is higher than that in more fresh water though the solubility is lower. Therefore, if a gradient of water salinity exist under conditions of hydrate stability, diffusion of methane induces hydrate formation by segregation on the outside a boundary fresher/saline water. Geochemical analysis of the interstitial fluids was used to define the mechanisms of GH accumulation and spatial distribution pattern of GHs in sediments from gas seeps abundant off NE Sakhaline Island (Sea of Okhotsk) (Matveeva et al., 2005; Mazurenko et al., submitted). A model of the ascending fluid discharge along one of the seeps named CHAOS was made based on the measured chlorinity (salinity function) of the pore waters and calculated chlorinity gradients. The chloride ion distributionprofiles with depth at the CHAOS site represent alike increasing and decreasing trends both in hydrate-bearing and hydrate-free cores. The model testifies an upward water infiltration of more saline water in vicinity of coring stations recovered GHs and relatively desalinated water mostly around those hydrate-free. It was established that GH formation at the CHAOS site is focused at the locations of intensive ascending flow of water enriched by salts that is probably function of gas solubility in water in the equilibrium with hydrate supposing that the feature is responsible for the hydrate formation just at the locations of the saline water up flows (other conditions being equal). Another case study supporting direct relation of GH formation with anomalous fluids and possible GH formation just on the interface of water flows with different salinity (defining chemical potentials of the water) is fresh-water GH accumulation at the Malenkiy fluid vent in the southern basin of Lake Baikal (Matveeva et al., 2003). The GH accumulation characterizes by heterogeneity in the spatial distribution of GH within a very small vent area. The spatial distribution of the GH-bearing and gas-saturated sediments suggests that several small fluid vents exist within the Malenkiy structure. Based on coring results, the size of these vents should not exceed a few meters. Interstitial water chemistry data indicates that water discharged within the Malenkiy vent is enriched with salts, especially Ca, Cl, and SO4 ions. The ascending water delivering gas into the GH stability zone is thought to be the main GH-forming fluid. Geochemical data suggest that the GH in the subsurface sediments of Lake Baikal originated from a deep source of water with anomalous composition assumed to be derived from buried paleolakes. As a whole, the GH accumulation corresponds to the area of the Malenkiy structure and is represented by several small scale GH occurrences coincident with local fluid discharge manifestations. The data obtained may serve as useful tool for development of geological and hydrogeochemical models of separate GH accumulations forming in the fluid discharge areas. The models on may also serve as a base for the gas inventory of the GH accumulations.

  15. Short term tolvaptan increases water intake and effectively decreases urinary calcium oxalate, calcium phosphate, and uric acid supersaturations

    PubMed Central

    Cheungpasitporn, Wisit; Erickson, Stephen B.; Rule, Andrew D.; Enders, Felicity; Lieske, John C.

    2016-01-01

    Purpose Many patients cannot effectively increase water intake and urine volume to prevent urinary stones. Tolvaptan, a V2 receptor antagonist, blocks water reabsorption in the collecting duct and should reduce urinary supersaturation (SS) of stone forming solutes, but this has never been proven. Materials and Methods We conducted a double blind, randomized, placebo-controlled, crossover study in 21 adult calcium urinary stone formers stratified as majority calcium oxalate(CaOx, n=10) or calcium phosphate(CaP, n=11). Patients received tolvaptan 45 mg/day or placebo for 1 week, followed by a washout week and crossover to tolvaptan or placebo for week 3. A 24h urines was collected at the end of weeks 1 and 3. Results Tolvaptan vs. placebo decreased urinary osmolality (204±96 vs 529±213 mOsm/kg, P<0.001) and increased urinary volume (4.8±2.9 vs 1.8±0.9 L, P<0.001). The majority of urinary solute excretion rates including sodium and calcium did not significantly change, although oxalate secretion slightly increased (23±8 to 15±8 mg/24h, P = 0.009). Urinary CaOx SS (−0.01±1.14 vs 0.95±0.87 DG, P<0.001), CaP SS (−1.66±1.17 vs −0.13±1.02 DG, P<0.001) and Uric Acid SS (−2.05±4.05 vs −5.24±3.12 DG, P=0.04) all dramatically decreased. Effects did not differ between CaOx and CaP groups (P>0.05 for all interactions). Conclusions Tolvaptan increases urine volume and decreases urinary SS in calcium stone formers. Further study is needed to determine if long term use of V2 receptor antagonists results in fewer stone events. PMID:26598423

  16. A Unified Theory on the Pathogenesis of Randall’s Plaques and Plugs

    PubMed Central

    Khan, Saeed R.; Canales, Benjamin K.

    2015-01-01

    Kidney stones develop attached to sub-epithelial plaques of calcium phosphate (CaP) crystals (termed Randall’s plaque) and/or form as a result of occlusion of the openings of the Ducts of Bellini by stone forming crystals (Randall’s plugs). These plaques and plugs eventually extrude into the urinary space, acting as a nidus for crystal overgrowth and stone formation. To better understand these regulatory mechanisms and the pathophysiology of idiopathic calcium stone disease, this review provides in-depth descriptions of the morphology and potential origins of these plaques and plugs, summarizes existing animal models of renal papillary interstitial deposits, and describes factors that are believed to regulate plaque formation and calcium overgrowth. Based on evidence provided within this review and from the vascular calcification literature, we propose a “unified” theory of plaque formation – one similar to pathological biomineralization observed elsewhere in the body. Abnormal urinary conditions (hypercalciuria, hyperoxaluria, hypocitraturia), renal stress or trauma, and perhaps even the normal aging process leads to transformation of renal epithelial cells into an osteblastic phenotype. With this de-differentiation comes an increased production of bone specific proteins (i.e. osteopontin), a reduction in crystallization inhibitors (such as fetuin and matrix-gla-protein), and creation of matrix vesicles, which support nucleation of CaP crystals. These small deposits promote aggregation and calcification of surrounding collagen. Mineralization continues by calcification of membranous cellular degradation products and other fibers until the plaque reaches the papillary epithelium. Through the activity of matrix metalloproteinases or perhaps by brute physical force produced by the large subepithelial crystalline mass, the surface is breached and further stone growth occurs by organic matrix-associated nucleation of CaOx or by the transformation of the outer layer of CaP crystals into CaOx crystals. Should this theory hold true, developing an understanding of the cellular mechanisms involved in progression of a small, basic interstitial plaque to that of an expanding, penetrating plaque could assist in the development of new therapies for stone prevention. PMID:25119506

  17. The Climate and its Impacts on deterioration and weathering rate of EI-Nadura Temple in El- Kharga Oasis, Western Desert of Egypt.

    NASA Astrophysics Data System (ADS)

    Ismael, Hossam

    2015-04-01

    Undoubtedly, El-Kharga Oasis monumental sites are considered an important part of our world's cultural heritage in the South Western Desert of Egypt. These sites are scattered on the floor of the oasis representing ancient civilizations. The Roman stone monuments in Kharga represent cultural heritage of an outstanding universal value. Such those monuments have suffered weathering deterioration. There are various elements which affect the weathering process of stone monuments: climate conditions, shapes of cultural heritages, exposed time periods, terrains, and vegetation around them, etc. Among these, climate conditions are the most significant factor affecting the deterioration of Archeological sites in Egypt. El- Kharga Oasis belongs administratively to the New Valley Governorate. It is located in the southern part of the western desert of Egypt, lies between latitudes 22°30'14" and 26°00'00" N, and between 30°27'00" and 30°47'00" E. The area of El Kharga Oasis covers about 7500 square kilometers. Pilot studies were carried out on the EI-Nadura Temple, composed of sandstones originating from the great sand sea. The major objective of this study is to monitor and measure the weathering features and the weathering rate affecting the building stones forming El-Nadora Roman building rocks in cubic cm. To achieve these aims, the present study used analysis of climatic data such as annual and seasonal solar radiation, Monthly average number of hours of sunshine, maximum and minimum air temperatures, wind speed, which have obtained from actual field measurements and data Meteorological Authority of El-Kharga station for the period 1977 to 2010 (33 years), and from the period 1941-2050 (110 years) as a long term of temperature data. Several samples were collected and examined by polarizing microscopy (PLM), X-ray diffraction analysis (XRD) and scanning electron microscopy equipped with an energy dispersive X-ray analysis system (SEM-EDX). The results were in agreement with the observed values in the study area. The deterioration of El-Nadora temple is above 45 % of original temple (138-161 BC), these deteriorations have occurred not only due to the age of the structures, but also due to the climate elements. It was found that the climate is the most important elements influencing weathering. El-Nadora temple is highly influenced by wind action because it was built on a hill top 180 meter in hyper arid climate and exposed to wind without any obstruction. Finally, El-Nadora Temple has lost about 42.46 % of its original size. And if the rate of deterioration continues, the major landmarks, symbols and inscriptions will fully disappear in 2150.

  18. Seasonal variations in urinary risk factors among patients with nephrolithiasis

    NASA Technical Reports Server (NTRS)

    Hill, K.; Poindexter, J.; Pak, C. Y.

    1991-01-01

    Twenty-four hour urine specimens from 5,677 stone-forming patients throughout the United States were analyzed for seasonal variations in urinary risk factors for nephrolithiasis. Determinations were performed for urine volume, pH, calcium, oxalate, phosphorus, sodium, magnesium, citrate, sulfate, uric acid, and the relative supersaturation (RS) of calcium oxalate, brushite, monosodium urate, and uric acid. Criteria for significant seasonal variation included a significant difference in monthly means of risk factors, seasonal grouping of the data by the Student-Newman-Keuls multiple range test, consistent year-to-year trends and a physiologically significant range. Minimum urine volume of 1.54 +/- 0.70 SD L/day occurred in October while a maximum urine volume of 1.76 +/- 0.78 SD L/day was observed during February. Minimum urine pH of 5.94 +/- 0.64 SD was observed during July and August while a maximum pH of 6.18 +/- 0.61 SD was observed during February. Daily urinary excretion of sodium was lowest during August, 158 +/- 74 SD mEq/day and highest during February 177 +/- 70 SD mEq/day. The RS of brushite and uric acid were found to display significant pH-dependent seasonal variation with a maximum RS of uric acid 2.26 +/- 1.98 SD in June and a low of 1.48 +/- 1.30 SD in February. Maximum RS of brushite 2.75 +/- 2.58 was observed during February. Minimum RS of brushite 1.93 +/- 1.70 SD was observed in June. Phosphorus excretion displayed seasonal variation about a spring-fall axis with a maximum value 1042 +/- 373 SD mg/day in April and a minimum value of 895 +/- 289 SD mg/day. Urine volume, sodium, and pH were significantly lower during the summer (June, July, August) than in the winter (December, January, February). The RS of uric acid was higher, but that of brushite and monosodium urate was lower in the summer than in the winter. The seasonal changes observed in urine volume, pH, sodium, and the RS of brushite and uric acid are consistent with summertime sweating and increased physical activity. Seasonal variations in phosphorus excretion are probably dietary in origin. The summertime was characterized by an increased propensity for the crystallization of uric acid but not of calcium oxalate or calcium phosphate.

  19. Artificial tektites: an experimental technique for capturing the shapes of spinning drops

    NASA Astrophysics Data System (ADS)

    Baldwin, K. A.

    2014-12-01

    Tektites are small stones formed from rapidly cooling drops of molten rock ejected from high velocity asteroid impacts with the Earth, that freeze into a myriad of shapes during flight. Many splash-form tektites have an elongated or dumb-bell shape owing to their rotation prior to solidification[1]. Here we present a novel method for creating 'artificial tektites' from spinning drops of molten wax, using diamagnetic levitation to suspend the drops[2]. We find that the solid wax models produced this way are the stable equilibrium shapes of a spinning liquid droplet held together by surface tension. In addition to the geophysical interest in tektite formation, the stable equilibrium shapes of liquid drops have implications for many physical phenomena, covering a wide range of length scales, from nuclear physics (e.g. in studies of rapidly rotating atomic nuclei), to astrophysics (e.g. in studies of the shapes of astronomical bodies such as asteroids, rapidly rotating stars and event horizons of rotating black holes). For liquid drops bound by surface tension, analytical and numerical methods predict a series of stable equilibrium shapes with increasing angular momentum. Slowly spinning drops have an oblate-like shape. With increasing angular momentum these shapes become secularly unstable to a series of triaxial pseudo-ellipsoids that then evolve into a family of two-lobed 'dumb-bell' shapes as the angular momentum is increased still further. Our experimental method allows accurate measurements of the drops to be taken, which are useful to validate numerical models. This method has provided a means for observing tektite formation, and has additionally confirmed experimentally the stable equilibrium shapes of liquid drops, distinct from the equivalent shapes of rotating astronomical bodies. Potentially, this technique could be applied to observe the non-equilibrium dynamic processes that are also important in real tektite formation, involving, e.g. viscoelastic effects, non-uniform solidification, surface wrinkling (Schlieren), and rapid separation/fission of dumb-bells via the Rayleigh-Plateau instability. [1] M. R. Stauffer and S. L. Butler, Earth Moon Planets, 107, 169 (2009). [2] R. J. A. Hill and L. Eaves, Phys. Rev. Lett. 101, 234501 (2008).

  20. The health benefits of calcium citrate malate: a review of the supporting science.

    PubMed

    Reinwald, Susan; Weaver, Connie M; Kester, Jeffrey J

    2008-01-01

    There has been considerable investigation into the health benefits of calcium citrate malate (CCM) since it was first patented in the late 1980s. This chapter is a comprehensive summary of the supporting science and available evidence on the bioavailability and health benefits of consuming CCM. It highlights the important roles that CCM can play during various life stages. CCM has been shown to facilitate calcium retention and bone accrual in children and adolescents. In adults, it effectively promotes the consolidation and maintenance of bone mass. In conjunction with vitamin D, CCM also decreases bone fracture risk in the elderly, slows the rate of bone loss in old age, and is of benefit to the health and well-being of postmenopausal women. CCM is exceptional in that it confers many unique benefits that go beyond bone health. Unlike other calcium sources that necessitate supplementation be in conjunction with a meal to ensure an appreciable benefit is derived, CCM can be consumed with or without food and delivers a significant nutritional benefit to individuals of all ages. The chemistry of CCM makes it a particularly beneficial calcium source for individuals with hypochlorydia or achlorydia, which generally includes the elderly and those on medications that decrease gastric acid secretion. CCM is also recognized as a calcium source that does not increase the risk of kidney stones, and in fact it protects against stone-forming potential. The versatile nature of CCM makes it a convenient and practical calcium salt for use in moist foods and beverages. The major factor that may preclude selection of CCM as a preferred calcium source is the higher cost compared to other sources of calcium commonly used for fortification (e.g., calcium carbonate and tricalcium phosphate). However, formation of CCM directly within beverages or other fluid foods and/or preparations, and the addition of a concentrated CCM solution or slurry, are relatively cost-effective methods by which CCM can be incorporated into finished food and beverage products. PMID:18291308