Benfotiamine exhibits direct antioxidative capacity and prevents induction of DNA damage in vitro.

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Schmid, Ursula; Stopper, Helga; Heidland, August; Schupp, Nicole

2008-01-01

Complications in diabetes mellitus are partially mediated by enhanced formation of reactive oxygen species. Among the factors involved in reactive oxygen species formation, advanced glycation end products play a key role. Owing to a reduced activity of the enzyme transketolase, which requires diphosphorylated thiamine (vitamin B(1)) as cofactor, an accumulation of those deleterious glucose metabolites especially in diabetic patients can be observed. Benfotiamine, a lipophilic thiamine diphosphate prodrug, prevented early renal and retinal changes in animal studies, and reduced neuropathic pain in clinical studies. Several mechanisms for these activities have been described. We investigated for the first time direct antioxidant abilities of benfotiamine. Additionally, a potential DNA protective effect of benfotiamine was analysed. Oxidative stress was detected by flow cytometry, antioxidative capacity was measured with the ferric reducing ability of plasma (FRAP) assay, two endpoints for genomic damage were assessed: the comet assay and the micronucleus test, and the expression and activity of transketolase was quantified. Benfotiamine prevented oxidative stress induced by the mutagen 4-nitroquinoline-1-oxide (NQO), the uremic toxin indoxyl sulfate, and the peptide hormone angiotensin II in three different kidney cell lines. Cell-free experiments showed a direct antioxidant effect of benfotiamine, which might account for the protective effect. Oxidative DNA damage, induced by angiotensin II, was completely prevented by benfotiamine. Incubation with benfotiamine increased transketolase expression and activity in the cells. Benfotiamine shows a direct antioxidant action. This effect of benfotiamine may be involved in the improvement of diabetic late complications, including peripheral neuropathy.

Anti-Inflammatory Effects of Benfotiamine are Mediated Through the Regulation of Arachidonic Acid Pathway in Macrophages

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Shoeb, Mohammad; Ramana, Kota V

2011-01-01

Benfotiamine, a lipid-soluble analogue of vitamin B1, is a potent anti-oxidant that is used as a food supplement for the treatment of diabetic complications. Our recent study indicates a novel role of benfotiamine in the prevention of bacterial endotoxin, lipopolysaccharide (LPS)-induced cytotoxicity and inflammatory response in murine macrophages. Nevertheless, it remains unclear how benfotiamine mediates anti-inflammatory effects. In this study, we investigated the anti-inflammatory role of...

Liver, plasma and erythrocyte levels of thiamine and its phosphate esters in rats with acute ethanol intoxication: a comparison of thiamine and benfotiamine administration.

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Portari, Guilherme Vannucchi; Vannucchi, Helio; Jordao, Alceu Afonso

2013-03-12

Thiamine and benfotiamine are vitamin B1 and pro-vitamin B1 substances, respectively. Vitamin B1 plays an essential role in energy metabolism, and its deficiency leads to neurologic and cardiovascular pathologies, as seen in alcoholics. This study presents new data about the effects of thiamine hydrochloride or benfotiamine treatment given to rats with acute alcohol intoxication, on the distribution of thiamine and its phosphate esters in liver, plasma and erythrocytes. The treatments were effective in increasing thiamine levels in plasma, erythrocytes and liver cells. The benfotiamine-treated group had its total plasma thiamine increased by 100%. In erythrocytes, thiamine levels were 4- and 25-fold higher in the groups treated with thiamine and benfotiamine, respectively, compared with the untreated groups. Liver thiamine was increased by 60% in the treated groups compared with the untreated groups. Thus, we verified the high bioavailability especially of benfotiamine within 6h of ethanol administration. Copyright © 2013 Elsevier B.V. All rights reserved.

Pharmacokinetics of thiamine derivatives especially of benfotiamine.

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Loew, D

1996-02-01

Pharmacokinetic data of orally administered lipid-soluble thiamine analogues like benfotiamine are reviewed and assessed. It is quite clear that benfotiamine is absorbed much more better than water-soluble thiamine salts: maximum plasma levels of thiamine are about 5 times higher after benfotiamine, the bioavailability is at maximum about 3.6 times as high as that of thiamine hydrochloride and better than other lipophilic thiamine derivates. The physiological activity (alphaETK) increased only after benfotiamine was given. Due to its excellent pharmacokinetic profile benfotiamine should be preferred in treatment of relevant indications.

The effect of benfotiamine on mu-opioid receptor mediated antinociception in experimental diabetes.

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Nacitarhan, C; Minareci, E; Sadan, G

2014-03-01

Diabetic neuropathy is a prevalent, disabling disorder. Currently, the only treatments available to patients with diabetic neuropathy are glucose control and pain management. B vitamin present neuroprotective effects, which are suggested to be related to their analgesic action in various models of neuropathic pain. According to our literature knowledge there is no report about antinociceptive effects of thiamine as benfotiamine and opioids together in diabetic mice. The purpose of this study was to determine the effects of benfotiamine on the antinociception produced by mu-opioid receptor agonist fentanyl in diabetic mice. The effects of benfotiamine on antinociception produced by fentanyl in diabetic mice were studied in 4 groups. Antinociceptive effect was determined with tail flick, hot plate and formalin test. Our results showed that, mu-opioid agonist fentanyl in benfotiamine applied diabetic group caused more potent antinociceptive effect than in diabetic group without benfotiamine treatment. In brief benfotiamine supplement in diet did not bring out antinociceptive effect itself, but during development of STZ diabetes, benfotiamine replacement increased the antinociceptive effect of fentanyl in mice tail-flick test. This effect is probably due to the replacement of benfotiamine efficiency occurring in diabetes mellitus. Finally, we suppose that oral benfotiamine replacement therapy may be useful to ameliorate analgesic effect of mu-opioid agonists on neuropathic pain in diabetic case. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer's Disease.

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Pan, Xiaoli; Chen, Zhichun; Fei, Guoqiang; Pan, Shumei; Bao, Weiqi; Ren, Shuhua; Guan, Yihui; Zhong, Chunjiu

2016-12-01

To date, we still lack disease-modifying therapies for Alzheimer's disease (AD). Here, we report that long-term administration of benfotiamine improved the cognitive ability of patients with AD. Five patients with mild to moderate AD received oral benfotiamine (300 mg daily) over 18 months. All patients were examined by positron emission tomography with Pittsburgh compound B (PiB-PET) and exhibited positive imaging with β-amyloid deposition, and three received PiB-PET imaging at follow-up. The five patients exhibited cognitive improvement as assayed by the Mini-Mental Status Examination (MMSE) with an average increase of 3.2 points at month 18 of benfotiamine administration. The three patients who received follow-up PiB-PET had a 36.7% increase in the average standardized uptake value ratio in the brain compared with that in the first scan. Importantly, the MMSE scores of these three had an average increase of 3 points during the same period. Benfotiamine significantly improved the cognitive abilities of mild to moderate AD patients independently of brain amyloid accumulation. Our study provides new insight to the development of disease-modifying therapy.

Benfotiamine counteracts smoking-induced vascular dysfunction in healthy smokers.

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Stirban, Alin; Nandrean, Simona; Kirana, Stanley; Götting, Christian; Veresiu, Ioan Andrei; Tschoepe, Diethelm

2012-01-01

Background. Smoking induces endothelial dysfunction (ED) mainly by exacerbating oxidative stress (OS) and inflammation. Benfotiamine, a thiamine prodrug with high bioavailability, prevents nicotine-induced vascular dysfunction in rats. It remained unknown whether this effect also occurs in humans. Methods. Therefore, 20 healthy volunteers (mean age: 38 years) were investigated twice, 7-10 days apart in a randomized, cross-over, and investigator-blinded design. Vascular function was assessed by flow-mediated vasodilatation (FMD) of the brachial artery and by measurements of the soluble vascular cell adhesion molecule (sVCAM)-1. Investigations were performed after an overnight fast as well as 20 minutes after one cigarette smoking. On another day, the same procedure was applied following a 3-day oral therapy with benfotiamine (1050 mg/day). Ten patients were randomized to start with smoking alone, and ten started with benfotiamine. Results. Results are expressed as (mean ± SEM). Smoking acutely induced a decrease in FMD by 50% ((∗∗)P benfotiamine treatment to 25%(∗§) ((∗)P benfotiamine. The endothelium-independent vasodilatation remained unaltered between days. Conclusion. In healthy volunteers, smoking blunts vascular function mirrored by a decrease in FMD and an increase in sVCAM-1. Short-term treatment with benfotiamine significantly reduces these effects, showing protective vascular properties.

Benfotiamine Counteracts Smoking-Induced Vascular Dysfunction in Healthy Smokers

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Alin Stirban

2012-01-01

Full Text Available Background. Smoking induces endothelial dysfunction (ED mainly by exacerbating oxidative stress (OS and inflammation. Benfotiamine, a thiamine prodrug with high bioavailability, prevents nicotine-induced vascular dysfunction in rats. It remained unknown whether this effect also occurs in humans. Methods. Therefore, 20 healthy volunteers (mean age: 38 years were investigated twice, 7–10 days apart in a randomized, cross-over, and investigator-blinded design. Vascular function was assessed by flow-mediated vasodilatation (FMD of the brachial artery and by measurements of the soluble vascular cell adhesion molecule (sVCAM-1. Investigations were performed after an overnight fast as well as 20 minutes after one cigarette smoking. On another day, the same procedure was applied following a 3-day oral therapy with benfotiamine (1050 mg/day. Ten patients were randomized to start with smoking alone, and ten started with benfotiamine. Results. Results are expressed as (mean ± SEM. Smoking acutely induced a decrease in FMD by 50% (∗∗P<0.001 versus baseline an effect significantly reduced by benfotiamine treatment to 25%∗§ (∗P<0.05 versus baseline, §P<0.05 versus smoking alone. Smoking-induced elevation in sVCAM-1 was also prevented by benfotiamine. The endothelium-independent vasodilatation remained unaltered between days. Conclusion. In healthy volunteers, smoking blunts vascular function mirrored by a decrease in FMD and an increase in sVCAM-1. Short-term treatment with benfotiamine significantly reduces these effects, showing protective vascular properties.

Benfotiamine in treatment of alcoholic polyneuropathy: an 8-week randomized controlled study (BAP I Study).

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Woelk, H; Lehrl, S; Bitsch, R; Köpcke, W

1998-01-01

A three-armed, randomized, multicentre, placebo-controlled double-blind study was used to examine the efficacy of benfotiamine vs a combination containing benfotiamine and vitamins B6 and B12 in out-patients with severe symptoms of alcoholic polyneuropathy (Benfotiamine in treatment of Alcoholic Polyneuropathy, BAP I). The study period was 8 weeks and 84 patients fulfilled all the prerequisite criteria and completed the study as planned. Benfotiamine led to significant improvement of alcoholic polyneuropathy. Vibration perception (measured at the tip of the great toe) significantly improved in the course of the study, as did motor function. and the overall score reflecting the entire range of symptoms of alcoholic polyneuropathy. A tendency toward improvement was evident for pain and co-ordination; no therapy-specific adverse effects were seen.

Antinociceptive interaction between benfotiamine and resveratrol in capsaicin-induced licking.

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Montiel-Ruiz, Rosa Mariana; Reyes-García, Gerardo; Flores-Murrieta, Francisco; Déciga-Campos, Myrna

2009-01-01

In an attempt to provide more direct evidence concerning the possible antinociceptive effect of resveratrol-benfotiamine combination on neurogenic pain, we investigated whether resveratrol and benfotiamine administered alone or in combination decrease capsaicin induced nociception in mice. Before testing, the animals were placed individually in transparent glass cylinders, 20 cm in diameter, serving as observation chambers. After the adaptation period, 20 microL of capsaicin (1.6 microg/paw) were injected under the skin of the dorsal of the right hind paw. Animals were observed individually for 5 min after capsaicin injection. The amount of time spent licking the injected paw was timed with a chronometer and was considered as indicative of nociception. Animals were pretreated with resveratrol (56.2-177 mg/kg, i.p.), benfotiamine (100-1000 mg/kg, p.o.) and their combinations (11:1, 22:2, 44:4; 88:8 mg/kg benfotiamine:resveratrol). It was observed that resveratrol (ED50 = 104 +/- 8.2 mg/kg) was able to produce more important decrement of capsaicin-induced licking than benfotiamine (ED50 = 529.4 +/- 85.2 mg/kg). In addition, a synergistic interaction was observed between benfotiamine and resveratrol, suggesting that this combination could be useful in neurogenic nociception.

The Effects of Long-Term Oral Benfotiamine Supplementation on Peripheral Nerve Function and Inflammatory Markers in Patients With Type 1 Diabetes

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Fraser, David A.; Diep, Lien M.; Hovden, Inger Anette; Nilsen, Kristian B.; Sveen, Kari Anne; Seljeflot, Ingebjørg; Hanssen, Kristian F.

2012-01-01

OBJECTIVE To study the effects of long-term oral benfotiamine supplementation on peripheral nerve function and soluble inflammatory markers in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS The study randomly assigned 67 patients with type 1 diabetes to receive 24-month benfotiamine (300 mg/day) or placebo supplementation. Peripheral nerve function and levels of soluble inflammatory variables were assessed at baseline and at 24 months. RESULTS Fifty-nine patients completed the study. Marked increases in whole-blood concentrations of thiamine and thiamine diphosphate were found in the benfotiamine group (both P benfotiamine (300 mg/day) supplementation over 24 months has no significant effects upon peripheral nerve function or soluble markers of inflammation in patients with type 1 diabetes. PMID:22446172

Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats.

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Stracke, H; Hammes, H P; Werkmann, D; Mavrakis, K; Bitsch, I; Netzel, M; Geyer, J; Köpcke, W; Sauerland, C; Bretzel, R G; Federlin, K F

2001-01-01

In rats with streptozotocin (STZ) induced diabetes the effect of (watersoluble) thiamine nitrate and of (lipidsoluble) benfotiamine on peripheral nerve function (motor nerve conduction velocity) as well as on the formation of advanced glycation end-products in peripheral nerve tissue was studied. In one group of animals drug administration was started immediately after diabetes induction (prevention study) and in another group two months after diabetes induction (treatment study). Motor nerve conduction velocity (NCV) dropped by 10.5% in diabetic animals, carboxymethyl-lysine (CML) rose to a 3.5fold concentration, deoxyglucosone (3DG)-type AGE formation was increased 5.1fold compared with controls. After three months preventive administration of both vitamin B(1) preparations NCV had increased substantially compared with results in diabetic controls. It was nearly normal after six months with benfotiamine, while the administration of thiamine nitrate resulted in no further amelioration. NCV was nearly normalized after six months of benfotiamine application but not with thiamine. Furthermore, benfotiamine induced a major inhibition of neural imidazole-type AGE formation and completely prevented diabetes induced glycoxidation products (CML). Treatment with thiamine did not significantly affect AGE or cmL levels. Unlike treatment with water-soluble thiamine nitrate timely administration of liposoluble prodrug benfotiamine was effective in the prevention of functional damage and of AGE and cmL formation in nerves of diabetic rats.

Synergistic antiallodynic interaction between gabapentin or carbamazepine and either benfotiamine or cyanocobalamin in neuropathic rats.

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Mixcoatl-Zecuatl, Teresa; Quinonez-Bastidas, Geovanna N; Caram-Salas, Nadia L; Ambriz-Tututi, Monica; Araiza-Saldana, Claudia I; Rocha-Gonzalez, Hector I; Medina-Santillan, Roberto; Reyes-Garcia, Gerardo; Granados-Soto, Vinicio

2008-01-01

Anticonvulsants, including gabapentin and carbamazepine, have shown activity against several types of neuropathic pain; however, they have limiting side effects that may minimize their use. In this study the possible synergistic interaction between anticonvulsants and benfotiamine or cyanocobalamin on spinal nerve ligation-induced tactile allodynia was assessed. Oral administration of gabapentin (15-300 mg/kg), carbamazepine (10-300 mg/kg), benfotiamine (30-600 mg/kg) or cyanocobalamin (0.3-6.0 mg/kg) significantly reduced tactile allodynia in rats. Maximal antiallodynic effects were reached with gabapentin 300 mg/kg (approximately 70%), carbamazepine 300 mg/kg (approximately 66%), benfotiamine 600 mg/kg (approximately 51%) and cyanocobalamin 6 mg/kg (approximately 59%). At the highest tested doses, gabapentin, but not carbamazepine, benfotiamine or cyanocobalamin, significantly reduced motor coordination. Coadministration of gabapentin or carbamazepine with benfotiamine or cyanocobalamin in a fixed ratio markedly reduced spinal nerve ligation-induced tactile allodynia, showing a synergistic interaction between anticonvulsants and B vitamins. Data indicate that combinations of anticonvulsants with benfotiamine or cyanocobalamin are able to reduce tactile allodynia without affecting motor coordination in rats, and suggest the possible clinical use of these combinations in the treatment of neuropathic pain in humans.

Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.

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Hammes, Hans-Peter; Du, Xueliang; Edelstein, Diane; Taguchi, Tetsuya; Matsumura, Takeshi; Ju, Qida; Lin, Jihong; Bierhaus, Angelika; Nawroth, Peter; Hannak, Dieter; Neumaier, Michael; Bergfeld, Regine; Giardino, Ida; Brownlee, Michael

2003-03-01

Three of the major biochemical pathways implicated in the pathogenesis of hyperglycemia induced vascular damage (the hexosamine pathway, the advanced glycation end product (AGE) formation pathway and the diacylglycerol (DAG)-protein kinase C (PKC) pathway) are activated by increased availability of the glycolytic metabolites glyceraldehyde-3-phosphate and fructose-6-phosphate. We have discovered that the lipid-soluble thiamine derivative benfotiamine can inhibit these three pathways, as well as hyperglycemia-associated NF-kappaB activation, by activating the pentose phosphate pathway enzyme transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars. In retinas of diabetic animals, benfotiamine treatment inhibited these three pathways and NF-kappaB activation by activating transketolase, and also prevented experimental diabetic retinopathy. The ability of benfotiamine to inhibit three major pathways simultaneously might be clinically useful in preventing the development and progression of diabetic complications.

Effect of benfotiamine in podocyte damage induced by peritoneal dialysis fluid.

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Müller-Krebs, Sandra; Nissle, Katharina; Tsobaneli, Julia; Zeier, Martin; Kihm, Lars Philipp; Kender, Zoltan; Fleming, Thomas; Nawroth, Peter Paul; Reiser, Jochen; Schwenger, Vedat

2015-01-01

In peritoneal dialysis (PD), residual renal function (RRF) fundamentally contributes to improved quality of life and patient survival. High glucose and advanced glycation end-products (AGE) contribute locally to peritoneal and systemically to renal damage. Integrity of podocyte structure and function is of special importance to preserve RRF. Benfotiamine could counteract the glucose and AGE-mediated toxicity by blocking hyperglycemia-associated podocyte damage via the pentose-phosphate pathway. A human differentiated podocyte cell line was incubated with control solution (control), 2.5% glucose solution (glucose), and 2.5% peritoneal dialysis fluid (PDF) for 48 h either ±50 μM benfotiamine. Podocyte damage and potential benefit of benfotiamine were analyzed using immunofluorescence, western blot analysis, and a functional migration assay. For quantitation, a semiquantitative score was used. When incubating podocytes with benfotiamine, glucose, and PDF-mediated damage was reduced, resulting in lower expression of AGE and intact podocin and ZO-1 localization. The reorganization of the actin cytoskeleton was restored in the presence of benfotiamine as functional podocyte motility reached control level. Decreased level of inflammation could be shown as well as reduced podocyte apoptosis. These data suggest that benfotiamine protects podocytes from glucose and PDF-mediated dysfunction and damage, in particular, with regard to cytoskeletal reorganization, motility, inflammation, and podocyte survival.

Antiglycation activity of thiamin-HCl and benfotiamine in diabetic condition.

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Kousar, Samina; Sheikh, Munir Ahmad; Asghar, Muhammad

2012-10-01

To observe the antiglycation effect of water-soluble vitamin, thiamin-hydrochloride (B1) and its fat-soluble derivative benfotiamine and their comparison with two different glycation assays in diabetics. Plasma of both the normal's and diabetic persons was taken for this experimental study which was conducted in the Department of Chemistry and Biochemistry, University of Agriculture, Faisalabad in 2008. Varying concentrations of both the glycation inhibitors and glucose were incubated for 5 weeks at 37 degrees C. Thiobarbituric acid and periodate borohydride assays were used to measure the antiglycation activity. The increase in glycation was observed from 1st to 3rd week of incubation, while it decreased after the 5th week due to the formation of advanced glycation end products. It was observed that 10mM concentration of benfotiamine and 5mM and 1mM concentrations of thiamine-hydrochloride produced fairly good response to decreased glycation. Comparison between two assays proved periodate borohydride to be more reliable and sensitive than thiobarbituric acid.

Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study).

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Haupt, E; Ledermann, H; Köpcke, W

2005-02-01

The aim of the study was to evaluate the efficacy of benfotiamine administered over three weeks (allithiamine; a lipid-soluble vitamin B1 prodrug with high bioavailability) to patients with diabetic polyneuropathy in a randomized, placebo-controlled, double-blind, two-center pilot study. Forty inpatients (23 male, 18 female, age range 18 - 70 years) with a history of type 1 or 2 diabetes and polyneuropathy of not longer than two years, were included in the study. Twenty Patients received two 50 mg benfotiamine tablets four times daily and 20 patients received placebo over the three-week study period. Two clinical units were involved with 10 patients receiving placebo and 10 patients benfotiamine in each. The neuropathy score according to Katzenwadel et al. [1987] was used to evaluate symptoms of polyneuropathy, vibration perception threshold and both the physician's and the patient's own assessment were documented. A statistically significant (p = 0.0287) improvement in the neuropathy score was observed in the group given active drug when compared to the placebo-treated controls. There was no statistically significant change observed in the tuning fork test. The most pronounced effect on complaints was a decrease in pain (p = 0.0414). More patients in the benfotiamine-treated group than in the placebo group considered their clinical condition to have improved (p = 0.052). No side effects attributable to benfotiamine were observed. The differences between the groups cannot be attributed to a change in metabolic parameters since there were no significant alterations in the HbA1 levels and blood sugar profiles. The body mass index of the two groups did not differ. This pilot investigation (BEDIP Study) has confirmed the results of two earlier randomized controlled trials and has provided further evidence for the beneficial effects of benfotiamine in patients with diabetic neuropathy.

Benfotiamine upregulates antioxidative system in activated BV-2 microglia cells

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Iva eBozic

2015-09-01

Full Text Available Chronic microglial activation and resulting sustained neuroinflammatory reaction are generally associated with neurodegeneration. Activated microglia acquires proinflammatory cellular profile that generates oxidative burst. Their persistent activation exacerbates inflammation, which damages healthy neurons via cytotoxic mediators, such as superoxide radical anion and nitric oxide. In our recent study, we have shown that benfotiamine (S-benzoylthiamine O-monophosphate possesses anti-inflammatory effects. Here, the effects of benfotiamine on the pro-oxidative component of activity of LPS-stimulated BV-2 cells were investigated. The activation of microglia was accompanied by upregulation of intracellular antioxidative defense, which was further promoted in the presence of benfotiamine. Namely, activated microglia exposed to non-cytotoxic doses of benfotiamine showed increased levels and activities of hydrogen peroxide- and superoxide-removing enzymes – catalase and glutathione system, and superoxide dismutase. In addition, benfotiamine showed the capacity to directly scavenge superoxide radical anion. As a consequence, benfotiamine suppressed the activation of microglia and provoked a decrease in NO and •O2- production and lipid peroxidation. In conclusion, benfotiamine might silence pro-oxidative activity of microglia to alleviate/prevent oxidative damage of neighboring CNS cells.

Benfotiamine upregulates antioxidative system in activated BV-2 microglia cells.

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Bozic, Iva; Savic, Danijela; Stevanovic, Ivana; Pekovic, Sanja; Nedeljkovic, Nadezda; Lavrnja, Irena

2015-01-01

Chronic microglial activation and resulting sustained neuroinflammatory reaction are generally associated with neurodegeneration. Activated microglia acquires proinflammatory cellular profile that generates oxidative burst. Their persistent activation exacerbates inflammation, which damages healthy neurons via cytotoxic mediators, such as superoxide radical anion and nitric oxide. In our recent study, we have shown that benfotiamine (S-benzoylthiamine O-monophosphate) possesses anti-inflammatory effects. Here, the effects of benfotiamine on the pro-oxidative component of activity of LPS-stimulated BV-2 cells were investigated. The activation of microglia was accompanied by upregulation of intracellular antioxidative defense, which was further promoted in the presence of benfotiamine. Namely, activated microglia exposed to non-cytotoxic doses of benfotiamine showed increased levels and activities of hydrogen peroxide- and superoxide-removing enzymes-catalase and glutathione system, and superoxide dismutase. In addition, benfotiamine showed the capacity to directly scavenge superoxide radical anion. As a consequence, benfotiamine suppressed the activation of microglia and provoked a decrease in NO and (·)O(-) 2 production and lipid peroxidation. In conclusion, benfotiamine might silence pro-oxidative activity of microglia to alleviate/prevent oxidative damage of neighboring CNS cells.

A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with diabetic nephropathy.

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Alkhalaf, Alaa; Klooster, Astrid; van Oeveren, Willem; Achenbach, Ulrike; Kleefstra, Nanne; Slingerland, Robbert J; Mijnhout, G Sophie; Bilo, Henk J G; Gans, Reinold O B; Navis, Gerjan J; Bakker, Stephan J L

2010-07-01

To investigate the effect of benfotiamine on urinary albumin excretion (UAE) and the tubular damage marker kidney injury molecule-1 (KIM-1) in patients with type 2 diabetes and nephropathy. Patients with type 2 diabetes and UAE equivalent to 15-300 mg/24 h, despite ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs), were randomly assigned to 12 weeks of benfotiamine (900 mg/day) (n = 39) or placebo (n = 43). Compared with placebo, benfotiamine treatment resulted in significant improvement of thiamine status (P Benfotiamine treatment did not significantly decrease 24-h UAE or 24-h KIM-1 excretion. In patients with type 2 diabetes and nephropathy, high-dose benfotiamine treatment for 12 weeks in addition to ACE-Is or ARBs did not reduce UAE or KIM-1 excretion, despite improvement of thiamine status.

Effect of benfotiamine in podocyte damage induced by peritoneal dialysis fluid

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Sandra eMüller-Krebs

2015-03-01

Full Text Available Background:In peritoneal dialysis (PD residual renal function (RRF fundamentally contributes to improved quality of life and patient survival. High glucose and advanced glycation end-products (AGE contribute locally to peritoneal and systemically to renal damage. Integrity of podocyte structure and function is of special importance to preserve RRF. Benfotiamine could counteract the glucose and AGE mediated toxicity by blocking hyperglycemia associated podocyte damage via the pentose phosphate pathway.Methods: A human differentiated podocyte cell line was incubated with control solution (Control, 2.5% glucose solution (Glucose and 2.5% PD fluid (PDF for 48 h either ± 50 μM benfotiamine.Podocyte damage and potential benefit of benfotiamine were analyzed using immunofluorescence, western blot analysis, and a functional migration assay. For quantitation, a semiquantitative score was used. Results:When incubating podocytes with benfotiamine, Glucose and PDF mediated damage was reduced resulting in lower expression of AGE and intact podocin and ZO-1 localization. The reorganization of the actin cytoskeleton was restored in the presence of benfotiamine as functional podocyte motility reached Control level. Decreased level of inflammation could be shown as well as reduced podocyte apoptosis.Conclusions:These data suggest that benfotiamine protects podocytes from Glucose and PDF mediated dysfunction and damage, in particular with regard to cytoskeletal reorganization, motility, inflammation and podocyte survival.

Pharmacokinetic study of benfotiamine and the bioavailability assessment compared to thiamine hydrochloride.

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Xie, Feifan; Cheng, Zeneng; Li, Sanwang; Liu, Xingling; Guo, Xin; Yu, Peng; Gu, Zhenkun

2014-06-01

Benfotiamine is a lipid-soluble thiamine precursor which can transform to thiamine in vivo and subsequently be metabolized to thiamine monophosphate (TMP) and thiamine diphosphate (TDP). This study investigated the pharmacokinetic profiles of thiamine and its phosphorylated metabolites after single- and multiple-dose administration of benfotiamine in healthy Chinese volunteers, and assessed the bioavailability of orally benfotiamine administration compared to thiamine hydrochloride. In addition, concentration of hippuric acid in urine which is produced in the transformation process of benfotiamine was determined. The results showed that thiamine and its phosphorylated metabolites exhibited different pharmacokinetic characteristics in plasma, blood and erythrocyte, and one-compartment model provided the best fit for pharmacokinetic profiles of thiamine. The transformation process of benfotiamine to thiamine produced large amount of hippuric acid. No accumulation of hippuric acid was observed after multiple-dose of benfotiamine. Compared to thiamine hydrochloride, the bioavailability of thiamine in plasma and TDP in erythrocyte after oral administration of benfotiamine were 1147.3 ± 490.3% and 195.8 ± 33.8%, respectively. The absorption rate and extent of benfotiamine systemic availability of thiamine were significantly increased indicating higher bioavailability of thiamine from oral dose of benfotiamine compared to oral dose of thiamine hydrochloride. © 2014, The American College of Clinical Pharmacology.

Benfotiamine protects against peritoneal and kidney damage in peritoneal dialysis.

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Kihm, Lars P; Müller-Krebs, Sandra; Klein, Julia; Ehrlich, Gregory; Mertes, Laura; Gross, Marie-Luise; Adaikalakoteswari, Antonysunil; Thornalley, Paul J; Hammes, Hans-Peter; Nawroth, Peter P; Zeier, Martin; Schwenger, Vedat

2011-05-01

Residual renal function and the integrity of the peritoneal membrane contribute to morbidity and mortality among patients treated with peritoneal dialysis. Glucose and its degradation products likely contribute to the deterioration of the remnant kidney and damage to the peritoneum. Benfotiamine decreases glucose-induced tissue damage, suggesting the potential for benefit in peritoneal dialysis. Here, in a model of peritoneal dialysis in uremic rats, treatment with benfotiamine decreased peritoneal fibrosis, markers of inflammation, and neovascularization, resulting in improved characteristics of peritoneal transport. Furthermore, rats treated with benfotiamine exhibited lower expression of advanced glycation endproducts and their receptor in the peritoneum and the kidney, reduced glomerular and tubulointerstitial damage, and less albuminuria. Increased activity of transketolase in tissue and blood contributed to the protective effects of benfotiamine. In primary human peritoneal mesothelial cells, the addition of benfotiamine led to enhanced transketolase activity and decreased expression of advanced glycation endproducts and their receptor. Taken together, these data suggest that benfotiamine protects the peritoneal membrane and remnant kidney in a rat model of peritoneal dialysis and uremia. Copyright © 2011 by the American Society of Nephrology

Double-blind, randomized placebo-controlled clinical trial of benfotiamine for severe alcohol dependence.

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Manzardo, Ann M; He, Jianghua; Poje, Albert; Penick, Elizabeth C; Campbell, Jan; Butler, Merlin G

2013-12-01

Alcohol dependence is associated with severe nutritional and vitamin deficiency. Vitamin B1 (thiamine) deficiency erodes neurological pathways that may influence the ability to drink in moderation. The present study examines tolerability of supplementation using the high-potency thiamine analog, benfotiamine (BF), and BF's effects on alcohol consumption in severely affected, self-identified, alcohol dependent subjects. A randomized, double-blind, placebo-controlled trial was conducted on 120 non-treatment seeking, actively drinking, alcohol dependent men and women volunteers (mean age=47 years) from the Kansas City area who met DSM-IV-TR criteria for current alcohol dependence. Subjects were randomized to receive 600 mg benfotiamine or placebo (PL) once daily by mouth for 24 weeks with 6 follow-up assessments scheduled at 4 week intervals. Side effects and daily alcohol consumption were recorded. Seventy (58%) subjects completed 24 weeks of study (N=21 women; N=49 men) with overall completion rates of 55% (N=33) for PL and 63% (N=37) for BF groups. No significant adverse events were noted and alcohol consumption decreased significantly for both treatment groups. Alcohol consumption decreased from baseline levels for 9 of 10 BF treated women after 1 month of treatment compared with 2 of 11 on PL. Reductions in total alcohol consumption over 6 months were significantly greater for BF treated women (BF: N=10, -611 ± 380 standard drinks; PL: N=11, -159 ± 562 standard drinks, p-value=0.02). BF supplementation of actively drinking alcohol dependent men and women was well-tolerated and may discourage alcohol consumption among women. The results do support expanded studies of BF treatment in alcoholism. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Benfotiamine relieves inflammatory and neuropathic pain in rats.

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Sánchez-Ramírez, Gabriela M; Caram-Salas, Nadia L; Rocha-González, Héctor I; Vidal-Cantú, Guadalupe C; Medina-Santillán, Roberto; Reyes-García, Gerardo; Granados-Soto, Vinicio

2006-01-13

Benfotiamine has shown therapeutic efficacy in the treatment of painful diabetic neuropathy in human beings. However, so far there is no evidence about the efficacy of this drug in preclinical models of pain. The purpose of this study was to assess the possible antinociceptive and antiallodynic effect of benfotiamine in inflammatory and neuropathic pain models in the rat. Inflammatory pain was induced by injection of formalin in non-diabetic and diabetic (2 weeks) rats. Reduction of flinching behavior was considered as antinociception. Neuropathic pain was induced by either ligation of left L5/L6 spinal nerves or administration of streptozotocin (50 mg/kg, i.p.) in Wistar rats. Benfotiamine significantly reduced inflammatory (10-300 mg/kg) and neuropathic (75-300 mg/kg) nociception in non-diabetic and diabetic rats. Results indicate that oral administration of benfotiamine is able to reduce tactile allodynia from different origin in the rat and they suggest the use of this drug to reduce inflammatory and neuropathic pain in humans.

Benfotiamine and Alpha-Lipoic Acid in the Treatment of Diabetic Cardiovascular Autonomic Neuropathy (Review of Literature and Own Researches

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V.O. Sergiyenko

2014-04-01

Full Text Available The analysis of current views on the mechanisms of fat-soluble form of vitamin B1 (benfotiamine and α-lipoic acid action, in particular features of their impact on carbohydrate and lipid metabolism, endothelial function, hemodynamics, vessel stiffness in cardiovascular diseases, cardiovascular autonomic neuropathy in type 2 diabetes mellitus, was perfomed. The results of experimental, randomized and own studies confirmed the value of the combined administration of benfotiamine and α-lipoic acid for the prevention and treatment of cardiovascular diseases, in particular cardiovascular autonomic neuropathy in patients with type 2 diabetes mellitus.

Efficient Transdermal Delivery of Benfotiamine in an Animal Model

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Gyula Varadi

2015-01-01

Full Text Available We designed a transdermal system to serve as a delivery platform for benfotiamine utilizing the attributes of passive penetration enhancing molecules to penetrate through the outer layers of skin combined with the advance of incorporating various peripherally-acting vasodilators to enhance drug uptake.  Benfotiamine, incorporated into this transdermal formulation, was applied to skin in an animal model in order to determine the ability to deliver this thiamine pro-drug effectively to the sub-epithelial layers.  In this proof of concept study in guinea pigs, we found that a single topical application of either a solubilized form of benfotiamine (15 mg or a microcrystalline suspension form (25 mg resulted in considerable increases of the dephosphorylated benfotiamine (S-benzoylthiamine in the skin tissue as well as in significant increases in the thiamine and thiamine phosphate pools compared to control animals.  The presence of a ~8000x increase in thiamine and increases in its phosphorylated derivatives in the epidermis and dermis tissue of the test animals gives a strong indication that the topical treatment with benfotiamine works very well for the desired outcome of producing an intracellular increase of the activating cofactor pool for transketolase enzyme, which is implicated in the pathophysiology of diabetic neuropathy.

The effects of long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory markers in patients with type 1 diabetes: a 24-month, double-blind, randomized, placebo-controlled trial.

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Fraser, David A; Diep, Lien M; Hovden, Inger Anette; Nilsen, Kristian B; Sveen, Kari Anne; Seljeflot, Ingebjørg; Hanssen, Kristian F

2012-05-01

To study the effects of long-term oral benfotiamine supplementation on peripheral nerve function and soluble inflammatory markers in patients with type 1 diabetes. The study randomly assigned 67 patients with type 1 diabetes to receive 24-month benfotiamine (300 mg/day) or placebo supplementation. Peripheral nerve function and levels of soluble inflammatory variables were assessed at baseline and at 24 months. Fifty-nine patients completed the study. Marked increases in whole-blood concentrations of thiamine and thiamine diphosphate were found in the benfotiamine group (both P benfotiamine (300 mg/day) supplementation over 24 months has no significant effects upon peripheral nerve function or soluble markers of inflammation in patients with type 1 diabetes.

Detection of transketolase in bone marrow-derived insulin-producing cells: benfotiamine enhances insulin synthesis and glucose metabolism.

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Oh, Seh-Hoon; Witek, Rafal P; Bae, Si-Hyun; Darwiche, Houda; Jung, Youngmi; Pi, Liya; Brown, Alicia; Petersen, Bryon E

2009-01-01

Adult bone marrow (BM)-derived insulin-producing cells (IPCs) are capable of regulating blood glucose levels in chemically induced hyperglycemic mice. Using cell transplantation therapy, fully functional BM-derived IPCs help to mediate treatment of diabetes mellitus. Here, we demonstrate the detection of the pentose phosphate pathway enzyme, transketolase (TK), in BM-derived IPCs cultured under high-glucose conditions. Benfotiamine, a known activator of TK, was not shown to affect the proliferation of insulinoma cell line, INS-1; however, when INS-1 cells were cultured with oxythiamine, an inhibitor of TK, cell proliferation was suppressed. Treatment with benfotiamine activated glucose metabolism in INS-1 cells in high-glucose culture conditions, and appeared to maximize the BM-derived IPCs ability to synthesize insulin. Benfotiamine was not shown to induce the glucose receptor Glut-2, however it was shown to activate glucokinase, the enzyme responsible for conversion of glucose to glucose-6-phosphate. Furthermore, benfotiamine-treated groups showed upregulation of the downstream glycolytic enzyme, glyceraldehyde phosphate dehydrogenase (GAPDH). However, in cells where the pentose phosphate pathway was blocked by oxythiamine treatment, there was a clear downregulation of Glut-2, glucokinase, insulin, and GAPDH. When benfotiamine was used to treat mice transplanted with BM-derived IPCs transplanted, their glucose level was brought to a normal range. The glucose challenge of normal mice treated with benfotiamine lead to rapidly normalized blood glucose levels. These results indicate that benfotiamine activates glucose metabolism and insulin synthesis to prevent glucose toxicity caused by high concentrations of blood glucose in diabetes mellitus.

Detection of Transketolase in Bone Marrow—Derived Insulin-Producing Cells: Benfotiamine Enhances Insulin Synthesis and Glucose Metabolism

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Witek, Rafal P.; Bae, Si-Hyun; Darwiche, Houda; Jung, Youngmi; Pi, Liya; Brown, Alicia; Petersen, Bryon E.

2009-01-01

Adult bone marrow (BM)-derived insulin-producing cells (IPCs) are capable of regulating blood glucose levels in chemically induced hyperglycemic mice. Using cell transplantation therapy, fully functional BM-derived IPCs help to mediate treatment of diabetes mellitus. Here, we demonstrate the detection of the pentose phosphate pathway enzyme, transketolase (TK), in BM-derived IPCs cultured under high-glucose conditions. Benfotiamine, a known activator of TK, was not shown to affect the proliferation of insulinoma cell line, INS-1; however, when INS-1 cells were cultured with oxythiamine, an inhibitor of TK, cell proliferation was suppressed. Treatment with benfotiamine activated glucose metabolism in INS-1 cells in high-glucose culture conditions, and appeared to maximize the BM-derived IPCs ability to synthesize insulin. Benfotiamine was not shown to induce the glucose receptor Glut-2, however it was shown to activate glucokinase, the enzyme responsible for conversion of glucose to glucose-6-phosphate. Furthermore, benfotiamine-treated groups showed upregulation of the downstream glycolytic enzyme, glyceraldehyde phosphate dehydrogenase (GAPDH). However, in cells where the pentose phosphate pathway was blocked by oxythiamine treatment, there was a clear downregulation of Glut-2, glucokinase, insulin, and GAPDH. When benfotiamine was used to treat mice transplanted with BM-derived IPCs transplanted, their glucose level was brought to a normal range. The glucose challenge of normal mice treated with benfotiamine lead to rapidly normalized blood glucose levels. These results indicate that benfotiamine activates glucose metabolism and insulin synthesis to prevent glucose toxicity caused by high concentrations of blood glucose in diabetes mellitus. PMID:18393672

Change in psychiatric symptomatology after benfotiamine treatment in males is related to lifetime alcoholism severity.

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Manzardo, Ann M; Pendleton, Tiffany; Poje, Albert; Penick, Elizabeth C; Butler, Merlin G

2015-07-01

Severe alcoholism can be associated with significant nutritional and vitamin deficiency, especially vitamin B1 (thiamine) which is associated with neurological deficits impacting mood and cognition. Alcohol consumption was reduced among female but not male alcoholics after supplementation with the high potency thiamine analog benfotiamine (BF). We examined the relationship between lifetime alcoholism severity, psychiatric symptoms and response to BF among the alcohol dependent men from this cohort. Eighty-five adult men (mean age=48±8 years) meeting DSM-IV-TR criteria for a current alcohol use disorder who were abstinent Alcoholism Severity Score (AS), Symptom Checklist 90R (SCL-90R), and the Barratt Impulsivity Scale (BIS) at baseline and at 6 months. Baseline SCL-90-R scale scores for men with high alcoholism severity (AS≥24; N=46 HAS) were significantly greater than for men with low alcoholism severity (ASalcoholism severity level interaction (F=2.5, dfnum=10, dfden=30, palcohol use disorder and should be considered for adjuvant therapy in alcohol rehabilitation. #NCT00680121 High Dose Vitamin B1 to Reduce Abusive Alcohol Use. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Oral benfotiamine plus alpha-lipoic acid normalises complication-causing pathways in type 1 diabetes.

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Du, X; Edelstein, D; Brownlee, M

2008-10-01

We determined whether fixed doses of benfotiamine in combination with slow-release alpha-lipoic acid normalise markers of reactive oxygen species-induced pathways of complications in humans. Male participants with and without type 1 diabetes were studied in the General Clinical Research Centre of the Albert Einstein College of Medicine. Glycaemic status was assessed by measuring baseline values of three different indicators of hyperglycaemia. Intracellular AGE formation, hexosamine pathway activity and prostacyclin synthase activity were measured initially, and after 2 and 4 weeks of treatment. In the nine participants with type 1 diabetes, treatment had no effect on any of the three indicators used to assess hyperglycaemia. However, treatment with benfotiamine plus alpha-lipoic acid completely normalised increased AGE formation, reduced increased monocyte hexosamine-modified proteins by 40% and normalised the 70% decrease in prostacyclin synthase activity from 1,709 +/- 586 pg/ml 6-keto-prostaglandin F(1alpha) to 4,696 +/- 533 pg/ml. These results show that the previously demonstrated beneficial effects of these agents on complication-causing pathways in rodent models of diabetic complications also occur in humans with type 1 diabetes.

Benfotiamine prevents increased β-amyloid production in HEK cells induced by high glucose.

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Sun, Xiao-Jing; Zhao, Lei; Zhao, Na; Pan, Xiao-Li; Fei, Guo-Qiang; Jin, Li-Rong; Zhong, Chun-Jiu

2012-10-01

To determine whether high glucose enhances β-amyloid (Aβ) production in HEK293 Swedish mutant (APPsw) cells with Aβ precursor protein (APP) overexpression, and whether under this condition benfotiamine reduces the increased Aβ production. HEK293 APPsw cells were cultured with different concentrations of glucose for different times. The Aβ content in the supernatant was determined by ELISA. To investigate the mechanism by which benfotiamine reduced Aβ production, glycogen synthase kinase-3 (GSK-3) activity and expression were measured after the cells were cultured with 5.5 g/L glucose for 12 h. With 1.0, 3.0, 4.5, 5.5, 6.5, 7.5, 8.5, or 10.5 g/L glucose, Aβ production by HEK293 APPsw cells was highest in the presence of 5.5 g/L glucose for 6 and 12 h. The difference in Aβ content between 5.5 and 1.0 g/L was most marked after incubation for 12 h. Benfotiamine at 20 and 40 μg/mL significantly reduced Aβ production in cells incubated with 5.5 g/L glucose for 12 h. Moreover, 40 μg/mL benfotiamine significantly enhanced the ratio of phosphorylated GSK-3 to total GSK-3, together with consistent down-regulation of GSK-3 activity. High glucose increases Aβ production by HEK293 APPsw cells while benfotiamine prevents this increase. This is correlated with the modulation of GSK-3 activity.

Thiamine and benfotiamine improve cognition and ameliorate GSK-3β-associated stress-induced behaviours in mice.

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Markova, Nataliia; Bazhenova, Nataliia; Anthony, Daniel C; Vignisse, Julie; Svistunov, Andrey; Lesch, Klaus-Peter; Bettendorff, Lucien; Strekalova, Tatyana

2017-04-03

Thiamine (vitamin B1) deficiency in the brain has been implicated in the development of dementia and symptoms of depression. Indirect evidence suggests that thiamine may contribute to these pathologies by controlling the activities of glycogen synthase kinase (GSK)-3β. While decreased GSK-3β activity appears to impair memory, increased GSK-3β activity is associated with the distressed/depressed state. However, hitherto direct evidence for the effects of thiamine on GSK-3β function has not been reported. Here, we administered thiamine or, the more bioavailable precursor, benfotiamine at 200mg/kg/day for 2weeks to C57BL/6J mice, to determine whether treatment might affect behaviours that are known to be sensitive to GSK-3β activity and whether such administration impacts on GSK-3β expression within the brain. The mice were tested in models of contextual conditioning and extinction, a 5-day rat exposure stress test, and a modified swim test with repeated testing. The tricyclic antidepressant imipramine (7.5mg/kg/day), was administered as a positive control for the effects of thiamine or benfotiamine. As for imipramine, both compounds inhibited the upregulation of GSK-3β induced by predator stress or repeated swimming, and reduced floating scores and the predator stress-induced behavioural changes in anxiety and exploration. Coincident, thiamine and benfotiamine improved learning and extinction of contextual fear, and the acquisition of the step-down avoidance task. Our data indicate that thiamine and benfotiamine have antidepressant/anti-stress effects in naïve animals that are associated with reduced GSK-3β expression and conditioning of adverse memories. Thus thiamine and benfotiamine may modulate GSK-3β functions in a manner that is dependent on whether the contextual conditioning is adaptive or maladaptive. Copyright © 2016 Elsevier Inc. All rights reserved.

High-dose benfotiamine rescues cardiomyocyte contractile dysfunction in streptozotocin-induced diabetes mellitus.

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Ceylan-Isik, Asli F; Wu, Shan; Li, Qun; Li, Shi-Yan; Ren, Jun

2006-01-01

Diabetic cardiomyopathy is characterized by cardiac dysfunction. This study was designed to examine the effect of benfotiamine, a lipophilic derivative of thiamine, on streptozotocin (STZ)-induced cardiac contractile dysfunction in mouse cardiomyocytes. Adult male FVB mice were made diabetic with a single injection of STZ (200 mg/kg ip). Fourteen days later, control and diabetic (fasting plasma glucose > 13.9 mM) mice were put on benfotiamine therapy (100 mg.kg(-1).day(-1) ip) for another 14 days. Mechanical and intracellular Ca2+ properties were evaluated in left ventricular myocytes using an IonOptix MyoCam system. The following indexes were evaluated: peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR90), maximal velocity of shortening/relengthening, resting and rise of intracellular Ca2+ in response to electrical stimulus, sarcoplasmic reticulum (SR) Ca2+ load, and intracellular Ca2+ decay rate (tau). Two- or four-week STZ treatment led to hyperglycemia, prolonged TPS and TR90, reduced SR Ca2+ load, elevated resting intracellular Ca2+ level and prolonged tau associated with normal PS, maximal velocity of shortening/relengthening, and intracellular Ca2+ rise in response to electrical stimulus. Benfotiamine treatment abolished prolongation in TPS, TR90, and tau, as well as reduction in SR Ca2+ load without affecting hyperglycemia and elevated resting intracellular Ca2+. Diabetes triggered oxidative stress, measured by GSH-to-GSSG ratio and formation of advanced glycation end product (AGE) in the hearts. Benfotiamine treatment alleviated oxidative stress without affecting AGE or protein carbonyl formation. Collectively, our results indicated that benfotiamine may rescue STZ-induced cardiomyocyte dysfunction but not AGE formation in short-term diabetes.

Efficient Transdermal Delivery of Benfotiamine in an Animal Model

OpenAIRE

Varadi, Gyula; Zhu, Zhen; G. Carter, Stephen

2015-01-01

We designed a transdermal system to serve as a delivery platform for benfotiamine utilizing the attributes of passive penetration enhancing molecules to penetrate through the outer layers of skin combined with the advance of incorporating various peripherally-acting vasodilators to enhance drug uptake.  Benfotiamine, incorporated into this transdermal formulation, was applied to skin in an animal model in order to determine the ability to deliver this thiamine pro-drug effectively to the sub-...

The defensive effect of benfotiamine in sodium arsenite-induced experimental vascular endothelial dysfunction.

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Verma, Sanjali; Reddy, Krishna; Balakumar, Pitchai

2010-10-01

The present study has been designed to investigate the effect of benfotiamine, a thiamine derivative, in sodium arsenite-induced vascular endothelial dysfunction (VED) in rats. Sodium arsenite (1.5 mg(-1) kg(-1) day(-1) i.p., 2 weeks) was administered in rats to produce VED. The development of VED was assessed by employing isolated aortic ring preparation and estimating the serum and aortic concentrations of nitrite/nitrate. Further, the integrity of vascular endothelium in thoracic aorta was assessed by scanning electron microscopy. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide anion generation. The administration of sodium arsenite markedly produced VED by attenuating acetylcholine-induced endothelium-dependent relaxation, decreasing serum and aortic concentrations of nitrite/nitrate, and impairing the integrity of vascular endothelium. Further, sodium arsenite produced oxidative stress by increasing serum TBARS and aortic superoxide generation. The treatment with benfotiamine (25, 50, and 100 mg(-1) kg(-1) day(-1) p.o.) or atorvastatin (30 mg(-1) kg(-1) day(-1) p.o., a standard agent) prevented sodium arsenite-induced VED and oxidative stress. However, the beneficial effects of benfotiamine in preventing the sodium arsenite-induced VED were attenuated by co-administration with N-omega-nitro-L: -arginine methyl ester (L: -NAME) (25 mg(-1) kg(-1) day(-1), i.p.), an inhibitor of NOS. Thus, it may be concluded that benfotiamine reduces oxidative stress and activates endothelial nitric oxide synthase to enhance the generation and bioavailability of NO and subsequently improves the integrity of vascular endothelium to prevent sodium arsenite-induced experimental VED.

Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine.

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Babaei-Jadidi, Roya; Karachalias, Nikolaos; Ahmed, Naila; Battah, Sinan; Thornalley, Paul J

2003-08-01

Accumulation of triosephosphates arising from high cytosolic glucose concentrations in hyperglycemia is the trigger for biochemical dysfunction leading to the development of diabetic nephropathy-a common complication of diabetes associated with a high risk of cardiovascular disease and mortality. Here we report that stimulation of the reductive pentosephosphate pathway by high-dose therapy with thiamine and the thiamine monophosphate derivative benfotiamine countered the accumulation of triosephosphates in experimental diabetes and inhibited the development of incipient nephropathy. High-dose thiamine and benfotiamine therapy increased transketolase expression in renal glomeruli, increased the conversion of triosephosphates to ribose-5-phosphate, and strongly inhibited the development of microalbuminuria. This was associated with decreased activation of protein kinase C and decreased protein glycation and oxidative stress-three major pathways of biochemical dysfunction in hyperglycemia. Benfotiamine also inhibited diabetes-induced hyperfiltration. This was achieved without change in elevated plasma glucose concentration and glycated hemoglobin in the diabetic state. High-dose thiamine and benfotiamine therapy is a potential novel strategy for the prevention of clinical diabetic nephropathy.

Effect of benfotiamine on advanced glycation endproducts and markers of endothelial dysfunction and inflammation in diabetic nephropathy.

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Alaa Alkhalaf

Full Text Available Formation of advanced glycation endproducts (AGEs, endothelial dysfunction, and low-grade inflammation are intermediate pathways of hyperglycemia-induced vascular complications. We investigated the effect of benfotiamine on markers of these pathways in patients with type 2 diabetes and nephropathy.Patients with type 2 diabetes and urinary albumin excretion in the high-normal and microalbuminuric range (15-300 mg/24h were randomized to receive benfotiamine (n = 39 or placebo (n = 43. Plasma and urinary AGEs (N(ε-(carboxymethyl lysine [CML], N(ε-(Carboxyethyl lysine [CEL], and 5-hydro-5-methylimidazolone [MG-H1] and plasma markers of endothelial dysfunction (soluble vascular cell adhesion molecule-1 [sVCAM-1], soluble intercellular adhesion molecule-1 [sICAM-1], soluble E-selectin and low-grade inflammation (high-sensitivity C-reactive protein [hs-CRP], serum amyloid-A [SAA], myeloperoxidase [MPO] were measured at baseline and after 6 and 12 weeks.Compared to placebo, benfotiamine did not result in significant reductions in plasma or urinary AGEs or plasma markers of endothelial dysfunction and low-grade inflammation.Benfotiamine for 12 weeks did not significantly affect intermediate pathways of hyperglycemia-induced vascular complications. TRIAL REGRISTRATION: ClinicalTrials.gov NCT00565318.

Effect of benfotiamine on advanced glycation endproducts and markers of endothelial dysfunction and inflammation in diabetic nephropathy.

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Alkhalaf, Alaa; Kleefstra, Nanne; Groenier, Klaas H; Bilo, Henk J G; Gans, Reinold O B; Heeringa, Peter; Scheijen, Jean L; Schalkwijk, Casper G; Navis, Gerjan J; Bakker, Stephan J L

2012-01-01

Formation of advanced glycation endproducts (AGEs), endothelial dysfunction, and low-grade inflammation are intermediate pathways of hyperglycemia-induced vascular complications. We investigated the effect of benfotiamine on markers of these pathways in patients with type 2 diabetes and nephropathy. Patients with type 2 diabetes and urinary albumin excretion in the high-normal and microalbuminuric range (15-300 mg/24h) were randomized to receive benfotiamine (n = 39) or placebo (n = 43). Plasma and urinary AGEs (N(ε)-(carboxymethyl) lysine [CML], N(ε)-(Carboxyethyl) lysine [CEL], and 5-hydro-5-methylimidazolone [MG-H1]) and plasma markers of endothelial dysfunction (soluble vascular cell adhesion molecule-1 [sVCAM-1], soluble intercellular adhesion molecule-1 [sICAM-1], soluble E-selectin) and low-grade inflammation (high-sensitivity C-reactive protein [hs-CRP], serum amyloid-A [SAA], myeloperoxidase [MPO]) were measured at baseline and after 6 and 12 weeks. Compared to placebo, benfotiamine did not result in significant reductions in plasma or urinary AGEs or plasma markers of endothelial dysfunction and low-grade inflammation. Benfotiamine for 12 weeks did not significantly affect intermediate pathways of hyperglycemia-induced vascular complications. TRIAL REGRISTRATION: ClinicalTrials.gov NCT00565318.

Benfotiamine Protects against Peritoneal and Kidney Damage in Peritoneal Dialysis

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Kihm, Lars P.; Müller-Krebs, Sandra; Klein, Julia; Ehrlich, Gregory; Mertes, Laura; Gross, Marie-Luise; Adaikalakoteswari, Antonysunil; Thornalley, Paul J.; Hammes, Hans-Peter; Nawroth, Peter P.; Zeier, Martin; Schwenger, Vedat

2011-01-01

Residual renal function and the integrity of the peritoneal membrane contribute to morbidity and mortality among patients treated with peritoneal dialysis. Glucose and its degradation products likely contribute to the deterioration of the remnant kidney and damage to the peritoneum. Benfotiamine decreases glucose-induced tissue damage, suggesting the potential for benefit in peritoneal dialysis. Here, in a model of peritoneal dialysis in uremic rats, treatment with benfotiamine decreased peri...

PP2A contributes to endothelial death in high glucose: inhibition by benfotiamine.

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Du, Y; Kowluru, A; Kern, T S

2010-12-01

Endothelial death is critical in diabetic vascular diseases, but regulating factors have been only partially elucidated. Phosphatases play important regulatory roles in cell metabolism, but have not previously been implicated in hyperglycemia-induced cell death. We investigated the role of the phosphatase, type 2A protein phosphatase (PP2A), in hyperglycemia-induced changes in signaling and death in bovine aortic endothelial cells (BAEC). We explored also the influence of benfotiamine on this phosphatase. Activation of PP2A was assessed in BAEC by the extent of methylation and measurement of activity, and the enzyme was inhibited using selective pharmacological (okadaic acid, sodium fostriecin) and molecular (small interfering RNA) approaches. BAECs cultured in 30 mM glucose significantly increased PP2A methylation and activity, and PP2A inhibitors blocked these abnormalities. PP2A activity was increased also in aorta and retina from diabetic rats. NF-κB activity and cell death in BAEC were significantly increased in 30 mM glucose and inhibited by PP2A inhibition. NF-κB played a role in the hyperglycemia-induced death of BAEC, since blocking its translocation with SN50 also inhibited cell death. Inhibition of PP2A blocked the hyperglycemia-induced dephosphorylation of NF-κB and Bad, thus favoring cell survival. Incubation of benfotiamine with BAEC inhibited the high glucose-induced activation of PP2A and NF-κB and cell death, as well as several other metabolic defects, which likewise were inhibited by inhibitors of PP2A. Activation of PP2A contributes to endothelial cell death in high glucose, and beneficial actions of benfotiamine are due, at least in part, to inhibition of PP2A activation.

Benfotiamine enhances antioxidant defenses and protects against cisplatin-induced DNA damage in nephrotoxic rats.

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Harisa, Gamaleldin I

2013-08-01

The objective of the present study was to assess superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), paraoxonase (PON1), glutathione reductase (GR), and catalase (CAT) activities ratio and their relationship with DNA oxidative damage in rats treated with cisplatin (3 mg/kg bwt/day) in the presence and absence of benfotiamine (100 mg/kg/day) for 25 days. Cisplatin-induced renal damage was evidenced by renal dysfunction and elevated oxidative stress markers. SOD activity and levels of nitric oxide, protein carbonyl, malondialdehyde, and 8-hydroxy-2'-deoxyguanosine were significantly increased by cisplatin treatment. Moreover, the ratios of GPx/GR, SOD/GPx, SOD/CAT, and SOD/PON1 were significantly increased compared to control. In contrast, glutathione levels were significantly decreased by cisplatin treatment. Simultaneous treatment of rats with cisplatin and benfotiamine ameliorate these variables to values near to those of control rats. This study suggests that benfotiamine can prevent cisplatin-induced nephrotoxicity by inhibiting formation reactive species of oxygen and nitrogen. © 2013 Wiley Periodicals, Inc.

Protective effect of treatment with thiamine or benfotiamine on liver oxidative damage in rat model of acute ethanol intoxication.

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Portari, Guilherme Vannucchi; Ovidio, Paula Payão; Deminice, Rafael; Jordão, Alceu Afonso

2016-10-01

The aim of this study was to evaluate possible beneficial effects of treatment with thiamine or benfotiamine in an animal model of acute ethanol intoxication. Thirty male Wistar rats were separated at random into three groups of 10 animals each: Ethanol (E), Ethanol treated with thiamine (T) and Ethanol treated with benfotiamine (BE). Rats were gavaged with single dose of ethanol (5g/kg, 40% v:v). After 30min of ethanol gavage the animals were treated with thiamine or benfotiamine. Six hours after first gavage, the animals were euthanized and blood and liver samples were collected for ethanol and oxidative stress biomarkers quantification. Serum ethanol levels were higher in animals treated with thiamine or benfotiamine while hepatic alcohol levels were higher in animals of the group treated with benfotiamine comparing to controls or thiamine treated groups. The lipid peroxidation biomarkers were diminished for the groups treated with thiamine or benfotiamine comparing to E animals. Concerning protein oxidative damage parameters, they were enhanced for animals treated with benfotiamine in relation to other groups. In conclusion, the treatment with thiamine or benfotiamine even 30min after the massive dose of ethanol has proven to be beneficial against liver damage. Improved results were obtained with benfotiamine in relation to oxidative damage from aqueous compartments. Copyright © 2016 Elsevier Inc. All rights reserved.

Thiamine and benfotiamine prevent increased apoptosis in endothelial cells and pericytes cultured in high glucose.

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Beltramo, E; Berrone, E; Buttiglieri, S; Porta, M

2004-01-01

High glucose induces pathological alterations in small and large vessels, possibly through increased formation of AGE, activation of aldose reductase and protein kinase C, and increased flux through the hexosamine pathway. We showed previously that thiamine and benfotiamine correct delayed replication and increase lactate production in endothelial cells subjected to high glucose. We now aim at verifying the effects of thiamine and benfotiamine on cell cycle, apoptosis, and expression of adhesion molecules in endothelial cells and pericytes, under high ambient glucose. Human umbilical vein endothelial cells and bovine retinal pericytes were cultured in normal (5.6 mmol/L) or high (28 mmol/L) glucose, with or without thiamine or benfotiamine, 50 or 100 micro mol/L. Apoptosis was determined by two separate ELISA methods, measuring DNA fragmentation and caspase-3 activity, respectively. Cell cycle and integrin subunits alpha3, alpha5, and beta1 concentration were measured by flow cytometry. Apoptosis was increased in high glucose after 3 days of culture, both in endothelium and pericytes. Thiamine and benfotiamine reversed such effects. Neither cell cycle traversal nor integrin concentrations were modified in these experimental conditions. Thiamine and benfotiamine correct increased apoptosis due to high glucose in cultured vascular cells. Further elucidations of the mechanisms through which they work could help set the basis for clinical use of this vitamin in the prevention and/or treatment of diabetic microangiopathy. Copyright 2004 John Wiley & Sons, Ltd.

Benfotiamine is similar to thiamine in correcting endothelial cell defects induced by high glucose.

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Pomero, F; Molinar Min, A; La Selva, M; Allione, A; Molinatti, G M; Porta, M

2001-01-01

We investigated the hypothesis that benfotiamine, a lipophilic derivative of thiamine, affects replication delay and generation of advanced glycosylation end-products (AGE) in human umbilical vein endothelial cells cultured in the presence of high glucose. Cells were grown in physiological (5.6 mM) and high (28.0 mM) concentrations of D-glucose, with and without 150 microM thiamine or benfotiamine. Cell proliferation was measured by mitochondrial dehydrogenase activity. AGE generation after 20 days was assessed fluorimetrically. Cell replication was impaired by high glucose (72.3%+/-5.1% of that in physiological glucose, p=0.001). This was corrected by the addition of either thiamine (80.6%+/-2.4%, p=0.005) or benfotiamine (87.5%+/-8.9%, p=0.006), although it not was completely normalized (p=0.001 and p=0.008, respectively) to that in physiological glucose. Increased AGE production in high glucose (159.7%+/-38.9% of fluorescence in physiological glucose, p=0.003) was reduced by thiamine (113.2%+/-16.3%, p=0.008 vs. high glucose alone) or benfotiamine (135.6%+/-49.8%, p=0.03 vs. high glucose alone) to levels similar to those observed in physiological glucose. Benfotiamine, a derivative of thiamine with better bioavailability, corrects defective replication and increased AGE generation in endothelial cells cultured in high glucose, to a similar extent as thiamine. These effects may result from normalization of accelerated glycolysis and the consequent decrease in metabolites that are extremely active in generating nonenzymatic protein glycation. The potential role of thiamine administration in the prevention or treatment of vascular complications of diabetes deserves further investigation.

Comparative autoradiographic investigations on the tissue distribution of benfotiamine versus thiamine in mice.

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Hilbig, R; Rahmann, H

1998-05-01

The tissue distribution of two therapeutically applied preparations of B-vitamins were investigated in blood and selected organs (liver, brain, muscle, kidney) of laboratory mice using autoradiographic techniques. Incorporation of lipid-soluble 3H-benfotiamine (CAS 22457-89-2) and water-soluble 3H-thiaminehydrochloride (CAS 67-03-8) (200 microCi, equivalent to 105 mg vitamin/kg body weight) was monitored between 0.75 and 168 h after an oral or subcutaneous administration. The labelled tissue slices were autoradiographically analysed after a differential histochemical extraction procedure to evaluate the respective total radioactivity, the uptake into lipid-soluble, water-soluble and residual macromolecular compounds. Evaluation of these autoradiographic data (given as mumol vitamin preparation/mg tissue equivalent) proved that benfotiamine is incorporated much better than thiaminehydrochloride independent of the administration mode. In muscle and brain tissue a 5 to 25 fold higher amount of tracer incorporation was registered following benfotiamine as compared with the thiamine application, whereas in all other organs the difference in the label was mostly between 10 and 40%. Concerning the organ specific distribution, liver and kidney were the structures labelled highest by both substances and administration procedures. In the liver, concerning all incorporation times, a higher proportion of residual macromolecular compounds was found, whereas in the kidney the proportions of lipid- as well as of water-soluble materials prevailed. These data should be clinically relevant.

Prostatic acid phosphatase is required for the antinociceptive effects of thiamine and benfotiamine.

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Hurt, Julie K; Coleman, Jennifer L; Fitzpatrick, Brendan J; Taylor-Blake, Bonnie; Bridges, Arlene S; Vihko, Pirkko; Zylka, Mark J

2012-01-01

Thiamine (Vitamin B1) is an essential vitamin that must be obtained from the diet for proper neurological function. At higher doses, thiamine and benfotiamine (S-benzoylthiamine O-monophosphate, BT)-a phosphorylated derivative of thiamine-have antinociceptive effects in animals and humans, although how these compounds inhibit pain is unknown. Here, we found that Prostatic acid phosphatase (PAP, ACPP) can dephosphorylate BT in vitro, in dorsal root ganglia (DRG) neurons and in primary-afferent axon terminals in the dorsal spinal cord. The dephosphorylated product S-benzoylthiamine (S-BT) then decomposes to O-benzoylthiamine (O-BT) and to thiamine in a pH-dependent manner, independent of additional enzymes. This unique reaction mechanism reveals that BT only requires a phosphatase for conversion to thiamine. However, we found that the antinociceptive effects of BT, thiamine monophosphate (TMP) and thiamine-a compound that is not phosphorylated-were entirely dependent on PAP at the spinal level. Moreover, pharmacokinetic studies with wild-type and Pap(-/-) mice revealed that PAP is not required for the conversion of BT to thiamine in vivo. Taken together, our study highlights an obligatory role for PAP in the antinociceptive effects of thiamine and phosphorylated thiamine analogs, and suggests a novel phosphatase-independent function for PAP.

Prostatic acid phosphatase is required for the antinociceptive effects of thiamine and benfotiamine.

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Julie K Hurt

Full Text Available Thiamine (Vitamin B1 is an essential vitamin that must be obtained from the diet for proper neurological function. At higher doses, thiamine and benfotiamine (S-benzoylthiamine O-monophosphate, BT-a phosphorylated derivative of thiamine-have antinociceptive effects in animals and humans, although how these compounds inhibit pain is unknown. Here, we found that Prostatic acid phosphatase (PAP, ACPP can dephosphorylate BT in vitro, in dorsal root ganglia (DRG neurons and in primary-afferent axon terminals in the dorsal spinal cord. The dephosphorylated product S-benzoylthiamine (S-BT then decomposes to O-benzoylthiamine (O-BT and to thiamine in a pH-dependent manner, independent of additional enzymes. This unique reaction mechanism reveals that BT only requires a phosphatase for conversion to thiamine. However, we found that the antinociceptive effects of BT, thiamine monophosphate (TMP and thiamine-a compound that is not phosphorylated-were entirely dependent on PAP at the spinal level. Moreover, pharmacokinetic studies with wild-type and Pap(-/- mice revealed that PAP is not required for the conversion of BT to thiamine in vivo. Taken together, our study highlights an obligatory role for PAP in the antinociceptive effects of thiamine and phosphorylated thiamine analogs, and suggests a novel phosphatase-independent function for PAP.

Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study.

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Stracke, H; Gaus, W; Achenbach, U; Federlin, K; Bretzel, R G

2008-11-01

Efficacy and safety of benfotiamine in treatment of diabetic polyneuropathy. Double blind, placebo-controlled, phase-III-study. 181 patients were screened. 165 patients with symmetrical, distal diabetic polyneuropathy were randomised to one of three treatment groups entering the wash-out phase and 133/124 patients were analysed in the ITT/PP analysis: Benfotiamine 600 mg per day (n=47/43), benfotiamine 300 mg per day (n=45/42) or placebo (n=41/39). After 6 weeks of treatment, the primary outcome parameter NSS (Neuropathy Symptom Score) differed significantly between the treatment groups (p=0.033) in the PP (per protocol) population. In the ITT (intention to treat) population, the improvement of NSS was slightly above significance (p=0.055). The TSS (Total Symptom Score) showed no significant differences after 6 weeks of treatment. The improvement was more pronounced at the higher benfotiamine dose and increased with treatment duration. In the TSS, best results were obtained for the symptom "pain". Treatment was well tolerated in all groups. Benfotiamine may extend the treatment option for patients with diabetic polyneuropathy based on causal influence on impaired glucose metabolism. Further studies should confirm the positive experiences.

Chemoreactomic analysis of thiamine disulfide, thiamine hydrochloride, and benfotiamine molecules

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O. A. Gromova

2017-01-01

Full Text Available Objective: to analyze the interactions that could indicate the potential pharmacological properties of the molecules of thiamin, thiamine disulfide, and others.Material and methods. The investigators simulated the properties of thiamine disulfide (bistiamin versus those of the reference molecules of thiamin hydrochloride and benfotiamine. The study was performed using chemoreactomic simulation that is the newest area in post-genome pharmacology.Results and discussion. Chemoreactomic analysis has shown that thiamine disulfide can inhibit the molecular receptors involved in blood pressure regulation: adrenoceptors, vasopressin receptor, and angiotensin receptor. Thiamine disulfide can inhibit the reuptake of serotonin, increase its levels, inhibit benzodiazepine receptor and dopamine reuptake, and enhance neuronal acetylcholine release to a large extent than benfotiamine. These molecular effects are consistent with the sedative and anticonvulsant action profile of thiamine disulfide. Simulation has indicated that thiamine disulfide has neuroprotective, anti-inflammatory, normolipidemic, and antitumor activities.Conclusion. The simulation results are confirmed by the available clinical and experimental findings and indicate the virtually unstudied molecular mechanisms of action of thiamine disulfide, benfotiamine, and thiamin hydrochloride. 

Solubility enhancement of benfotiamine, a lipid derivative of thiamine by solid dispersion technique.

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Patel, S M; Patel, R P; Prajapati, B G

2012-03-01

The present study was aimed to increase the solubility of the poorly water soluble drug benfotiamine using hydrophilic polymers (PVP K-30 and HPMC E4). Solid dispersions were prepared by kneading method. Phase solubility study, in-vitro dissolution of pure drug, physical mixtures and solid dispersions were carried out. PVP and HPMC were found to be effective in increasing the dissolution of Benfotiamine in solid dispersions when compared to pure drug. FT-IR, differential scanning calorimetry and X-ray diffractometry studies were carried out in order to characterize the drug and solid dispersion. To conclude that, the prepared solid dispersion of PVP-30 may to effectively used for the enhancement of solubility of poorly water soluble drugs such as benfotiamine.

Solubility enhancement of benfotiamine, a lipid derivative of thiamine by solid dispersion technique

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S M Patel

2012-01-01

Full Text Available The present study was aimed to increase the solubility of the poorly water soluble drug benfotiamine using hydrophilic polymers (PVP K-30 and HPMC E4. Solid dispersions were prepared by kneading method. Phase solubility study, in-vitro dissolution of pure drug, physical mixtures and solid dispersions were carried out. PVP and HPMC were found to be effective in increasing the dissolution of Benfotiamine in solid dispersions when compared to pure drug. FT-IR, differential scanning calorimetry and X-ray diffractometry studies were carried out in order to characterize the drug and solid dispersion. To conclude that, the prepared solid dispersion of PVP-30 may to effectively used for the enhancement of solubility of poorly water soluble drugs such as benfotiamine.

Ameliorative effect of combination of benfotiamine and fenofibrate in diabetes-induced vascular endothelial dysfunction and nephropathy in the rat.

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Balakumar, Pitchai; Chakkarwar, Vishal Arvind; Singh, Manjeet

2009-01-01

The study has been designed to investigate the effect of benfotiamine and fenofibrate in diabetes-induced experimental vascular endothelial dysfunction (VED) and nephropathy. The single administration of streptozotocin (STZ) (50 mg/kg, i.p.) produced diabetes, which was noted to develop VED and nephropathy in 8 weeks. The diabetes produced VED by attenuating acetylcholine-induced endothelium dependent relaxation, impairing the integrity of vascular endothelium, decreasing serum nitrite/nitrate concentration and increasing serum TBARS and aortic superoxide anion generation. Further, diabetes altered the lipid profile by increasing the serum cholesterol, triglycerides and decreasing the high density lipoprotein. The nephropathy was noted to be developed in the diabetic rat that was assessed in terms of increase in serum creatinine, blood urea, proteinuria, and glomerular damage. The benfotiamine (70 mg/kg, p.o.) and fenofibrate (32 mg/kg, p.o.) or lisinopril (1 mg/kg, p.o., a standard agent) treatments were started in diabetic rats after 1 week of STZ administration and continued for 7 weeks. The treatment with benfotiamine and fenofibrate either alone or in combination attenuated diabetes-induced VED and nephropathy. In addition, the combination of benfotiamine and fenofibrate was noted to be more effective in attenuating the diabetes-induced VED and nephropathy when compared to treatment with either drug alone or lisinopril. Treatment with fenofibrate normalizes the altered lipid profile in diabetic rats, whereas benfotiamine treatment has no effect on lipid alteration in diabetic rats. It may be concluded that diabetes-induced oxidative stress, lipids alteration, and consequent development of VED may be responsible for the induction of nephropathy in diabetic rats. Concurrent administration of benfotiamine and fenofibrate may provide synergistic benefits in preventing the development of diabetes-induced nephropathy by reducing the oxidative stress and lipid

Benfotiamine increases glucose oxidation and downregulates NADPH oxidase 4 expression in cultured human myotubes exposed to both normal and high glucose concentrations.

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Fraser, D A; Hessvik, N P; Nikolić, N; Aas, V; Hanssen, K F; Bøhn, S K; Thoresen, G H; Rustan, A C

2012-07-01

The aim of the present work was to study the effects of benfotiamine (S-benzoylthiamine O-monophosphate) on glucose and lipid metabolism and gene expression in differentiated human skeletal muscle cells (myotubes) incubated for 4 days under normal (5.5 mM glucose) and hyperglycemic (20 mM glucose) conditions. Myotubes established from lean, healthy volunteers were treated with benfotiamine for 4 days. Glucose and lipid metabolism were studied with labeled precursors. Gene expression was measured using real-time polymerase chain reaction (qPCR) and microarray technology. Benfotiamine significantly increased glucose oxidation under normoglycemic (35 and 49% increase at 100 and 200 μM benfotiamine, respectively) as well as hyperglycemic conditions (70% increase at 200 μM benfotiamine). Benfotiamine also increased glucose uptake. In comparison, thiamine (200 μM) increased overall glucose metabolism but did not change glucose oxidation. In contrast to glucose, mitochondrial lipid oxidation and overall lipid metabolism were unchanged by benfotiamine. The expression of NADPH oxidase 4 (NOX4) was significantly downregulated by benfotiamine treatment under both normo- and hyperglycemic conditions. Gene set enrichment analysis (GSEA) showed that befotiamine increased peroxisomal lipid oxidation and organelle (mitochondrial) membrane function. In conclusion, benfotiamine increases mitochondrial glucose oxidation in myotubes and downregulates NOX4 expression. These findings may be of relevance to type 2 diabetes where reversal of reduced glucose oxidation and mitochondrial capacity is a desirable goal.

Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes.

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Stirban, Alin; Negrean, Monica; Stratmann, Bernd; Gawlowski, Thomas; Horstmann, Tina; Götting, Christian; Kleesiek, Knut; Mueller-Roesel, Michaela; Koschinsky, Theodor; Uribarri, Jaime; Vlassara, Helen; Tschoepe, Diethelm

2006-09-01

Diabetes is characterized by marked postprandial endothelial dysfunction induced by hyperglycemia, hypertriglyceridemia, advanced glycation end products (AGEs), and dicarbonyls (e.g., methylglyoxal [MG]). In vitro hyperglycemia-induced MG formation and endothelial dysfunction could be blocked by benfotiamine, but in vivo effects of benfotiamine on postprandial endothelial dysfunction and MG synthesis have not been investigated in humans until now. Thirteen people with type 2 diabetes were given a heat-processed test meal with a high AGE content (HAGE; 15.100 AGE kU, 580 kcal, 54 g protein, 17 g lipids, and 48 g carbohydrates) before and after a 3-day therapy with benfotiamine (1,050 mg/day). Macrovascular flow-mediated dilatation (FMD) and microvascular reactive hyperemia, along with serum markers of endothelial disfunction (E-selectin, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1), oxidative stress, AGE, and MG were measured during both test meal days after an overnight fast and then at 2, 4, and 6 h postprandially. The HAGE induced a maximum reactive hyperemia decrease of -60.0% after 2 h and a maximum FMD impairment of -35.1% after 4 h, without affecting endothelium-independent vasodilatation. The effects of HAGE on both FMD and reactive hyperemia were completely prevented by benfotiamine. Serum markers of endothelial dysfunction and oxidative stress, as well as AGE, increased after HAGE. These effects were significantly reduced by benfotiamine. Our study confirms micro- and macrovascular endothelial dysfunction accompanied by increased oxidative stress following a real-life, heat-processed, AGE-rich meal in individuals with type 2 diabetes and suggests benfotiamine as a potential treatment.

Benfotiamine attenuates nicotine and uric acid-induced vascular endothelial dysfunction in the rat.

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Balakumar, Pitchai; Sharma, Ramica; Singh, Manjeet

2008-01-01

The study has been designed to investigate the effect of benfotiamine, a thiamine derivative, in nicotine and uric acid-induced vascular endothelial dysfunction (VED) in rats. Nicotine (2 mg kg(-1)day(-1), i.p., 4 weeks) and uric acid (150 mg kg(-1)day(-1), i.p., 3 weeks) were administered to produce VED in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum and aortic concentration of nitrite/nitrate. Further, the integrity of vascular endothelium was assessed using the scanning electron microscopy (SEM) of thoracic aorta. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide anion generation. The administration of nicotine and uric acid produced VED by impairing the integrity of vascular endothelium and subsequently decreasing serum and aortic concentration of nitrite/nitrate and attenuating acetylcholine-induced endothelium dependent relaxation. Further, nicotine and uric acid produced oxidative stress, which was assessed in terms of increase in serum TBARS and aortic superoxide generation. However, treatment with benfotiamine (70 mg kg(-1)day(-1), p.o.) or atorvastatin (30 mg kg(-1)day(-1) p.o., a standard agent) markedly prevented nicotine and uric acid-induced VED and oxidative stress by improving the integrity of vascular endothelium, increasing the concentration of serum and aortic nitrite/nitrate, enhancing the acetylcholine-induced endothelium dependent relaxation and decreasing serum TBARS and aortic superoxide anion generation. Thus, it may be concluded that benfotiamine reduces the oxidative stress and consequently improves the integrity of vascular endothelium and enhances the generation of nitric oxide to prevent nicotine and uric acid-induced experimental VED.

Variability of skin autofluorescence measurement over 6 and 12 weeks and the influence of benfotiamine treatment.

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Stirban, Alin; Pop, Alexandra; Fischer, Annelie; Heckermann, Sascha; Tschoepe, Diethelm

2013-09-01

Measurements of skin autofluorescence (SAF) allow for a simple and noninvasive quantification of tissue advanced glycation end-products (AGEs), a marker linked to the risk of diabetes complications. The aim of this study was to test the repeatability of SAF over 6 and 12 weeks and to test whether benfotiamine, a thiamine prodrug suggested to reduce AGEs formation under hyperglycemic conditions, is able to attenuate SAF when administered over 6 weeks. In a double-blind, placebo-controlled, randomized, crossover study, 22 patients with type 2 diabetes mellitus (T2DM) received 900 mg/day benfotiamine or placebo for 6 weeks (washout period of 6 weeks between). At the beginning and at the end of each treatment period, SAF was assessed in the fasting state, as well as 2, 4, and 6 h following a mixed test meal. The respective intra-individual and inter-individual variability of fasting SAF was 6.9% and 24.5% within 6 weeks and 10.9% and 23.1% within 12 weeks. The respective variability calculated for triplicate comparisons was 9.9% and 27.7%. A short-term therapy with benfotiamine did not influence SAF significantly, nor did we find a significant postprandial SAF increase. In patients with T2DM, repeated, timely spaced SAF measurements have an intra-subject variability of below 11%. Using these data, sample sizes were calculated for interventional studies aiming at reducing SAF. Benfotiamine treatment for 6 weeks did not significantly influence SAF; for this, a longer-term therapy is probably needed.

Effects of benfotiamine and coenzyme Q10 on kidney damage induced gentamicin.

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Ustuner, Mehmet Alperen; Kaman, Dilara; Colakoglu, Neriman

2017-12-01

Gentamicin (GM) is an effective antibiotic against severe infection but has limitations related to nephrotoxicity. In this study, we investigated whether benfotiamine (BFT) and coenzyme Q10 (CoQ10), could ameliorate the nephrotoxic effect of GM in rats. Rats were divided into five groups. Group 1 and 2 served as control and sham respectively, Group 3 as GM group, Group 4 as GM+CoQ10 and Group 5 as GM+BFT for 8days. At the end of the study, all rats were euthanized by cervical decapitation and then blood samples and kidneys were collected for further analysis. Serum urea, creatinine, cytokine TNF-a, oxidant and antioxidant parameters, as well as histopathological examination of kidney tissues were assessed. Gentamicin administration caused a severe nephrotoxicity which was evidenced by an elevated serum creatinine, urea and KIM-1 level as compared with the controls. Moreover, a significant increase in serum malondialdehyde, reduced glutathione. Histopathological examination of renal tissue in gentamisin administered group, there were extremly pronounced necrotic tubules in the renal cortex and hyalen cast accumulation in the medullar tubuli. BFT given to GM rats reduced these nephrotoxicity parameters. Serum creatinine, urea, and KIM-1 were almost normalized in the GM+BFT group. Benfotiamin treatment was significantly decreased necrotic tubuli and hyalen deposition in gentamisin plus benfotiamin group. CoQ10 given to GM rats did not cause any statistically significant alterations in these nephrotoxicity parameters when compared with GM group but histopathological examination of renal tissue in GM+CoQ10 administered group, CoQ10 treatment was decreased necrotic tubuli rate and hyalen accumulation in tubuli. The results from our study indicate that BFT supplement attenuates gentamicin-induced renal injury via the amelioration of oxidative stress and inflammation of renal tubular cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives.

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Volvert, Marie-Laure; Seyen, Sandrine; Piette, Marie; Evrard, Brigitte; Gangolf, Marjorie; Plumier, Jean-Christophe; Bettendorff, Lucien

2008-06-12

Lipid-soluble thiamine precursors have a much higher bioavailability than genuine thiamine and therefore are more suitable for therapeutic purposes. Benfotiamine (S-benzoylthiamine O-monophosphate), an amphiphilic S-acyl thiamine derivative, prevents the progression of diabetic complications, probably by increasing tissue levels of thiamine diphosphate and so enhancing transketolase activity. As the brain is particularly sensitive to thiamine deficiency, we wanted to test whether intracellular thiamine and thiamine phosphate levels are increased in the brain after oral benfotiamine administration. Benfotiamine that is practically insoluble in water, organic solvents or oil was solubilized in 200 mM hydroxypropyl-beta-cyclodextrin and the mice received a single oral administration of 100 mg/kg. Though thiamine levels rapidly increased in blood and liver to reach a maximum after one or two hours, no significant increase was observed in the brain. When mice received a daily oral administration of benfotiamine for 14 days, thiamine derivatives were increased significantly in the liver but not in the brain, compared to control mice. In addition, incubation of cultured neuroblastoma cells with 10 muM benfotiamine did not lead to increased intracellular thiamine levels. Moreover, in thiamine-depleted neuroblastoma cells, intracellular thiamine contents increased more rapidly after addition of thiamine to the culture medium than after addition of benfotiamine for which a lag period was observed. Our results show that, though benfotiamine strongly increases thiamine levels in blood and liver, it has no significant effect in the brain. This would explain why beneficial effects of benfotiamine have only been observed in peripheral tissues, while sulbutiamine, a lipid-soluble thiamine disulfide derivative, that increases thiamine derivatives in the brain as well as in cultured cells, acts as a central nervous system drug. We propose that benfotiamine only penetrates the cells

Bioavailability assessment of the lipophilic benfotiamine as compared to a water-soluble thiamin derivative.

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Bitsch, R; Wolf, M; Möller, J; Heuzeroth, L; Grüneklee, D

1991-01-01

The bioequivalence of thiamin in 2 therapeutically used preparations was tested in 10 healthy young men. Thiamin was orally administered either as lipophilic benfotiamine or as water-soluble thiamin mononitrate. Biokinetic data, measured as area under the curve and maximal concentration in plasma and hemolysate after ingestion, demonstrated a significantly improved bioavailability from the lipophilic derivative despite an ingested dose of only 40% as compared with the water-soluble salt. A superior cellular efficacy of benfotiamine was also concluded from the short-term stimulation of the thiamin-dependent transketolase activity in erythrocytes.

Benfotiamine alleviates diabetes-induced cerebral oxidative damage independent of advanced glycation end-product, tissue factor and TNF-alpha.

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Wu, Shan; Ren, Jun

2006-02-13

Diabetes mellitus leads to thiamine deficiency and multiple organ damage including diabetic neuropathy. This study was designed to examine the effect of benfotiamine, a lipophilic derivative of thiamine, on streptozotocin (STZ)-induced cerebral oxidative stress. Adult male FVB mice were made diabetic with a single injection of STZ (200 mg/kg, i.p.). Fourteen days later, control and diabetic (fasting blood glucose >13.9 mM) mice received benfotiamine (100 mg/kg/day, i.p.) for 14 days. Oxidative stress and protein damage were evaluated by glutathione/glutathione disulfide (GSH/GSSG) assay and protein carbonyl formation, respectively. Pro-oxidative or pro-inflammatory factors including advanced glycation end-product (AGE), tissue factor and tumor necrosis factor-alpha (TNF-alpha) were evaluated by immunoblot analysis. Four weeks STZ treatment led to hyperglycemia, enhanced cerebral oxidative stress (reduced GSH/GSSG ratio), elevated TNF-alpha and AGE levels without changes in protein carbonyl or tissue factor. Benfotiamine alleviated diabetes-induced cerebral oxidative stress without affecting levels of AGE, protein carbonyl, tissue factor and TNF-alpha. Collectively, our results indicated benfotiamine may antagonize diabetes-induced cerebral oxidative stress through a mechanism unrelated to AGE, tissue factor and TNF-alpha.

Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes.

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Karachalias, N; Babaei-Jadidi, R; Rabbani, N; Thornalley, P J

2010-07-01

The aim of this study was to quantify protein damage by glycation, oxidation and nitration in a rat model of diabetes at the sites of development of microvascular complications, including the effects of thiamine and benfotiamine therapy. Diabetes was induced in male Sprague-Dawley rats by 55 mg/kg streptozotocin and moderated by insulin (2 U twice daily). Diabetic and control rats were given thiamine or benfotiamine (7 or 70 mg kg(-1) day(-1)) over 24 weeks. Plasma, urine and tissues were collected and analysed for protein damage by stable isotopic dilution analysis MS. There were two- to fourfold increases in fructosyl-lysine and AGE content of glomerular, retinal, sciatic nerve and plasma protein in diabetes. Increases in AGEs were reversed by thiamine and benfotiamine therapy but increases in fructosyl-lysine were not. Methionine sulfoxide content of plasma protein and 3-nitrotyrosine content of sciatic nerve protein were increased in diabetes. Plasma glycation free adducts were increased up to twofold in diabetes; the increases were reversed by thiamine. Urinary excretion of glycation, oxidation and nitration free adducts was increased by seven- to 27-fold in diabetes. These increases were reversed by thiamine and benfotiamine therapy. AGEs, particularly arginine-derived hydroimidazolones, accumulate at sites of microvascular complication development and have markedly increased urinary excretion rates in experimental diabetes. Thiamine and benfotiamine supplementation prevented tissue accumulation and increased urinary excretion of protein glycation, oxidation and nitration adducts. Similar effects may contribute to the reversal of early-stage clinical diabetic nephropathy by thiamine.

A Double-Blind, Randomized, Placebo-Controlled Clinical Trial on Benfotiamine Treatment in Patients With Diabetic Nephropathy

NARCIS (Netherlands)

Alkhalaf, Alaa; Klooster, Astrid; van Oeveren, Willem; Achenbach, Ulrike; Kleefstra, Nanne; Slingerland, Robbert J.; Mijnhout, G. Sophie; Bilo, Henk J. G.; Gans, Reinold O. B.; Navis, Gerjan J.; Bakker, Stephan J. L.

OBJECTIVE - To investigate the effect of benfotiamine on urinary albumin excretion (UAE) and the tubular damage marker kidney injury molecule-1 (KIM-1) in patients with type 2 diabetes and nephropathy. RESEARCH DESIGN AND METHODS - Patients with type 2 diabetes and UAE equivalent to 15-300 mg/24 h,

Effectiveness of egg immersion in aqueous solutions of thiamine and thiamine analogs for reducing early mortality syndrome

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Brown, S.B.; Brown, L.R.; Brown, M.; Moore, K.; Villella, M.; Fitzsimons, J.D.; Williston, B.; Honeyfield, D.C.; Hinterkopf, J.P.; Tillitt, D.E.; Zajicek, J.L.; Wolgamood, M.

2005-01-01

Protocols used for therapeutic thiamine treatments in salmonine early mortality syndrome (EMS) were investigated in lake trout Salvelinus namaycush and coho salmon Oncorhynchus kisutch to assess their efficacy. At least 500 mg of thiamine HCl/L added to egg baths was required to produce a sustained elevation of thiamine content in lake trout eggs. Thiamine uptake from egg baths was not influenced by a pH ranging from 5.5 to 7.5 or by a water hardness between 2 and 200 mg CaCO3/L. There was poorer thiamine uptake when initial thiamine levels were low, suggesting that current treatment regimes may not be as effective when thiamine levels are severely depressed and that higher treatment doses are necessary. Exposure of eggs to the more lipid-soluble thiamine analog allithiamine (1,000 mg/L) during water hardening increased egg thiamine levels by 1.5-2.5 nmol/g and was completely effective at reversing EMS. Another more lipid-soluble thiamine analog, benfotiamine (100 mg/L), reduced EMS but did not produce detectable increases in egg thiamine content. Although benfotiamine may be more effective than thiamine at mitigating EMS, it is more expensive than thiamine HCl or allithiamine. In addition, there still needs to be a more thorough examination of dose-response relationships. We conclude that allithiamine is an alternative to the use of thiamine in egg baths as a therapeutic treatment for salmonid EMS. ?? Copyright by the American Fisheries Society 2005.

Benfotiamine upregulates antioxidative system in activated BV-2 microglia cells

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Bozic, Iva; Savic, Danijela; Stevanovic, Ivana; Pekovic, Sanja; Nedeljkovic, Nadezda; Lavrnja, Irena

2015-01-01

Chronic microglial activation and resulting sustained neuroinflammatory reaction are generally associated with neurodegeneration. Activated microglia acquires proinflammatory cellular profile that generates oxidative burst. Their persistent activation exacerbates inflammation, which damages healthy neurons via cytotoxic mediators, such as superoxide radical anion and nitric oxide. In our recent study, we have shown that benfotiamine (S-benzoylthiamine O-monophosphate) possesses anti-inflammat...

Effects of thiamine and benfotiamine on intracellular glucose metabolism and relevance in the prevention of diabetic complications.

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Beltramo, Elena; Berrone, Elena; Tarallo, Sonia; Porta, Massimo

2008-09-01

Thiamine (vitamin B1) is an essential cofactor in most organisms and is required at several stages of anabolic and catabolic intermediary metabolism, such as intracellular glucose metabolism, and is also a modulator of neuronal and neuro-muscular transmission. Lack of thiamine or defects in its intracellular transport can cause a number of severe disorders. Thiamine acts as a coenzyme for transketolase (TK) and for the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes, enzymes which play a fundamental role for intracellular glucose metabolism. In particular, TK is able to shift excess fructose-6-phosphate and glycerhaldeyde-3-phosphate from glycolysis into the pentose-phosphate shunt, thus eliminating these potentially damaging metabolites from the cytosol. Diabetes might be considered a thiamine-deficient state, if not in absolute terms at least relative to the increased requirements deriving from accelerated and amplified glucose metabolism in non-insulin dependent tissues that, like the vessel wall, are prone to complications. A thiamine/TK activity deficiency has been described in diabetic patients, the correction of which by thiamine and/or its lipophilic derivative, benfotiamine, has been demonstrated in vitro to counteract the damaging effects of hyperglycaemia on vascular cells. Little is known, however, on the positive effects of thiamine/benfotiamine administration in diabetic patients, apart from the possible amelioration of neuropathic symptoms. Clinical trials on diabetic patients would be necessary to test this vitamin as a potential and inexpensive approach to the prevention and/or treatment of diabetic vascular complications.

Thiamine and benfotiamine prevent stress-induced suppression of hippocampal neurogenesis in mice exposed to predation without affecting brain thiamine diphosphate levels.

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Vignisse, Julie; Sambon, Margaux; Gorlova, Anna; Pavlov, Dmitrii; Caron, Nicolas; Malgrange, Brigitte; Shevtsova, Elena; Svistunov, Andrey; Anthony, Daniel C; Markova, Natalyia; Bazhenova, Natalyia; Coumans, Bernard; Lakaye, Bernard; Wins, Pierre; Strekalova, Tatyana; Bettendorff, Lucien

2017-07-01

Thiamine is essential for normal brain function and its deficiency causes metabolic impairment, specific lesions, oxidative damage and reduced adult hippocampal neurogenesis (AHN). Thiamine precursors with increased bioavailability, especially benfotiamine, exert neuroprotective effects not only for thiamine deficiency (TD), but also in mouse models of neurodegeneration. As it is known that AHN is impaired by stress in rodents, we exposed C57BL6/J mice to predator stress for 5 consecutive nights and studied the proliferation (number of Ki67-positive cells) and survival (number of BrdU-positive cells) of newborn immature neurons in the subgranular zone of the dentate gyrus. In stressed mice, the number of Ki67- and BrdU-positive cells was reduced compared to non-stressed animals. This reduction was prevented when the mice were treated (200mg/kg/day in drinking water for 20days) with thiamine or benfotiamine, that were recently found to prevent stress-induced behavioral changes and glycogen synthase kinase-3β (GSK-3β) upregulation in the CNS. Moreover, we show that thiamine and benfotiamine counteract stress-induced bodyweight loss and suppress stress-induced anxiety-like behavior. Both treatments induced a modest increase in the brain content of free thiamine while the level of thiamine diphosphate (ThDP) remained unchanged, suggesting that the beneficial effects observed are not linked to the role of this coenzyme in energy metabolism. Predator stress increased hippocampal protein carbonylation, an indicator of oxidative stress. This effect was antagonized by both thiamine and benfotiamine. Moreover, using cultured mouse neuroblastoma cells, we show that in particular benfotiamine protects against paraquat-induced oxidative stress. We therefore hypothesize that thiamine compounds may act by boosting anti-oxidant cellular defenses, by a mechanism that still remains to be unveiled. Our study demonstrates, for the first time, that thiamine and benfotiamine prevent

Benfotiamine counteracts glucose toxicity effects on endothelial progenitor cell differentiation via Akt/FoxO signaling.

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Marchetti, Valentina; Menghini, Rossella; Rizza, Stefano; Vivanti, Alessia; Feccia, Tiziana; Lauro, Davide; Fukamizu, Akiyoshi; Lauro, Renato; Federici, Massimo

2006-08-01

Dysfunction of mature endothelial cells is thought to play a major role in both micro- and macrovascular complications of diabetes. However, recent advances in biology of endothelial progenitor cells (EPCs) have highlighted their involvement in diabetes complications. To determine the effect of glucotoxicity on EPCs, human EPCs have been isolated from peripheral blood mononuclear cells of healthy donors and cultured in the presence or absence of high glucose (33 mmol/l) or high glucose plus benfotiamine to scavenge glucotoxicity. Morphological analysis revealed that high glucose significantly affected the number of endothelial cell colony forming units, uptake and binding of acLDL and Lectin-1, and the ability to differentiate into CD31- and vascular endothelial growth factor receptor 2-positive cells. Functional analysis outlined a reduced EPC involvement in de novo tube formation, when cocultured with mature endothelial cells (human umbilical vein endothelial cells) on matrigel. To explain the observed phenotypes, we have investigated the signal transduction pathways known to be involved in EPC growth and differentiation. Our results indicate that hyperglycemia impairs EPC differentiation and that the process can be restored by benfotiamine administration, via the modulation of Akt/FoxO1 activity.

Chemoreactomic analysis of thiamine disulfide, thiamine hydrochloride, and benfotiamine molecules

OpenAIRE

O. A. Gromova; I. Yu. Torshin; L. V. Stakhovskaya; L. E. Fedotova

2017-01-01

Objective: to analyze the interactions that could indicate the potential pharmacological properties of the molecules of thiamin, thiamine disulfide, and others.Material and methods. The investigators simulated the properties of thiamine disulfide (bistiamin) versus those of the reference molecules of thiamin hydrochloride and benfotiamine. The study was performed using chemoreactomic simulation that is the newest area in post-genome pharmacology.Results and discussion. Chemoreactomic analysis...

[The immunometaboic effects of benfotiamine and riboxine on hemolytic anemia].

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Uteshev, B S; Lazareva, G A; Prokopenko, L G

2002-01-01

Single (80 mg/kg) or multiply repeated (30 mg/kg) intramuscular injections of phenylhydrazine decrease the functional activity of mononuclear blood cells and the reduces immunological reactivity of the organism. Benfotiamine and riboxin decrease the extent of changes in the immunological response to a single administration of phenylhydrazine but do not significantly influence the immunological functions impaired by repeated injections of the hemolytic toxin.

Use of α-Lipoic Acid and Benfotiamine for Correction of Disturbance of Gastric Motor-Evacuation Function in Type 1 Diabetic Patients

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I.O. Kostitska

2015-09-01

Full Text Available The therapeutic effectiveness of α-lipoic acid and benfotiamine in treating symptoms of gastroparesis in type 1 diabetic patients was evaluated. Pathogenetic correlations between increased concentration of peripheral myelin protein and a decrease in the gastric motor-evacuation function were determined. The results of a three-month course of pathogenetic therapy demonstrate the effectiveness of combination therapy which is not associated with an improved compensation of carbohydrate and lipid metabolism. It is a result of the direct effect of preparations on the investigated metabolic processes and restoration of myelination of the nerve fibers.

Regulation of intracellular glucose and polyol pathway by thiamine and benfotiamine in vascular cells cultured in high glucose.

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Berrone, Elena; Beltramo, Elena; Solimine, Carmela; Ape, Alessandro Ubertalli; Porta, Massimo

2006-04-07

Hyperglycemia is a causal factor in the development of the vascular complications of diabetes. One of the biochemical mechanisms activated by excess glucose is the polyol pathway, the key enzyme of which, aldose reductase, transforms d-glucose into d-sorbitol, leading to imbalances of intracellular homeostasis. We aimed at verifying the effects of thiamine and benfotiamine on the polyol pathway, transketolase activity, and intracellular glucose in endothelial cells and pericytes under high ambient glucose. Human umbilical vein endothelial cells and bovine retinal pericytes were cultured in normal (5.6 mmol/liter) or high (28 mmol/liter) glucose, with or without thiamine or benfotiamine 50 or 100 mumol/liter. Transketolase and aldose reductase mRNA expression was determined by reverse transcription-PCR, and their activity was measured spectrophotometrically; sorbitol concentrations were quantified by gas chromatography-mass spectrometry and intracellular glucose concentrations by fluorescent enzyme-linked immunosorbent assay method. Thiamine and benfotiamine reduce aldose reductase mRNA expression, activity, sorbitol concentrations, and intracellular glucose while increasing the expression and activity of transketolase, for which it is a coenzyme, in human endothelial cells and bovine retinal pericytes cultured in high glucose. Thiamine and benfotiamine correct polyol pathway activation induced by high glucose in vascular cells. Activation of transketolase may shift excess glycolytic metabolites into the pentose phosphate cycle, accelerate the glycolytic flux, and reduce intracellular free glucose, thereby preventing its conversion to sorbitol. This effect on the polyol pathway, together with other beneficial effects reported for thiamine in high glucose, could justify testing thiamine as a potential approach to the prevention and/or treatment of diabetic complications.

Change in Psychiatric Symptomatology after Benfotiamine Treatment in Males is a Function of Lifetime Alcoholism Severity

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Manzardo, Ann M.; Pendleton, Tiffany; Poje, Albert; Penick, Elizabeth C.; Butler, Merlin G.

2015-01-01

Background Severe alcoholism can be associated with significant nutritional and vitamin deficiency, especially vitamin B1 (thiamine) which is associated with serious illness and neurological deficits that influence mood and cognition. We previously reported reduced alcohol consumption among female but not male alcoholics after supplementation with the high potency thiamine analog benfotiamine (BF). As a follow-up, we have examined the relationship between lifetime alcoholism severity and psychiatric symptoms among the alcohol dependent men from this cohort and their response to BF treatment. Methods Eighty-five adult men (mean age = 48 ± 8 yrs) meeting DSM-IV-TR criteria for current alcohol dependence participated in a randomized, double-blind, placebo-controlled trial of 600 mg BF vs placebo (PL) for 6 months. Psychometric testing included a derived Lifetime Alcoholism Severity Score (AS), Symptom Checklist 90R (SCL-90R), and the Barratt Impulsivity Scale (BIS) at baseline and at 6 months with data analyzed using ANOVA and MANOVA modeling. Results Baseline SCL-90-R scale scores for men with high alcoholism severity (AS ≥ 24; N=46 HAS) were significantly greater than for men with low alcoholism severity (AS < 24; N=39 LAS), but BIS scores did not differ. MANOVA modeling identified a significant treatment effect (F=2.5, df=10, p<0.03) and treatment x alcoholism severity level interaction (F=2.5, dfnum=10, dfden=30, p<0.03) with SCL-90-R scores showing a reduction in symptoms among BF treated, high severity males. Conclustion BF appears to reduce psychiatric distress and may facilitate recovery in severely affected males with lifetime alcohol dependence and should be considered for adjuvant therapy in alcohol rehabilitation. PMID:25908323

Effectiveness and retention of thiamine and its analogs administered to steelhead and landlocked Atlantic salmon

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Ketola, H.G.; Isaacs, G.R.; Robins, J.S.; Lloyd, R.C.

2008-01-01

We investigated the feasibility of enhancing the reproduction of steelhead Oncorhynchus mykiss and landlocked Atlantic salmon Salmo salar in lakes where the consumption of alewives Alosa pseudoharengus and other forage fishes containing thiaminase can cause them to become thiamine deficient and thereby reduce the survival of their fry. We evaluated feeding fingerling steelhead excess thiamine hydrochloride (THCl) for 1 or 2 weeks or equimolar amounts of thiamine mononitrate, thiamine-tetrahydrofurfuryl-disulfide, benfotiamine, or dibenzoyl thiamine (DBT). We found minimal internal reserves of thiamine after 6 months. We also compared the ability of injections of thiamine and its analogs to prevent mortality in thiamine-deficient steelhead and Atlantic salmon sac fry and found all forms to be effective, although benfotiamine was the least effective on an equimolar basis. Further, we injected yearling steelhead and found that DBT was tolerated at approximately 11,200 nmol/g of body weight, about 10 times more than thiamine in any other form. When yearling steelhead were injected with near-maximal doses of thiamine hydrochloride and several analogs and then fed a thiamine-deficient diet, DBT was retained for approximately 2 years - in contrast to other forms, which were retained for less than about 6 months. Therefore, these results suggest that neither feeding nor injecting young hatchery salmonids with DBT is likely to enhance their reproduction for more than 2 years after stocking. However, injecting DBT in nearly mature fish (either cultured fish from hatcheries or wild fish captured in lakes) may provide them with enough thiamine to successfully spawn within 2 years even though they consume mainly thiaminase-containing forage fishes. ?? Copyright by the American Fisheries Society 2008.

Benfotiamine increases glucose oxidation and downregulates NADPH oxidase 4 expression in cultured human myotubes exposed to both normal and high glucose concentrations

OpenAIRE

Fraser, D. A.; Hessvik, N. P.; Nikolić, N.; Aas, V.; Hanssen, K. F.; Bøhn, S. K.; Thoresen, G. H.; Rustan, A. C.

2011-01-01

The aim of the present work was to study the effects of benfotiamine (S-benzoylthiamine O-monophosphate) on glucose and lipid metabolism and gene expression in differentiated human skeletal muscle cells (myotubes) incubated for 4 days under normal (5.5 mM glucose) and hyperglycemic (20 mM glucose) conditions. Myotubes established from lean, healthy volunteers were treated with benfotiamine for 4 days. Glucose and lipid metabolism were studied with labeled precursors. Gene expression was measu...

Effect of Benfotiamine in Podocyte Damage Induced by Peritoneal Dialysis Fluid

OpenAIRE

M?ller-Krebs, Sandra; Nissle, Katharina; Tsobaneli, Julia; Zeier, Martin; Kihm, Lars Philipp; Kender, Zoltan; Fleming, Thomas; Nawroth, Peter Paul; Reiser, Jochen; Schwenger, Vedat

2015-01-01

Background: In peritoneal dialysis (PD), residual renal function (RRF) fundamentally contributes to improved quality of life and patient survival. High glucose and advanced glycation end-products (AGE) contribute locally to peritoneal and systemically to renal damage. Integrity of podocyte structure and function is of special importance to preserve RRF. Benfotiamine could counteract the glucose and AGE-mediated toxicity by blocking hyperglycemia-associated podocyte damage via the pentose-phos...

Chromatographic Analysis of a Multicomponent Mixture of B1, B6, B12, Benfotiamine, and Diclofenac; Part I: HPLC and UPLC Methods for the Simultaneous Quantification of These Five Components in Tablets and Capsules.

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Fayed, Ahmed Salah; Hegazy, Maha Abdel-Monem; Wahab, Nada Sayed Abdel

2016-11-01

New, simple, highly sensitive, precise, and accurate gradient reversed-phase chromatographic methods were developed using HPLC and ultra-HPLC (UPLC) systems for the determination of five components, namely thiamine, pyridoxine, cyanocobalamin, benfotiamine, and diclofenac in tablets and capsules. The methods were compared for their efficiency in the separation and determination of these five compounds using two different C18 columns (250 × 4.6 mm, 5 μm; and 100 × 4.6 mm, 2.6 μm) for HPLC and UPLC, respectively. Chromatographic separation was performed with a mobile phase containing acetonitrile and 0.025 M phosphate buffer (pH 3.5), with a gradient program and a flow rate of 1.5 and 1.0 mL/min for both methods, respectively. The methods were validated according to International Conference on Harmonization guidelines. Linearity was achieved in the range of 5.00 to 150.00 μg/mL for each of the five compounds. Ruggedness and intermediate precision were confirmed by different analysts on different columns on different days. Moreover, the components were subjected to an accelerated stability study under acidic, alkaline, and oxidative stress conditions and no interfering peaks were observed. The five compounds were efficiently separated in <20 min by HPLC, whereas for UPLC, separation was achieved in <8 min, which dramatically decreased the consumption of organic solvents.

A randomized, double-blind, crossover, placebo-controlled trial of 6 weeks benfotiamine treatment on postprandial vascular function and variables of autonomic nerve function in Type 2 diabetes.

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Stirban, A; Pop, A; Tschoepe, D

2013-10-01

In a pilot study we suggested that benfotiamine, a thiamine prodrug, prevents postprandial endothelial dysfunction in people with Type 2 diabetes mellitus. The aim of this study was to test these effects in a larger population. In a double-blind, placebo-controlled, randomized, crossover study, 31 people with Type 2 diabetes received 900 mg/day benfotiamine or a placebo for 6 weeks (with a washout period of 6 weeks between). At the end of each treatment period, macrovascular and microvascular function were assessed, together with variables of autonomic nervous function in a fasting state, as well as 2, 4 and 6 h following a heated, mixed test meal. Participants had an impaired baseline flow-mediated dilatation (2.63 ± 2.49%). Compared with the fasting state, neither variable changed postprandially following the placebo treatment. The 6 weeks' treatment with high doses of benfotiamine did not alter this pattern, either in the fasting state or postprandially. Among a subgroup of patients with the highest flow-mediated dilatation, following placebo treatment there was a significant postprandial flow-mediated dilatation decrease, while this effect was attenuated by benfotiamine pretreatment. In people with Type 2 diabetes and markedly impaired fasting flow-mediated dilatation, a mixed test meal does not further deteriorate flow-mediated dilatation or variables of microvascular or autonomic nervous function. Because no significant deterioration of postprandial flow-mediated dilatation, microvascular or autonomic nervous function tests occurred after placebo treatment, a prevention of the postprandial deterioration of these variables with benfotiamine was not feasible. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.

Thiamine and benfotiamine prevent apoptosis induced by high glucose-conditioned extracellular matrix in human retinal pericytes.

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Beltramo, Elena; Nizheradze, Konstantin; Berrone, Elena; Tarallo, Sonia; Porta, Massimo

2009-10-01

Early and selective loss of pericytes and thickening of the basement membrane are hallmarks of diabetic retinopathy. We reported reduced adhesion, but no changes in apoptosis, of bovine retinal pericytes cultured on extracellular matrix (ECM) produced by endothelial cells in high glucose (HG). Since human and bovine pericytes may behave differently in conditions mimicking the diabetic milieu, we verified the behaviour of human retinal pericytes cultured on HG-conditioned ECM. Pericytes were cultured in physiological/HG on ECM produced by human umbilical vein endothelial cells in physiological/HG, alone or in the presence of thiamine and benfotiamine. Adhesion, proliferation, apoptosis, p53 and Bcl-2/Bax ratio (mRNA levels and protein concentrations) were measured in wild-type and immortalized human pericytes. Both types of pericytes adhered less to HG-conditioned ECM and plastic than to physiological glucose-conditioned ECM. DNA synthesis was impaired in pericytes cultured in HG on the three different surfaces but there were no differences in proliferation. DNA fragmentation and Bcl-2/Bax ratio were greatly enhanced by HG-conditioned ECM in pericytes kept in both physiological and HG. Addition of thiamine and benfotiamine to HG during ECM production completely prevented these damaging effects. Apoptosis is strongly increased in pericytes cultured on ECM produced by endothelium in HG, probably due to impairment of the Bcl-2/Bax ratio. Thiamine and benfotiamine completely revert this effect. This behaviour is therefore completely different from that of bovine pericytes, underlining the importance of establishing species-specific cell models to study the mechanisms of diabetic retinopathy. (c) 2009 John Wiley & Sons, Ltd.

Effect of Benfotiamine on Advanced Glycation Endproducts and Markers of Endothelial Dysfunction and Inflammation in Diabetic Nephropathy

NARCIS (Netherlands)

Alkhalaf, Alaa; Kleefstra, Nanne; Groenier, Klaas H.; Bilo, Henk J. G.; Gans, Reinold O. B.; Heeringa, Peter; Scheijen, Jean L.; Schalkwijk, Casper G.; Navis, Gerjan J.; Bakker, Stephan J. L.

2012-01-01

Background: Formation of advanced glycation endproducts (AGEs), endothelial dysfunction, and low-grade inflammation are intermediate pathways of hyperglycemia-induced vascular complications. We investigated the effect of benfotiamine on markers of these pathways in patients with type 2 diabetes and

RANKING RELATIONS USING ANALOGIES IN BIOLOGICAL AND INFORMATION NETWORKS1

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Silva, Ricardo; Heller, Katherine; Ghahramani, Zoubin; Airoldi, Edoardo M.

2013-01-01

Analogical reasoning depends fundamentally on the ability to learn and generalize about relations between objects. We develop an approach to relational learning which, given a set of pairs of objects S = {A(1) : B(1), A(2) : B(2), …, A(N) : B(N)}, measures how well other pairs A : B fit in with the set S. Our work addresses the following question: is the relation between objects A and B analogous to those relations found in S? Such questions are particularly relevant in information retrieval, where an investigator might want to search for analogous pairs of objects that match the query set of interest. There are many ways in which objects can be related, making the task of measuring analogies very challenging. Our approach combines a similarity measure on function spaces with Bayesian analysis to produce a ranking. It requires data containing features of the objects of interest and a link matrix specifying which relationships exist; no further attributes of such relationships are necessary. We illustrate the potential of our method on text analysis and information networks. An application on discovering functional interactions between pairs of proteins is discussed in detail, where we show that our approach can work in practice even if a small set of protein pairs is provided. PMID:24587838

Nucleoside Analog-treated Chronic Hepatitis B Patients showed Reduced Expression of PECAM-1 Gene in Peripheral Blood Mononuclear Cells in Bangladesh

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Tabassum, Shahina; Ullah Munshi, Saif; Hossain, Marufa; Imam, Akhter

2014-01-01

ABSTRACT Background and aim Assessment of therapeutic response is important for monitoring the prognosis and to take decision for cessation of nucleoside analogues therapy in chronic hepatitis B patients. In addition to serum alanine aminotransferase (ALT), hepatitis B virus (HBV) deoxyribonucleic acid (DNA) load and HBeAg status, identification of molecular markers associated with host immune response would be essential to assess therapeutic response. In this regard the current study was performed with the aim to detect expression of platelet endothelial cell adhesion molecule (PECAM)-I gene in peripheral blood monocytes (PBMCs) of treated chronic hepatitis B patients and also to correlate expression of this gene with serum HBV DNA load and serum ALT levels. Materials and methods The study analyzed 60 chronic hepatitis B (CHB) patients, including 30 untreated and 30 nucleoside analogs treated and 10 healthy controls. PECAM-1 gene expression/ transcripts were detected by conventional RT-PCR. Results The expression PECAM-1 mRNA in the PBMCs of CHB patients was significantly higher in untreated (3.17 ± 0.75) than the treated patients (1.64 ± 0.29) (p Tabassum S, Munshi SU, Hossain M, Imam A. Nucleoside Analog-treated Chronic Hepatitis B Patients showed Reduced Expression of PECAM-1 Gene in Peripheral Blood Mononuclear Cells in Bangladesh. Euroasian J Hepato-Gastroenterol 2014;4(2):87-91. PMID:29699354

Detection of Transketolase in Bone Marrow—Derived Insulin-Producing Cells: Benfotiamine Enhances Insulin Synthesis and Glucose Metabolism

OpenAIRE

Oh, Seh-Hoon; Witek, Rafal P.; Bae, Si-Hyun; Darwiche, Houda; Jung, Youngmi; Pi, Liya; Brown, Alicia; Petersen, Bryon E.

2009-01-01

Adult bone marrow (BM)-derived insulin-producing cells (IPCs) are capable of regulating blood glucose levels in chemically induced hyperglycemic mice. Using cell transplantation therapy, fully functional BM-derived IPCs help to mediate treatment of diabetes mellitus. Here, we demonstrate the detection of the pentose phosphate pathway enzyme, transketolase (TK), in BM-derived IPCs cultured under high-glucose conditions. Benfotiamine, a known activator of TK, was not shown to affect the prolife...

Novel (1E,3E,5E-1,6-bis(Substituted phenylhexa-1,3,5-triene Analogs Inhibit Melanogenesis in B16F10 Cells and Zebrafish

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Jisun Oh

2018-04-01

Full Text Available The present study aimed to evaluate the anti-melanogenic activity of 1,6-diphenyl-1,3,5-hexatriene and its derivatives in B16F10 murine melanoma cells and zebrafish embryos. Twenty five (1E,3E,5E-1,6-bis(substituted phenylhexa-1,3,5-triene analogs were synthesized and their non-cytotoxic effects were predictively analyzed using three-dimensional quantitative structure-activity relationship approach. Inhibitory activities of these synthetic compounds against melanin synthesis were determined by evaluating melanin content and melanogenic regulatory enzyme expression in B16F10 cells. The anti-melanogenic activity was verified by observing body pigmentation in zebrafishes treated with these compounds. Compound #2, #4, and #6 effectively decreased melanogenesis induced by α-melanocyte-stimulating hormone. In particular, compound #2 remarkably lowered the mRNA and protein expression levels of microphthalmia-associated transcription factor (MITF, tyrosinase (TYR, tyrosinase-related protein 1 (TYRP1, and TYRP2 in B16F10 cells and substantially reduced skin pigmentation in the developed larvae of zebrafish. These findings suggest that compound #2 may be used as an anti-melanogenic agent for cosmetic purpose.

Pharmacokinetics of the transdermal delivery of benfotiamine.

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Zhu, Zhen; Varadi, Gyula; Carter, Stephen G

2016-04-01

Accumulation of advanced glycation endpoints is a trigger to the development of diabetic peripheral neuropathy, which is a common complication of diabetes. Oral administration of benfotiamine (BFT) has shown some preclinical and clinical promise as a treatment for diabetic peripheral neuropathy. The purpose of this study was to evaluate the method of transdermal delivery of BFT as a possible, viable route of administration for the treatment of diabetic peripheral neuropathy. A single application of 10 mg of BFT was given to guinea pigs topically. The levels of thiamine (T), thiamine monophosphate, thiamine diphosphate, S-benzoylthiamine and BFT were measured in the blood, skin and muscle at different time points within 24 h. At the 24-h time point, following the single BFT dose, the T level was increased 10× in the blood, more than 7× in the skin and almost 4× in the muscle compared to the untreated animals. The total T content (total) was increased 7× in the blood, 17× in the skin and 3× in the muscle compared to the untreated animals. This strong increase in the tissue levels of T and the associated metabolic derivatives levels found in the blood and local tissues following a single dose indicate that topically applied BFT may be a viable and advantageous delivery method for the treatment of diabetic peripheral neuropathy.

Dienone-phenol Rearrangement of C-9 Oxygenated Decalinic Dienone and Analogs through B-Ring Cleavage

Institute of Scientific and Technical Information of China (English)

无

2003-01-01

Dehydrogenation of 9-hydroxy decalinic enones and analogs with DDQ resulted in a formal dienone-phenol type rearrangement via B-ring cleavage, while the corresponding dienone acetates underwent base-catalyzed formal dienone-phenol type rearrangement analogously.

New oral dosage form for elderly patients. II. Release behavior of benfotiamine from silk fibroin gel.

Science.gov (United States)

Hanawa, T; Watanabe, A; Tsuchiya, T; Ikoma, R; Hidaka, M; Sugihara, M

1995-05-01

Silk fibroin gel (SFG) containing benfotiamine (BTMP) was prepared. The release behavior of BTMP from SFG was studied as a function of silk fibroin (SF) content and glycerol content, and the influence of the existence of beta-cyclodextrin (beta-CD) on the physicochemical properties of SFG were investigated. The release rate of BTMP from SFG was retarded by an increase in SF concentration. The addition of beta-CD affected both the release properties and rheological properties of the SFG. It was found from the results of the "paddle-bead method" that the release profiles of BTMP from SFG were inversely proportional to the SFG firmness.

Analogical scaffolding: Making meaning in physics through representation and analogy

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Podolefsky, Noah Solomon

This work reviews the literature on analogy, introduces a new model of analogy, and presents a series of experiments that test and confirm the utility of this model to describe and predict student learning in physics with analogy. Pilot studies demonstrate that representations (e.g., diagrams) can play a key role in students' use of analogy. A new model of analogy, Analogical Scaffolding, is developed to explain these initial empirical results. This model will be described in detail, and then applied to describe and predict the outcomes of further experiments. Two large-scale (N>100) studies will demonstrate that: (1) students taught with analogies, according to the Analogical Scaffolding model, outperform students taught without analogies on pre-post assessments focused on electromagnetic waves; (2) the representational forms used to teach with analogy can play a significant role in student learning, with students in one treatment group outperforming students in other treatment groups by factors of two or three. It will be demonstrated that Analogical Scaffolding can be used to predict these results, as well as finer-grained results such as the types of distracters students choose in different treatment groups, and to describe and analyze student reasoning in interviews. Abstraction in physics is reconsidered using Analogical Scaffolding. An operational definition of abstraction is developed within the Analogical Scaffolding framework and employed to explain (a) why physicists consider some ideas more abstract than others in physics, and (b) how students conceptions of these ideas can be modeled. This new approach to abstraction suggests novel approaches to curriculum design in physics using Analogical Scaffolding.

The roles of the analogy with natural selection in B.F. Skinner's philosophy.

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Smith, Terry L

2018-02-17

Beginning in the 1950s, B.F. Skinner made increasing reference to an analogy between operant conditioning and natural selection. This analogy is the basis of an argument that, in contrast to Skinner's other critiques of cognitive science, is neither epistemological nor pragmatic. Instead, it is based on the claim that ontogenetic adaptation is due to a special mode of causation he called "selection by consequences." He argued that this mode of causation conflicts with explanations that attribute action to an autonomous agent with reasons for acting. This argument dismisses ordinary explanations of action, and has implications not only for cognitive science but also for morals. Skinner cited the latter implications to counter objections to the application of behavior analysis to the reform of society and its institutions. Skinner's critique, however, rests upon empirical assumptions that have been criticized by other behavior analysts. Although for Skinner the major role of the analogy was to propose an empirical thesis, it also can play a metaphysical role-namely, to demonstrate the possibility of ontogenetic adaptation without reference to agents who have reasons for acting. These two roles, empirical and metaphysical, are the mirror image of the empirical and metaphysical roles of the computer analogy for cognitive science. That analogy also can be (and has been) interpreted as an empirical thesis. Its empirical implications, however, have been difficult to confirm. It also, however, has played a metaphysical role-namely, to demonstrate the possibility that a physical process could perform logical operations on states having propositional content. Neither analogy provides a well-confirmed, general answer to the question of how to explain the process of ontogenetic adaptation. But together they show there are two metaphysically coherent, but conflicting, answers to this question. Depending upon one's epistemology, the analogy with natural selection may provide a

Tracking cognitive phases in analogical reasoning with event-related potentials.

Science.gov (United States)

Maguire, Mandy J; McClelland, M Michelle; Donovan, Colin M; Tillman, Gail D; Krawczyk, Daniel C

2012-03-01

Analogical reasoning consists of multiple phases. Four-term analogies (A:B::C:D) have an encoding period in which the A:B pair is evaluated prior to a mapping phase. The electrophysiological timing associated with analogical reasoning has remained unclear. We used event-related potentials to identify neural timing related to analogical reasoning relative to perceptual and semantic control conditions. Spatiotemporal principal-components analyses revealed differences primarily in left frontal electrodes during encoding and mapping phases of analogies relative to the other conditions. The timing of the activity differed depending upon the phase of the problem. During the encoding of A:B terms, analogies elicited a positive deflection compared to the control conditions between 400 and 1,200 ms, but for the mapping phase analogical processing elicited a negative deflection that occurred earlier and for a shorter time period, between 350 and 625 ms. These results provide neural and behavioral evidence that 4-term analogy problems involve a highly active evaluation phase of the A:B pair. 2012 APA, all rights reserved

Anticonvulsant activity of B2, an adenosine analog, on chemical convulsant-induced seizures.

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Min Li

Full Text Available Epilepsy is a chronic neurological disorder characterized by recurrent seizures. However, approximately one-third of epilepsy patients still suffer from uncontrolled seizures. Effective treatments for epilepsy are yet to be developed. N (6-(3-methoxyl-4-hydroxybenzyl adenine riboside (B2 is a N(6-substitued adenosine analog. Here we describe an investigation of the effects and mechanisms of B2 on chemical convulsant-induced seizures. Seizures were induced in mice by administration of 4-aminopyridine (4-AP, pentylenetetrazol (PTZ, picrotoxin, kainite acid (KA, or strychnine. B2 has a dose-related anticonvulsant effect in these chemical-induced seizure models. The protective effects of B2 include increased latency of seizure onset, decreased seizure occurrence, shorter seizure duration and reduced mortality rate. Radioligand binding and cAMP accumulation assays indicated that B2 might be a functional ligand for both adenosine A1 and A2A receptors. Furthermore, DPCPX, a selective A1 receptor antagonist, but not SCH58261, a selective A2A receptor antagonist, blocked the anticonvulsant effect of B2 on PTZ-induced seizure. c-Fos is a cellular marker for neuronal activity. Immunohistochemical and western blot analyses indicated that B2 significantly reversed PTZ-induced c-Fos expression in the hippocampus. Together, these results indicate that B2 has significant anticonvulsant effects. The anticonvulsant effects of B2 may be attributed to adenosine A1 receptor activation and reduced neuronal excitability in the hippocampus. These observations also support that the use of adenosine receptor agonist may be a promising approach for the treatment of epilepsy.

Monovalent cation and amiloride analog modulation of adrenergic ligand binding to the unglycosylated alpha 2B-adrenergic receptor subtype

International Nuclear Information System (INIS)

Wilson, A.L.; Seibert, K.; Brandon, S.; Cragoe, E.J. Jr.; Limbird, L.E.

1991-01-01

The unglycosylated alpha 2B subtype of the alpha 2-adrenergic receptor found in NG-108-15 cells possesses allosteric regulation of adrenergic ligand binding by monovalent cations and 5-amino-substituted amiloride analogs. These findings demonstrate that allosteric modulation of adrenergic ligand binding is not a property unique to the alpha 2A subtype. The observation that amiloride analogs as well as monovalent cations can modulate adrenergic ligand binding to the nonglycosylated alpha 2B subtype indicates that charge shielding due to carbohydrate moieties does not play a role in this allosteric modulation but, rather, these regulatory effects result from interactions of cations and amiloride analogs with the protein moiety of the receptor. Furthermore, the observation that both alpha 2A and alpha 2B receptor subtypes are modulated by amiloride analogs suggests that structural domains that are conserved between the two are likely to be involved in this allosteric modulation

CMOS analog baseband circuitry for an IEEE 802.11 b/g/n WLAN transceiver

International Nuclear Information System (INIS)

Gong Zheng; Chu Xiaojie; Shi Yin; Lei Qianqian; Lin Min

2012-01-01

An analog baseband circuit for a direct conversion wireless local area network (WLAN) transceiver in a standard 0.13-μm CMOS occupying 1.26 mm 2 is presented. The circuit consists of active-RC receiver (RX) 4th order elliptic lowpass filters(LPFs), transmit (PGAs) with DC offset cancellation (DCOC) servo loops, and on-chip output buffers. The RX baseband gain can be programmed in the range of −11 to 49 dB in 2 dB steps with 50–30.2 nV/√Hz input referred noise (IRN) and a 21 to −41 dBm in-band 3rd order interception point (IIP3). The RX/TX LPF cutoff frequencies can be switched between 5 MHz, 10 MHz, and 20 MHz to fulfill the multimode 802.11b/g/n requirements. The TX baseband gain of the I/Q paths are tuned separately from −1.6 to 0.9 dB in 0.1 dB steps to calibrate TX I/Q gain mismatches. By using an identical integrator based elliptic filter synthesis method together with global compensation applied to the LPF capacitor array, the power consumption of the RX LPF is considerably reduced and the proposed chip draws 26.8 mA/8 mA by the RX/TX baseband paths from a 1.2 V supply. (semiconductor integrated circuits)

CMOS analog baseband circuitry for an IEEE 802.11 b/g/n WLAN transceiver

Science.gov (United States)

Zheng, Gong; Xiaojie, Chu; Qianqian, Lei; Min, Lin; Yin, Shi

2012-11-01

An analog baseband circuit for a direct conversion wireless local area network (WLAN) transceiver in a standard 0.13-μm CMOS occupying 1.26 mm2 is presented. The circuit consists of active-RC receiver (RX) 4th order elliptic lowpass filters(LPFs), transmit (PGAs) with DC offset cancellation (DCOC) servo loops, and on-chip output buffers. The RX baseband gain can be programmed in the range of -11 to 49 dB in 2 dB steps with 50-30.2 nV/√Hz input referred noise (IRN) and a 21 to -41 dBm in-band 3rd order interception point (IIP3). The RX/TX LPF cutoff frequencies can be switched between 5 MHz, 10 MHz, and 20 MHz to fulfill the multimode 802.11b/g/n requirements. The TX baseband gain of the I/Q paths are tuned separately from -1.6 to 0.9 dB in 0.1 dB steps to calibrate TX I/Q gain mismatches. By using an identical integrator based elliptic filter synthesis method together with global compensation applied to the LPF capacitor array, the power consumption of the RX LPF is considerably reduced and the proposed chip draws 26.8 mA/8 mA by the RX/TX baseband paths from a 1.2 V supply.

Asperentin B, a New Inhibitor of the Protein Tyrosine Phosphatase 1B.

Science.gov (United States)

Wiese, Jutta; Aldemir, Hülya; Schmaljohann, Rolf; Gulder, Tobias A M; Imhoff, Johannes F

2017-06-21

In the frame of studies on secondary metabolites produced by fungi from deep-sea environments we have investigated inhibitors of enzymes playing key roles in signaling cascades of biochemical pathways relevant for the treatment of diseases. Here we report on a new inhibitor of the human protein tyrosine phosphatase 1B (PTP1B), a target in the signaling pathway of insulin. A new asperentin analog is produced by an Aspergillus sydowii strain isolated from the sediment of the deep Mediterranean Sea. Asperentin B ( 1 ) contains an additional phenolic hydroxy function at C-6 and exhibits an IC 50 value against PTP1B of 2 μM in vitro, which is six times stronger than the positive control, suramin. Interestingly, asperentin ( 2 ) did not show any inhibition of this enzymatic activity. Asperentin B ( 1 ) is discussed as possible therapeutic agents for type 2 diabetes and sleeping sickness.

Asteroseismology of the Solar Analogs 16 Cyg A and B from Kepler Observations

DEFF Research Database (Denmark)

Metcalfe, T. S.; Chaplin, W. J.; Appourchaux, T.

2012-01-01

The evolved solar-type stars 16 Cyg A and B have long been studied as solar analogs, yielding a glimpse into the future of our own Sun. The orbital period of the binary system is too long to provide meaningful dynamical constraints on the stellar properties, but asteroseismology can help because...

[The effect of benfothiamine in the therapy of diabetic polyneuropathy].

Science.gov (United States)

Nikolić, Ana; Kacar, Aleksandra; Lavrnić, Dragana; Basta, Ivana; Apostolski, Slobodan

2009-01-01

Diabetic polyneuropathy (DPN) is one of the most common diabetic complications, which can result in a significant functional impairment and reduction of the quality of life in affected individuals. It occurs due to alterations in different biochemical mechanisms which require the presence of thiamine, which is why this vitamin is used in the therapy of DPN. Due to the low bioavailability of the hydrosolubile forms of thiamine, its liposolubile preparations (benfotiamine) are preferentially used. The aim of this study was to determine the efficacy of benfotiamine in combination with vitamin B6 in the therapy of DPN. The study group comprised of 22 patients with DPN who were treated with the combination of benfotiamine and vitamin B6 during 45 days. The effect of the therapy was evaluated by the analysis of different clinical, laboratory and electrophysiological parameters before and after conducted treatment. After the treatment period, a statistically highly significant reduction of pain (p benfotiamine therapy only in 22.7% of patients, while hyperpathy was initially present in 90.9%, and after treatment in 31.8% of patients (p benfotiamine was good starting choice for the treatment of diabetic polyneuropathy.

Asteroseismology of the solar analogs 16 Cyg A and B from Kepler observations

NARCIS (Netherlands)

Metcalfe, T.; Chaplin, W.J.; Appourchaux, T.; Garcia, R.A.; Basu, S.; Brandão, I.; Creevey, O.L.; Deheuvels, S.; Doğan, G.; Eggenberger, P.; Karoff, C.; Miglio, A.; Stello, D.; Yıldız, M.; Çelik, Z.; Antia, H.M.; Benomar, O.; Howe, R.; Régulo, C.; Salabert, D.; Stahn, T.; Bedding, T.R.; Davies, G.R.; Elsworth, Y.; Gizon, L.; Hekker, S.; Mathur, S.; Mosser, B.; Bryson, S.T.; Still, M.D.; Christensen-Dalsgaard, J.; Gilliland, R.L.; Kawaler, S.D.; Kjeldsen, H.; Ibrahim, K.A.; Klaus, T.C.; Li, J.

2012-01-01

The evolved solar-type stars 16 Cyg A and B have long been studied as solar analogs, yielding a glimpse into the future of our own Sun. The orbital period of the binary system is too long to provide meaningful dynamical constraints on the stellar properties, but asteroseismology can help because the

Analogical proportions: another logical view

Science.gov (United States)

Prade, Henri; Richard, Gilles

This paper investigates the logical formalization of a restricted form of analogical reasoning based on analogical proportions, i.e. statements of the form a is to b as c is to d. Starting from a naive set theoretic interpretation, we highlight the existence of two noticeable companion proportions: one states that a is to b the converse of what c is to d (reverse analogy), while the other called paralogical proportion expresses that what a and b have in common, c and d have it also. We identify the characteristic postulates of the three types of proportions and examine their consequences from an abstract viewpoint. We further study the properties of the set theoretic interpretation and of the Boolean logic interpretation, and we provide another light on the understanding of the role of permutations in the modeling of the three types of proportions. Finally, we address the use of these proportions as a basis for inference in a propositional setting, and relate it to more general schemes of analogical reasoning. The differences between analogy, reverse-analogy, and paralogy is still emphasized in a three-valued setting, which is also briefly presented.

Synthesis of Novel Homo-N-Nucleoside Analogs Composed of a Homo-1,4-Dioxane Sugar Analog and Substituted 1,3,5-Triazine Base Equivalents

Directory of Open Access Journals (Sweden)

Qiang Yu

2008-12-01

Full Text Available Enantioselective syntheses from dimethyl tartrate of 1,3,5-triazine homo-N-nucleoside analogs, containing a 1,4-dioxane moiety replacing the sugar unit in natural nucleosides, were accomplished. The triazine heterocycle in the nucleoside analogs was further substituted with combinations of NH2, OH and Cl in the 2,4-triazine positions.

Priming analogical reasoning with false memories.

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Howe, Mark L; Garner, Sarah R; Threadgold, Emma; Ball, Linden J

2015-08-01

Like true memories, false memories are capable of priming answers to insight-based problems. Recent research has attempted to extend this paradigm to more advanced problem-solving tasks, including those involving verbal analogical reasoning. However, these experiments are constrained inasmuch as problem solutions could be generated via spreading activation mechanisms (much like false memories themselves) rather than using complex reasoning processes. In three experiments we examined false memory priming of complex analogical reasoning tasks in the absence of simple semantic associations. In Experiment 1, we demonstrated the robustness of false memory priming in analogical reasoning when backward associative strength among the problem terms was eliminated. In Experiments 2a and 2b, we extended these findings by demonstrating priming on newly created homonym analogies that can only be solved by inhibiting semantic associations within the analogy. Overall, the findings of the present experiments provide evidence that the efficacy of false memory priming extends to complex analogical reasoning problems.

Children's analogical reasoning about natural phenomena.

Science.gov (United States)

Pauen, S; Wilkening, F

1997-10-01

This report investigates children's analogical reasoning in a physics task, using an analogy generated by the children rather than by the experimenter. A total of 127 elementary school children took part in three related studies. Children learned to predict the behavior of a balance scale. Later, they were asked to solve a force interaction problem. Two versions of the balance scale training were devised: version A suggested an incorrect solution to the target problem (negative analogy), and version B suggested a correct solution to the target problem (positive analogy). In Study 1, 9- to 10-year-olds showed spontaneous transfer in both training conditions. In Study 2, 7-year-olds did not show any transfer in the positive analogy condition. Study 3 revealed that the lack of transfer in younger children was not due to a failure either to notice the analogy or to perform the mapping. Instead, 7-year-olds transferred only selected aspects of the correct solution. Copyright 1997 Academic Press.

21 CFR 582.5477 - Methionine hydroxy analog and its calcium salts.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Methionine hydroxy analog and its calcium salts... Nutrients and/or Dietary Supplements 1 § 582.5477 Methionine hydroxy analog and its calcium salts. (a) Product. Methionine hydroxy analog and its calcium salts. (b) [Reserved] (c) Limitations, restrictions, or...

Component Processes in Analogical Reasoning

Science.gov (United States)

Sternberg, Robert J.

1977-01-01

Describes alternative theoretical positions regarding (a) the component information processes used in analogical reasoning and (b) strategies for combining these processes. Also presents results from three experiments on analogical reasoning. (Author/RK)

Function-Oriented Synthesis of Marine Phidianidine Derivatives as Potential PTP1B Inhibitors with Specific Selectivity

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Jin Liu

2018-03-01

Full Text Available Phidianidines A and B are two novel marine indole alkaloids bearing an uncommon 1,2,4-oxadiazole ring and exhibiting various biological activities. Our previous research showed that the synthesized phidianidine analogs had the potential to inhibit the activity of protein tyrosine phosphatase 1B (PTP1B, a validated target for Type II diabetes, which indicates that these analogs are worth further structural modification. Therefore, in this paper, a series of phidianidine derivatives were designed and rapidly synthesized with a function-oriented synthesis (FOS strategy. Their inhibitory effects on PTP1B and T-cell protein tyrosine phosphatase (TCPTP were evaluated, and several compounds displayed significant inhibitory potency and specific selectivity over PTP1B. The structure–activity relationship (SAR and molecular docking analyses are also described.

Function-Oriented Synthesis of Marine Phidianidine Derivatives as Potential PTP1B Inhibitors with Specific Selectivity.

Science.gov (United States)

Liu, Jin; Chen, Yu; Li, Jing-Ya; Luo, Cheng; Li, Jia; Chen, Kai-Xian; Li, Xu-Wen; Guo, Yue-Wei

2018-03-20

Phidianidines A and B are two novel marine indole alkaloids bearing an uncommon 1,2,4-oxadiazole ring and exhibiting various biological activities. Our previous research showed that the synthesized phidianidine analogs had the potential to inhibit the activity of protein tyrosine phosphatase 1B (PTP1B), a validated target for Type II diabetes, which indicates that these analogs are worth further structural modification. Therefore, in this paper, a series of phidianidine derivatives were designed and rapidly synthesized with a function-oriented synthesis (FOS) strategy. Their inhibitory effects on PTP1B and T-cell protein tyrosine phosphatase (TCPTP) were evaluated, and several compounds displayed significant inhibitory potency and specific selectivity over PTP1B. The structure-activity relationship (SAR) and molecular docking analyses are also described.

Analog front-end for pixel sensors in a 3D CMOS technology for the SuperB Layer0

International Nuclear Information System (INIS)

Manazza, A.; Gaioni, L.; Re, V.

2011-01-01

This work is concerned with the design of two different analog channels for hybrid and monolithic pixels readout in view of applications to the SVT at the SuperB Factory. The circuits have been designed in a 130nm CMOS, vertically integrated technology, which, among others, may provide some advantages in terms of functional density and electrical isolation between the analog and the digital sections of the front-end.

Pre-Steady State Kinetic Investigation of the Incorporation of Anti-Hepatitis B Nucleotide Analogs Catalyzed by Non-Canonical Human DNA Polymerases

Science.gov (United States)

Brown, Jessica A.; Pack, Lindsey R.; Fowler, Jason D.; Suo, Zucai

2011-01-01

Antiviral nucleoside analogs have been developed to inhibit the enzymatic activities of the hepatitis B virus (HBV) polymerase, thereby preventing the replication and production of HBV. However, the usage of these analogs can be limited by drug toxicity because the 5′-triphosphates of these nucleoside analogs (nucleotide analogs) are potential substrates for human DNA polymerases to incorporate into host DNA. Although they are poor substrates for human replicative DNA polymerases, it remains to be established whether these nucleotide analogs are substrates for the recently discovered human X- and Y-family DNA polymerases. Using pre-steady state kinetic techniques, we have measured the substrate specificity values for human DNA polymerases β, λ, η, ι, κ, and Rev1 incorporating the active forms of the following anti-HBV nucleoside analogs approved for clinical use: adefovir, tenofovir, lamivudine, telbivudine, and entecavir. Compared to the incorporation of a natural nucleotide, most of the nucleotide analogs were incorporated less efficiently (2 to >122,000) by the six human DNA polymerases. In addition, the potential for entecavir and telbivudine, two drugs which possess a 3′-hydroxyl, to become embedded into human DNA was examined by primer extension and DNA ligation assays. These results suggested that telbivudine functions as a chain terminator while entecavir was efficiently extended by the six enzymes and was a substrate for human DNA ligase I. Our findings suggested that incorporation of anti-HBV nucleotide analogs catalyzed by human X- and Y-family polymerases may contribute to clinical toxicity. PMID:22132702

[The effect of long-chain polyunsaturated higher ω-3 fatty acids, benfotiamine and α-lipoic acid on the lipid metabolism in patients with diabetes mellitus type 2 and cardiovascular autonomic neuropathy].

Science.gov (United States)

Sergienko, V A; Segin, V B; Samir, A; Sergienko, A A

2013-01-01

Eighty-one patients with diabetes mellitus type 2 (DM) and cardiovascular autonomic neuropathy were studied. The combined treatment with ω-3 PUFA, benfotiamine, and α-lipoic acid resulted in significant positive changes in total cholesterol, triacylglycerol, LDL and HDL cholesterol levels. The efficacy of this treatment was not associated with the improved compensation of DM but was a result of the direct influence of pharmacological agents on the metabolic rate studied.

1,2-HOIQO--A highly versatile 1,2-HOPO analog

Energy Technology Data Exchange (ETDEWEB)

Seitz, Michael; Pluth, Michael D.; Raymond, Kenneth N.

2006-08-07

A cyclic, bidentate hydroxamic acid binding unit based on an isoquinoline scaffold has been utilized for the synthesis of a hexadentate tripodal ligand based on the TREN backbone. This prototype for a new class of multidentate chelators forms mononuclear iron(III) complexes and one-dimensional coordination polymers with lanthanide(III) cations. The latter has been determined by single crystal X-ray analysis of the cerium species. The solid state structure in the monoclinic space group P2{sub 1}/c (C{sub 36}H{sub 34}CeN{sub 7}O{sub 11}, a = 12.341(2){angstrom}, b = 26.649(4){angstrom}, c = 10.621(2){angstrom}, {alpha} = {gamma} = 90{sup o}, {beta} = 96.753(3){sup o}, V = 3468.6(9) {angstrom}{sup 3}, Z = 4) exhibits a trigonal-dodecahedral environment around the cerium cation. The proof of concept for the versatility of the new scaffold has been shown by the modification of the crucial precursor 3-carboxyiso-coumarin through electrophilic aromatic substitutions to yield the corresponding chlorosulfonated and nitrated analogs.

Antioxidant and anti-inflammatory properties of 1,2,4-oxadiazole analogs of resveratrol.

Science.gov (United States)

Gobec, Martina; Tomašič, Tihomir; Markovič, Tijana; Mlinarič-Raščan, Irena; Dolenc, Marija Sollner; Jakopin, Žiga

2015-10-05

The chemopreventive properties of resveratrol are ascribed mostly to its antioxidant activity, in particular its scavenging ability for reactive oxygen species (ROS), and to the inhibition of NF-κB pathway which has also been suggested as an important underlying mechanism of its reported properties. In present study, a small library of nine 1,2,4-oxadiazole-based structural analogs of resveratrol were assayed for their antioxidant and anti-inflammatory activities. Several compounds showed significant inhibitory activities against NF-κB and/or ROS production. Compound 2, incorporating two para-hydroxyphenyl moieties connected by the 1,2,4-oxadiazole ring, was the most active, its potency in inhibiting activation of NF-κB and ROS scavenging abilities surpassing that of resveratrol. Additionally, we elucidated the mechanisms underlying the NF-κB inhibitory activity of compound 2. Finally, in contrast to resveratrol, compound 2 significantly reduced the LPS-induced release of pro-inflammatory cytokines, indicating its prominent anti-inflammatory potential. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Inhibition of macrophage oxidative stress prevents the reduction of ABCA-1 transporter induced by advanced glycated albumin.

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de Souza Pinto, Raphael; Castilho, Gabriela; Paim, Bruno Alves; Machado-Lima, Adriana; Inada, Natalia M; Nakandakare, Edna Regina; Vercesi, Aníbal Eugênio; Passarelli, Marisa

2012-05-01

We investigated the role of aminoguanidine and benfotiamine on the inhibition of reactive oxygen species (ROS) generation in macrophages induced by advanced glycated albumin (AGE-albumin) and its relationship with cell cholesterol homeostasis, emphasizing the expression of the ATP binding cassette transporter A-1 (ABCA-1). AGE-albumin was made by incubating fatty acid-free albumin with 10 mM glycolaldehyde. ROS production and ABCA-1 protein level were determined by flow cytometry in J774 macrophages treated along time with control (C) or AGE-albumin alone or in the presence of aminoguanidine or benfotiamine. Mitochondrial function was evaluated by oxygraphy. Compared to C-albumin, AGE-albumin increased ROS production in macrophages, which was ascribed to the activities of NADPH oxidase and of the mitochondrial system. Mitochondrial respiratory chain activity was reduced in cells incubated with AGE-albumin. ROS generation along time was associated with the reduction in macrophage ABCA-1 protein level. Aminoguanidine prevented ROS elevation and restored the ABCA-1 content in macrophages; on the other hand, benfotiamine that promoted a lesser reduction in ROS generation was not able to restore ABCA-1 levels. Inhibition of oxidative stress induced by AGE-albumin prevents disturbances in reverse cholesterol transport by curbing the reduction of ABCA-1 elicited by advanced glycation in macrophages and therefore may contribute to the prevention of atherosclerosis in diabetes mellitus.

Facile synthesis of cyclopentenone B1- and L1-type Phytoprostanes

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Alexandre eGuy

2015-07-01

Full Text Available Phytoprostanes (PhytoPs represent non-enzymatic metabolites of α-linolenic acid (ALA, the essential omega-3 polyunsaturated fatty acid (PUFA derived from plants. PhytoPs are present in the plant kingdom and represent endogenous mediators capable of protecting cells from oxidative stress damages in plants. Recently, it was found that such metabolites are present in cooking oil in high quantities, and also that B1-PhytoPs protect immature neurons from oxidant injury and promote differentiation of oligodendrocyte progenitors through PPAR-γ activation. We report a novel and facile synthesis of natural 2,3-substituted cyclopentenone PhytoPs, 16-B1-PhytoP and 9-L1-PhytoP. Our strategy is based on reductive alkylation at the 2-position of 1,3-cyclopentanedione using a recent protocol developed by Ramachary et al., and on a cross-coupling metathesis to access conjugate dienone system. In conclusion, this strategy permitted access to B1- and L1-PhytoPs in a relative short sequence process, and afford the possibility to easily develop analogs of PhytoPs.

Context, cortex, and associations: a connectionist developmental approach to verbal analogies

Science.gov (United States)

Kollias, Pavlos; McClelland, James L.

2013-01-01

We present a PDP model of binary choice verbal analogy problems (A:B as C:[D1|D2], where D1 and D2 represent choice alternatives). We train a recurrent neural network in item-relation-item triples and use this network to test performance on analogy questions. Without training on analogy problems per se, the model explains the developmental shift from associative to relational responding as an emergent consequence of learning upon the environment's statistics. Such learning allows gradual, item-specific acquisition of relational knowledge to overcome the influence of unbalanced association frequency, accounting for association effects of analogical reasoning seen in cognitive development. The network also captures the overall degradation in performance after anterior temporal damage by deleting a fraction of learned connections, while capturing the return of associative dominance after frontal damage by treating frontal structures as necessary for maintaining activation of A and B while seeking a relation between C and D. While our theory is still far from being complete it provides a unified explanation of findings that need to be considered together in any integrated account of analogical reasoning. PMID:24312068

Context, cortex, and associations: a connectionist developmental approach to verbal analogies

Directory of Open Access Journals (Sweden)

Pavlos eKollias

2013-11-01

Full Text Available We present a PDP model of binary choice verbal analogy problems (A:B as C:[D1|D2], where D1 and D2 represent choice alternatives. We train a recurrent neural network in item-relation- item triples and use this network to test performance on analogy questions. Without training on analogy problems per se, the model explains the developmental shift from associative to relational responding as an emergent consequence of learning upon the environment’s statistics. Such learning allows gradual, item-specific acquisition of relational knowledge to overcome the influence of unbalanced association frequency, accounting for association effects of analogical reasoning seen in cognitive development. The network also captures the overall degradation in performance after anterior temporal damage by deleting a fraction of learned connections, while capturing the return of associative dominance after frontal damage by treating frontal structures as necessary for maintaining activation of A and B while seeking a relation between C and D. While our theory is still far from being complete it provides a unified explanation of findings that need to be considered together in any integrated account of analogical reasoning.

Context, cortex, and associations: a connectionist developmental approach to verbal analogies.

Science.gov (United States)

Kollias, Pavlos; McClelland, James L

2013-01-01

We present a PDP model of binary choice verbal analogy problems (A:B as C:[D1|D2], where D1 and D2 represent choice alternatives). We train a recurrent neural network in item-relation-item triples and use this network to test performance on analogy questions. Without training on analogy problems per se, the model explains the developmental shift from associative to relational responding as an emergent consequence of learning upon the environment's statistics. Such learning allows gradual, item-specific acquisition of relational knowledge to overcome the influence of unbalanced association frequency, accounting for association effects of analogical reasoning seen in cognitive development. The network also captures the overall degradation in performance after anterior temporal damage by deleting a fraction of learned connections, while capturing the return of associative dominance after frontal damage by treating frontal structures as necessary for maintaining activation of A and B while seeking a relation between C and D. While our theory is still far from being complete it provides a unified explanation of findings that need to be considered together in any integrated account of analogical reasoning.

Anticancer effects of monocarbonyl analogs of curcumin: oxidative stress, nuclear translocation and modulation of AP-1 and NF-κB

Directory of Open Access Journals (Sweden)

Brian Adams

2015-01-01

Full Text Available Purpose: In order to elucidate anticancer effects of monocarbonyl analogs of curcumin (MACs, we have undertaken the present study to obtain information regarding drug targets by using a microarray approach, and to study the cellular localization of EF24 and the activity of two key transcription factors, AP-1 and NF-κB, involved in complex cellular responses of cell survival and death. Methods: Cytotoxic activity of various drugs was evaluated using a Neutral Red Dye assay. Cellular localization of biotinylated EF24 (active and reduced EF24 (inactive was determined using light and confocal microscopy. Measurement of transcription factor binding was carried out using Transfactor ELISA kits (BD Clontech, Palo Alto, CA. Gene microarray processing was performed at Expression Analysis, Inc (Durham, NC using Affymetrix Human U133A Gene Chips.Results: In this study, we demonstrated that EF24 and UBS109 exhibit much more potent cytotoxic activity against pancreatic cancer than the current standard chemotherapeutic agent gemcitabine. EF24, rapidly localizes to the cell nucleus. The compound modulates the DNA binding activity of NF-κB and AP-1 in MDA-MB-231 human breast cancer cells and DU-145 human prostate cancer cells. Immunohistochemical studies utilizing biotinylated-EF24 and chemically-reduced EF24 show that the unsaturated compound and biotinylated EF24, but not reduced EF24, translocates to the nucleus within 30 minutes after the addition of drug. Through a gene microarray study, EF24 is shown to affect genes directly involved in cytoprotection, tumor growth, angiogenesis, metastasis and apoptosis. Conclusion: EF24 and UBS109 warrant further investigation for development of pancreatic cancer therapy. The dualistic modulations of gene expression may be a manifestation of the cell responses for survival against oxidative stress by EF24. However, the cytotoxic action of EF24 ultimately prevails to kill the cells.

Low liver stiffness among cirrhotic patients with hepatitis B after prolonged treatment with nucleoside analogs

DEFF Research Database (Denmark)

Andersen, Ellen Sloth; Weiland, Ola; Leutscher, Peter

2011-01-01

Abstract Objective. Case reports and short-term clinical trials have suggested that treatment for chronic hepatitis B (CHB) may lead to improvement of cirrhosis. The aim of the present study was to measure liver stiffness in patients diagnosed with advanced fibrosis or cirrhosis prior to prolonged...... treatment with nucleoside or nucleotide analogs (NUCs) for CHB. Materials and methods. Patients with CHB and advanced fibrosis or cirrhosis prior to treatment with NUCs for at least 1 year were offered inclusion in the study. We measured liver stiffness using transient elastography (TE) at follow-up. TE cut...... duration was 50.5 months. Among patients with cirrhosis prior to treatment, 26 (49%) had liver stiffness below 11.0 kPa at follow-up, suggesting regression of cirrhosis. Among patients with advanced fibrosis (F3) prior to treatment, 10 (77%) had liver stiffness below 8.1 kPa after treatment, suggesting...

The impact of semantic distance and induced stress on analogical reasoning: a neurocomputational account.

Science.gov (United States)

Vendetti, Michael; Knowlton, Barbara J; Holyoak, Keith J

2012-12-01

In a study of reasoning with four-term verbal analogy problems, we explored the relationship between the effects of an acute, mild stressor and the complexity of the reasoning process. Participants judged whether analogy problems in the form A:B :: C:D were valid or invalid, on the basis of whether the relation in the A:B term matched that in the C:D term. Half of the problems contained a C:D pair semantically near the A:B pair (e.g., NOSE:SCENT :: TONGUE:TASTE), and the other half contained ones semantically far from A:B (e.g., NOSE:SCENT :: ANTENNA:SIGNAL). After an initial block without stress, participants were randomly assigned to count backward by 13 s from 1,000 while being told to go faster, or to count forward by 1 s from 0. The stress-induced participants reported a significant increase in state anxiety as compared to controls immediately after the mental arithmetic task. Stressed participants performed less accurately (as measured by d') on both near and far analogy problems, mainly due to an increase in false alarms. We were able to model the influence of semantic distance using the "learning and inference with schemas and analogies" (LISA) model. Our findings indicated that even mild increases in stress impair analogical reasoning. However, the decrement does not seem to directly involve the integration of relations, but rather is due to a shift in decision strategy: Under stress, people show an increased tendency to endorse analogies as valid when the terms in the individual pairs are semantically related to each other, even if the overall analogical relationship is not valid.

Role of sphingolipids in murine radiation-induced lung injury: protection by sphingosine 1-phosphate analogs

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Mathew, Biji; Jacobson, Jeffrey R.; Berdyshev, Evgeny; Huang, Yong; Sun, Xiaoguang; Zhao, Yutong; Gerhold, Lynnette M.; Siegler, Jessica; Evenoski, Carrie; Wang, Ting; Zhou, Tong; Zaidi, Rafe; Moreno-Vinasco, Liliana; Bittman, Robert; Chen, Chin Tu; LaRiviere, Patrick J.; Sammani, Saad; Lussier, Yves A.; Dudek, Steven M.; Natarajan, Viswanathan; Weichselbaum, Ralph R.; Garcia, Joe G. N.

2011-01-01

Clinically significant radiation-induced lung injury (RILI) is a common toxicity in patients administered thoracic radiotherapy. Although the molecular etiology is poorly understood, we previously characterized a murine model of RILI in which alterations in lung barrier integrity surfaced as a potentially important pathobiological event and genome-wide lung gene mRNA levels identified dysregulation of sphingolipid metabolic pathway genes. We hypothesized that sphingolipid signaling components serve as modulators and novel therapeutic targets of RILI. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to sphingosine 1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage fluid, and lung tissue. Mice with a targeted deletion of SphK1 (SphK1−/−) or with reduced expression of S1P receptors (S1PR1+/−, S1PR2−/−, and S1PR3−/−) exhibited marked RILI susceptibility. Finally, studies of 3 potent vascular barrier-protective S1P analogs, FTY720, (S)-FTY720-phosphonate (fTyS), and SEW-2871, identified significant RILI attenuation and radiation-induced gene dysregulation by the phosphonate analog, fTyS (0.1 and 1 mg/kg i.p., 2×/wk) and to a lesser degree by SEW-2871 (1 mg/kg i.p., 2×/wk), compared with those in controls. These results support the targeting of S1P signaling as a novel therapeutic strategy in RILI.—Mathew, B., Jacobson, J. R., Berdyshev, E., Huang, Y., Sun, X., Zhao, Y., Gerhold, L. M., Siegler, J., Evenoski, C., Wang, T., Zhou, T., Zaidi, R., Moreno-Vinasco, L., Bittman, R., Chen, C. T., LaRiviere, P. J., Sammani, S., Lussier, Y. A., Dudek, S. M., Natarajan, V., Weichselbaum, R. R., Garcia, J. G. N. Role of sphingolipids in murine radiation-induced lung injury: protection by sphingosine 1-phosphate analogs. PMID:21712494

Effects of high glucose and thiamine on the balance between matrix metalloproteinases and their tissue inhibitors in vascular cells.

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Tarallo, Sonia; Beltramo, Elena; Berrone, Elena; Dentelli, Patrizia; Porta, Massimo

2010-06-01

Pericyte survival in diabetic retinopathy depends also on interactions with extracellular matrix (ECM) proteins, which are degraded by matrix metalloproteinases (MMP). Elevated glucose influences ECM turnover, through expression of MMP and their tissue inhibitors, TIMP. We reported on reduced pericyte adhesion to high glucose-conditioned ECM and correction by thiamine. We aimed at verifying the effects of thiamine and benfotiamine on MMP-2, MMP-9 and TIMP expression and activity in human vascular cells with high glucose. In HRP, MMP-2 activity, though not expression, increased with high glucose and decreased with thiamine and benfotiamine; TIMP-1 expression increased with high glucose plus thiamine and benfotiamine; MMP-9 was not expressed. In EC, MMP-9 and MMP-2 expression and activity increased with high glucose, but thiamine and benfotiamine had no effects; TIMP-1 expression was unchanged. Neither glucose nor thiamine modified TIMP-2 and TIMP-3 expression. TIMP-1 concentrations did not change in either HRP or EC. High glucose imbalances MMP/TIMP regulation, leading to increased ECM turnover. Thiamine and benfotiamine correct the increase in MMP-2 activity due to high glucose in HRP, while increasing TIMP-1.

2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors

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Legoabe LJ

2015-07-01

Full Text Available Lesetja J Legoabe,1 Anél Petzer,1 Jacobus P Petzer1,21Centre of Excellence for Pharmaceutical Sciences, 2Department of Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South AfricaAbstract: Based on a previous report that substituted 2-acetylphenols may be promising leads for the design of novel monoamine oxidase (MAO inhibitors, a series of C5-substituted 2-acetylphenol analogs (15 and related compounds (two were synthesized and evaluated as inhibitors of human MAO-A and MAO-B. Generally, the study compounds exhibited inhibitory activities against both MAO-A and MAO-B, with selectivity for the B isoform. Among the compounds evaluated, seven compounds exhibited IC50 values <0.01 µM for MAO-B inhibition, with the most selective compound being 17,000-fold selective for MAO-B over the MAO-A isoform. Analyses of the structure–activity relationships for MAO inhibition show that substitution on the C5 position of the 2-acetylphenol moiety is a requirement for MAO-B inhibition, and the benzyloxy substituent is particularly favorable in this regard. This study concludes that C5-substituted 2-acetylphenol analogs are potent and selective MAO-B inhibitors, appropriate for the design of therapies for neurodegenerative disorders such as Parkinson’s disease.Keywords: monoamine oxidase, MAO, inhibition, 2-acetylphenol, structure–activity relationship

EPOXYEICOSATRIENOIC ACID ANALOG ATTENUATES ANGIOTENSIN II HYPERTENSION AND KIDNEY INJURY

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Md. Abdul Hye Khan

2014-09-01

Full Text Available Epoxyeicosatrienoic acids (EETs contribute to blood pressure regulation leading to the concept that EETs can be therapeutically targeted for hypertension and the associated end-organ damage. In the present study, we investigated anti-hypertensive and kidney protective actions of an EET analog, EET-B in angiotensin II (ANG II-induced hypertension. EET-B was administered in drinking water for 14 days (10mg/kg/d and resulted in a decreased blood pressure elevation in ANG II hypertension. At the end of the two-week period, blood pressure was 30 mmHg lower in EET analog-treated ANG II hypertensive rats. The vasodilation of mesenteric resistance arteries to acetylcholine was impaired in ANG II hypertension; however, it was improved with EET-B treatment. Further, EET-B protected the kidney in ANG II hypertension as evidenced by a marked 90% decrease in albuminuria and 54% decrease in nephrinuria. Kidney histology demonstrated a decrease in renal tubular cast formation in EET analog-treated hypertensive rats. In ANG II hypertension, EET-B treatment markedly lowered renal inflammation. Urinary monocyte chemoattractant protein-1 excretion was decreased by 55% and kidney macrophage infiltration was reduced by 52% with EET-B treatment. Overall, our results demonstrate that EET-B has anti-hypertensive properties, improves vascular function, and decreases renal inflammation and injury in ANG II hypertension.

Analogical processes in children's understanding of spatial representations.

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Yuan, Lei; Uttal, David; Gentner, Dedre

2017-06-01

We propose that map reading can be construed as a form of analogical mapping. We tested 2 predictions that follow from this claim: First, young children's patterns of performance in map reading tasks should parallel those found in analogical mapping tasks; and, second, children will benefit from guided alignment instructions that help them see the relational correspondences between the map and the space. In 4 experiments, 3-year-olds completed a map reading task in which they were asked to find hidden objects in a miniature room, using a corresponding map. We manipulated the availability of guided alignment (showing children the analogical mapping between maps and spaces; Experiments 1, 2, and 3a), the format of guided alignment (gesture or relational language; Experiment 2), and the iconicity of maps (Experiments 3a and 3b). We found that (a) young children's difficulties in map reading follow from known patterns of analogical development-for example, focusing on object similarity over relational similarity; and (b) guided alignment based on analogical reasoning led to substantially better performance. Results also indicated that children's map reading performance was affected by the format of guided alignment, the iconicity of the maps, and the order of tasks. The results bear on the developmental mechanisms underlying young children's learning of spatial representations and also suggest ways to support this learning. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

HEK. VI. On the Dearth of Galilean Analogs in Kepler, and the Exomoon Candidate Kepler-1625b I

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Teachey, A.; Kipping, D. M.; Schmitt, A. R.

2018-01-01

Exomoons represent an outstanding challenge in modern astronomy, with the potential to provide rich insights into planet formation theory and habitability. In this work, we stack the phase-folded transits of 284 viable moon hosting Kepler planetary candidates, in order to search for satellites. These planets range from Earth- to Jupiter-sized and from ∼0.1 to 1.0 au in separation—so-called “warm” planets. Our data processing includes two-pass harmonic detrending, transit timing variations, model selection, and careful data quality vetting to produce a grand light curve with an rms of 5.1 ppm. We find that the occurrence rate of Galilean analog moon systems for planets orbiting between ∼0.1 and 1.0 au can be constrained to be η population of short-period moons with radii ∼0.5 R ⊕ orbiting at 5–10 planetary radii. However, we stress that the low Bayes factor of just 2 in this region means it should be treated as no more than a hint at this time. Splitting our data into various physically motivated subsets reveals no strong signal. The dearth of Galilean analogs around warm planets places the first strong constraint on exomoon formation models to date. Finally, we report evidence for an exomoon candidate Kepler-1625b I, which we briefly describe ahead of scheduled observations of the target with the Hubble Space Telescope.

DESAIN DAN SINTESIS SENYAWA ACES (ANALOG CURCUMIN SERIES DENGAN METODE SOLID PHASE REACTION SEBAGAI SENYAWA ANTIKANKER POTEN DENGAN MEKANISME MENGHAMBAT PROTEIN NF-kB

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Monica Sabrina Widiapranolo

2016-04-01

Full Text Available Abstract: Analog of curcumin in forms of enone and dienone aromatic is known for their activity as an NF-κB inhibitor. In this study, will be synthesize 2-(4'-N, N-dimethylamino benzilidine cyclohexane-1,3-dione as an analog that predicted has an activity as an NF-κB inhibitor. This research was conducted based on the crossed aldol condensation reaction by reacting 3 mmole pN,N-dimethylamino benzaldehide and 6 mmole cyclohexane-1,3-dione with hydrochloric acid as the catalyst using solid phase reaction method. Based on computational analysis, 2-(4'-N,Ndimethylamino benzilidine cyclohexane-1,3-dione showed a better interaction with NF-κB protein with PLANTSPLP score was -69,7895. The outcome of the reaction was yellow colored powder, no odor and soluble in hydrochloric acid 3N. The yield value was 78.8%. Liquid chromatography showed 100% purity. The melting point range was 237.5-240.3°C. The results of structure elucidation by 1H-NMR, infrared and mass spectroscopy tests indicated the compound was 2-(4-(dimetilaminobenzilidena-4-(3-oksosiklohex-1-enil sikloheksana-1,3-dion. Key words: 2-(4'-N, N-dimethylamino benzilidine cyclohexane-1,3-dione, crossed aldol condensation, solid phase reaction.

Compressional effects in nonneutral plasmas, a shallow water analogy and m=1 instability

International Nuclear Information System (INIS)

Finn, J.M.; Del-Castillo-Negrete, D.; Barnes, D.C.

1999-01-01

Diocotron instabilities form an important class of ExB shear flow instabilities which occur in nonneutral plasmas. The case of a single-species plasma confined in a cylindrical Penning trap, with an axisymmetric, hollow (nonmonotonic) density profile is studied. According to the standard linear theory, the m=1, k z =0 diocotron mode is always stable. On the other hand, experiments by Driscoll [Phys. Rev. Lett. 64, 645 (1990)] show a robust exponential growth of m=1 diocotron perturbations in hollow density profiles. The apparent contradiction between these experimental results and linear theory has been an outstanding problem in the theory of nonneutral plasmas. A new instability mechanism due to the radial variation of the equilibrium plasma length is proposed in this paper. This mechanism involves the compression of the plasma parallel to the magnetic field and implies the conservation of the line integrated density. The predicted growth rate, frequency, and mode structure are in reasonable agreement with the experiment. The effect of a linear perturbation of the plasma length is also shown to give instability with a comparable growth rate. The conservation of the line integrated density in the plasma is analogous to the conservation of the potential vorticity in the shallow water equations used in geophysical fluid dynamics. In particular, there is an analog of Rossby waves in nonneutral plasmas. copyright 1999 American Institute of Physics

ALMA 1.3 Millimeter Map of the HD 95086 System -- A Young Analog of the HR 8799 System

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Su, Kate; MacGregor, Meredith Ann; Booth, Mark; Wilner, David; Malhotra, Renu; Morrison, Sarah; OST STDT

2018-01-01

Planets and minor bodies such as asteroids, Kuiper-belt objects and comets are integral components of a planetary system. Interactions among them leave clues about the formation process of a planetary system. The signature of such interactions is best illustrated through resolved observations of its debris disk. Here we present ALMA 1.3 mm observations of HD 95086, a young analog of the HR 8799 system, that hosts a directly imaged giant planet b and a massive debris disk with both asteroid- and Kuiper-belt analogs. The location of the Kuiper-belt analog is resolved for the first time. Our deep ALMA map also reveals a bright source located near the edge of the ring. The properties of the source, based on limited data, are consistent with it being a luminous star-forming galaxy at high redshift. We will discuss future, resolved observations of debris disks, highlighting the potential of the Origins Space Telescope (OST), one of the four science and technology definition studies commissioned by NASA Headquarters for the 2020 Astronomy and Astrophysics Decadal survey.

The optical analogy for vector fields

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Parker, E. N. (Editor)

1991-01-01

This paper develops the optical analogy for a general vector field. The optical analogy allows the examination of certain aspects of a vector field that are not otherwise readily accessible. In particular, in the cases of a stationary Eulerian flow v of an ideal fluid and a magnetostatic field B, the vectors v and B have surface loci in common with their curls. The intrinsic discontinuities around local maxima in absolute values of v and B take the form of vortex sheets and current sheets, respectively, the former playing a fundamental role in the development of hydrodyamic turbulence and the latter playing a major role in heating the X-ray coronas of stars and galaxies.

Two analogy strategies: the cases of mind metaphors and introspection

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Fischer, Eugen

2018-04-01

Analogical reasoning is often employed in problem-solving and metaphor interpretation. This paper submits that, as a default, analogical reasoning addressing these different tasks employs different mapping strategies. In problem-solving, it employs analogy-maximising strategies (like structure mapping, Gentner, D., & Markman, A. B. (1997). Structure mapping in analogy and similarity. American Psychologist, 52, 45-56); in metaphor interpretation, analogy-minimising strategies (like ATT-Meta, Barnden, J. A. (2015). Open-ended elaborations in creative metaphor. In T. R. Besold, M. Schorlemmer, & A. Smaill (Eds.), Computational creativity research: Towards creative machines (pp. 217-242). Berlin: Springer). The two strategies interact in analogical reasoning with conceptual metaphors. This interaction leads to predictable fallacies. The paper supports these hypotheses through case-studies on "mind" metaphors from ordinary discourse, and abstract problem-solving in the philosophy of mind, respectively. It shows that (1) default metaphorical interpretations for vision- and space-cognition metaphors can be derived with a variant of the analogy-minimising ATT-Meta approach, (2) philosophically influential introspective conceptions of the mind can be derived with conceptual metaphors only through an analogy-maximising strategy, and (3) the interaction of these strategies leads to hitherto unrecognised fallacies in analogical reasoning with metaphors. This yields a debunking explanation of introspective conceptions.

Nitazoxanide Analogs Require Nitroreduction for Antimicrobial Activity in Mycobacterium smegmatis.

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Buchieri, Maria V; Cimino, Mena; Rebollo-Ramirez, Sonia; Beauvineau, Claire; Cascioferro, Alessandro; Favre-Rochex, Sandrine; Helynck, Olivier; Naud-Martin, Delphine; Larrouy-Maumus, Gerald; Munier-Lehmann, Hélène; Gicquel, Brigitte

2017-09-14

In this study, we aimed to decipher the natural resistance mechanisms of mycobacteria against novel compounds isolated by whole-cell-based high-throughput screening (HTS). We identified active compounds using Mycobacterium aurum. Further analyses were performed to determine the resistance mechanism of M. smegmatis against one hit, 3-bromo-N-(5-nitrothiazol-2-yl)-4-propoxybenzamide (3), which turned out to be an analog of the drug nitazoxanide (1). We found that the repression of the gene nfnB coding for the nitroreductase NfnB was responsible for the natural resistance of M. smegmatis against 3. The overexpression of nfnB resulted in sensitivity of M. smegmatis to 3. This compound must be metabolized into hydroxylamine intermediate for exhibiting antibacterial activity. Thus, we describe, for the first time, the activity of a mycobacterial nitroreductase against 1 analogs, highlighting the differences in the metabolism of nitro compounds among mycobacterial species and emphasizing the potential of nitro drugs as antibacterials in various bacterial species.

Centrally acting serotonergic and dopaminergic agents. 1. Synthesis and structure-activity relationships of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives.

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Lin, C H; Haadsma-Svensson, S R; Lahti, R A; McCall, R B; Piercey, M F; Schreur, P J; Von Voigtlander, P F; Smith, M W; Chidester, C G

1993-04-16

The synthesis and structure-activity relationships (SAR) of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives (3) are described. These compounds are conformationally restricted, angular tricyclic analogs of 2-aminotetralin. The synthesis was achieved in several steps from the corresponding 2-tetralones. The enantiomers of the cis analogs were obtained from either fractional recrystallizations of the diastereomeric salts of di-p-toluoyl-L-(or D)-tartaric acid or an asymmetric synthesis using chiral (R)-alpha-methylbenzylamine. All analogs were evaluated in the in vitro 5-HT1A and D2 binding assays and selected analogs were investigated further in biochemical and behavioral tests. Analogs with 9-methoxy substitution (R1 in 3) showed mixed 5-HT1A agonist and dopamine antagonist activities whereas the corresponding 9-hydroxy analogs displayed selective 5-HT1A agonist activity. The cis analogs were found to be more potent than the corresponding trans analogs and in the cis series, the (3aR)-(-)-enantiomers displayed higher potency. Nitrogen substitution (R2 in 3) with either an n-propyl or an allyl group produced similar activities whereas replacement with a bulky alpha-methylbenzyl group resulted in loss of activity. Analogs without aromatic substitution (R1 = H in 3) still showed good 5-HT1A agonist activity, although less potent than the 9-methoxy series. In this case, the trans analogs possessed equal or higher in vitro 5-HT1A affinity than the corresponding cis analogs. Analogs with either 6-methoxy or 6-hydroxy substitution (R1 in 3) were found to display dopamine antagonist properties. However, only N-allyl analogs showed this activity. In the 6-methoxy-N-allyl series, the cis analog was found to be more potent than the trans analog. Again, between the pair of cis enantiomers, the (3aR)-(-)-enantiomer showed higher potency. Incorporation of an additional methyl group into 9-methoxy cis analogs at C-2 resulted in retention of potent 5-HT1A agonist activity.

Human Health Countermeasures - Partial-Gravity Analogs Workshop

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Barr, Yael; Clement, Gilles; Norsk, Peter

2016-01-01

The experimental conditions that were deemed the most interesting by the HHC Element lead scientists are those permitting studies of the long-term effects of exposure to (a) chronic rotation when supine or in head down tilt (ground-based); and (b) long-radius centrifugation (space based). It is interesting to note that chronic ground based slow rotation room studies have not been performed since the 1960's, when the USA and USSR were investigating the potential use of AG for long-duration space missions. On the other hand, the other partial gravity analogs, i.e., parabolic flight, HUT, suspension, and short-radius centrifugation, have been regularly used in the last three decades (see review in Clément et al. 2015). Based on the workshop evaluations and the scores by the HHC scientific disciplines indicated in tables 3 and 4, simulation of partial G between 0 and 1 should be prioritized as follows: Priority 1. Chronic space-based partial-G analogs: a. Chronic space-based long-radius centrifugation. The ideal scenario would be chronic long-radius centrifugation of cells, animals and humans in a translational research approach - ideally beyond low earth orbit under deep space environmental effects and at various rotations - to obtain different G-effects. In this scenario, all physiological systems could be evaluated and the relationship between physiological response and G level established. This would be the most integrative way of defining, for the first time ever, G-thresholds for each physiological system. b. Chronic space-based centrifugation of animals. Chronic centrifugation of rodents at various G levels in space would allow for determination of AG thresholds of protection for each physiological system. In this case, all physiological systems will be of interest. Intermittent centrifugation will be of secondary interest. c. Chronic space-based centrifugation of cell cultures (RWV). Bioreactor studies of cells and cell cultures of various tissues at various G

Clinical Trial Assessing the Efficacy of Gabapentin Plus B Complex (B1/B12 versus Pregabalin for Treating Painful Diabetic Neuropathy

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Alberto Mimenza Alvarado

2016-01-01

Full Text Available Introduction. Painful diabetic neuropathy (PDN is a prevalent and impairing disorder. The objective of this study was to show the efficacy and safety of gabapentin (GBP plus complex B vitamins: thiamine (B1 and cyanocobalamine (B12 compared to pregabalin in patients with moderate to severe intensity PDN. Method. Multicenter, randomized, blind study. Two hundred and seventy patients were evaluated, 147 with GBP/B1/B12 and 123 with PGB, with a 7/10 pain intensity on the Visual Analog Scale (VAS. Five visits (12 weeks were scheduled. The GBP/B1 (100 mg/B12 (20 mg group started with 300 mg at visit 1 to 3600 mg at visit 5. The PGB group started with 75 mg/d at visit 1 to 600 mg/d at visit 5. Different safety and efficacy scales were applied, as well as adverse event assessment. Results. Both drugs showed reduction of pain intensity, without significant statistical difference (P=0.900. In the GBP/B1/B12 group, an improvement of at least 30% on VAS correlated to a 900 mg/d dose, compared with PGB 300 mg/d. Likewise, occurrence of vertigo was lower in the GBP/B1-B12 group, with a significant statistical difference, P=0.014. Conclusions. Our study shows that GPB/B1-B12 combination is as effective as PGB. Nonetheless, pain intensity reduction is achieved with 50% of the minimum required gabapentin dose alone (800 to 1600 mg/d in classic NDD trials. Less vertigo and dizziness occurrence was also observed in the GBP/B1/B12 group. This trial is registered with ClinicalTrials.gov NCT01364298.

Chemical, physical, and sensory characteristics of analog rice developed from the mocaf, arrowroof, and red bean flour

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Wahjuningsih, S. B.; Susanti, S.

2018-01-01

This research was aimed to analyze the chemical, physical, and sensory characteristics of the analog rice developed from a composite formula consisting of mocaf, arrowroot, and red bean flour. Experiment was designed into 5 different composition types i.e B1 (90%: 0%: 10%), B2 (80%:10%: 10%), B3 (70% : 20% : 10%), B4 (60%: 30%:10%), and B5 (50%: 40%: 10%) which in each type was repeated in 4 times. Carrageenan was used as a binder in the making process of those analog rice. Investigation procedure was carried out into several stages such as preparation and characterization of raw materials, production of analog rice in composite formula, then the testing of its chemical and sensory properties. Chemical characteristics were evaluated about the level of starch, amylose, dietary fiber, and resistant starch while sensory characteristics were examined about the texture, flavor, and aroma. The result showed that based on the sensory test, the best composite formula of rice analog was B2 (ratio flour of mocaf: Arrowroot: Red bean = 80:10:10). In addition, B2 formula possessed the chemical characteristics similar with the truth rice either in water content (12.18%), ash (2.63%), protein (6.17%), fat (1.31%), carbohydrate (89.88%), starch (73.29%), amylose (24.91%), total dietary fiber (7.04%), or resistant starch (6.71%). Furthermore, the higher of arrowroot flour proportion, the greater of amylose, dietary fiber and resistant starch containing in the rice analog. In the opposite, its starch content was getting down.

Effects of Multimedia and Schema Induced Analogical Reasoning on Science Learning

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Zheng, R. Z.; Yang, W.; Garcia, D.; McCadden, E. P.

2008-01-01

The present study investigates the effects of multimedia and schema induced analogical reasoning on science learning. It involves 89 fourth grade elementary students in the north-east of the United States. Participants are randomly assigned into four conditions: (a) multimedia with analogy; (b) multimedia without analogy; (c) analogy without…

High-dose thiamine therapy counters dyslipidemia and advanced glycation of plasma protein in streptozotocin-induced diabetic rats.

Science.gov (United States)

Karachalias, Nikolaos; Babaei-Jadidi, Roya; Kupich, Christian; Ahmed, Naila; Thornalley, Paul J

2005-06-01

The streptozotocin-induced (STZ) diabetic rat experimental model of diabetes on insulin maintenance therapy exhibits dyslipidemia, mild thiamine deficiency, and increased plasma protein advanced glycation end products (AGEs). The reversal of thiamine deficiency by high-dose thiamine and S-benzoylthiamine monophosphate (benfotiamine) prevented the development of incipient nephropathy. Recently, we reported that high-dose thiamine (but not benfotiamine) countered diabetic dyslipidemia. To understand further the differences between the effects of thiamine and benfotiamine therapy, we quantified the levels of the AGEs in plasma protein. We found hydroimidazolone AGE residues derived from glyoxal and methylglyoxal, G-H1 and MG-H1, were increased 115% and 68% in STZ diabetic rats, with respect to normal controls, and were normalized by both thiamine and benfotiamine; whereas N-carboxymethyl-lysine (CML) and N-carboxyethyl-lysine (CEL) residues were increased 74% and 118% in STZ diabetic rats and were normalized by thiamine only. The lack of effect of benfotiamine on plasma CML and CEL residue concentrations suggests there may be important precursors of plasma protein CML and CEL residues other than glyoxal and methylglyoxal. These are probably lipid-derived aldehydes.

Synthesis and antimicrobial properties of 1,3,4-oxadiazole analogs containing dibenzosuberone moiety

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Moger, Manjunath [Mangalore University, Karnataka (India). Department of Chemistry; Satam, Vijay; Paniraj, A.S.; Gopinath, Vadiraj S.; Hindupur, Rama Mohan; Pati, Hari N., E-mail: hari.pati@advinus.com [Advinus Therapeutics Ltd., 21 and 22, Phase II, Peenya Industrial Area, Karnataka (India); Govindaraju, Darshan Raj C. [Department of Bio-Medicinal Research, Vidya Herbs Pvt. Ltd., Karnataka (India)

2014-01-15

A series of ten novel 1,3,4-oxadiazole analogs containing dibenzosuberone moiety were synthesized using linear as well as convergent synthesis approach. All the compounds were characterized by mass spectrometry, infrared (IR), {sup 1}H and {sup 13}C nuclear magnetic resonance ({sup 1}H NMR and {sup 13}C NMR) spectroscopies and elemental analysis. These compounds were evaluated for antibacterial and antifungal activities. Among ten analogs, four compounds, namely, 8a, 8d, 8e and 8j were found to be highly active antibacterial and antifungal agents (author)

Substrate analog interaction with MCR-1 offers insight into the rising threat of the plasmid-mediated transferable colistin resistance.

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Wei, Pengcheng; Song, Guangji; Shi, Mengyang; Zhou, Yafei; Liu, Yang; Lei, Jun; Chen, Peng; Yin, Lei

2018-02-01

Colistin is considered a last-resort antibiotic against most gram-negative bacteria. Recent discoveries of a plasmid-mediated, transferable mobilized colistin-resistance gene ( mcr-1) on all continents have heralded the imminent emergence of pan-drug-resistant superbacteria. The inner-membrane protein MCR-1 can catalyze the transfer of phosphoethanolamine (PEA) to lipid A, resulting in colistin resistance. However, little is known about the mechanism, and few drugs exist to address this issue. We present crystal structures revealing the MCR-1 catalytic domain (cMCR-1) as a monozinc metalloprotein with ethanolamine (ETA) and d-glucose, respectively, thus highlighting 2 possible substrate-binding pockets in the MCR-1-catalyzed PEA transfer reaction. Mutation of the residues involved in ETA and d-glucose binding impairs colistin resistance in recombinant Escherichia coli containing full-length MCR-1. Partial analogs of the substrate are used for cocrystallization with cMCR-1, providing valuable information about the family of PEA transferases. One of the analogs, ETA, causes clear inhibition of polymyxin B resistance, highlighting its potential for drug development. These data demonstrate the crucial role of the PEA- and lipid A-binding pockets and provide novel insights into the structure-based mechanisms, important drug-target hot spots, and a drug template for further drug development to combat the urgent, rising threat of MCR-1-mediated antibiotic resistance.-Wei, P., Song, G., Shi, M., Zhou, Y., Liu, Y., Lei, J., Chen, P., Yin, L. Substrate analog interaction with MCR-1 offers insight into the rising threat of the plasmid-mediated transferable colistin resistance.

Using ultra-rapid insulin analogs in children and adolescents with type 1 diabetes mellitus

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О.V. Bolshova

2017-11-01

Full Text Available Background. The purpose of the study was a retrospective comparative analysis of using insulin analogues of the prolonged and ultra-short action and human genetically engineered insulins of middle and short action in children and adolescents with type 1 diabetes mellitus (DM. Materials and methods. The influence of ultra-rapid insulin analog in comparison with human rapid-action insulin on the course of type 1 DM in 100 children and adolescents was studied. It was applied as basal-bolus regimen of insulin therapy. Analysis of parameters which reflect criteria of insulin therapy effectiveness, positive effect of ultra-rapid insulin analog on the course of DM has been performed. Results. Application of ultra-rapid insulin analog before each meal improved parameters of pre- and postprandial glycemia, decreased the range of fluctuations of blood sugar during the day, reduced and maintained HbA1c level without augmentation of frequency and intensity of hypoglycaemia, and also decreased the level of noctural hypoglycaemia. Conclusions. The ultra-rapid insulin analog is the drug of choice for the effective use in insulin pumps.

Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064.

Science.gov (United States)

Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y; Caldwell, Richard D; Caravella, Justin A; Chen, Lihong; Creech, Katrina L; Deaton, David N; Jones, Stacey A; Kaldor, Istvan; Liu, Yaping; Madauss, Kevin P; Marr, Harry B; McFadyen, Robert B; Miller, Aaron B; Navas, Frank; Parks, Derek J; Spearing, Paul K; Todd, Dan; Williams, Shawn P; Wisely, G Bruce

2008-08-01

Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.

Analogical reasoning and aging: the processing speed and inhibition hypothesis.

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Bugaiska, Aurélia; Thibaut, Jean-Pierre

2015-01-01

This study was designed to investigate the effect of aging on analogical reasoning by manipulating the strength of semantic association (LowAssoc or HighAssoc) and the number of distracters' semantic analogies of the A:B::C:D type and to determine which factors might be responsible for the age-related differences on analogical reasoning by testing two different theoretical frameworks: the inhibition hypothesis and the speed mediation hypothesis. We compared young adults and two groups of aging people (old and old-old) with word analogies of the A:B::C:D format. Results indicate an age-related effect on analogical reasoning, this effect being greatest with LowAssoc analogies. It was not associated with the presence of semantic distractors. Moreover, the results show that the variance part of the analogy task due to age was mainly explained by processing speed (rather than by inhibition) in the case of old participants and by both processing speed and inhibition in the old-old group. These results are discussed in relation to current models of aging and their interaction with the processes involved in analogical reasoning.

Acetyl analogs of combretastatin A-4: synthesis and biological studies.

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Babu, Balaji; Lee, Megan; Lee, Lauren; Strobel, Raymond; Brockway, Olivia; Nickols, Alexis; Sjoholm, Robert; Tzou, Samuel; Chavda, Sameer; Desta, Dereje; Fraley, Gregory; Siegfried, Adam; Pennington, William; Hartley, Rachel M; Westbrook, Cara; Mooberry, Susan L; Kiakos, Konstantinos; Hartley, John A; Lee, Moses

2011-04-01

The combretastatins have received significant attention because of their simple chemical structures, excellent antitumor efficacy and novel antivascular mechanisms of action. Herein, we report the synthesis of 20 novel acetyl analogs of CA-4 (1), synthesized from 3,4,5-trimethoxyphenylacetone that comprises the A ring of CA-4 with different aromatic aldehydes as the B ring. Molecular modeling studies indicate that these new compounds possess a 'twisted' conformation similar to CA-4. The new analogs effectively inhibit the growth of human and murine cancer cells. The most potent compounds 6k, 6s and 6t, have IC(50) values in the sub-μM range. Analog 6t has an IC(50) of 182 nM in MDA-MB-435 cells and has advantages over earlier analogs due to its enhanced water solubility (456 μM). This compound initiates microtubule depolymerization with an EC(50) value of 1.8 μM in A-10 cells. In a murine L1210 syngeneic tumor model 6t had antitumor activity and no apparent toxicity. Copyright © 2011 Elsevier Ltd. All rights reserved.

Estrogenic effects of several BPA analogs in the developing zebrafish brain

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Joel eCano-Nicolau

2016-03-01

Full Text Available Important set of studies have demonstrated the endocrine disrupting activity of Bisphenol A (BPA. The present work aimed at defining estrogenic-like activity of several BPA structural analogs, including BPS, BPF, BPAF, and BPAP, on 4-day or 7-day post-fertilization (dpf zebrafish larva as an in vivo model. We measured the induction level of the estrogen-sensitive marker cyp19a1b gene (Aromatase B, expressed in the brain, using three different in situ/in vivo strategies: 1 Quantification of cyp19a1b transcripts using RT-qPCR in wild type 7-dpf larva brains exposed to bisphenols ; 2 Detection and distribution of cyp19a1b transcripts using in situ hybridization on 7-dpf brain sections (hypothalamus; and 3 Quantification of the cyp19a1b promoter activity in live cyp19a1b-GFP transgenic zebrafish (EASZY assay at 4-dpf larval stage. These three different experimental approaches demonstrated that BPS, BPF or BPAF exposure, similarly to BPA, significantly activates the expression of the estrogenic marker in the brain of developing zebrafish. In vitro experiments using both reporter gene assay in a glial cell context and competitive ligand binding assays strongly suggested that up-regulation of cyp19a1b is largely mediated by the zebrafish estrogen nuclear receptor alpha (zfERα. Importantly, and in contrast to other tested bisphenol A analogs, the bisphenol AP (BPAP did not show estrogenic activity in our model.

Eye Movements Reveal Optimal Strategies for Analogical Reasoning.

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Vendetti, Michael S; Starr, Ariel; Johnson, Elizabeth L; Modavi, Kiana; Bunge, Silvia A

2017-01-01

Analogical reasoning refers to the process of drawing inferences on the basis of the relational similarity between two domains. Although this complex cognitive ability has been the focus of inquiry for many years, most models rely on measures that cannot capture individuals' thought processes moment by moment. In the present study, we used participants' eye movements to investigate reasoning strategies in real time while solving visual propositional analogy problems (A:B::C:D). We included both a semantic and a perceptual lure on every trial to determine how these types of distracting information influence reasoning strategies. Participants spent more time fixating the analogy terms and the target relative to the other response choices, and made more saccades between the A and B items than between any other items. Participants' eyes were initially drawn to perceptual lures when looking at response choices, but they nonetheless performed the task accurately. We used participants' gaze sequences to classify each trial as representing one of three classic analogy problem solving strategies and related strategy usage to analogical reasoning performance. A project-first strategy, in which participants first extrapolate the relation between the AB pair and then generalize that relation for the C item, was both the most commonly used strategy as well as the optimal strategy for solving visual analogy problems. These findings provide new insight into the role of strategic processing in analogical problem solving.

Eye Movements Reveal Optimal Strategies for Analogical Reasoning

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Michael S. Vendetti

2017-06-01

Full Text Available Analogical reasoning refers to the process of drawing inferences on the basis of the relational similarity between two domains. Although this complex cognitive ability has been the focus of inquiry for many years, most models rely on measures that cannot capture individuals' thought processes moment by moment. In the present study, we used participants' eye movements to investigate reasoning strategies in real time while solving visual propositional analogy problems (A:B::C:D. We included both a semantic and a perceptual lure on every trial to determine how these types of distracting information influence reasoning strategies. Participants spent more time fixating the analogy terms and the target relative to the other response choices, and made more saccades between the A and B items than between any other items. Participants' eyes were initially drawn to perceptual lures when looking at response choices, but they nonetheless performed the task accurately. We used participants' gaze sequences to classify each trial as representing one of three classic analogy problem solving strategies and related strategy usage to analogical reasoning performance. A project-first strategy, in which participants first extrapolate the relation between the AB pair and then generalize that relation for the C item, was both the most commonly used strategy as well as the optimal strategy for solving visual analogy problems. These findings provide new insight into the role of strategic processing in analogical problem solving.

Glucagon-like peptide-1 analogs against antipsychotic-induced weight gain: potential physiological benefits

Science.gov (United States)

2012-01-01

Background Antipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia. Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1). Moreover, we account for similarities in brain changes between schizophrenia and overweight patients. Discussion Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed. Conclusions We propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted. PMID:22891821

Glucagon-like peptide-1 analogs against antipsychotic-induced weight gain: potential physiological benefits

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Ebdrup Bjørn H

2012-08-01

Full Text Available Abstract Background Antipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia. Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1. Moreover, we account for similarities in brain changes between schizophrenia and overweight patients. Discussion Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed. Conclusions We propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted.

Isolation of the antibiotic pseudopyronine B and SAR evaluation of C3/C6 alkyl analogs.

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Bouthillette, Leah M; Darcey, Catherine A; Handy, Tess E; Seaton, Sarah C; Wolfe, Amanda L

2017-06-15

Natural products are an abundant source of structurally diverse compounds with antibacterial activity that can be used to develop new and potent antibiotics. One such class of natural products is the pseudopyronines. Here we present the isolation of pseudopyronine B (2) from a Pseudomonas species found in garden soil in Western North Carolina, and SAR evaluation of C3 and C6 alkyl analogs of the natural product for antibacterial activity against Gram-positive and Gram-negative bacteria. We found a direct relationship between antibacterial activity and C3/C6 alkyl chain length. For inhibition of Gram-positive bacteria, alkyl chain lengths between 6 and 7 carbons were found to be the most active (IC 50 =0.04-3.8µg/mL) whereas short alkyl chain analogs showed modest activity against Gram-negative bacteria (IC 50 =223-304µg/mL). This demonstrates the potential for this class of natural products to be optimized for selective activity against either Gram-positive or Gram-negative bacteria. Copyright © 2017 Elsevier Ltd. All rights reserved.

Analogy, an Alternative Model.
 Critics to the standard model of analogical problems solving and proposals for an alternative one

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Ricardo A. Minervino

2016-02-01

Full Text Available The authors made an extension of Hofstadter‘s criticisms against the standard approach in analogical thinking represented by the structure-mapping theory of Gentner and the multiconstraint theory of Holyoak and Thagard. Based on this extension, they proposed a non-serial model of analogical problem solving. Against the standard approach, the model postulates that: (a people detect and evaluate differences between mapped elements before the subprocess of inference generation and consider them in order to control it, and (b properties of an element that explain why the element could fill a certain role in the base problem resolution (PERs play a crucial role in these detection and evaluation operations, and also in post-inferences subprocesses. An experiment showed that: (a people detect and evaluate the relevance of differences between mapped elements before inference generation, (b that they inhibit the generation of literal inferences when they face relevant differences, and (c that they stop the subprocess when they recognize insuperable ones. The results also showed that base PERs are reactivated at different moments of analogical transfer. The data obtained are incompatible with the standard theories of analogical thinking, which treat inference generation as a syntactic mechanism and exclude contextual semantic analysis from the study of analogy. 

Analog insulin detemir for patients with type 1 and type 2 diabetes: a review

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Gregory E Peterson

2009-05-01

Full Text Available Gregory E PetersonDepartment of Internal Medicine, Des Moines University, USAObjective: To review insulin detemir for clinical use to better manage patients with type 1 and type 2 diabetes.Methods: A MEDLINE search, in English, from June 30, 2006 to December 1, 2008, using the terms “insulin analogs,” “insulin detemir” and “long-acting insulin analog.”Results: Insulin detemir improves glycemic control, based on HbA1C reduction and fasting glucose levels, without increasing the risk of hypoglycemia and weight gain. Insulin detemir has lower glycemic variability, with less intra-subject variability in blood glucose levels in patients with type 1 and type 2 diabetes, without increasing the risk of hypoglycemia. When added to oral anti-diabetes agents (OADs in type 2 diabetes, insulin detemir demonstrates superiority to other basal insulin options.Conclusion: Insulin detemir appears to provide better glycemic control with a lower risk of hypoglycemia and less weight gain in the treatment of patients with type 1 and type 2 diabetes.Keywords: type 1 diabetes, type 2 diabetes, insulin analogs, insulin detemir

Synthesis of 1-Substituted Carbazolyl-1,2,3,4-tetrahydro- and Carbazolyl-3,4-dihydro-β-carboline Analogs as Potential Antitumor Agents

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Ji-Wang Chern

2011-02-01

Full Text Available A series of 1-substituted carbazolyl-1,2,3,4-tetrahydro- and carbazolyl-3,4-dihydro-b-carboline analogs have been synthesized and evaluated for antitumor activity against human tumor cells including KB, DLD, NCI-H661, Hepa, and HepG2/A2 cell lines. Among these, compounds 2, 6, 7, and 9 exhibited the most potent and selective activity against the tested tumor cells. As for inhibition of topoisomerase II, compounds 1–14 and 18 showed better activity than etoposide. Among them, compounds 3, 4, 7, 9, and 10 exhibited potent activity. The structure and activity relationship (SAR study revealed correlation between carbon numbers of the side chain and biological activities. The molecular complex with DNA for compound 2 was proposed.

Children's Failure in Analogical Reasoning Tasks: A Problem of Focus of Attention and Information Integration?

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Glady, Yannick; French, Robert M; Thibaut, Jean-Pierre

2017-01-01

Children's improved performance with age in analogy tasks has been explained by an increase in semantic knowledge of the items and the relations between them or by the development of an increased ability to inhibit irrelevant information. We tested the so-called "unbalanced attentional focus hypothesis" that claims that a failure to choose the "analogical" match can be the result of a difficulty to focus on all the relevant information available. Previous eye-tracking research has suggested, in analogies of the A:B::C:D format, that 5-6 year-olds organize their search around the C item. They focused significantly less than adults on the A:B pair, thereby hindering their discovering the relation(s) between A and B. We hypothesized that inducing them to focus their attention on the A:B pair at the beginning of the trial would affect their performance. In Experiment 1, increasing children's focus on the A:B pair did, indeed, lead to better performance. In contrast, in Experiment 2, focusing their attention on the A:B pair impaired performance when the most salient relation holding between A and B was, in fact, irrelevant for the analogy. By contrast, the obvious-but-irrelevant relation in the A:B pair had no negative effect on performance when no explicit A:B focusing was induced. These results are discussed in terms of the temporal organization of the task and availability of information, and of children's difficulties to disengage from the main goal of the task, when necessary.

Oligomerization of a Glucagon-like Peptide 1 Analog: Bridging Experiment and Simulations

DEFF Research Database (Denmark)

Frederiksen, Tine Maja; Sønderby, Pernille; Ryberg, Line A.

2015-01-01

The glucagon-like peptide 1 (GLP-1) analog, liraglutide, is a GLP-1 agonist and is used in the treatment of type-2 diabetes mellitus and obesity. From a pharmaceutical perspective, it is important to know the oligomerization state of liraglutide with respect to stability. Compared to GLP-1...

Annexin V Imaging Detects Diabetes-Accelerated Apoptosis and Monitors the Efficacy of Benfotiamine Treatment in Ischemic Limbs of Mice

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Kyung-Ho Jung

2014-05-01

Full Text Available The role of apoptosis imaging for monitoring treatment response in ischemic limbs has not been properly explored. In this study, we investigated the ability of annexin V (AnxV imaging to assess the efficacy of antiapoptotic treatment in ischemic limbs of diabetic mice. Normal C57BL/6 mice and streptozotocin-induced diabetic mice were subject to hindlimb ischemia. AnxV-conjugated fluorescent streptavidin probes were intravenously injected, and optical imaging was performed. Tissue apoptosis was quantified by histochemistry and Western blotting. The AnxV probes showed specific targeting to apoptotic cells on confocal microscopy and flow cytometry. Intravenous AnxV probes displayed substantially greater accumulation in ischemic limbs of diabetic mice. Benfotiamine (BFT treatment of diabetic mice led to better perfusion recovery on laser Doppler imaging and reduced AnxV binding on optical imaging. TUNEL staining and cleaved caspase-3 Western blots confirmed accelerated apoptosis by diabetes and its suppression by BFT treatment. Furthermore, AnxV-SAv-PEcy5.5 uptake in the ischemic limbs closely correlated to cleaved caspase-3 expression. Thus, AnxV imaging may be useful for monitoring the efficacy of therapeutic agents designed to suppress ischemia-induced apoptosis.

Annexin V imaging detects diabetes-accelerated apoptosis and monitors the efficacy of benfotiamine treatment in ischemic limbs of mice.

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Jung, Kyung-Ho; Lee, Jin Hee; Park, Jin Won; Paik, Jin Young; Quach, Cung Hoa Thien; Lee, Eun Jeong; Lee, Kyung-Han

2014-01-01

The role of apoptosis imaging for monitoring treatment response in ischemic limbs has not been properly explored. In this study, we investigated the ability of annexin V (AnxV) imaging to assess the efficacy of antiapoptotic treatment in ischemic limbs of diabetic mice. Normal C57BL/6 mice and streptozotocin-induced diabetic mice were subject to hindlimb ischemia. AnxV-conjugated fluorescent streptavidin probes were intravenously injected, and optical imaging was performed. Tissue apoptosis was quantified by histochemistry and Western blotting. The AnxV probes showed specific targeting to apoptotic cells on confocal microscopy and flow cytometry. Intravenous AnxV probes displayed substantially greater accumulation in ischemic limbs of diabetic mice. Benfotiamine (BFT) treatment of diabetic mice led to better perfusion recovery on laser Doppler imaging and reduced AnxV binding on optical imaging. TUNEL staining and cleaved caspase-3 Western blots confirmed accelerated apoptosis by diabetes and its suppression by BFT treatment. Furthermore, AnxV-SAv-PEcy5.5 uptake in the ischemic limbs closely correlated to cleaved caspase-3 expression. Thus, AnxV imaging may be useful for monitoring the efficacy of therapeutic agents designed to suppress ischemia-induced apoptosis.

Vitamin E analogs trigger apoptosis in HER2/erbB2-overexpressing breast cancer cells by signaling via the mitochondrial pathway

Czech Academy of Sciences Publication Activity Database

Wang, X.-F.; Witting, P. K.; Salvatore, B.A.; Neužil, Jiří

2005-01-01

Roč. 326, č. 4 (2005), s. 282-289 ISSN 0006-291X Institutional research plan: CEZ:AV0Z5052915; CEZ:AV0Z50520514 Keywords : vitamin E analogs * apoptosis * ErbB2 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.000, year: 2005

Detecting analogical resemblance without retrieving the source analogy.

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Kostic, Bogdan; Cleary, Anne M; Severin, Kaye; Miller, Samuel W

2010-06-01

We examined whether people can detect analogical resemblance to an earlier experimental episode without being able to recall the experimental source of the analogical resemblance. We used four-word analogies (e.g., robin-nest/beaver-dam), in a variation of the recognition-without-cued-recall method (Cleary, 2004). Participants studied word pairs (e.g., robin-nest) and were shown new word pairs at test, half of which analogically related to studied word pairs (e.g., beaver-dam) and half of which did not. For each test pair, participants first attempted to recall an analogically similar pair from the study list. Then, regardless of whether successful recall occurred, participants were prompted to rate the familiarity of the test pair, which was said to indicate the likelihood that a pair that was analogically similar to the test pair had been studied. Across three experiments, participants demonstrated an ability to detect analogical resemblance without recalling the source analogy. Findings are discussed in terms of their potential relevance to the study of analogical reasoning and insight, as well as to the study of familiarity and recognition memory.

High thiamine diphosphate concentrations in erythrocytes can be achieved in dialysis patients by oral administration of benfontiamine.

Science.gov (United States)

Frank, T; Bitsch, R; Maiwald, J; Stein, G

2000-06-01

The influence of either orally administered S-benzoylthiamine-O-monophosphate (benfotiamine) or thiamine nitrate on the thiamine status was tested in a randomised, two-group comparison study in 20 end-stage renal disease (ESRD) patients. Main outcome measures were the pharmacokinetics of thiamine diphosphate (TDP) in blood, the in vitro erythrocyte transketolase activity, its activation coefficient (alpha-ETK) and the TDP concentration in erythrocytes. After ingestion of a single dose of either 100 mg thiamine nitrate (corresponding to 305 micromol thiamine) or 100 mg benfotiamine (corresponding to 214 micromol thiamine), the blood levels of thiamine phosphate esters were analysed by means of high-performance liquid chromatography for a 24-h period. The TDP concentration in erythrocytes was calculated using the haematocrit and TDP concentration in blood. Erythrocyte transketolase activity and alpha-ETK were measured before and 10 h after administration. The pharmacokinetics of TDP in blood were compared with healthy subjects of other studies retrieved from database query. Regarding the blood concentrations of TDP, the patients with ESRD had a 4.3 times higher area under the concentration time curve after benfotiamine administration than after thiamine nitrate. After benfotiamine administration, the peak plasma concentration of TDP exceeded that in healthy subjects by 51%. In the ESRD patients, after 24 h, the mean TDP concentration in erythrocytes increased from 158.7+/-30.9 ng/ml initially to 325.8+/-50.9 ng/ml after administration of benfotiamine and from 166.2+/-51.9 ng/ml to 200.5+/-50.0 ng/ml after thiamine nitrate administration. The ratio between the maximum erythrocyte TDP concentration and basal concentration was 2.66+/-0.6 in the benfotiamine group and 1.44+/-0.2 in the group receiving thiamine nitrate (P benfotiamine intake (P = 0.02) and from 3.71+/-0.8 microkat/l to 4.02+/-0.7 microkat/l after thiamine nitrate intake (P = 0.08). Likewise, alpha

Synthesis and antimicrobial activity of some new substituted 9-(1H-Pyrazolo [3, 4-b] Quinolin-1-YL) Acridines

International Nuclear Information System (INIS)

Thakor, S.; Parmar, P.; Patel, M.; Patel, R.

2008-01-01

2-chloro-6-methyl/methoxy-3-formylquinoline upon condensation with substituted 9-hydrazino-acridine afforded corresponding hydrazones which were cyclized under alkaline condition to give 9-(6-substituted-1H-pyrazolo [3, 4-b] quinolin-1-yl) acridine analoges. All of the synthesized compounds were characterized by their elemental analysis, IR and NMR spectral studies. Biological screenings of the prepared compounds have been screened on some strain of bacteria and fungus. (author)

A novel analog/digital reconfigurable automatic gain control with a novel DC offset cancellation circuit

Energy Technology Data Exchange (ETDEWEB)

He Xiaofeng; Ye Tianchun [Institute of Microelectronics, Chinese Academy of Science, Beijing 100029 (China); Mo Taishan; Ma Chengyan, E-mail: hexiaofeng@casic.ac.cn [Hangzhou Zhongke Microelectronics Co, Ltd, Hangzhou 310053 (China)

2011-02-15

An analog/digital reconfigurable automatic gain control (AGC) circuit with a novel DC offset cancellation circuit for a direct-conversion receiver is presented. The AGC is analog/digital reconfigurable in order to be compatible with different baseband chips. What's more, a novel DC offset cancellation (DCOC) circuit with an HPCF (high pass cutoff frequency) less than 10 kHz is proposed. The AGC is fabricated by a 0.18 {mu}m CMOS process. Under analog control mode, the AGC achieves a 70 dB dynamic range with a 3 dB-bandwidth larger than 60 MHz. Under digital control mode, through a 5-bit digital control word, the AGC shows a 64 dB gain control range by 2 dB each step with a gain error of less than 0.3 dB. The DC offset cancellation circuits can suppress the output DC offset voltage to be less than 1.5 mV, while the offset voltage of 40 mV is introduced into the input. The overall power consumption is less than 3.5 mA, and the die area is 800 x 300 {mu}m{sup 2}. (semiconductor integrated circuits)

The future of vitamin D analogs

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Carlien eLeyssens

2014-04-01

Full Text Available The active form of vitamin D3, 1,25-dihydroxyvitamin D3, is a major regulator of bone and calcium homeostasis. In addition, this hormone also inhibits the proliferation and stimulates the differentiation of normal as well as malignant cells. Supraphysiological doses of 1,25-dihydroxyvitamin D3 are required to reduce cancer cell proliferation. However, these doses will lead in vivo to calcemic side effects such as hypercalcemia and hypercalciuria. During the last 25 years, many structural analogs of 1,25-dihydroxyvitamin D3 have been synthesized by the introduction of chemical modifications in the A-ring, central CD-ring region or side chain of 1,25-dihydroxyvitamin D3 in the hope to find molecules with a clear dissociation between the beneficial antiproliferative effects and adverse calcemic side effects. One example of such an analog with a good dissociation ratio is calcipotriol (DaivonexR, which is clinically used to treat the hyperproliferative skin disease psoriasis. Other vitamin D analogs were clinically approved for the treatment of osteoporosis or secondary hyperparathyroidism. No vitamin D analog is currently used in the clinic for the treatment of cancer although several analogs have been shown to be potent drugs in animal models of cancer. Omics studies as well as in vitro cell biological experiments unraveled basic mechanisms involved in the antineoplastic effects of vitamin D and its analogs. 1,25-dihydroxyvitamin D3 and analogs act in a cell type- and tissue-specific manner. Moreover, a blockade in the transition of the G0/1 towards S phase of the cell cycle, induction of apoptosis, inhibition of migration and invasion of tumor cells together with effects on angiogenesis and inflammation have been implicated in the pleiotropic effects of 1,25-dihydroxyvitamin D3 and its analogs. In this review we will give an overview of the action of vitamin D analogs in tumor cells and look forward how these compounds could be introduced in the

Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes

Science.gov (United States)

de Graaf, Chris; Donnelly, Dan; Wootten, Denise; Lau, Jesper; Sexton, Patrick M.; Miller, Laurence J.; Ahn, Jung-Mo; Liao, Jiayu; Fletcher, Madeleine M.; Brown, Alastair J. H.; Zhou, Caihong; Deng, Jiejie; Wang, Ming-Wei

2016-01-01

The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein–coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain–binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders. PMID:27630114

Potencies of vitamin D analogs, 1α-hydroxyvitamin D3 , 1α-hydroxyvitamin D2 and 25-hydroxyvitamin D3 , in lowering cholesterol in hypercholesterolemic mice in vivo.

Science.gov (United States)

Quach, Holly P; Dzekic, Tamara; Bukuroshi, Paola; Pang, K Sandy

2018-04-01

Vitamin D 3 and the synthetic vitamin D analogs, 1α-hydroxyvitamin D 3 [1α(OH)D 3 ], 1α-hydroxyvitamin D 2 [1α(OH)D 2 ] and 25-hydroxyvitamin D 3 [25(OH)D 3 ] were appraised for their vitamin D receptor (VDR) associated-potencies as cholesterol lowering agents in mice in vivo. These precursors are activated in vivo: 1α(OH)D 3 and 1α(OH)D 2 are transformed by liver CYP2R1 and CYP27A1 to active VDR ligands, 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] and 1α,25-dihydroxyvitamin D 2 [1,25(OH) 2 D 2 ] , respectively. 1α(OH)D 2 may also be activated by CYP24A1 to 1α,24-dihydroxyvitamin D 2 [1,24(OH) 2 D 2 ], another active VDR ligand. 25(OH)D 3 , the metabolite formed via CYP2R1 and or CYP27A1 in liver from vitamin D 3 , is activated by CYP27B1 in the kidney to 1,25(OH) 2 D 3 . In C57BL/6 mice fed the high fat/high cholesterol Western diet for 3 weeks, vitamin D analogs were administered every other day intraperitoneally during the last week of the diet. The rank order for cholesterol lowering, achieved via mouse liver small heterodimer partner (Shp) inhibition and increased cholesterol 7α-hydroxylase (Cyp7a1) expression, was: 1.75 nmol/kg 1α(OH)D 3  > 1248 nmol/kg 25(OH)D 3 (dose ratio of 0.0014) > > 1625 nmol/kg vitamin D 3 . Except for 1.21 nmol/kg 1α(OH)D 2 that failed to lower liver and plasma cholesterol contents, a significant negative correlation was observed between the liver concentration of 1,25(OH) 2 D 3 formed from the precursors and liver cholesterol levels. The composite results show that vitamin D analogs 1α(OH)D 3 and 25(OH)D 3 exhibit cholesterol lowering properties upon activation to 1,25(OH) 2 D 3 : 1α(OH)D 3 is rapidly activated by liver enzymes and 25(OH)D 3 is slowly activated by renal Cyp27b1 in mouse. Copyright © 2018 John Wiley & Sons, Ltd.

Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties

Directory of Open Access Journals (Sweden)

Catalin V. Maftei

2013-10-01

Full Text Available Taking into consideration the biological activity of the only natural products containing a 1,2,4-oxadiazole ring in their structure (quisqualic acid and phidianidines A and B, the natural product analogs 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-ylphenylpyrrolidine-2,5-dione (4 and 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-ylphenyl-1H-pyrrole-2,5-dione (7 were synthesized starting from 4-(3-tert-butyl-1,2,4-oxadiazol-5-ylaniline (1 in two steps by isolating the intermediates 4-(4-(3-tert-butyl-1,2,4-oxadiazol-5-ylphenylamino-4-oxobutanoic acid (3 and (Z-4-(4-(3-tert-butyl-1,2,4-oxadiazol-5-ylphenylamino-4-oxobut-2-enoic acid (6. The two natural product analogs 4 and 7 were then tested for antitumor activity toward a panel of 11 cell lines in vitro by using a monolayer cell-survival and proliferation assay. Compound 7 was the most potent and exhibited a mean IC50 value of approximately 9.4 µM. Aniline 1 was synthesized by two routes in one-pot reactions starting from tert-butylamidoxime and 4-aminobenzoic acid or 4-nitrobenzonitrile. The structures of compounds 1, 2, 4, 5 and 6 were confirmed by X-ray crystallography.

Achiral Mannich-Base Curcumin Analogs Induce Unfolded Protein Response and Mitochondrial Membrane Depolarization in PANC-1 Cells

Directory of Open Access Journals (Sweden)

Gábor J. Szebeni

2017-10-01

Full Text Available Achiral Mannich-type curcumin analogs have been synthetized and assayed for their cytotoxic activity. The anti-proliferative and cytotoxic activity of curcuminoids has been tested on human non-small-cell lung carcinoma (A549, hepatocellular carcinoma (HepG2 and pancreatic cancer cell line (PANC-1. Based on the highest anti-proliferative activity nine drug candidates were further tested and proved to cause phosphatidylserine exposure as an early sign of apoptosis. Curcumin analogs with the highest apoptotic activity were selected for mechanistic studies in the most sensitive PANC-1 cells. Cytotoxic activity was accompanied by cytostatic effect since curcumin and analogs treatment led to G0/G1 cell cycle arrest. Moreover, cytotoxic effect could be also detected via the accumulation of curcuminoids in the endoplasmic reticulum (ER and the up-regulation of ER stress-related unfolded protein response (UPR genes: HSPA5, ATF4, XBP1, and DDIT3. The activated UPR induced mitochondrial membrane depolarization, caspase-3 activation and subsequent DNA breakdown in PANC-1 cells. Achiral curcumin analogs, C509, C521 and C524 possessed superior, 40-times more potent cytotoxic activity compared to natural dihydroxy-dimetoxycurcumin in PANC-1 cells.

Indicators of Discontinuous Change in the Development of Analogical Reasoning

Science.gov (United States)

Hosenfeld; van der Maas HLJ; van den Boom DC

1997-03-01

In a longitudinal study, five indicators of a transition in the development of analogical reasoning were examined in young elementary school children, (a) bimodality and (b) inaccessibility in the frequency distributions of test performance, and in the responses of the transitional subjects, respectively, (c) sudden jumps, (d) anomalous variance, and (e) critical slowing down. An open-ended geometric-analogies test was administered eight times during a period of six months to eighty children in Grades 1 and 2 (six- to eight-year-olds). Strong evidence for bimodality was found in the distribution of the test scores and weaker evidence for inaccessibility. In the performance curves of the transitional subjects sudden jumps were demonstrated. Furthermore, the transitional subjects displayed a temporary increase of inconsistent solution behavior and solution time near the sudden jump. The characteristic changes in the analogy performance of the transitional subjects were interpreted as a strategy shift.

BERAS ANALOG SEBAGAI PANGAN FUNGSIONAL DENGAN INDEKS GLIKEMIK RENDAH

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Santi Noviasari

2016-04-01

Full Text Available ABSTRACTThe objective of this research was to produce rice analogue as functional food with low glycemic index. The rice was made from white corn and sorghum with additional soybean flour. The physicochemical properties of rice analogue being analysed were resistant starch content, total phenolic content, dietary fiber, color (L*, +a, +b values and whiteness (oHue. Rice analogue was potentially used as functional food indicated by high level of resistant starch 2.59%-3.31%, total phenolic content 0.18-0.25 mg GAE/g sample and dietary fiber 5.35%-6.14%. Rice analogue from white corn with and without soybean flour was further tested for glycemic index. Rice analogue from white corn has 69 GI value, while rice analogue from white corn with 10% soybean flour addition has 50 GI value.Keywords: functional food, glycemic index, rice analogueABSTRAKTujuan penelitian ini adalah untuk mendapatkan beras analog yang berpotensi sebagai pangan fungsional dan bernilai indeks glikemik rendah. Beras analog dibuat dari bahan baku jagung putih dan sorgum dengan penambahan tepung kedelai. Sifat fisiko kimia beras analog yang dianalisis adalah pati resisten, total fenol, serat pangan, warna (nilai L*, +a, +b dan derajat putih (oHue. Beras analog berpotensi sebagai pangan fungsional, yang ditunjukkan dengan tingginya kadar pati resisten yaitu sebanyak 2,59%-3,31%, total fenol sekitar 0,18-0,25 mg GAE/g sampel dan serat pangan antara 5,35%-6,14%. Beras analog berbahan baku jagung putih dengan dan tanpa penambahan kedelai dipilih untuk uji indeks glikemik. Beras analog dari jagung putih memiliki nilai IG 69 sedangkan beras analog dari jagung putih dengan penambahan tepung kedelai 10% memiliki nilai IG 50.Kata kunci: beras analog, indeks glikemik, pangan fungsional

Automatic Generation of Analogy Questions for Student Assessment: An Ontology-Based Approach

Science.gov (United States)

Alsubait, Tahani; Parsia, Bijan; Sattler, Uli

2012-01-01

Different computational models for generating analogies of the form "A is to B as C is to D" have been proposed over the past 35 years. However, analogy generation is a challenging problem that requires further research. In this article, we present a new approach for generating analogies in Multiple Choice Question (MCQ) format that can be used…

A 1.4-V 48-μW current-mode front-end circuit for analog hearing aids with frequency compensation

International Nuclear Information System (INIS)

Wang Xiaoyu; Yang Haigang; Li Fanyang; Yin Tao; Liu Fei

2012-01-01

A current-mode front-end circuit with low voltage and low power for analog hearing aids is presented. The circuit consists of a current-mode AGC (automatic gain control) and a current-mode adaptive filter. Compared with its conventional voltage-mode counterparts, the proposed front-end circuit has the identified features of frequency compensation based on the state space theory and continuous gain with an exponential characteristic. The frequency compensation which appears only in the DSP unit of the digital hearing aid can upgrade the performance of the analog hearing aid in the field of low-frequency hearing loss. The continuous gain should meet the requirement of any input amplitude level, while its exponential characteristic leads to a large input dynamic range in accordance with the dB SPL (sound pressure level). Furthermore, the front-end circuit also provides a discrete knee point and discrete compression ratio to allow for high calibration flexibility. These features can accommodate users whose ears have different pain thresholds. Taking advantage of the current-mode technique, the MOS transistors work in the subthreshold region so that the quiescent current is small. Moreover, the input current can be compressed to a low voltage signal for processing according to the compression principle from the current-domain to the voltage-domain. Therefore, the objective of low voltage and low power (48 μW at 1.4 V) can be easily achieved in a high threshold-voltage CMOS process of 0.35 μm (V TON + |V TOP |≈ 1.35 V). The THD is below −45 dB. The fabricated chip only occupies the area of 1 × 0.5 mm 2 and 1 × 1 mm 2 .

Achiral Mannich-Base Curcumin Analogs Induce Unfolded Protein Response and Mitochondrial Membrane Depolarization in PANC-1 Cells.

Science.gov (United States)

Szebeni, Gábor J; Balázs, Árpád; Madarász, Ildikó; Pócz, Gábor; Ayaydin, Ferhan; Kanizsai, Iván; Fajka-Boja, Roberta; Alföldi, Róbert; Hackler, László; Puskás, László G

2017-10-07

Achiral Mannich-type curcumin analogs have been synthetized and assayed for their cytotoxic activity. The anti-proliferative and cytotoxic activity of curcuminoids has been tested on human non-small-cell lung carcinoma (A549), hepatocellular carcinoma (HepG2) and pancreatic cancer cell line (PANC-1). Based on the highest anti-proliferative activity nine drug candidates were further tested and proved to cause phosphatidylserine exposure as an early sign of apoptosis. Curcumin analogs with the highest apoptotic activity were selected for mechanistic studies in the most sensitive PANC-1 cells. Cytotoxic activity was accompanied by cytostatic effect since curcumin and analogs treatment led to G₀/G₁ cell cycle arrest. Moreover, cytotoxic effect could be also detected via the accumulation of curcuminoids in the endoplasmic reticulum (ER) and the up-regulation of ER stress-related unfolded protein response (UPR) genes: HSPA5 , ATF4, XBP1 , and DDIT3 . The activated UPR induced mitochondrial membrane depolarization, caspase-3 activation and subsequent DNA breakdown in PANC-1 cells. Achiral curcumin analogs, C509, C521 and C524 possessed superior, 40-times more potent cytotoxic activity compared to natural dihydroxy-dimetoxycurcumin in PANC-1 cells.

Synthesis and anti-HIV activity of novel N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT).

Science.gov (United States)

Pontikis, R; Benhida, R; Aubertin, A M; Grierson, D S; Monneret, C

1997-06-06

A series of 33 N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (1, HEPT) were synthesized and evaluated for their anti-HIV-1 activity. In particular, the influence of substitution of the terminal hydroxy group of the acyclic structure of HEPT and the structural rigidity of this side chain were investigated. Halo (7, 8), azido (9), and amino (10-15) derivatives were synthesized from HEPT via the p-tosylate derivative 6. Acylation of the primary amine 15 afforded the amido analogs 16-20. The diaryl derivatives 26-29 were prepared by reaction of HEPT, or of the 6-(2-pyridylthio) analog 23, with diaryl disulfides in the presence of tri-n-butylphosphine. Compounds 39-41, in which the N-1 side chain is rigidified by incorporation of an E-configured double bond, were obtained by palladium(0)-catalyzed coupling of several different 6-(arylthio)uracil derivatives (37, 38) with allyl acetates 33. Compounds 13, 40a,c,d,f, and 41, incorporating an aromatic ring at the end of the acyclic side chain, were found to be more potent than the known diphenyl-substituted HEPT analog BPT (2), two of them, 40c,d, being 10-fold more active.

Alcohol binding in the C1 (C1A + C1B) domain of protein kinase C epsilon

Science.gov (United States)

Pany, Satyabrata; Das, Joydip

2015-01-01

Background Alcohol regulates the expression and function of protein kinase C epsilon (PKCε). In a previous study we identified an alcohol binding site in the C1B, one of the twin C1 subdomains of PKCε. Methods In this study, we investigated alcohol binding in the entire C1 domain (combined C1A and C1B) of PKCε. Fluorescent phorbol ester, SAPD and fluorescent diacylglycerol (DAG) analog, dansyl-DAG were used to study the effect of ethanol, butanol, and octanol on the ligand binding using fluorescence resonance energy transfer (FRET). To identify alcohol binding site(s), PKCεC1 was photolabeled with 3-azibutanol and 3-azioctanol, and analyzed by mass spectrometry. The effects of alcohols and the azialcohols on PKCε were studied in NG108-15 cells. Results In the presence of alcohol, SAPD and dansyl-DAG showed different extent of FRET, indicating differential effects of alcohol on the C1A and C1B subdomains. Effects of alcohols and azialcohols on PKCε in NG108-15 cells were comparable. Azialcohols labeled Tyr-176 of C1A and Tyr-250 of C1B. Inspection of the model structure of PKCεC1 reveals that these residues are 40 Å apart from each other indicating that these residues form two different alcohol binding sites. Conclusions The present results provide evidence for the presence of multiple alcohol-binding sites on PKCε and underscore the importance of targeting this PKC isoform in developing alcohol antagonists. PMID:26210390

Pharmacogenetic characterization of naturally occurring germline NT5C1A variants to chemotherapeutic nucleoside analogs

Science.gov (United States)

Saliba, Jason; Zabriskie, Ryan; Ghosh, Rajarshi; Powell, Bradford C; Hicks, Stephanie; Kimmel, Marek; Meng, Qingchang; Ritter, Deborah I; Wheeler, David A; Gibbs, Richard A; Tsai, Francis T F; Plon, Sharon E

2016-01-01

Background Mutations or alteration in expression of the 5’ nucleotidase gene family can confer altered responses to treatment with nucleoside analogs. While investigating leukemia susceptibility genes, we discovered a very rare p.L254P NT5C1A missense variant in the substrate recognition motif. Given the paucity of cellular drug response data from NT5C1A germline variation, we characterized p.L254P and eight rare variants of NT5C1A from genomic databases. Methods Through lentiviral infection, we created HEK293 cell lines that stably overexpress wildtype NT5C1A, p.L254P, or eight NT5C1A variants reported in the NHLBI Exome Variant server (one truncating and seven missense). IC50 values were determined by cytotoxicity assays after exposure to chemotherapeutic nucleoside analogs (Cladribine, Gemcitabine, 5-Fluorouracil). In addition, we used structure-based homology modeling to generate a 3D model for the C-terminal region of NT5C1A. Results The p.R180X (truncating), p.A214T, and p.L254P missense changes were the only variants that significantly impaired protein function across all nucleotide analogs tested (>5-fold difference versus WT; p<.05). Several of the remaining variants individually displayed differential effects (both more and less resistant) across the analogs tested. The homology model provided a structural framework to understand the impact of NT5C1A mutants on catalysis and drug processing. The model predicted active site residues within NT5C1A motif III and we experimentally confirmed that p.K314 (not p.K320) is required for NT5C1A activity. Conclusion We characterized germline variation and predicted protein structures of NT5C1A. Individual missense changes showed substantial variation in response to the different nucleoside analogs tested, which may impact patients’ responses to treatment. PMID:26906009

Detecting analogies unconsciously

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Thomas Peter Reber

2014-01-01

Full Text Available Analogies may arise from the conscious detection of similarities between a present and a past situation. In this functional magnetic resonance imaging study, we tested whether young volunteers would detect analogies unconsciously between a current supraliminal (visible and a past subliminal (invisible situation. The subliminal encoding of the past situation precludes awareness of analogy detection in the current situation. First, participants encoded subliminal pairs of unrelated words in either one or nine encoding trials. Later, they judged the semantic fit of supraliminally presented new words that either retained a previously encoded semantic relation (‘analog’ or not (‘broken analog’. Words in analogs versus broken analogs were judged closer semantically, which reflects unconscious analogy detection. Hippocampal activity associated with subliminal encoding correlated with the behavioral measure of unconscious analogy detection. Analogs versus broken analogs were processed with reduced prefrontal but enhanced medial temporal activity. We conclude that analogous episodes can be detected even unconsciously drawing on the episodic memory network.

An analog of Hölder's inequality for the spectral radius of Hadamard products

KAUST Repository

Li, Muxingzi

2017-12-03

We prove new inequalities related to the spectral radius ρ of Hadamard products (denoted by ◦ ) of complex matrices. Let p, q ∈ [1 , ∞ ] satisfy 1/p + 1/q = 1, we show an analog of Hölder’s inequality on the space of n × n complex matrices ρ ( A ◦ B ) ≤ ρ ( | A |^( ◦ p) ) ^(1/p) ρ ( | B |^( ◦ q) ) ^(1/q)  for all A, B ∈ C n × n , where |·| denotes entry-wise absolute values, and ( · ) ^ (◦ p) represents the entry-wise Hadamard power. We derive a sharper inequality for the special case p = q = 2. Given A, B ∈ C ^(n × n) , for some β ∈ (0 , 1] depending on A and B , ρ ( A ◦ B ) ≤ βρ ( | A ◦ A | ) ^(1/2) ρ ( | B ◦ B | )^ (1/2) . Analysis for another special case p = 1 and q = ∞ is also included.

Musik som analogi og metafor

DEFF Research Database (Denmark)

Bonde, Lars Ole

2014-01-01

Indeholder underkapitlerne: 2.5.1 Musik som analogi 2.5.2 Musik som metafor 2.5.3 Musikkens psykologiske funktioner - en taxonomi og metaforisk lytning til fire baroksatser......Indeholder underkapitlerne: 2.5.1 Musik som analogi 2.5.2 Musik som metafor 2.5.3 Musikkens psykologiske funktioner - en taxonomi og metaforisk lytning til fire baroksatser...

Antimicrobial activity against Porphyromonas gingivalis and mechanism of action of the cationic octadecapeptide AmyI-1-18 and its amino acid-substituted analogs.

Science.gov (United States)

Taniguchi, Masayuki; Ochiai, Akihito; Takahashi, Kiyoshi; Nakamichi, Shun-Ichi; Nomoto, Takafumi; Saitoh, Eiichi; Kato, Tetsuo; Tanaka, Takaaki

2016-12-01

The antimicrobial peptide AmyI-1-18 is a cationic α-helical octadecapeptide derived from α-amylase in rice (Oryza sativa L. japonica) that contains four cationic amino acid residues (two arginines and two lysines). To enhance the antibacterial activity of AmyI-1-18 against Porphyromonas gingivalis (a bacterium associated with periodontal disease), we synthesized 12 analogs bearing substitutions with alanine, leucine, and/or arginine that were designed based on helical wheel projections and investigated their antibacterial properties. The antibacterial properties of four analogs bearing substitution of a single arginine or lysine with alanine were almost similar to those of AmyI-1-18, suggesting that the antibacterial properties depend on the presence of three cationic amino acid residues. Of three single arginine-substituted analogs, AmyI-1-18(G12R) exhibited an antibacterial activity 2.8-fold higher [50% growth-inhibitory concentration (IC 50 ): 4.6 μM] than that of AmyI-1-18 (IC 50 : 13 μM). Likewise, the antibacterial properties of two single leucine-substituted analogs were significantly enhanced; in particular, AmyI-1-18(N3L) exhibited an antibacterial activity (IC 50 : 2.5 μM) 5.2-fold higher than that of AmyI-1-18. The hemolytic activity of AmyI-1-18(N3L) against mammalian red blood cells was low (2% at 50 μM). A membrane-depolarization assay using a membrane potential-sensitive fluorescent dye revealed that, similar to AmyI-1-18, the antibacterial activity of AmyI-1-18(N3L) was not dependent on its membrane-disrupting activity. Our results demonstrate that the antibacterial properties of AmyI-1-18 against P. gingivalis are significantly improved, without a significant increase in hemolytic activity, by replacing asparagine with leucine at position 3. Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Infection with E1B-mutant adenovirus stabilizes p53 but blocks p53 acetylation and activity through E1A

DEFF Research Database (Denmark)

Savelyeva, I.; Dobbelstein, M.

2011-01-01

to the suppression of p21 transcription. Depending on the E1A conserved region 3, E1B-defective adenovirus impaired the ability of the transcription factor Sp1 to bind the p21 promoter. Moreover, the amino terminal region of E1A, binding the acetyl transferases p300 and CREB-binding protein, blocked p53 K382...... accumulation of p53, without obvious defects in p53 localization, phosphorylation, conformation and oligomerization. Nonetheless, p53 completely failed to induce its target genes in this scenario, for example, p21/CDKN1A, Mdm2 and PUMA. Two regions of the E1A gene products independently contributed...... acetylation in infected cells. Mutating either of these E1A regions, in addition to E1B, partially restored p21 mRNA levels. Our findings argue that adenovirus attenuates p53-mediated p21 induction, through at least two E1B-independent mechanisms. Other virus species and cancer cells may employ analogous...

MENUMBUHKAN DAYA NALAR ( POWER OF REASON SISWA MELALUI PEMBELAJARAN ANALOGI MATEMATIKA

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Rahayu Kariadinata

2012-02-01

Full Text Available Learning mathematical analogy is one alternative learning that can be applied in order to cultivate the power of reason (power of reason students. Through mathematical analogy students are required to be able to look for similarities or relationship nature of the two concepts are the same or different by comparison, then draw a conclusion from the similitude. Thus the analogy can be used as an explanation or as the basis of reasoning. Before starting the analogy of learning mathematics, teachers should examine the ability of understanding mathematical concepts of students, because of the level of understanding of students will affect the power of reason. Tasks (problems mathematical analogy included non-routine matter, therefore the required readiness of teachers to make it. In each question contained mathematical analogy same or different concepts, so it takes quite a lot of material. Steps to make about the mathematical analogy, are: a assemble all the concepts in mathematics student has learned; b Similarly stacking properties / relationships contained in any concept, and c select materials that have a nature / relationship analogous. In this paper is given two forms of matter of mathematical analogy is the analogy of mathematical models and mathematical analogy 1 models 2. Learning mathematical analogy should be carried out after a number of concepts learned. It is better to be given in classes end for many of the concepts that have been learned by the students. Reasoning power (power of reason the student becomes an important part in the process of learning to drive them toward their future as citizens are intelligent, which will be led by the power of reason (the brain and not by the strength (muscle only. As noted by former US President Thomas Jefferson (in Copi, 1978: vii, which states: "In a republican nation, Whose citizens are to be led by reason and persuasion and not by force, the art of reasoning Becomes of first importance"

An fMRI investigation of cognitive stages in reasoning by analogy.

Science.gov (United States)

Krawczyk, Daniel C; McClelland, M Michelle; Donovan, Colin M; Tillman, Gail D; Maguire, Mandy J

2010-06-25

We compared reasoning about four-term analogy problems in the format (A:B::C: D) to semantic and perceptual control conditions that required matching without analogical mapping. We investigated distinct phases of the problem solving process divided into encoding, mapping/inference, and response. Using fMRI, we assessed the brain activation relevant to each of these phases with an emphasis on achieving a better understanding of analogical reasoning relative to these other matching conditions. We predicted that the analogical condition would involve the most cognitive effort in the encoding and mapping/inference phases, while the control conditions were expected to engage greater prefrontal cortex (PFC) activation at the response period. Results showed greater activation for the analogical condition relative to the control conditions at the encoding phase in several predominantly left lateralized and medial areas of the PFC. Similar results were observed for the mapping/inference phase, though this difference was limited to the left PFC and rostral PFC. The response phase resulted in the fastest and most accurate responses in the analogy condition relative to the control conditions. This was accompanied by greater processing within the left lateral and the medial PFC for the control conditions relative to the analogy condition, consistent with most of the cognitive processing of the analogy condition having occurred in the prior task phases. Overall we demonstrate that the left ventral and dorsal lateral, medial, and rostral PFC are important in both the encoding of relational information, mapping and inference processes, and verification of semantic and perceptual responses in four term analogical reasoning. Copyright 2010 Elsevier B.V. All rights reserved.

Automatic activation of categorical and abstract analogical relations in analogical reasoning.

Science.gov (United States)

Green, Adam E; Fugelsang, Jonathan A; Dunbar, Kevin N

2006-10-01

We examined activation of concepts during analogical reasoning. Subjects made either analogical judgments or categorical judgments about four-word sets. After each four-word set, they named the ink color of a single word in a modified Stroop task. Words that referred to category relations were primed (as indicated by longer response times on Stroop color naming) subsequent to analogical judgments and categorical judgments. This finding suggests that activation of category concepts plays a fundamental role in analogical thinking. When colored words referred to analogical relations, priming occurred subsequent to analogical judgments, but not to categorical judgments, even though identical four-word stimuli were used for both types of judgments. This finding lends empirical support to the hypothesis that, when people comprehend the analogy between two items, they activate an abstract analogical relation that is distinct from the specific content items that compose the analogy.

FGF growth factor analogs

Science.gov (United States)

Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY; Takahashi, Kazuyuki [Germantown, MD

2012-07-24

The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

Understanding the generative capacity of analogies as a tool for explanation

Science.gov (United States)

Wong, E. David

1993-12-01

Psychological studies have typically portrayed analogical reasoning as a process of schema transfer from a familiar domain of understanding to a problem situation. These studies have usually examined analogical reasoning in contexts where (a) individuals possess or have been provided with appropriate, problem-specific schema, (b) the nature of the problem and/or solution is fairly well defined, and (c) ideal analogies are provided or suggested by an outside source. This study examines analogical reasoning in contexts where understanding is generated from loosely organized, incomplete prior knowledge rather than transferred from a well-structured domain of understanding. In addition, participants were asked to create, apply, and modify their own analogies - as opposed to applying a given analogy - as a heuristic for constructing, evaluating, and modifying their explanations for a particular scientific phenomena. The results provide empirical support for the generative properties of analogies; that is, analogies can stimulate new inferences and insight. Furthermore, under specific conditions, individuals can productively harness the generative capacity of their own analogies to advance their conceptual understanding of scientific phenomena.

Karakterisasi Mutu dan Nilai Gizi Nasi Mocaf dari Beras Analog - (Characterization of Quality and Nutrition Value of Cooked Rice Mocaf from Rice Analog

Directory of Open Access Journals (Sweden)

Enny Hawani Loebis

2017-06-01

Full Text Available Dependence on rice consumption needs to be reduced to overcome the problems of rice supply and health problems. Alternative proposed is producing mocaf-based rice analog. This research aims to study the quality characterization and nutritional value of mocaf-based rice analog. Rice mocaf was made based on mixture of mocaf, rice flour, water and palm oil using variable: 50, 60 and 70% mocaf.  Mocaf rice then cooked by using rice cooker, steamer or microwave. The results showed mocaf rice 60% yield highest calorific value.  The best cooking method  was steaming that resulted nutrient content and calorific value consisting of 49.15% water; 2.05% fat; 2.09% protein; 46.45% carbohydrate; 35.8 mg/kg of iron; 403.4 mg/kg of potassium; 193.8 mg/kg of calcium, 2.0 mg/kg of vitamin B1 and 212.53 ca/100 g calorific value.Keywords: mocaf, nutritional value, quality characterisation, rice ABSTRAKKetergantungan pada konsumsi beras perlu dikurangi untuk mengatasi permasalahan pasokan beras dan masalah kesehatan. Alternatif yang dapat diusulkan adalah dengan pembuatan beras analog berbasis mocaf. Penelitian ini bertujuan mempelajari karakterisasi mutu dan nilai gizi nasi mocaf dari beras analog. Beras mocaf dibuat berdasarkan campuran mocaf, tepung beras, air dan minyak goreng sawit, dengan komposisi mocaf  50, 60 dan 70%. Beras mocaf kemudian dimasak dengan cara menggunakan rice cooker, pengukusan atau microwave. Hasil penelitian menunjukkan beras mocaf 60% menghasilkan nasi mocaf dengan nilai kalori tertinggi. Pemasakan terbaik adalah dengan cara pengukusan dengan kandungan gizi dan nilai kalori yang dihasilkan terdiri dari 49,15%  air; 2,05% lemak; 2,09% protein; 46,45% karbohidrat; 35,8 mg/kg besi; 403,4 mg/kg kalium; 193,8 mg/kg kalsium, 2,0 mg/kg vitamin B1 dan 212,53 kal/100 g nilai kalori.Kata kunci: beras, karakterisasi mutu, mocaf, nilai gizi

Producing and Recognizing Analogical Relations

Science.gov (United States)

Lipkens, Regina; Hayes, Steven C

2009-01-01

Analogical reasoning is an important component of intelligent behavior, and a key test of any approach to human language and cognition. Only a limited amount of empirical work has been conducted from a behavior analytic point of view, most of that within Relational Frame Theory (RFT), which views analogy as a matter of deriving relations among relations. The present series of four studies expands previous work by exploring the applicability of this model of analogy to topography-based rather than merely selection-based responses and by extending the work into additional relations, including nonsymmetrical ones. In each of the four studies participants pretrained in contextual control over nonarbitrary stimulus relations of sameness and opposition, or of sameness, smaller than, and larger than, learned arbitrary stimulus relations in the presence of these relational cues and derived analogies involving directly trained relations and derived relations of mutual and combinatorial entailment, measured using a variety of productive and selection-based measures. In Experiment 1 participants successfully recognized analogies among stimulus networks containing same and opposite relations; in Experiment 2 analogy was successfully used to extend derived relations to pairs of novel stimuli; in Experiment 3 the procedure used in Experiment 1 was extended to nonsymmetrical comparative relations; in Experiment 4 the procedure used in Experiment 2 was extended to nonsymmetrical comparative relations. Although not every participant showed the effects predicted, overall the procedures occasioned relational responses consistent with an RFT account that have not yet been demonstrated in a behavior-analytic laboratory setting, including productive responding on the basis of analogies. PMID:19230515

Permeability of the blood-brain barrier to the neurotensin8-13 analog NT1.

Science.gov (United States)

Banks, W A; Wustrow, D J; Cody, W L; Davis, M D; Kastin, A J

1995-10-09

Neurotensin (NT) has been suggested to be a neuropeptide with therapeutic potential. We used multiple-time regression analysis to measure the unidirectional influx constant (Ki) of a tritiated analog of NT8-13, NT1, with improved metabolic stability. The Ki of [3H]NT1 across the blood-brain barrier (BBB) was 5.12(10(-4)) ml/g-min and was decreased 66% by unlabeled NT1 system. The amount of NT1 crossing the BBB, 0.087% of the injected dose per gram of brain, is consistent with its exerting central effects after peripheral administration. The stable [3H]NT1 crossed the BBB in intact form as assessed by HPLC and completely crossed the endothelial cells that comprise the BBB as assessed by the capillary depletion method. The presence of a transport system could be important for the development of NT analogs.

Resistance analysis and characterization of NITD008 as an adenosine analog inhibitor against hepatitis C virus.

Science.gov (United States)

Qing, Jie; Luo, Rui; Wang, Yaxin; Nong, Junxiu; Wu, Ming; Shao, Yan; Tang, Ruoyi; Yu, Xi; Yin, Zheng; Sun, Yuna

2016-02-01

Hepatitis disease caused by hepatitis C virus (HCV) is a severe threat to global public health, affecting approximately 3% of the world's population. Sofosbuvir (PSI-7977), a uridine nucleotide analog inhibitor targeting the HCV NS5B polymerase, was approved by FDA at the end of 2013 and represents a key step towards a new era in the management of HCV infection. Previous study identified NITD008, an adenosine nucleoside analog, as the specific inhibitor against dengue virus and showed good antiviral effect on other flaviviruses or enteroviruses. In this report, we systematically analyzed the anti-HCV profile of NITD008, which was discovered to effectively suppress the replication of different strains of HCV in human hepatoma cells with a low nanomolar activity. On genotype 2a virus, or 2a, 1a, and 1b replicon cells, EC50 values were 8.7 nM, 93.3 nM, 60.0 nM and 67.2 nM, and selective index values were >2298.9, >214.4, >333.3, >298.5 respectively. We demonstrated that resistance to NITD008 was conferred by mutation in NS5B (S282T) in the HCV infectious virus genotype 2a (JFH-1). Then, we compared the resistant profiles of NITD008 and PSI-7977, and found that the folds change of EC50 of NITD008 to full replicon cells containing mutation S282T was much bigger than PSI-7977(folds 76.50 vs. 4.52). Analysis of NITD008 cross-resistance against previously reported NS5B drug-selected mutations showed that the resistance pattern of NITD008 was not completely similar to PSI-7977, and meanwhile, S282T resistant mutation to NITD008 emerge more easily in cell culture than PSI-7977. Interestingly, NITD008 displayed significant synergistic effects with the NS5B polymerase inhibitor PSI-7977, however, only additive effects with alpha interferon (IFNα-2b), ribavirin, and an NS3 protease inhibitor. These results verify that NITD008 is an effective analog inhibitor against hepatitis C virus and a good research tool as a supplement to other types of nucleoside analogs. Copyright �

Synthesis, resolution and biological evaluation of cyclopropyl analogs of abscisic acid.

Science.gov (United States)

Han, Xiaoqiang; Fan, Jinlong; Lu, Huizhe; Wan, Chuan; Li, Xiuyun; Li, Hong; Yang, Dongyan; Zhang, Yuanzhi; Xiao, Yumei; Qin, Zhaohai

2015-09-15

cis-2,3-Cyclopropanated abscisic acid (cis-CpABA) has high photostability and good ABA-like activity. To further investigate its activity and action mechanism, 2S,3S-2,3-cyclopropanated ABA (3a) and 2R,3R-2,3-cyclopropanated ABA (3b) were synthesized. Bioassay showed that 3a displayed higher inhibitory activity in germination than that of 3b and ABA at the concentration of 3.0 μM, but 3a and 3b had much weaker inhibitory activity in inhibition seedling growth compared to ABA. The study of photostability revealed that 3a and 3b showed high stability under UV light exposure, which were 4 times and 3 times greater than (±)-ABA, respectively. Action mechanism study showed that 3a presented higher inhibition on phosphatase activity of HAB1 than 3b, although they all inferior to ABA. Molecular docking studies of 3a, 3b and ABA receptor PYL10 were agreement with the bioassay data and confirmed the importance of the configuration of the 2,3-cyclopropyl ABA analogs for their bioactivity in somewhat. This study provides a new approach for the design of ABA analogs, and the results validated structure-based design for this target class. Copyright © 2015 Elsevier Ltd. All rights reserved.

Design and Analysis of Reconfigurable Analog System

Science.gov (United States)

2011-02-01

34010010" �" �" �" �" �" �" �±" N3 N2 N± P1 P2 P3 * Current sources $RR = 1; *Ramp Rate (slope of the...2008/12/12/31e83bac-500f-4182- acca -4d360295fd9c.pdf, Analog Devices, Analog Dialogue 39-06, June 2005. [15] D. A. Johns, K. Martin "Analog Integrated

Analog computing

CERN Document Server

Ulmann, Bernd

2013-01-01

This book is a comprehensive introduction to analog computing. As most textbooks about this powerful computing paradigm date back to the 1960s and 1970s, it fills a void and forges a bridge from the early days of analog computing to future applications. The idea of analog computing is not new. In fact, this computing paradigm is nearly forgotten, although it offers a path to both high-speed and low-power computing, which are in even more demand now than they were back in the heyday of electronic analog computers.

A novel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-κB and Nrf2-Keap1 signaling pathways

Energy Technology Data Exchange (ETDEWEB)

Gan, Fei-Fei; Ling, Hui; Ang, Xiaohui; Reddy, Shridhivya A.; Lee, Stephanie S-H.; Yang, Hong; Tan, Sock-Hoon [Department of Pharmacy, Faculty of Science, National University of Singapore (Singapore); Hayes, John D. [Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland (United Kingdom); Chui, Wai-Keung [Department of Pharmacy, Faculty of Science, National University of Singapore (Singapore); Chew, Eng-Hui, E-mail: phaceh@nus.edu.sg [Department of Pharmacy, Faculty of Science, National University of Singapore (Singapore)

2013-11-01

Natural compounds containing vanilloid and Michael acceptor moieties appear to possess anti-cancer and chemopreventive properties. The ginger constituent shogaol represents one such compound. In this study, the anti-cancer potential of a synthetic novel shogaol analog 3-phenyl-3-shogaol (3-Ph-3-SG) was assessed by evaluating its effects on signaling pathways. At non-toxic concentrations, 3-Ph-3-SG suppressed cancer cell invasion in MDA-MB-231 and MCF-7 breast carcinoma cells through inhibition of PMA-activated MMP-9 expression. At similar concentrations, 3-Ph-3-SG reduced expression of the inflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and prostanglandin-E{sub 2} (PGE{sub 2}) in RAW 264.7 macrophage-like cells. Inhibition of cancer cell invasion and inflammation by 3-Ph-3-SG were mediated through suppression of the nuclear factor-kappaB (NF-κB) signaling pathway. The 3-Ph-3-SG also demonstrated cytoprotective effects by inducing the antioxidant response element (ARE)-driven genes NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1). Cytoprotection by 3-Ph-3-SG was achieved at least partly through modification of cysteine residues in the E3 ubiquitin ligase substrate adaptor Kelch-like ECH-associated protein 1 (Keap1), which resulted in accumulation of transcription factor NF-E2 p45-related factor 2 (Nrf2). The activities of 3-Ph-3-SG were comparable to those of 6-shogaol, the most abundant naturally-occurring shogaol, and stronger than those of 4-hydroxyl-null deshydroxy-3-phenyl-3-shogaol, which attested the importance of the 4-hydroxy substituent in the vanilloid moiety for bioactivity. In summary, 3-Ph-3-SG is shown to possess activities that modulate stress-associated pathways relevant to multiple steps in carcinogenesis. Therefore, it warrants further investigation of this compound as a promising candidate for use in chemotherapeutic and chemopreventive strategies. - Highlights: �

In Alzheimer's disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism

DEFF Research Database (Denmark)

Gejl, Michael; Gjedde, Albert; Egefjord, Lærke

2016-01-01

In animal models, the incretin hormone GLP-1 affects Alzheimer's disease (AD). We hypothesized that treatment with GLP-1 or an analog of GLP-1 would prevent accumulation of Aβ and raise, or prevent decline of, glucose metabolism (CMRglc) in AD. In this 26-week trial, we randomized 38 patients...... with AD to treatment with the GLP-1 analog liraglutide (n = 18), or placebo (n = 20). We measured Aβ load in brain with tracer [11C]PIB (PIB), CMRglc with [18F]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe...

Acid-Labile Amphiphilic PEO-b-PPO-b-PEO Copolymers: Degradable Poloxamer Analogs.

Science.gov (United States)

Worm, Matthias; Kang, Biao; Dingels, Carsten; Wurm, Frederik R; Frey, Holger

2016-05-01

Poly ((ethylene oxide)-b-(propylene oxide)-b-(ethylene oxide)) triblock copolymers commonly known as poloxamers or Pluronics constitute an important class of nonionic, biocompatible surfactants. Here, a method is reported to incorporate two acid-labile acetal moieties in the backbone of poloxamers to generate acid-cleavable nonionic surfactants. Poly(propylene oxide) is functionalized by means of an acetate-protected vinyl ether to introduce acetal units. Three cleavable PEO-PPO-PEO triblock copolymers (Mn,total = 6600, 8000, 9150 g·mol(-1) ; Mn,PEO = 2200, 3600, 4750 g·mol(-1) ) have been synthesized using anionic ring-opening polymerization. The amphiphilic copolymers exhibit narrow molecular weight distributions (Ð = 1.06-1.08). Surface tension measurements reveal surface-active behavior in aqueous solution comparable to established noncleavable poloxamers. Complete hydrolysis of the labile junctions after acidic treatment is verified by size exclusion chromatography. The block copolymers have been employed as surfactants in a miniemulsion polymerization to generate polystyrene (PS) nanoparticles with mean diameters of ≈200 nm and narrow size distribution, as determined by dynamic light scattering and scanning electron microscopy. Acid-triggered precipitation facilitates removal of surfactant fragments from the nanoparticles, which simplifies purification and enables nanoparticle precipitation "on demand." © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The interplay of conflict and analogy in multidisciplinary teams.

Science.gov (United States)

Paletz, Susannah B F; Schunn, Christian D; Kim, Kevin H

2013-01-01

Creative teamwork in multidisciplinary teams is a topic of interest to cognitive psychologists on the one hand, and to both social and organizational psychologists on the other. However, the interconnections between cognitive and social layers have been rarely explored. Drawing on mental models and dissonance theories, the current study takes a central variable studied by cognitive psychologists-analogy-and examines its relationship to a central variable examined by social psychologists-conflict. In an observational, field study, over 11h of audio-video data from conversations of the Mars Exploration Rover scientists were coded for different types of analogy and micro-conflicts that reveal the character of underlying psychological mechanisms. Two different types of time-lagged logistic models applied to these data revealed asymmetric patterns of associations between analogy and conflict. Within-domain analogies, but not within-discipline or outside-discipline analogies, preceded science and work process conflicts, suggesting that in multidisciplinary teams, representational gaps in very close domains will be more likely to spark conflict. But analogies also occurred in reaction to conflict: Process and negative conflicts, but not task conflicts, preceded within-discipline analogies, but not to within-domain or outside-discipline analogies. This study demonstrates ways in which cognition can be bidirectionally tied to social processes and discourse. Copyright © 2012 Elsevier B.V. All rights reserved.

Anti-Plasmodium activity of ceramide analogs

Directory of Open Access Journals (Sweden)

Gatt Shimon

2004-12-01

Full Text Available Abstract Background Sphingolipids are key molecules regulating many essential functions in eukaryotic cells and ceramide plays a central role in sphingolipid metabolism. A sphingolipid metabolism occurs in the intraerythrocytic stages of Plasmodium falciparum and is associated with essential biological processes. It constitutes an attractive and potential target for the development of new antimalarial drugs. Methods The anti-Plasmodium activity of a series of ceramide analogs containing different linkages (amide, methylene or thiourea linkages between the fatty acid part of ceramide and the sphingoid core was investigated in culture and compared to the sphingolipid analog PPMP (d,1-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol. This analog is known to inhibit the parasite sphingomyelin synthase activity and block parasite development by preventing the formation of the tubovesicular network that extends from the parasitophorous vacuole to the red cell membrane and delivers essential extracellular nutrients to the parasite. Results Analogs containing methylene linkage showed a considerably higher anti-Plasmodium activity (IC50 in the low nanomolar range than PPMP and their counterparts with a natural amide linkage (IC50 in the micromolar range. The methylene analogs blocked irreversibly P. falciparum development leading to parasite eradication in contrast to PPMP whose effect is cytostatic. A high sensitivity of action towards the parasite was observed when compared to their effect on the human MRC-5 cell growth. The toxicity towards parasites did not correlate with the inhibition by methylene analogs of the parasite sphingomyelin synthase activity and the tubovesicular network formation, indicating that this enzyme is not their primary target. Conclusions It has been shown that ceramide analogs were potent inhibitors of P. falciparum growth in culture. Interestingly, the nature of the linkage between the fatty acid part and the

ASTEROSEISMOLOGY OF THE SOLAR ANALOGS 16 Cyg A AND B FROM KEPLER OBSERVATIONS

Energy Technology Data Exchange (ETDEWEB)

Metcalfe, T. S.; Dogan, G. [High Altitude Observatory, NCAR, P.O. Box 3000, Boulder, CO 80307 (United States); Chaplin, W. J.; Garcia, R. A.; Basu, S.; Deheuvels, S.; Miglio, A. [Kavli Institute for Theoretical Physics, Kohn Hall, University of California, Santa Barbara, CA 93106 (United States); Appourchaux, T. [Institut d' Astrophysique Spatiale, Univ Paris-Sud, UMR8617, CNRS, Batiment 121, 91405 Orsay Cedex (France); Brandao, I. [Centro de Astrofisica and Faculdade de Ciencias, Universidade do Porto, Rua das Estrelas, 4150-762 Porto (Portugal); Creevey, O. L.; Salabert, D. [Laboratoire Lagrange, UMR7293, Observatoire de la Cote d' Azur, Universite de Nice Sophia-Antipolis, CNRS, BP 4229, 06304 Nice Cedex 4 (France); Eggenberger, P. [Observatoire de Geneve, Universite de Geneve, 51 Ch. des Maillettes, CH-1290 Sauverny (Switzerland); Karoff, C. [Department of Physics and Astronomy, Aarhus University, DK-8000 Aarhus C (Denmark); Stello, D.; Benomar, O. [Sydney Institute for Astronomy (SIfA), School of Physics, University of Sydney, NSW 2006 (Australia); Y Latin-Small-Letter-Dotless-I ld Latin-Small-Letter-Dotless-I z, M.; Celik, Z. [Department of Astronomy and Space Sciences, Ege University, Bornova, 35100 Izmir (Turkey); Antia, H. M. [Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai 400005 (India); Howe, R. [School of Physics and Astronomy, University of Birmingham, Edgbaston, Birmingham B15 2TT (United Kingdom); Regulo, C. [Instituto de Astrofisica de Canarias, 38205 La Laguna, Tenerife (Spain); and others

2012-03-20

The evolved solar-type stars 16 Cyg A and B have long been studied as solar analogs, yielding a glimpse into the future of our own Sun. The orbital period of the binary system is too long to provide meaningful dynamical constraints on the stellar properties, but asteroseismology can help because the stars are among the brightest in the Kepler field. We present an analysis of three months of nearly uninterrupted photometry of 16 Cyg A and B from the Kepler space telescope. We extract a total of 46 and 41 oscillation frequencies for the two components, respectively, including a clear detection of octupole (l = 3) modes in both stars. We derive the properties of each star independently using the Asteroseismic Modeling Portal, fitting the individual oscillation frequencies and other observational constraints simultaneously. We evaluate the systematic uncertainties from an ensemble of results generated by a variety of stellar evolution codes and fitting methods. The optimal models derived by fitting each component individually yield a common age (t = 6.8 {+-} 0.4 Gyr) and initial composition (Z{sub i} = 0.024 {+-} 0.002, Y{sub i} = 0.25 {+-} 0.01) within the uncertainties, as expected for the components of a binary system, bolstering our confidence in the reliability of asteroseismic techniques. The longer data sets that will ultimately become available will allow future studies of differential rotation, convection zone depths, and long-term changes due to stellar activity cycles.

Science Teachers' Analogical Reasoning

Science.gov (United States)

Mozzer, Nilmara Braga; Justi, Rosária

2013-08-01

Analogies can play a relevant role in students' learning. However, for the effective use of analogies, teachers should not only have a well-prepared repertoire of validated analogies, which could serve as bridges between the students' prior knowledge and the scientific knowledge they desire them to understand, but also know how to introduce analogies in their lessons. Both aspects have been discussed in the literature in the last few decades. However, almost nothing is known about how teachers draw their own analogies for instructional purposes or, in other words, about how they reason analogically when planning and conducting teaching. This is the focus of this paper. Six secondary teachers were individually interviewed; the aim was to characterize how they perform each of the analogical reasoning subprocesses, as well as to identify their views on analogies and their use in science teaching. The results were analyzed by considering elements of both theories about analogical reasoning: the structural mapping proposed by Gentner and the analogical mechanism described by Vosniadou. A comprehensive discussion of our results makes it evident that teachers' content knowledge on scientific topics and on analogies as well as their pedagogical content knowledge on the use of analogies influence all their analogical reasoning subprocesses. Our results also point to the need for improving teachers' knowledge about analogies and their ability to perform analogical reasoning.

Fast multichannel analog storage system

International Nuclear Information System (INIS)

Freytag, D.R.

1982-11-01

A Multichannel Analog Storage System based on a commercial 32-channel parallel in/serial out (PISO) analog shift register is described. The basic unit is a single width CAMAC module containing 512 analog cells and the associated logic for data storage and subsequent readout. At sampling rates of up to 30 MHz the signals are strobed directly into the PISO. At higher rates signals are strobed into a fast presampling stage and subsequently transferred in block form into an array of PISO's. Sampling rates of 300 MHz have been achieved with the present device and 1000 MHz are possible with improved signal drivers. The system is well suited for simultaneous handling of many signal channels with moderate numbers of samples in each channel. RMS noise over full scale signal has been measured as 1:3000 (approx. = 11 bit). However, nonlinearities in the response and differences in sensitivity of the analog cells require an elaborate calibration system in order to realize 11 bit accuracy for the analog information

Children’s Failure in Analogical Reasoning Tasks: A Problem of Focus of Attention and Information Integration?

Directory of Open Access Journals (Sweden)

Yannick Glady

2017-05-01

Full Text Available Children’s improved performance with age in analogy tasks has been explained by an increase in semantic knowledge of the items and the relations between them or by the development of an increased ability to inhibit irrelevant information. We tested the so-called “unbalanced attentional focus hypothesis” that claims that a failure to choose the “analogical” match can be the result of a difficulty to focus on all the relevant information available. Previous eye-tracking research has suggested, in analogies of the A:B::C:D format, that 5–6 year-olds organize their search around the C item. They focused significantly less than adults on the A:B pair, thereby hindering their discovering the relation(s between A and B. We hypothesized that inducing them to focus their attention on the A:B pair at the beginning of the trial would affect their performance. In Experiment 1, increasing children’s focus on the A:B pair did, indeed, lead to better performance. In contrast, in Experiment 2, focusing their attention on the A:B pair impaired performance when the most salient relation holding between A and B was, in fact, irrelevant for the analogy. By contrast, the obvious-but-irrelevant relation in the A:B pair had no negative effect on performance when no explicit A:B focusing was induced. These results are discussed in terms of the temporal organization of the task and availability of information, and of children’s difficulties to disengage from the main goal of the task, when necessary.

Children’s Failure in Analogical Reasoning Tasks: A Problem of Focus of Attention and Information Integration?

Science.gov (United States)

Glady, Yannick; French, Robert M.; Thibaut, Jean-Pierre

2017-01-01

Children’s improved performance with age in analogy tasks has been explained by an increase in semantic knowledge of the items and the relations between them or by the development of an increased ability to inhibit irrelevant information. We tested the so-called “unbalanced attentional focus hypothesis” that claims that a failure to choose the “analogical” match can be the result of a difficulty to focus on all the relevant information available. Previous eye-tracking research has suggested, in analogies of the A:B::C:D format, that 5–6 year-olds organize their search around the C item. They focused significantly less than adults on the A:B pair, thereby hindering their discovering the relation(s) between A and B. We hypothesized that inducing them to focus their attention on the A:B pair at the beginning of the trial would affect their performance. In Experiment 1, increasing children’s focus on the A:B pair did, indeed, lead to better performance. In contrast, in Experiment 2, focusing their attention on the A:B pair impaired performance when the most salient relation holding between A and B was, in fact, irrelevant for the analogy. By contrast, the obvious-but-irrelevant relation in the A:B pair had no negative effect on performance when no explicit A:B focusing was induced. These results are discussed in terms of the temporal organization of the task and availability of information, and of children’s difficulties to disengage from the main goal of the task, when necessary. PMID:28588516

Analog synthetic biology.

Science.gov (United States)

Sarpeshkar, R

2014-03-28

We analyse the pros and cons of analog versus digital computation in living cells. Our analysis is based on fundamental laws of noise in gene and protein expression, which set limits on the energy, time, space, molecular count and part-count resources needed to compute at a given level of precision. We conclude that analog computation is significantly more efficient in its use of resources than deterministic digital computation even at relatively high levels of precision in the cell. Based on this analysis, we conclude that synthetic biology must use analog, collective analog, probabilistic and hybrid analog-digital computational approaches; otherwise, even relatively simple synthetic computations in cells such as addition will exceed energy and molecular-count budgets. We present schematics for efficiently representing analog DNA-protein computation in cells. Analog electronic flow in subthreshold transistors and analog molecular flux in chemical reactions obey Boltzmann exponential laws of thermodynamics and are described by astoundingly similar logarithmic electrochemical potentials. Therefore, cytomorphic circuits can help to map circuit designs between electronic and biochemical domains. We review recent work that uses positive-feedback linearization circuits to architect wide-dynamic-range logarithmic analog computation in Escherichia coli using three transcription factors, nearly two orders of magnitude more efficient in parts than prior digital implementations.

Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism.

Science.gov (United States)

Levy, Bruce D; Lukacs, Nicholas W; Berlin, Aaron A; Schmidt, Birgitta; Guilford, William J; Serhan, Charles N; Parkinson, John F

2007-12-01

Cellular recruitment during inflammatory/immune responses is tightly regulated. The ability to dampen inflammation is imperative for prevention of chronic immune responses, as in asthma. Here we investigated the ability of lipoxin A4 (LXA4) stable analogs to regulate airway responses in two allergen-driven models of inflammation. A 15-epi-LXA4 analog (ATLa) and a 3-oxa-15-epi-LXA4 analog (ZK-994) prevented excessive eosinophil and T lymphocyte accumulation and activation after mice were sensitized and aerosol-challenged with ovalbumin. At 50% and to a greater extent than equivalent doses of the CysLT1 receptor antagonist montelukast. Distinct from montelukast, ATLa treatment led to marked reductions in cysteinyl leukotrienes, interleukin-4 (IL-4), and IL-10, and both ATLa and ZK-994 inhibited levels of IL-13. In cockroach allergen-induced airway responses, both intraperitoneal and oral administration of ZK-994 significantly reduced parameters of airway inflammation and hyper-responsiveness in a dose-dependent manner. ZK-994 also significantly changed the balance of Th1/Th2-specific cytokine levels. Thus, the ATLa/LXA4 analog actions are distinct from CysLT1 antagonism and potently block both allergic airway inflammation and hyper-reactivity. Moreover, these results demonstrate these analogs' therapeutic potential as new agonists for the resolution of inflammation.

Potential anticancer activity of curcumin analogs containing sulfone on human cancer cells

Directory of Open Access Journals (Sweden)

Zhang Qiuyan

2016-01-01

Full Text Available Three curcumin analogs(S1-S3 containing sulfone were investigated for their effects on human prostate cancer PC-3, colon cancer HT-29, lung cancer H1299 and pancreatic cancer BxPC-3 cells. The three compounds were approximately 16-to 96-fold more active than curcumin in these cell lines as determined by the MTT assay. The effects of these compounds on cell growth were further studied in prostate cancer PC-3 cells in both two dimensional (2D and three dimensional (3D cultures. S1-S3strongly inhibited the growth and induced cell death in PC-3 cells, and the effects of these compounds were associated with suppression of nuclear factor kappa B (NF-κB transcriptional activity. Moreover, treatment of PC-3 cells with all three compounds caused a decrease in the level of phosphorylated signal transducer and activator of transcription-3 (p-STAT3 (Tyr705,but not p-STAT3(Ser727. Only S1and S2decreased the presence of phosphorylated Akt (p-Akt in PC-3 cells. These curcumin analogs warrant further in vivo studies for anticancer activities in suitable animal models.

Benfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response.

Science.gov (United States)

Katare, Rajesh; Caporali, Andrea; Emanueli, Costanza; Madeddu, Paolo

2010-10-01

Benfotiamine (BFT) is a transketolase activator that directs glucose to the pentose phosphate pathway. The present study investigated whether BFT improves the recovery after myocardial infarction (MI) and explored underlying mechanisms of protection. Non-diabetic and streptozotocin-induced type 1 diabetic mice were supplemented with BFT (70 mg/kg/day in drinking water) for 4 weeks and then subjected to MI or sham operation. Cardiac function was monitored by echocardiography. At two weeks post-MI, intra-ventricular pressure was measured by Millar tip-catheter and hearts were collected for biochemical, immunohistochemical and expressional analyses. No treatment effect was observed in sham-operated mice. Post-MI mortality was higher in diabetic mice and hemodynamic studies confirmed the worsening effect of diabetes on functional recovery. Furthermore, diabetic mice demonstrated increased cardiomyocyte apoptosis, reduced reparative angiogenesis, larger scars, enhanced oxidative stress, and blunted activation of the pro-survival VEGF receptor-2/Akt/Pim-1 signaling pathway. BFT improved post-MI survival, functional recovery and neovascularization and reduced cardiomyocyte apoptosis and neurohormonal activation in diabetic as well as in non-diabetic mice. In addition, BFT stimulated the activity of pentose phosphate pathway enzymes, leading to reduction of oxidative stress, phosphorylation/activation of VEGF receptor-2 and Akt and increased Pim-1, pBad and Bcl-2 levels. These effects were contrasted on silencing glucose-6-phosphate dehydrogenase, the key enzyme in pentose phosphate pathway, or inhibiting Akt. BFT benefits post-MI recovery through stimulation of pro-survival mechanisms and containment of neurohormonal response. These results may have implications for the treatment of myocardial ischemia. Copyright © 2010 Elsevier Ltd. All rights reserved.

PI3K-delta mediates double-stranded RNA-induced upregulation of B7-H1 in BEAS-2B airway epithelial cells

International Nuclear Information System (INIS)

Kan-o, Keiko; Matsumoto, Koichiro; Asai-Tajiri, Yukari; Fukuyama, Satoru; Hamano, Saaka; Seki, Nanae; Nakanishi, Yoichi; Inoue, Hiromasa

2013-01-01

Highlights: •Double-stranded RNA upregulates B7-H1 on BEAS-2B airway epithelial cells. •The upregulation of B7-H1 is attenuated by inhibition of PI3Kδ isoform. •PI3Kδ-mediated upregulation of B7-H1 is independent of NF-κB activation. •Inhibition of PI3Kδ may prevent persistent viral infection induced by B7-H1. -- Abstract: Airway viral infection disturbs the health-related quality of life. B7-H1 (also known as PD-L1) is a coinhibitory molecule associated with the escape of viruses from the mucosal immunity, leading to persistent infection. Most respiratory viruses generate double-stranded (ds) RNA during replication. The stimulation of cultured airway epithelial cells with an analog of viral dsRNA, polyinosinic-polycytidylic acid (poly IC) upregulates the expression of B7-H1 via activation of the nuclear factor κB(NF-κB). The mechanism of upregulation was investigated in association with phosphatidylinositol 3-kinases (PI3Ks). Poly IC-induced upregulation of B7-H1 was profoundly suppressed by a pan-PI3K inhibitor and partially by an inhibitor or a small interfering (si)RNA for PI3Kδ in BEAS-2B cells. Similar results were observed in the respiratory syncytial virus-infected cells. The expression of p110δ was detected by Western blot and suppressed by pretreatment with PI3Kδ siRNA. The activation of PI3Kδ is typically induced by oxidative stress. The generation of reactive oxygen species was increased by poly IC. Poly IC-induced upregulation of B7-H1 was attenuated by N-acetyl-L-cysteine, an antioxidant, or by oxypurinol, an inhibitor of xanthine oxidase. Poly IC-induced activation of NF-κB was suppressed by a pan-PI3K inhibitor but not by a PI3Kδ inhibitor. These results suggest that PI3Kδ mediates dsRNA-induced upregulation of B7-H1 without affecting the activation of NF-κB

Is the Link from Working Memory to Analogy Causal? No Analogy Improvements following Working Memory Training Gains

Science.gov (United States)

Richey, J. Elizabeth; Phillips, Jeffrey S.; Schunn, Christian D.; Schneider, Walter

2014-01-01

Analogical reasoning has been hypothesized to critically depend upon working memory through correlational data [1], but less work has tested this relationship through experimental manipulation [2]. An opportunity for examining the connection between working memory and analogical reasoning has emerged from the growing, although somewhat controversial, body of literature suggests complex working memory training can sometimes lead to working memory improvements that transfer to novel working memory tasks. This study investigated whether working memory improvements, if replicated, would increase analogical reasoning ability. We assessed participants’ performance on verbal and visual analogy tasks after a complex working memory training program incorporating verbal and spatial tasks [3], [4]. Participants’ improvements on the working memory training tasks transferred to other short-term and working memory tasks, supporting the possibility of broad effects of working memory training. However, we found no effects on analogical reasoning. We propose several possible explanations for the lack of an impact of working memory improvements on analogical reasoning. PMID:25188356

Cyclopentanoid analogs of phosphatidylcholine: susceptibility to phospholipase A2.

Science.gov (United States)

Lister, M D; Hancock, A J

1988-10-01

Six isomers of dipalmitoylcyclopentanetriol phosphocholine (cyclopentano-lecithin) were tested as potential substrates for phospholipase A2. Since each of these analogs possesses a configuration that mimics a narrow range of conformations of a glycerophospholipid molecule, the analogs were used to assess the enzyme's conformational requirements. Studies showed that all of the analogs containing the phosphocholine at the C-1 (or C-3) position could be hydrolyzed, while only one of the three analogs that contains the polar head group at the C-2 position was susceptible. Kinetic studies, however, revealed that only the all-trans-(1,3/2-1P)-cyclopentano-lecithin gave initial rates of hydrolysis that were measurable by pH-stat. Acyl group specificity of the enzyme towards the all-trans isomer was determined with an analog was acyl groups were distinguishable. The synthesis of this mixed-acid-cyclopentano-PC is described herein. When this analog was enzymatically assayed, results unequivocally showed the enzyme to be specific for C-2 acyl hydrolysis. This specificity, and data showing that the all-trans analog is stereospecifically hydrolyzed, indicate that it is acted on in an analogous manner to dipalmitoylphosphatidylcholine. These studies indicate that although the configuration of the analog is not necessarily a prerequisite for hydrolysis, there does appear to be an optimal spatial orientation for enzymatic activity. The analogy between the susceptibilities of all-trans-(1,3/2-1P)-cyclopentano-lecithin and glycero-lecithin suggests that the conformation of the glycero-lecithin during phospholipase A2-mediated hydrolysis may be best simulated by the all-trans orientation of C-O bonds in the artificial substrate.

A 16 b 2 GHz digital-to-analog converter in 0.18 μm CMOS with digital calibration technology

International Nuclear Information System (INIS)

Yang Weidong; Pu Jie; Zhang Ruitao; Chen Chao; Zang Jiandong; Li Tiehu; Luo Pu

2015-01-01

This paper presents a 16-bit 2 GSPS digital-to-analog converter (DAC) in 0.18 μm CMOS technology. This DAC is implemented using time division multiplex access system architecture in the digital domain. The input data is received with a two-channel LVDS interface. The DLL technology is introduced to meet the timing requirements between phases of the LVDS data and the data sampling clock. A FIFO is designed to absorb the phase difference between the data clock and DAC system clock. A delay controller is integrated to adjust the phase relationship between the high speed digital clock and analog clock, obtaining a sampling rate of 2 GSPS. The current source mismatch at higher bits is calibrated in the digital domain. Test results show that the DAC achieves 74.02 dBC SFDR at analog output of 36 MHz, and DNL less than ±2.1 LSB and INL less than ±4.3 LSB after the chip is calibrated. (paper)

Rhetoric and analogies

OpenAIRE

Aragonès, Enriqueta; Gilboa, Itzhak; Postlewaite, Andrew; Schmeidler, David; Universitat Autònoma de Barcelona. Unitat de Fonaments de l'Anàlisi Econòmica; Universitat Autònoma de Barcelona. Institut d'Anàlisi Econòmica

2013-01-01

The art of rhetoric may be defined as changing other people's minds (opinions, beliefs) without providing them new information. One tech- nique heavily used by rhetoric employs analogies. Using analogies, one may draw the listener's attention to similarities between cases and to re-organize existing information in a way that highlights certain reg- ularities. In this paper we offer two models of analogies, discuss their theoretical equivalence, and show that finding good analogies is a com- p...

Trends in Hepatitis B Virus Resistance to Nucleoside/Nucleotide Analogs in North China from 2009 to 2016: A Retrospective Study.

Science.gov (United States)

Guo, Xianghua; Wu, Jushan; Wei, Feili; Ouyang, Yabo; Li, Qing; Liu, Kai; Wang, Yanjun; Zhang, Yulin; Chen, Dexi

2018-04-11

Nucleos(t)ide analogs (NAs) are widely used in anti-hepatitis B virus (HBV) therapy for effective inhibition of HBV replication. However, HBV resistance to NAs has emerged, resulting in virus reactivation and disease recurrence. Big data on the current dynamic of HBV resistance profiles are still rare in China. Herein, we analyzed 4,491 plasma samples with HBV primary genotypic resistance mutations representative of the general HBV resistance situation in northern China from 2009 to 2016. We found that entecavir (ETV), representing 52.8% of 12,713 NAs users in the North of China in 2016, has become the major NA for treating Chinese patients infected with HBV. Despite more than 50% of M204I/V±L180M among all HBV resistance cases annually and extensive exposure of the patients to lamivudine (LAM), telbivudine (LdT), and adefovir dipivoxil (ADV), ETV resistance also showed dramatically increased incidence, which climbed to 17.1% in 2016. Moreover, A181T/V, ETV-resistant mutations, and multidrug-resistant mutations were found more frequently in HBV genotype C than in HBV genotype B, 21.2% vs. 8.5%, 12.5% vs. 7.9%, and 5.9% vs. 3%, respectively, whereas M204I and N236T were more predominant in genotype B than in genotype C, 40.3% vs. 20.8%, and 11.3% vs. 1.8%, respectively. In conclusion, we have reported dynamic changes of HBV NA-resistance mutation patterns and the current NA usage profile for anti-HBV treatment in North China in the past 8 years. Our data provides valuable information on HBV NA resistance that is an important reference for clinics to devise more effective treatment regimens for individual patients. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Intuitive analog circuit design

CERN Document Server

Thompson, Marc

2013-01-01

Intuitive Analog Circuit Design outlines ways of thinking about analog circuits and systems that let you develop a feel for what a good, working analog circuit design should be. This book reflects author Marc Thompson's 30 years of experience designing analog and power electronics circuits and teaching graduate-level analog circuit design, and is the ideal reference for anyone who needs a straightforward introduction to the subject. In this book, Dr. Thompson describes intuitive and ""back-of-the-envelope"" techniques for designing and analyzing analog circuits, including transistor amplifi

Analisis interferensi T-DAB dan TV Analog pada pita Very High Frequency (VHF

Directory of Open Access Journals (Sweden)

Kasmad Ariansyah

2014-09-01

Full Text Available Kehadiran teknologi digital telah membawa perubahan di dalam berbagai aspek kehidupan, tak terkecuali di dunia penyiaran. Digitalisasi dibidang penyiaran diyakini dapat memberikan manfaat dalam hal efisiensi spektrum frekuensi radio. Berkaitan dengan penyiaran radio, Menteri  Komunikasi  dan  Informatika telah menetapkan DAB family sebagai standard penyiaran radio digital di Indonesia. Kajian dilakukan untuk mendapatkan jarak minimum yang diperlukan  antara sistem T-DAB dan TV analog sebagai solusi terhadap kemungkinan interferensi. Analisis dilakukan dengan bantuan SEAMCAT. Berdasarkan hasil analisis disimpulkan bahwa  kanal  A  T-DAB  merupakan  kanal yang paling rentan terhadap interferensi; Untuk mencapai probabilitas interferensi maksimum 5%, separasi geograpis minimum antara cakupan terluar TV analog kanal n dan transmitter terluar pada jaringan SFN T-DAB untuk kanal (n- 1D, nA, nB, nC berturut-turut adalah 220 Km, 290 Km, 145 Km dan  40  Km.  Sedangkan  untuk  kanal  nD  dan  (n+1A  dapat dioperasikan tanpa separasi geograpis dengan TV analog.

Ny behandling af kronisk hepatitis B

DEFF Research Database (Denmark)

Andersen, Ellen Sloth; Weis, Nina M; Weis, Nina M

2008-01-01

Worldwide, 350 million people are infected with chronic hepatitis B. Over the last few years, it has been possible to treat chronic hepatitis B. Treatment very often consists of nucleos(t)ide analogs and in a few cases of pegylated alpha-interferon. In 2007, a new nucleoside analog, Telbivudine......, was approved to treat chronic hepatitis B. In phase II and ongoing phase III studies, Telbivudine has proven more effective than the nucleoside analog, Lamivudine, which was very often used up until recently. Udgivelsesdato: 2008-Nov-24...

Modulation of the human equilibrative nucleoside transporter1 (hENT1) activity by IL-4 and PMA in B cells from chronic lymphocytic leukemia.

Science.gov (United States)

Fernández Calotti, Paula; Galmarini, Carlos María; Cañones, Cristian; Gamberale, Romina; Saénz, Daniel; Avalos, Julio Sánchez; Chianelli, Mónica; Rosenstein, Ruth; Giordano, Mirta

2008-02-15

Nucleoside transporters (NTs) are essential for the uptake of therapeutic nucleoside analogs, broadly used in cancer treatment. The mechanisms responsible for NT regulation are largely unknown. IL-4 is a pro-survival signal for chronic lymphocytic leukemia (CLL) cells and has been shown to confer resistance to nucleoside analogs. The aim of this study was to investigate whether IL-4 is able to modulate the expression and function of the human equilibrative NT1 (hENT1) in primary cultures of CLL cells and, consequently, to affect cytotoxicity induced by therapeutic nucleosides analogs. We found that treatment with IL-4 (20 ng/ml for 24 h) increased mRNA hENT1 expression in CLL cells without affecting that of normal B cells. Given that the enhanced mRNA levels of hENT1 in CLL cells did not result in increased transport activity, we examined the possibility that hENT1 induced by IL-4 may require post-translational modifications to become active. We found that the acute stimulation of PKC in IL-4-treated CLL cells by short-term incubation with PMA significantly increased hENT1 transport activity and favoured fludarabine-induced apoptosis. By contrast, and in line with previous reports, IL-4 plus PMA protected CLL cells from a variety of cytotoxic agents. Our findings indicate that the combined treatment with IL-4 and PMA enhances hENT1 activity and specifically sensitizes CLL cells to undergo apoptosis induced by fludarabine.

A reconfigurable analog baseband circuit for WLAN, WCDMA, and Bluetooth

International Nuclear Information System (INIS)

Tong Tao; Chi Baoyong; Wang Ziqiang; Zhang Ying; Jiang Hanjun; Wang Zhihua

2010-01-01

A reconfigurable analog baseband circuit for WLAN, WCDMA, and Bluetooth in 0.35 μm CMOS is presented. The circuit consists of two variable gain amplifiers (VGA) in cascade and a G m -C elliptic low-pass filter (LPF). The filter-order and the cut-off frequency of the LPF can be reconfigured to satisfy the requirements of various applications. In order to achieve the optimum power consumption, the bandwidth of the VGAs can also be dynamically reconfigured and some G m cells can be cut off in the given application. Simulation results show that the analog baseband circuit consumes 16.8 mW for WLAN, 8.9 mW for WCDMA and only 6.5 mW for Bluetooth, all with a 3 V power supply. The analog baseband circuit could provide -10 to +40 dB variable gain, third-order low pass filtering with 1 MHz cut-off frequency for Bluetooth, fourth-order low pass filtering with 2.2 MHz cut-off frequency for WCDMA, and fifth-order low pass filtering with 11 MHz cut-off frequency for WLAN, respectively. (semiconductor integrated circuits)

A reconfigurable analog baseband circuit for WLAN, WCDMA, and Bluetooth

Energy Technology Data Exchange (ETDEWEB)

Tong Tao; Chi Baoyong; Wang Ziqiang; Zhang Ying; Jiang Hanjun; Wang Zhihua, E-mail: tongt05@gmail.co [Institute of Microelectronics, Tsinghua University, Beijing 100084 (China)

2010-05-15

A reconfigurable analog baseband circuit for WLAN, WCDMA, and Bluetooth in 0.35 {mu}m CMOS is presented. The circuit consists of two variable gain amplifiers (VGA) in cascade and a G{sub m}-C elliptic low-pass filter (LPF). The filter-order and the cut-off frequency of the LPF can be reconfigured to satisfy the requirements of various applications. In order to achieve the optimum power consumption, the bandwidth of the VGAs can also be dynamically reconfigured and some G{sub m} cells can be cut off in the given application. Simulation results show that the analog baseband circuit consumes 16.8 mW for WLAN, 8.9 mW for WCDMA and only 6.5 mW for Bluetooth, all with a 3 V power supply. The analog baseband circuit could provide -10 to +40 dB variable gain, third-order low pass filtering with 1 MHz cut-off frequency for Bluetooth, fourth-order low pass filtering with 2.2 MHz cut-off frequency for WCDMA, and fifth-order low pass filtering with 11 MHz cut-off frequency for WLAN, respectively. (semiconductor integrated circuits)

Temperature dependence of the CP/sup N-1/ model and the analogy with quantum chromodynamics

International Nuclear Information System (INIS)

Actor, A.

1985-01-01

The two-dimensional CP/sup N-1/ model - a simple field-theoretic analogue of four-dimensional quantum chromodynamics (QCD) - is analysed and reviewed. The major themes are the temperature dependence of the CP/sup N-1/ model, and the analogy between CP/sup N-1/ and QCD. A detailed treatment of the 1/N approximation of the CP/sup N-1/ model is given. The main results emerging from this approximation are discussed at length. These are: asymptotic freedom, dimensional transmutation, confinement and topological charge nonquantization at zero temperature T = 0, screening and topological charge quantization at finite temperature T. The analogy with QCD is explained in detail. A new, qualitative, analysis of the CP/sup N-1/ model at finite temperature is introduced. This approach exploits the conformal invariance of the model to 'heat' an arbitrary CP/sup N-1/ field from T = 0 to finite temperature. This is achieved by conformal-transforming the flat Euclidean space-time of the T = 0 theory to the cylindrical space-time of the finite temperature theory. (author)

A novel synthetic analog of militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells

International Nuclear Information System (INIS)

Yoon, Deok Hyo; Lim, Mi-Hee; Lee, Yu Ran; Sung, Gi-Ho; Lee, Tae-Ho; Jeon, Byeong Hwa; Cho, Jae Youl; Song, Won O.; Park, Haeil; Choi, Sunga; Kim, Tae Woong

2013-01-01

A synthetic Militarin analog-1[(2R,3R,4R,5R)-1,6-bis(4-(2,4,4-trimethylpentan-2-yl)phenoxy) hexane-2,3,4,5-tetraol] is a novel derivative of constituents from Cordyceps militaris, which has been used to treat a variety of chronic diseases including inflammation, diabetes, hyperglycemia and cancers. Here, we report for the first time the synthesis of Militarin analog-1 (MA-1) and the apoptotic mechanism of MA-1 against human lung cancer cell lines. Treatment with MA-1 significantly inhibited the viability of 3 human lung cancer cell lines. The inhibition of viability and growth in MA-1-treated A549 cells with an IC 50 of 5 μM were mediated through apoptosis induction, as demonstrated by an increase in DNA fragmentation, sub-G 0 /G 1 -DNA fraction, nuclear condensation, and phosphatidylserine exposure. The apoptotic cell death caused mitochondrial membrane permeabilization through regulation of expression of the Bcl-2 family proteins, leading to cytochrome c release in a time-dependent manner. Subsequently, the final stage of apoptosis, activation of caspase-9/-3 and cleavage of poly (ADP ribose) polymerase, was induced. Furthermore, A549 lung cancer cells were more responsive to MA-1 than a bronchial epithelial cell line (BEAS-2B), involving the rapid generation of reactive oxygen species (ROS), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation. The pharmacological inhibition of ROS generation and JNK/p38 MAPK exhibited attenuated DNA fragmentation in MA-1-induced apoptosis. Oral administration of MA-1 also retarded growth of A549 orthotopic xenografts. In conclusion, the present study indicates that the new synthetic derivative MA-1 triggers mitochondrial apoptosis through ROS generation and regulation of MAPKs and may be a potent therapeutic agent against human lung cancer. - Highlights: • We report a novel synthesized derivative, militarin analog-1 (MA-1). • MA-1-induced cancer cell death was triggered by the ROS

A novel synthetic analog of militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells

Energy Technology Data Exchange (ETDEWEB)

Yoon, Deok Hyo; Lim, Mi-Hee [Department of Biochemistry, Kangwon National University, Chuncheon 200-701 (Korea, Republic of); Lee, Yu Ran [Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-747 (Korea, Republic of); Sung, Gi-Ho [Mushroom Research Division, National Institute of Horticultural and Herbal Science, Rural Development Administration, Suwon 404-707 (Korea, Republic of); Lee, Tae-Ho [R and D Center, Dong-A Pharmaceutical Co, Ltd, Yongin 446-905 (Korea, Republic of); Jeon, Byeong Hwa [Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-747 (Korea, Republic of); Cho, Jae Youl [Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Song, Won O. [Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824 (United States); Park, Haeil [College of Pharmacy, Kangwon National University, Chuncheon 200-701 (Korea, Republic of); Choi, Sunga, E-mail: sachoi@cnu.ac.kr [Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-747 (Korea, Republic of); Kim, Tae Woong, E-mail: tawkim@kangwon.ac.kr [Department of Biochemistry, Kangwon National University, Chuncheon 200-701 (Korea, Republic of)

2013-12-15

A synthetic Militarin analog-1[(2R,3R,4R,5R)-1,6-bis(4-(2,4,4-trimethylpentan-2-yl)phenoxy) hexane-2,3,4,5-tetraol] is a novel derivative of constituents from Cordyceps militaris, which has been used to treat a variety of chronic diseases including inflammation, diabetes, hyperglycemia and cancers. Here, we report for the first time the synthesis of Militarin analog-1 (MA-1) and the apoptotic mechanism of MA-1 against human lung cancer cell lines. Treatment with MA-1 significantly inhibited the viability of 3 human lung cancer cell lines. The inhibition of viability and growth in MA-1-treated A549 cells with an IC{sub 50} of 5 μM were mediated through apoptosis induction, as demonstrated by an increase in DNA fragmentation, sub-G{sub 0}/G{sub 1}-DNA fraction, nuclear condensation, and phosphatidylserine exposure. The apoptotic cell death caused mitochondrial membrane permeabilization through regulation of expression of the Bcl-2 family proteins, leading to cytochrome c release in a time-dependent manner. Subsequently, the final stage of apoptosis, activation of caspase-9/-3 and cleavage of poly (ADP ribose) polymerase, was induced. Furthermore, A549 lung cancer cells were more responsive to MA-1 than a bronchial epithelial cell line (BEAS-2B), involving the rapid generation of reactive oxygen species (ROS), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation. The pharmacological inhibition of ROS generation and JNK/p38 MAPK exhibited attenuated DNA fragmentation in MA-1-induced apoptosis. Oral administration of MA-1 also retarded growth of A549 orthotopic xenografts. In conclusion, the present study indicates that the new synthetic derivative MA-1 triggers mitochondrial apoptosis through ROS generation and regulation of MAPKs and may be a potent therapeutic agent against human lung cancer. - Highlights: • We report a novel synthesized derivative, militarin analog-1 (MA-1). • MA-1-induced cancer cell death was triggered by

The neuromechanism underlying verbal analogical reasoning of metaphorical relations: an event-related potentials study.

Science.gov (United States)

Zhao, Ming; Meng, Huishan; Xu, Zhiyuan; Du, Fenglei; Liu, Tao; Li, Yongxin; Chen, Feiyan

2011-11-24

Using event-related potentials (ERPs), this study investigated the neuromechanism underlying verbal analogical reasoning of two different metaphorical relations: attributive metaphor and relational metaphor. The analogical reasoning of attributive metaphor (AM-AR) involves a superficial similarity between analogues, while the analogical reasoning of relational metaphor (RM-AR) requires a structural similarity. Subjects were asked to judge whether one word pair was semantically analogous to another word pair. Results showed that the schema induction stage elicited a greater N400 component at the right anterior scalp for the AM-AR and RM-AR tasks, possibly attributable to semantic processing of metaphorical word pairs. The N400 was then followed by a widely distributed P300 and a late negative component (LNC1) at the left anterior scalp. The P300 was possibly related to the formation of a relational category, while the LNC1 was possibly related to the maintenance of a reasoning cue in working memory. The analogy mapping stage elicited broadly distributed N400 and LNC2, which might indicate the presence of semantic retrieval and analogical transfer. In the answer production stage, all conditions elicited the P2 component due to early stimulus encoding. The largest P2 amplitude was in the RM-AR task. The RM-AR elicited a larger LPC than did the AM-AR, even though the baseline correction was taken as a control for the differential P2 effect. The LPC effect might suggest that relational metaphors involved more integration processing than attributive metaphors. Copyright © 2011 Elsevier B.V. All rights reserved.

Terrestrial Analogs to Mars

Science.gov (United States)

Farr, T. G.; Arcone, S.; Arvidson, R. W.; Baker, V.; Barlow, N. G.; Beaty, D.; Bell, M. S.; Blankenship, D. D.; Bridges, N.; Briggs, G.; Bulmer, M.; Carsey, F.; Clifford, S. M.; Craddock, R. A.; Dickerson, P. W.; Duxbury, N.; Galford, G. L.; Garvin, J.; Grant, J.; Green, J. R.; Gregg, T. K. P.; Guinness, E.; Hansen, V. L.; Hecht, M. H.; Holt, J.; Howard, A.; Keszthelyi, L. P.; Lee, P.; Lanagan, P. D.; Lentz, R. C. F.; Leverington, D. W.; Marinangeli, L.; Moersch, J. E.; Morris-Smith, P. A.; Mouginis-Mark, P.; Olhoeft, G. R.; Ori, G. G.; Paillou, P.; Reilly, J. F., II; Rice, J. W., Jr.; Robinson, C. A.; Sheridan, M.; Snook, K.; Thomson, B. J.; Watson, K.; Williams, K.; Yoshikawa, K.

2002-08-01

It is well recognized that interpretations of Mars must begin with the Earth as a reference. The most successful comparisons have focused on understanding geologic processes on the Earth well enough to extrapolate to Mars' environment. Several facets of terrestrial analog studies have been pursued and are continuing. These studies include field workshops, characterization of terrestrial analog sites, instrument tests, laboratory measurements (including analysis of Martian meteorites), and computer and laboratory modeling. The combination of all these activities allows scientists to constrain the processes operating in specific terrestrial environments and extrapolate how similar processes could affect Mars. The Terrestrial Analogs for Mars Community Panel has considered the following two key questions: (1) How do terrestrial analog studies tie in to the Mars Exploration Payload Assessment Group science questions about life, past climate, and geologic evolution of Mars, and (2) How can future instrumentation be used to address these questions. The panel has considered the issues of data collection, value of field workshops, data archiving, laboratory measurements and modeling, human exploration issues, association with other areas of solar system exploration, and education and public outreach activities.

Method for transmitting analog data over a fiber-optic link

International Nuclear Information System (INIS)

Dyer, G.R.

1981-01-01

The transmission of high-speed analog dat across an insulating break is a common requirement for present fusion experiments, and it will be a necessity for a reactor-like device. Presently available systems tend to be complex, slow, and expensive. A method is described for implementing a fiber-optic link with analog data input and output. Two realizations of the method are given. A medium-speed system using monolithic circuitry is capable of a dc to 20-KHz bandwidth with excellent linearity and a dynamic range of at least 60 dB. A higher-speed system uses some discrete circuitry to attain a 500-KHz bandwidth with at least a 40-dB dynamic range. Both systems use a relatively inexpensive digital optical link kit combined with a duty cycle modulation scheme for data tramsmission. This method achieves accurate reproduction of complex waveforms without introducing the quantization errors inherent in analog-to-digital conversion, offers bipolar response with low offset and drift, and maintains a constant bandwidth regardless of signal level

A fast multichannel analog storage system

International Nuclear Information System (INIS)

Freytag, D.R.

1983-01-01

A Multichannel Analog Storage System based on a commercial 32-channel parallel in/serial out (PISO) analog shift register is described. The basic unit is a single width CAMAC module containing 512 analog cells and the associated logic for data storage and subsequent readout. At sampling rates of up to 30 MHz the signals are strobed directly into the PISO. At higher rates signals are strobed into a fast presampling stage and subsequently transferred in block form into an array of PISO's. Sampling rates of 300 MHz have been achieved with the present device and 1000 MHz are possible with improved signal drivers. The system is well suited for simultaneous handling of many signal channels with moderate numbers of samples in each channel. RMS noise over full scale signal has been measured as 1:3000 (approx. =11 bit). However, nonlinearities in the response and differences in sensitivity of the analog cells require an elaborate calibration system in order to realize 11 bit accuracy for the analog information

High-speed and high-resolution analog-to-digital and digital-to-analog converters

NARCIS (Netherlands)

van de Plassche, R.J.

1989-01-01

Analog-to-digital and digital-to-analog converters are important building blocks connecting the analog world of transducers with the digital world of computing, signal processing and data acquisition systems. In chapter two the converter as part of a system is described. Requirements of analog

Combined Palmer Type 1A and 1B Traumatic Lesions of the Triangular Fibrocartilage Complex A New Category.

Science.gov (United States)

Nance, Erin; Ayalon, Omri; Yang, Steven

2016-06-01

We present a series of eight patients who underwent wrist arthroscopy for presumed solitary tears of the triangular fibrocartilage (TFC) and were, instead, found to have combined 1A (central tear) and 1B (ulnar avulsion) tears. The Palmer Classification does not currently categorize this combined pattern. All but one patient had a traumatic injury. Each subject had preoperative radiographs and MRI scans. TFC tears were evident on all MRI scans, though only one was suggestive of a combined tear pat - tern. Surgical management included arthroscopic central tear debridement and ulnar peripheral repair. Average follow-up was 22 months. Grip strength in the affected hand improved from 16% deficit as compared to the unaffected side, to 3.5% deficit postoperatively (p = 0.003), and visual analog scores (VAS) decreased from an average of 7.1/10 preoperatively to 2.3/10 postoperatively (p < 0.001). There was no statistically significant change in wrist range of motion (ROM), however. Arthroscopic debridement of the central perforation (1A lesion) with concomitant repair of the ulnar detachment (1B lesion) resulted in functional and symptomatic improvement. This combined 1A/1B TFC injury is not reliably diagnosed preoperatively and should be considered a new subset in the Palmer classification, as this will raise awareness of its presence and assist in preoperative planning of such lesions.

Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor.

Science.gov (United States)

Lin, Wenwei; Yang, Lei; Chai, Sergio C; Lu, Yan; Chen, Taosheng

2016-01-27

Constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) are master regulators of endobiotic and xenobiotic metabolism and disposition. Because CAR is constitutively active in certain cellular contexts, inhibiting CAR might reduce drug-induced hepatotoxicity and resensitize drug-resistant cancer cells to chemotherapeutic drugs. We recently reported a novel CAR inhibitor/inverse agonist CINPA1 (11). Here, we have obtained or designed 54 analogs of CINPA1 and used a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to evaluate their CAR inhibition potency. Many of the 54 analogs showed CAR inverse agonistic activities higher than those of CINPA1, which has an IC50 value of 687 nM. Among them, 72 has an IC50 value of 11.7 nM, which is about 59-fold more potent than CINPA1 and over 10-fold more potent than clotrimazole (an IC50 value of 126.9 nM), the most potent CAR inverse agonist in a biochemical assay previously reported by others. Docking studies provide a molecular explanation of the structure-activity relationship (SAR) observed experimentally. To our knowledge, this effort is the first chemistry endeavor in designing and identifying potent CAR inverse agonists based on a novel chemical scaffold, leading to 72 as the most potent CAR inverse agonist so far. The 54 chemicals presented are novel and unique tools for characterizing CAR's function, and the SAR information gained from these 54 analogs could guide future efforts to develop improved CAR inverse agonists. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

The effect of benfothiamine in the therapy of diabetic polyneuropathy

Directory of Open Access Journals (Sweden)

Nikolić Ana

2009-01-01

Full Text Available Introduction. Diabetic polyneuropathy (DPN is one of the most common diabetic complications, which can result in a significant functional impairment and reduction of the quality of life in affected individuals. It occurs due to alterations in different biochemical mechanisms which require the presence of thiamine, which is why this vitamin is used in the therapy of DPN. Due to the low bioavailability of the hydrosolubile forms of thiamine, its liposolubile preparations (benfotiamine are preferentially used. Objective. The aim of this study was to determine the efficacy of benfotiamine in combination with vitamin B6 in the therapy of DPN. Methods. The study group comprised of 22 patients with DPN who were treated with the combination of benfotiamine and vitamin B6 during 45 days. The effect of the therapy was evaluated by the analysis of different clinical, laboratory and electrophysiological parameters before and after conducted treatment. Results. After the treatment period, a statistically highly significant reduction of pain (p<0.01 was noted with the reduction of pain score on visual analogue scale in 86.4% of patients. A significant reduction of subjective complaints was also noted, with decreased modified total symptom score in 95.5% of patients (p<0.01. The presence of alodynia was reported at the beginning of the study in 77.3%, and after the benfotiamine therapy only in 22.7% of patients, while hyperpathy was initially present in 90.9%, and after treatment in 31.8% of patients (p<0,01. Neurophysiological parameters of polyneuropathy also significantly improved, with the improvement of the compound muscle action potential amplitude in 68.2% (p<0.01 and motor conduction velocity of the peroneal nerve in 45.5% of patients (p<0.01. The improvement of the sensory nerve action potential amplitude (p<0.01 and sensory conduction velocity (p=0.05 of the sural nerve was found in 45.5% of patients. After the treatment period, there was a highly

Bandwidth tunable microwave photonic filter based on digital and analog modulation

Science.gov (United States)

Zhang, Qi; Zhang, Jie; Li, Qiang; Wang, Yubing; Sun, Xian; Dong, Wei; Zhang, Xindong

2018-05-01

A bandwidth tunable microwave photonic filter based on digital and analog modulation is proposed and experimentally demonstrated. The digital modulation is used to broaden the effective gain spectrum and the analog modulation is to get optical lines. By changing the symbol rate of data pattern, the bandwidth is tunable from 50 MHz to 700 MHz. The interval of optical lines is set according to the bandwidth of gain spectrum which is related to the symbol rate. Several times of bandwidth increase are achieved compared to a single analog modulation and the selectivity of the response is increased by 3.7 dB compared to a single digital modulation.

Structured Analog CMOS Design

CERN Document Server

Stefanovic, Danica

2008-01-01

Structured Analog CMOS Design describes a structured analog design approach that makes it possible to simplify complex analog design problems and develop a design strategy that can be used for the design of large number of analog cells. It intentionally avoids treating the analog design as a mathematical problem, developing a design procedure based on the understanding of device physics and approximations that give insight into parameter interdependences. The proposed transistor-level design procedure is based on the EKV modeling approach and relies on the device inversion level as a fundament

Analog and hybrid computing

CERN Document Server

Hyndman, D E

2013-01-01

Analog and Hybrid Computing focuses on the operations of analog and hybrid computers. The book first outlines the history of computing devices that influenced the creation of analog and digital computers. The types of problems to be solved on computers, computing systems, and digital computers are discussed. The text looks at the theory and operation of electronic analog computers, including linear and non-linear computing units and use of analog computers as operational amplifiers. The monograph examines the preparation of problems to be deciphered on computers. Flow diagrams, methods of ampl

Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis.

Science.gov (United States)

Gustafsson, Tomas N; Osman, Harer; Werngren, Jim; Hoffner, Sven; Engman, Lars; Holmgren, Arne

2016-06-01

Bacillus anthracis is the causative agent of anthrax, a disease associated with a very high mortality rate in its invasive forms. We studied a number of ebselen analogs as inhibitors of B. anthracis thioredoxin reductase and their antibacterial activity on Bacillus subtilis, Staphylococcus aureus, Bacillus cereus and Mycobacterium tuberculosis. The most potent compounds in the series gave IC(50) values down to 70 nM for the pure enzyme and minimal inhibitory concentrations (MICs) down to 0.4 μM (0.12 μg/ml) for B. subtilis, 1.5 μM (0.64 μg/ml) for S. aureus, 2 μM (0.86 μg/ml) for B. cereus and 10 μg/ml for M. tuberculosis. Minimal bactericidal concentrations (MBCs) were found at 1-1.5 times the MIC, indicating a general, class-dependent, bactericidal mode of action. The combined bacteriological and enzymological data were used to construct a preliminary structure-activity-relationship for the benzoisoselenazol class of compounds. When S. aureus and B. subtilis were exposed to ebselen, we were unable to isolate resistant mutants on both solid and in liquid medium suggesting a high resistance barrier. These results suggest that ebselen and analogs thereof could be developed into a novel antibiotic class, useful for the treatment of infections caused by B. anthracis, S. aureus, M. tuberculosis and other clinically important bacteria. Furthermore, the high barrier against resistance development is encouraging for further drug development. We have characterized the thioredoxin system from B. anthracis as a novel drug target and ebselen and analogs thereof as a potential new class of antibiotics targeting several important human pathogens. Copyright © 2016 Elsevier B.V. All rights reserved.

Analog-to-digital conversion

CERN Document Server

Pelgrom, Marcel J M

2010-01-01

The design of an analog-to-digital converter or digital-to-analog converter is one of the most fascinating tasks in micro-electronics. In a converter the analog world with all its intricacies meets the realm of the formal digital abstraction. Both disciplines must be understood for an optimum conversion solution. In a converter also system challenges meet technology opportunities. Modern systems rely on analog-to-digital converters as an essential part of the complex chain to access the physical world. And processors need the ultimate performance of digital-to-analog converters to present the results of their complex algorithms. The same progress in CMOS technology that enables these VLSI digital systems creates new challenges for analog-to-digital converters: lower signal swings, less power and variability issues. Last but not least, the analog-to-digital converter must follow the cost reduction trend. These changing boundary conditions require micro-electronics engineers to consider their design choices for...

Foxp1 controls mature B cell survival and the development of follicular and B-1 B cells

Science.gov (United States)

Patzelt, Thomas; Keppler, Selina J.; Gorka, Oliver; Thoene, Silvia; Wartewig, Tim; Reth, Michael; Förster, Irmgard; Lang, Roland; Buchner, Maike; Ruland, Jürgen

2018-01-01

The transcription factor Foxp1 is critical for early B cell development. Despite frequent deregulation of Foxp1 in B cell lymphoma, the physiological functions of Foxp1 in mature B cells remain unknown. Here, we used conditional gene targeting in the B cell lineage and report that Foxp1 disruption in developing and mature B cells results in reduced numbers and frequencies of follicular and B-1 B cells and in impaired antibody production upon T cell-independent immunization in vivo. Moreover, Foxp1-deficient B cells are impaired in survival even though they exhibit an increased capacity to proliferate. Transcriptional analysis identified defective expression of the prosurvival Bcl-2 family gene Bcl2l1 encoding Bcl-xl in Foxp1-deficient B cells, and we identified Foxp1 binding in the regulatory region of Bcl2l1. Transgenic overexpression of Bcl2 rescued the survival defect in Foxp1-deficient mature B cells in vivo and restored peripheral B cell numbers. Thus, our results identify Foxp1 as a physiological regulator of mature B cell survival mediated in part via the control of Bcl-xl expression and imply that this pathway might contribute to the pathogenic function of aberrant Foxp1 expression in lymphoma. PMID:29507226

High speed, wide dynamic range analog signal processing for avalanche photodiode

CERN Document Server

Walder, J P; Pangaud, P

2000-01-01

A wide dynamic range multi-gain analog transimpedance amplifier integrated circuit has been developed for avalanche photodiode signal processing. The 96 dB input dynamic range is divided into four ranges of 12-bits each in order to provide 40 MHz analog sampled data to a 12-bits ADC. This concept which has been integrated in both BiCMOS and full complementary bipolar technology along with fitted design techniques will be presented.

High speed, wide dynamic range analog signal processing for avalanche photodiode

International Nuclear Information System (INIS)

Walder, J.P.; El Mamouni, Houmani; Pangaud, Patrick

2000-01-01

A wide dynamic range multi-gain analog transimpedance amplifier integrated circuit has been developed for avalanche photodiode signal processing. The 96 dB input dynamic range is divided into four ranges of 12-bits each in order to provide 40 MHz analog sampled data to a 12-bits ADC. This concept which has been integrated in both BiCMOS and full complementary bipolar technology along with fitted design techniques will be presented

High speed, wide dynamic range analog signal processing for avalanche photodiode

Energy Technology Data Exchange (ETDEWEB)

Walder, J.P. E-mail: walder@in2p3.fr; El Mamouni, Houmani; Pangaud, Patrick

2000-03-11

A wide dynamic range multi-gain analog transimpedance amplifier integrated circuit has been developed for avalanche photodiode signal processing. The 96 dB input dynamic range is divided into four ranges of 12-bits each in order to provide 40 MHz analog sampled data to a 12-bits ADC. This concept which has been integrated in both BiCMOS and full complementary bipolar technology along with fitted design techniques will be presented.

Analogies and surprising differences between recombinant nitric oxide synthase-like proteins from Staphylococcus aureus and Bacillus anthracis in their interactions with l-arginine analogs and iron ligands.

Science.gov (United States)

Salard, Isabelle; Mercey, Emilie; Rekka, Eleni; Boucher, Jean-Luc; Nioche, Pierre; Mikula, Ivan; Martasek, Pavel; Raman, C S; Mansuy, Daniel

2006-12-01

Genome sequencing has recently shown the presence of genes coding for NO-synthase (NOS)-like proteins in bacteria. The roles of these proteins remain unclear. The interactions of a series of l-arginine (l-arg) analogs and iron ligands with two recombinant NOS-like proteins from Staphylococcus aureus (saNOS) and Bacillus anthracis (baNOS) have been studied by UV-visible spectroscopy. SaNOS and baNOS in their ferric native state, as well as their complexes with l-arg analogs and with various ligands, exhibit spectral characteristics highly similar to the corresponding complexes of heme-thiolate proteins such as cytochromes P450 and NOSs. However, saNOS greatly differs from baNOS at the level of three main properties: (i) native saNOS mainly exists under an hexacoordinated low-spin ferric state whereas native baNOS is mainly high-spin, (ii) the addition of tetrahydrobiopterin (H4B) or H4B analogs leads to an increase of the affinity of l-arg for saNOS but not for baNOS, and (iii) saNOS Fe(II), contrary to baNOS, binds relatively bulky ligands such as nitrosoalkanes and tert-butylisocyanide. Thus, saNOS exhibits properties very similar to those of the oxygenase domain of inducible NOS (iNOS(oxy)) not containing H4B, as expected for a NOSoxy-like protein that does not contain H4B. By contrast, the properties of baNOS which look like those of H4B-containing iNOS(oxy) are unexpected for a NOS-like protein not containing H4B. The origin of these surprising properties of baNOS remains to be determined.

Analog earthquakes

International Nuclear Information System (INIS)

Hofmann, R.B.

1995-01-01

Analogs are used to understand complex or poorly understood phenomena for which little data may be available at the actual repository site. Earthquakes are complex phenomena, and they can have a large number of effects on the natural system, as well as on engineered structures. Instrumental data close to the source of large earthquakes are rarely obtained. The rare events for which measurements are available may be used, with modfications, as analogs for potential large earthquakes at sites where no earthquake data are available. In the following, several examples of nuclear reactor and liquified natural gas facility siting are discussed. A potential use of analog earthquakes is proposed for a high-level nuclear waste (HLW) repository

Incidência de fumonisina B1, aflatoxinas B1, B2, G1 e G2, ocratoxina A e zearalenona em produtos de milho Occurrence of fumonisin B1, aflatoxins B1, B2, G1, and G2, ochratoxin A and zearalenone in corn products

Directory of Open Access Journals (Sweden)

Luciane Mie Kawashima

2006-09-01

Full Text Available Levantamentos de ocorrência de micotoxinas em alimentos foram realizados nas últimas duas décadas nas regiões Sudeste e Sul do Brasil. Levantamentos em alimentos comercializados em outras regiões têm-se limitado a aflatoxinas em amendoim e castanhas do Brasil. O presente trabalho pesquisou a presença de fumonisina B1, aflatoxinas B1, B2, G1 e G2, ocratoxina A e zearalenona em 74 amostras de produtos a base de milho adquiridas no comércio da cidade de Recife, PE, durante o período de 1999 a 2001. Fumonisina B1 foi determinada por cromatografia líquida de alta eficiência com detecção por fluorescência e as demais toxinas foram determinadas por cromatografia em camada delgada. Fumonisina B1 foi encontrada em 94,6% das amostras em concentrações variando de 20 a 8600 µg/kg. Apenas 5 amostras continham aflatoxina B1 e o teor máximo encontrado foi 20 µg/kg. Duas amostras ultrapassaram o limite de 20 µg/kg para a somatória das aflatoxinas B1, B2, G1 e G2 (farinha de milho pré-cozida com 21,5 µg/kg e quirera (xerém com 23,3 µg/kg. As aflatoxinas G1 e G2, ocratoxina A e zearalenona não foram detectadas em nenhuma das amostras. Todas as amostras contaminadas com aflatoxinas também apresentaram fumonisina B1.Research concerning the presence of mycotoxin in food has been conducted in the Southwest and South regions of Brazil over the last two decades. Research in other regions has been limited to aflatoxin in peanuts and Brazil nuts. The aim of this work is to study the presence of fumonisin B1, aflatoxins B1, B2, G1, and G2, ochratoxin A and zearalenone in 74 samples of corn products acquired in shops and food markets in the city of Recife (PE from 1999 to 2001. Fumonisin B1 was determined by high performance liquid chromatography and fluorescence was detected. The other toxins were determined by thin layer chromatography. Fumonisin B1 was found in 94.6% of the samples in levels from 20 to 8600 µg/kg. Only 5 samples contained

Neural underpinnings of divergent production of rules in numerical analogical reasoning.

Science.gov (United States)

Wu, Xiaofei; Jung, Rex E; Zhang, Hao

2016-05-01

Creativity plays an important role in numerical problem solving. Although the neural underpinnings of creativity have been studied over decades, very little is known about neural mechanisms of the creative process that relates to numerical problem solving. In the present study, we employed a numerical analogical reasoning task with functional Magnetic Resonance Imaging (fMRI) to investigate the neural correlates of divergent production of rules in numerical analogical reasoning. Participants performed two tasks: a multiple solution analogical reasoning task and a single solution analogical reasoning task. Results revealed that divergent production of rules involves significant activations at Brodmann area (BA) 10 in the right middle frontal cortex, BA 40 in the left inferior parietal lobule, and BA 8 in the superior frontal cortex. The results suggest that right BA 10 and left BA 40 are involved in the generation of novel rules, and BA 8 is associated with the inhibition of initial rules in numerical analogical reasoning. The findings shed light on the neural mechanisms of creativity in numerical processing. Copyright © 2016 Elsevier B.V. All rights reserved.

Ny behandling af kronisk hepatitis B

DEFF Research Database (Denmark)

Andersen, Ellen Sloth; Weis, Nina M

2008-01-01

Worldwide, 350 million people are infected with chronic hepatitis B. Over the last few years, it has been possible to treat chronic hepatitis B. Treatment very often consists of nucleos(t)ide analogs and in a few cases of pegylated alpha-interferon. In 2007, a new nucleoside analog, Telbivudine...

New treatment of chronic hepatitis B

DEFF Research Database (Denmark)

Andersen, E.S.; Weis, Nina

2008-01-01

Worldwide, 350 million people are infected with chronic hepatitis B. Over the last few years, it has been possible to treat chronic hepatitis B. Treatment very often consists of nucleos(t)ide analogs and in a few cases of pegylated alpha-interferon. In 2007, a new nucleoside analog, Telbivudine...

Cyclic Fatigue Resistance of 3 Proprietary Rotary File Brands and their Analogous EdgeEndo Counterparts.

Science.gov (United States)

2018-04-26

Resistance of 3 Proprietary Rotary File Brands and their Analogous EdgeEndo Counterparts. 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Sd...Endodontics 14. ABSTRACT Cyclic Fatigue Resistance of 3 Proprietary Rotary File Brands and their Analogous EdgeEndo Counterparts. David J. Weyh DDS...Resistance of 3 Proprietary Rotary File Brands and their Analogous EdgeEndo Counterparts. David J. Weyh DDS Jarom J. Ray DDS Introduction: The aim of this

Analog circuit design

CERN Document Server

Dobkin, Bob

2012-01-01

Analog circuit and system design today is more essential than ever before. With the growth of digital systems, wireless communications, complex industrial and automotive systems, designers are being challenged to develop sophisticated analog solutions. This comprehensive source book of circuit design solutions aids engineers with elegant and practical design techniques that focus on common analog challenges. The book's in-depth application examples provide insight into circuit design and application solutions that you can apply in today's demanding designs. <

Optical analogy. Synthesis report

International Nuclear Information System (INIS)

1965-01-01

The authors report the study of conditions under which light attenuation (reflection, diffusion, absorption) and the attenuation of some radiations (notably thermal neutrons) can be described with analogical calculations. The analogy between light physical properties and neutron properties is not searched for, but the analogy between their attenuation characteristics. After having discussed this possible analogy, they propose a mathematical formulation of neutron and optical phenomena which could theoretically justify the optical analogy. The second part reports a more practical study of optics problems such as the study of simple optics materials and illumination measurements, or more precisely the study of angular distributions of optical reflections, a determination of such angular distributions, and an experimental determination of the albedo

Inhibitory Effects of Resveratrol Analogs on Mushroom Tyrosinase Activity

Directory of Open Access Journals (Sweden)

Nádia Rezende Barbosa Raposo

2012-10-01

Full Text Available Skin pigmentation disorders typically involve an overproduction or uneven distribution of melanin, which results in skin spots. Resveratrol can inhibit tyrosinase, the active enzyme in the synthesis of melanin, but it does not inhibit the synthesis of melanin to an extent that enables its use alone as a skin whitening agent in pharmaceutical formulations, so its use as a coadjuvant in treatment of hyperpigmentation is suggested. Six resveratrol analogs were tested for tyrosinase inhibitory activity in vitro. Among the analogs tested, compound D was the most powerful tyrosinase inhibitor (IC50 = 28.66 µg/mL, two times more active than resveratrol (IC50 = 57.05 µg/mL, followed by the analogs A, E, B, F and C, respectively. This demonstrated that the hydroxylation at C4' on the phenolic ring was the molecular modification with most importance for the observed activity.

MX chains: 1-D analog of CuO planes?

International Nuclear Information System (INIS)

Gammel, J.T.; Batistic, I.; Bishop, A.R.; Loh, E.Y. Jr.; Marianer, S.

1989-01-01

We study a two-band Peierls-Hubbard model for halogen-bridged mixed-valence transition metal linear chain complexes (MX chains). We include electron-electron correlations (both Hubbard and PPP-like expressions) using several techniques including calculations in the zero-hopping limit, exact diagonalization of small systems, mean field approximation, and a Gutzwiller-like Ansatz for quantum phonons. The adiabatic optical absorption and phonon spectra for both photo-excited and doping induced defects (kinks, polarons, bipolarons, and excitons) are discussed. A long period phase which occurs even at commensurate filling for certain parameter values may be related to twinning. The effect of including the electron-phonon in addition to the electron-electron interaction on the polaron/bipolaron (pairing) competition is especially interesting when this class of compounds is viewed as a 1-D analog of high-temperature superconductors. 6 refs., 4 figs

[Pathomechanism of diabetic neuropathy: background of the pathogenesis-oriented therapy].

Science.gov (United States)

Winkler, Gábor; Kempler, Péter

2010-06-13

The pathomechanism of diabetic neuropathy remains still poorly understood, however, a broad spectrum of novel findings associated with therapeutic consequences emerged during the last decades. Both disturbed function of primary hemostasis and increased activity of coagulation system contribute to the reduced endoneurial blood flow. Increased superoxide anion production induced by hyperglycemia leads to decreased activity of glycerinaldehid-3-phosphate dehydrogenase and to consequential increased activity of alternative pathways, including the polyol-, hexosamine-, diacilglycerol protein kinase-C- and advanced glycation pathways. Advanced glycation endproducts increase the activity of the nuclear-factor kappa-B, as well as the production of vasoactive factors and cytokines (interleukin-1, -6, tumor necrosis factor alpha). The aim of pathogenetic oriented treatment is to slow down, stop or reverse the progression of neuropathy. Components of pathogenetic oriented treatment are glycaemic control, management of risk factors, benfotiamine and alpha-lipoic acid. On one hand, transketolase-activator benfotiamine inhibits alternative pathways induced by hyperglycemia (the polyol-, hexosamine-, diacilglycerol protein kinase-C-, and advanced glycation pathways), while, on the other hand, it increases the activity of the pentose-phosphate-shunt. The clinical effectiveness of benfotiamine has been shown in many international and Hungarian trials. Alpha-lipoic acid as a powerful antioxidant decreases oxidative stress and this way increases the activity of glycerinaldehid-3-phosphate dehydrogenase. Alpha-lipoic acid administered in infusion or oral treatment decreases both symptoms of neuropathy and neuropathic deficit. In conclusion, the case of diabetic neuropathy illustrates well, how widening of our knowledge on pathogenesis might contribute to successful therapy.

Are all analogies created equal? Prefrontal cortical functioning may predict types of analogical reasoning.

Science.gov (United States)

Chrysikou, Evangelia G; Thompson-Schill, Sharon L

2010-06-01

Abstract The proposed theory can account for analogies based on learned relationships between elements in the source and target domains. However, its explanatory power regarding the discovery of new relationships during analogical reasoning is limited. We offer an alternative perspective for the role of PFC in analogical thought that may better address different types of analogical mappings.

Is the Link from Working Memory to Analogy Causal? No Analogy Improvements following Working Memory Training Gains

OpenAIRE

Richey, J. Elizabeth; Phillips, Jeffrey S.; Schunn, Christian D.; Schneider, Walter

2014-01-01

Analogical reasoning has been hypothesized to critically depend upon working memory through correlational data [1], but less work has tested this relationship through experimental manipulation [2]. An opportunity for examining the connection between working memory and analogical reasoning has emerged from the growing, although somewhat controversial, body of literature suggests complex working memory training can sometimes lead to working memory improvements that transfer to novel working mem...

Molecular docking studies of (1E,3E,5E)-1,6-Bis(substituted phenyl)hexa-1,3,5-triene and 1,4-Bis(substituted trans-styryl)benzene analogs as novel tyrosinase inhibitors.

Science.gov (United States)

Ha, Young Mi; Lee, Hye Jin; Park, Daeui; Jeong, Hyoung Oh; Park, Ji Young; Park, Yun Jung; Lee, Kyung Jin; Lee, Ji Yeon; Moon, Hyung Ryong; Chung, Hae Young

2013-01-01

We simulated the docking of the tertiary structure of mushroom tyrosinase with our compounds. From the structure-tyrosinase inhibitory activity relationship, it is notable that compounds 4, 8 and 11 showed similar or better activity rates than kojic acid which was used as a positive control. Compounds 17, 21, and 23 among benzene analogs that possess the same substituent showed significantly lower tyrosinase inhibitory effects. Therefore, we have confirmed that among the compounds showing better tyrosinase inhibitory effects than kojic acid, the compounds with triene analogs have better tyrosinase inhibitory effect than the compounds with benzene analogs. Docking simulation suggested the mechanism of compounds by several key residues which had possible hydrogen bonding interactions. The pharmacophore model underlined the features of active compounds, 4,4'-((1E,3E,5E)-hexa-1,3,5-triene-1,6-diyl)diphenol, 5,5'-((1E,3E,5E)-hexa-1,3,5-triene-1,6-diyl)bis(2-methoxy-phenol), and 5,5'-((1E,3E,5E)-hexa-1,3,5-triene-1,6-diyl)dibenzene-1,3-diol among triene derivatives which had several hydrogen bond groups on both terminal rings. The soundness of the docking results and the agreement with the pharmacophores suggest that it can be conveniently exploited to design inhibitors with an improved affinity for tyrosinase.

Receptor scintigraphy with a somatostin analog in oncology

International Nuclear Information System (INIS)

Krenning, E.P.; Bakker, W.H.; Lamberts, S.W.J.

1990-01-01

The use of ortreotide, a somatostin analog, in the scintiscanning of tumors is described. Octreotide labeled with Iodine 124 is intravenous injected, after which the body is scanned with a gamma camera. The technique is relatively cheap and patient friendly. Prospective research is indicated to examine somatostin scintiscanning further. (R.B.). 11 refs.; 4 figs

Troubleshooting analog circuits

CERN Document Server

Pease, Robert A

1991-01-01

Troubleshooting Analog Circuits is a guidebook for solving product or process related problems in analog circuits. The book also provides advice in selecting equipment, preventing problems, and general tips. The coverage of the book includes the philosophy of troubleshooting; the modes of failure of various components; and preventive measures. The text also deals with the active components of analog circuits, including diodes and rectifiers, optically coupled devices, solar cells, and batteries. The book will be of great use to both students and practitioners of electronics engineering. Other

GLP-1 analog raises glucose transport capacity of blood-brain barrier in Alzheimer's disease

DEFF Research Database (Denmark)

Gejl, M.; Brock, B.; Egefjord, L.

2017-01-01

transport capacity (Tmax) with [18F]FDG (FDG) (ClinicalTrials.gov NCT01469351). Results: In both groups, the Tmax estimates declined in proportion to the duration of AD. The GLP-1 analog treatment very significantly (P cerebral cortex as a whole compared...... and degeneration. Hypothesis: The incretin hormone GLP-1 prevents the decline of the cerebral metabolic rate of glucose that signifies cognitive impairment, synaptic dysfunction, and disease evolution in AD, and GLP-1 may directly activate GLUT1 transport in brain capillary endothelium. For this reason, we here...

Characterisation of the BCM1F Analog Opto Hybrids for the CMS experiment

CERN Document Server

Srinidhi, Bheesette

2013-01-01

The BCM1F system in the CMS detector is used for measuring the beam-background and more importantly the real time luminosity and sits 1.8 m from the interaction point (IP5).There has been a proposal to upgrade the BCM1F when it would be installed for the LHC run in 2014. The BCM1F is fitted with Analog Opto-Hybrid(AOH) boards which consists of three Linear Laser Drivers (LLD) and three laser diodes. These AOH boards are affected by radiation and temperature in a long term and short term respectively. This paper studies the characteristics and behavior of these AOH boards.

Characterisation of the BCM1F Analog Opto Hybrids for the CMS experiment

CERN Document Server

Bheesette, Srinidhi

2013-01-01

The BCM1F system used in the CMS is used for measuring the beam-background and more importantly the real time luminosity and sits 1.8 m from the interaction point (IP5).There has been a proposal to upgrade the BCM1F when it would be installed for the LHC run in 2014. The BCM1F is fitted with Analog Opto-Hybrid(AOH) boards which consists of three Linear Laser Drivers (LLD) and three laser diodes. These AOH boards are affected by radiation and temperature in a long term and short term respectively. This paper studies the characteristics and behavior of these AOH boards.

SEMICONDUCTOR INTEGRATED CIRCUITS: A reconfigurable analog baseband circuit for WLAN, WCDMA, and Bluetooth

Science.gov (United States)

Tao, Tong; Baoyong, Chi; Ziqiang, Wang; Ying, Zhang; Hanjun, Jiang; Zhihua, Wang

2010-05-01

A reconfigurable analog baseband circuit for WLAN, WCDMA, and Bluetooth in 0.35 μm CMOS is presented. The circuit consists of two variable gain amplifiers (VGA) in cascade and a Gm-C elliptic low-pass filter (LPF). The filter-order and the cut-off frequency of the LPF can be reconfigured to satisfy the requirements of various applications. In order to achieve the optimum power consumption, the bandwidth of the VGAs can also be dynamically reconfigured and some Gm cells can be cut off in the given application. Simulation results show that the analog baseband circuit consumes 16.8 mW for WLAN, 8.9 mW for WCDMA and only 6.5 mW for Bluetooth, all with a 3 V power supply. The analog baseband circuit could provide -10 to +40 dB variable gain, third-order low pass filtering with 1 MHz cut-off frequency for Bluetooth, fourth-order low pass filtering with 2.2 MHz cut-off frequency for WCDMA, and fifth-order low pass filtering with 11 MHz cut-off frequency for WLAN, respectively.

Somatic drivers of B-ALL in a model of ETV6-RUNX1; Pax5+/− leukemia

International Nuclear Information System (INIS)

Weyden, Louise van der; Giotopoulos, George; Wong, Kim; Rust, Alistair G.; Robles-Espinoza, Carla Daniela; Osaki, Hikari; Huntly, Brian J.; Adams, David J.

2015-01-01

B-cell precursor acute lymphoblastic leukemia (B-ALL) is amongst the leading causes of childhood cancer-related mortality. Its most common chromosomal aberration is the ETV6-RUNX1 fusion gene, with ~25 % of ETV6-RUNX1 patients also carrying PAX5 alterations. We have recreated this mutation background by inter-crossing Etv6-RUNX1 (Etv6 RUNX1-SB ) and Pax5 +/− mice and performed an in vivo analysis to find driver genes using Sleeping Beauty transposon-mediated mutagenesis and also exome sequencing. Combination of Etv6-RUNX1 and Pax5 +/− alleles generated a transplantable B220 + CD19+ B-ALL with a significant disease incidence. RNA-seq analysis showed a gene expression pattern consistent with arrest at the pre-B stage. Analysis of the transposon common insertion sites identified genes involved in B-cell development (Zfp423) and the JAK/STAT signaling pathway (Jak1, Stat5 and Il2rb), while exome sequencing revealed somatic hotspot mutations in Jak1 and Jak3 at residues analogous to those mutated in human leukemias, and also mutation of Trp53. Powerful synergies exists in our model suggesting STAT pathway activation and mutation of Trp53 are potent drivers of B-ALL in the context of Etv6-RUNX1;Pax5 +/− . The online version of this article (doi:10.1186/s12885-015-1586-1) contains supplementary material, which is available to authorized users

Analogical Reasoning in Geometry Education

Science.gov (United States)

Magdas, Ioana

2015-01-01

The analogical reasoning isn't used only in mathematics but also in everyday life. In this article we approach the analogical reasoning in Geometry Education. The novelty of this article is a classification of geometrical analogies by reasoning type and their exemplification. Our classification includes: analogies for understanding and setting a…

Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor

OpenAIRE

Lin, Wenwei; Yang, Lei; Chai, Sergio C.; Lu, Yan; Chen, Taosheng

2015-01-01

Constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) are master regulators of endobiotic and xenobiotic metabolism and disposition. Because CAR is constitutively active in certain cellular contexts, inhibiting CAR might reduce drug-induced hepatotoxicity and resensitize drug-resistant cancer cells to chemotherapeutic drugs. We recently reported a novel CAR inhibitor/inverse agonist CINPA1 (11). Here, we have obtained or designed 54 analogs of CINPA1 and used a ti...

Part 1: Notch-sparing γ-secretase inhibitors: The identification of novel naphthyl and benzofuranyl amide analogs.

Science.gov (United States)

Lu, Dai; Wei, Han-Xun; Zhang, Jing; Gu, Yongli; Osenkowski, Pamela; Ye, Wenjuan; Selkoe, Dennis J; Wolfe, Michael S; Augelli-Szafran, Corinne E

2016-05-01

γ-Secretase is one of two proteases directly involved in the production of the amyloid β-peptide (Aβ), which is pathogenic in Alzheimer's disease. Inhibition of γ-secretase to suppress the production of Aβ should not block processing of one of its alternative substrates, Notch1 receptors, as interference with Notch1 signaling leads to severe toxic effects. In the course of our studies to identify γ-secretase inhibitors with selectivity for APP over Notch, 1 [3-(benzyl(isopropyl)amino)-1-(naphthalen-2-yl)propan-1-one] was found to inhibit γ-secretase-mediated Aβ production without interfering with γ-secretase-mediated Notch processing in purified enzyme assays. As 1 is chemically unstable, efforts to increase the stability of this compound led to the identification of 2 [naphthalene-2-carboxylic acid benzyl-isopropyl-amide] which showed similar biological activity to compound 1. Synthesis and evaluation of a series of amide analogs resulted in benzofuranyl amide analogs that showed promising Notch-sparing γ-secretase inhibitory effects. This class of compounds may serve as a novel lead series for further study in the development of γ-secretase inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Young Solar Analogs Project

Science.gov (United States)

Gray, Richard O.; Saken, J. M.; Corbally, C. J.; Seeds, M. F.; Morrison, S. S.

2012-01-01

We are carrying out a long-term project of measuring chromospheric activity and brightness variations in 31 young solar analogs (YSAs) using the Dark Sky Observatory (DSO -- Appalachian State University) 32-inch telescope and the G/M spectrograph. These YSAs are solar-type (spectral types F8 - K2) stars with ages ranging from 0.3 - 1.5 Gyr. The goal of this project is to gain better understanding of the magnetic activity of the early Sun, and especially how that activity may have impacted the development of life on the Earth. This project will also yield insights into the space environments experienced by young Earth analogs. We are currently in our 5th year of obtaining Ca II K & H chromospheric flux measurements, and are beginning to see signs of long-term activity cycles in a number of our stars. In addition, rotational modulation of the chromospheric fluxes is detectable in our data, and we have determined rotational periods for many of our stars. Short timescale increases in the K & H fluxes have been observed in a number of our stars; these events may be related to stellar flares. VATTSpec, a new moderate-resolution spectrograph on the 1.8-m Vatican Telescope in Arizona, has recently become involved with the project. This spectrograph will increase our ability to detect short-term changes in stellar activity on timescales of hours to minutes. We have been monitoring the program stars for one year in a multi-band photometric system consisting of Stromgren-v, and Johnson B, V, and R filters. We will soon add a narrow-band H-alpha filter to the system. Photometry is being carried out with a small piggy-back telescope on the 32-inch, but a robotic photometric telescope is currently being installed at DSO for this purpose. This project is supported by the National Science Foundation.

Abnormal Thiamine-Dependent Processes in Alzheimer’s Disease. Lessons from Diabetes

Science.gov (United States)

Gibson, Gary E.; Hirsch, Joseph A.; Cirio, Rosanna T.; Jordan, Barry D.; Fonzetti, Pasquale; Elder, Jessica

2013-01-01

Reduced glucose metabolism is an invariant feature of Alzheimer’s Disease (AD) and an outstanding biomarker of disease progression. Glucose metabolism may be an attractive therapeutic target, whether the decline initiates AD pathophysiology or is a critical component of a cascade. The cause of cerebral regional glucose hypometabolism remains unclear. Thiamine-dependent processes are critical in glucose metabolism and are diminished in brains of AD patients at autopsy. Further, the reductions in thiamine-dependent processes are highly correlated to the decline in clinical dementia rating scales. In animal models, thiamine deficiency exacerbates plaque formation, promotes phosphorylation of tau and impairs memory. In contrast, treatment of mouse models of AD with the thiamine derivative benfotiamine diminishes plaques, decreases phosphorylation of tau and reverses memory deficits. Diabetes predisposes to AD, which suggests they may share some common mechanisms. Benfotiamine diminishes peripheral neuropathy in diabetic humans and animals. In diabetes, benfotiamine induces key thiamine-dependent enzymes of the pentose shunt to reduce accumulation of toxic metabolites including advanced glycation end products (AGE). Related mechanisms may lead to reversal of plaque formation by benfotiamine in animals. If so, the use of benfotiamine could provide a safe intervention to reverse biological and clinical processes of AD progression. PMID:22982063

Analog and mixed-signal electronics

CERN Document Server

Stephan, Karl

2015-01-01

A practical guide to analog and mixed-signal electronics, with an emphasis on design problems and applications This book provides an in-depth coverage of essential analog and mixed-signal topics such as power amplifiers, active filters, noise and dynamic range, analog-to-digital and digital-to-analog conversion techniques, phase-locked loops, and switching power supplies. Readers will learn the basics of linear systems, types of nonlinearities and their effects, op-amp circuits, the high-gain analog filter-amplifier, and signal generation. The author uses system design examples to motivate

Organization of fluorescent cholesterol analogs in lipid bilayers - lessons from cyclodextrin extraction.

Science.gov (United States)

Milles, Sigrid; Meyer, Thomas; Scheidt, Holger A; Schwarzer, Roland; Thomas, Lars; Marek, Magdalena; Szente, Lajos; Bittman, Robert; Herrmann, Andreas; Günther Pomorski, Thomas; Huster, Daniel; Müller, Peter

2013-08-01

To characterize the structure and dynamics of cholesterol in membranes, fluorescent analogs of the native molecule have widely been employed. The cholesterol content in membranes is in general manipulated by using water-soluble cyclodextrins. Since the interactions between cyclodextrins and fluorescent-labeled cholesterol have not been investigated in detail so far, we have compared the cyclodextrin-mediated membrane extraction of three different fluorescent cholesterol analogs (one bearing a NBD and two bearing BODIPY moieties). Extraction of these analogs was followed by measuring the Förster resonance energy transfer between a rhodamine moiety linked to phosphatidylethanolamine and the labeled cholesterol. The extraction kinetics revealed that the analogs are differently extracted from membranes. We examined the orientation of the analogs within the membrane and their influence on lipid condensation using NMR and EPR spectroscopies. Our data indicate that the extraction of fluorescent sterols from membranes is determined by several parameters, including their impact on lipid order, their hydrophobicity, their intermolecular interactions with surrounding lipids, their orientation within the bilayer, and their affinity with the exogenous acceptor. Copyright © 2013 Elsevier B.V. All rights reserved.

Meat analog: a review.

Science.gov (United States)

Malav, O P; Talukder, S; Gokulakrishnan, P; Chand, S

2015-01-01

The health-conscious consumers are in search of nutritious and convenient food item which can be best suited in their busy life. The vegetarianism is the key for the search of such food which resembles the meat in respect of nutrition and sensory characters, but not of animal origin and contains vegetable or its modified form, this is the point when meat analog evolved out and gets shape. The consumers gets full satisfaction by consumption of meat analog due to its typical meaty texture, appearance and the flavor which are being imparted during the skilled production of meat analog. The supplement of protein in vegetarian diet through meat alike food can be fulfilled by incorporating protein-rich vegetative food grade materials in meat analog and by adopting proper technological process which can promote the proper fabrication of meat analog with acceptable meat like texture, appearance, flavor, etc. The easily available vegetables, cereals, and pulses in India have great advantages and prospects to be used in food products and it can improve the nutritional and functional characters of the food items. The various form and functional characters of food items are available world over and attracts the meat technologists and the food processors to bring some innovativeness in meat analog and its presentation and marketability so that the acceptability of meat analog can be overgrown by the consumers.

Digital and analog communication systems

Science.gov (United States)

Shanmugam, K. S.

1979-01-01

The book presents an introductory treatment of digital and analog communication systems with emphasis on digital systems. Attention is given to the following topics: systems and signal analysis, random signal theory, information and channel capacity, baseband data transmission, analog signal transmission, noise in analog communication systems, digital carrier modulation schemes, error control coding, and the digital transmission of analog signals.

Reactions of 1,3-dioxacycloalkanes and their 2-arsena, 2-bora, 2-germa, 2-sila, and 2-thia analogs with nitriles

International Nuclear Information System (INIS)

Kuznetsov, V.V.

2005-01-01

New reactions of five-, six-, and seven-membered 1,3-dioxacycloalkanes and their 2-arsena, 2-bora, 2-germa, 2-sila, and 2-thia analogs with nitriles giving rise to 1,3-oxazacycloalkanes and then to amino alcohols are surveyed. The reactions under consideration, including the reactions of boronic and boric acid esters with nitriles, supplement the known chemical transformations of 1,3-dioxacycloalkanes and their 2-hetero atomic analogs and provide a wide scope for the synthesis of diverse functional derivatives on their basis [ru

Vitamin B1

Science.gov (United States)

... Prize Alfred Nobel's Life and Work Teachers' Questionnaire Vitamin B1 - About The Chicken Farm educational game and ... the game window. Reading: "Christian Eijkman, Beriberi and Vitamin B1" - Who was Eijkman and why did he ...

Evaluation of a curcumin analog as an anti-cancer agent inducing ER stress-mediated apoptosis in non-small cell lung cancer cells

International Nuclear Information System (INIS)

Liu, Zhiguo; Wang, Yi; Sun, Yusheng; Ren, Luqing; Huang, Yi; Cai, Yuepiao; Weng, Qiaoyou; Shen, Xueqian; Li, Xiaokun; Liang, Guang

2013-01-01

Recent advances have highlighted the importance of the endoplasmic reticulum (ER) in cell death processes. Pharmacological interventions that effectively enhance tumor cell death through activating ER stress have attracted a great deal of attention for anti-cancer therapy. A bio-evaluation on 113 curcumin analogs against four cancer cell lines was performed through MTT assay. Furthermore, real time cell assay and flow cytometer were used to evaluate the apoptotic induction of (1E,4E)-1,5-bis(5-bromo-2-ethoxyphenyl)penta-1,4-dien-3-one (B82). Western blot, RT-qPCR, and siRNA were then utilized to confirm whether B82-induced apoptosis is mediated through activating ER stress pathway. Finally, the in vivo anti-tumor effect of B82 was evaluated. B82 exhibited strong anti-tumor activity in non-small cell lung cancer (NSCLC) H460 cells. Treatment with B82 significantly induced apoptosis in H460 cells in vitro and inhibited H460 tumor growth in vivo. Further studies demonstrated that the B82-induced apoptosis is mediated by activating ER stress both in vitro and in vivo. A new monocarbonyl analog of curcumin, B82, exhibited anti-tumor effects on H460 cells via an ER stress-mediated mechanism. B82 could be further explored as a potential anticancer agent for the treatment of NSCLC

Comparative Pharmacokinetic Analysis of Thiamine and Its Phosphorylated Metabolites Administered as Multivitamin Preparations.

Science.gov (United States)

Park, Wan-Su; Lee, Jongtae; Hong, Taegon; Park, Gabjin; Youn, Sunil; Seo, Youngwhan; Lee, Sanghun; Han, Seunghoon

2016-10-01

Fursultiamine and benfotiamine are lipophilic thiamine derivatives used as oral sources of thiamine. Although there are many publications on the pharmacokinetic (PK) properties of thiamine-containing products, no direct comparisons between these agents . We aimed to compare the PK profiles of these lipophilic thiamine derivatives and to compare the extent of the increase in bioavailability to that of naïve thiamine. Two randomized, single-dose, 2-way crossover, full PK studies were conducted in healthy Korean male subjects (n = 24 per group). Among the test compounds, fursultiamine was compared with benfotiamine (reference A in study A) and thiamine nitrate (reference B in study B). All formulations were multivitamin preparations containing the test or reference formulation as the major thiamine source. In study A, the plasma and hemolysate concentrations of thiamine and its metabolites were measured, while only the plasma thiamine concentration was assayed in study B. The systemic thiamine exposure of the test compound was slightly greater than that of reference A, based on the geometric mean ratio (%) of the AUC last value for plasma (116.6%) and hemolysate (137.5%). The thiamine diphosphate (TDP) distribution between plasma and hemolysate showed clear differences according to the formulations, in that more TDP was present in the hemolysate when thiamine was given as the test formulation. The AUC last value of plasma thiamine showed a >300% increase when thiamine was given as the test formulation in study B. The summed total exposure to thiamine (thiamine + TDP in both plasma and hemolysate) observed as a point estimate after the administration of fursultiamine was slightly greater than that with benfotiamine; however, the 90% CI was within the conventional bioequivalence range. These findings support clear benefits of lipophilic thiamine derivatives in the absorption of thiamine in healthy volunteers. Clinical Research Information Service identifiers: KCT

Children's Development of Analogical Reasoning: Insights from Scene Analogy Problems

Science.gov (United States)

Richland, Lindsey E.; Morrison, Robert G.; Holyoak, Keith J.

2006-01-01

We explored how relational complexity and featural distraction, as varied in scene analogy problems, affect children's analogical reasoning performance. Results with 3- and 4-year-olds, 6- and 7-year-olds, 9- to 11-year-olds, and 13- and 14-year-olds indicate that when children can identify the critical structural relations in a scene analogy…

Observations and Measurements of Orbitally Excited L=1 B Mesons at the D0 Experiment

Energy Technology Data Exchange (ETDEWEB)

Williams, Mark Richard James [Lancaster Univ. (United Kingdom)

2008-09-01

This thesis describes investigations of the first set of orbitally excited (L = 1) states for both the B_d⁰ and B_s⁰ meson systems (B**_d and B**_s). The data sample corresponds to 1.35 fb^-1 of integrated luminosity, collected in 2002-2006 by the D0 detector, during the Run IIa operation of the Tevatron p$\\bar{p}$ colliding beam accelerator. The B**_d states are fully reconstructed in decays to B^(*)+ π^-, with B^(*)+ → γ J/ΨK⁺, J/Ψ → μ⁺μ^-, yielding 662 ± 91 events, and providing the first strong evidence for the resolution of two narrow resonances, B₁ and B*₂. The masses are extracted from a binned Χ² fit to the invariant mass distribution, giving M(B₁) = 5720.7 ± 2.4(stat.) ± 1.3(syst.) ± 0.5 (PDG) MeV/c² and M(B*₂) = 5746.9 ± 2.4(stat.) ± 1.0(syst.) ± 0.5(PDG) MeV/c². The production rate of narrow B**_d → Bπ resonances relative to the B⁺ meson is determined to be [13.9 ± 1.9(stat.) ± 3.2(syst.)]%. The same B⁺ sample is also used to reconstruct the analogous states in the B_s⁰ system, in decays B**_s → B^(*)+ K^-. A single resonance in the invariant mass distribution is found with a statistical significance of 5σ, interpreted as the B*_s2 state. The mass is determined to be M(B*_s2) = 5839.6 ± 1.1(stat.) ± 0.4(syst.) ± 0.5(PDG) MeV/c ², and the production rate of B*_s2 → BK resonances is measured to be a fraction (2.14 ± 0.43 ± 0.24)% of the corresponding rate for B⁺ mesons. Alternative fitting hypotheses give inconclusive evidence for the presence of the lighter B_s1 meson.

Suppression of phospho-p85α-GTP-Rac1 lipid raft interaction by bichalcone analog attenuates cancer cell invasion.

Science.gov (United States)

Lu, Hui-Li; Chen, Shih-Shun; Hsu, Wen-Tung; Lu, Yao-Cheng; Lee, Chuan-Chun; Wu, Tian-Shung; Lin, Meng-Liang

2016-12-01

The p85α subunit of phosphatidylinositol 3-kinase (PI3K) acts as a key regulator of cell proliferation and motility, which mediates signals that confer chemoresistance to many human cancer cells. Using small interfering RNAs against matrix metalloproteinase-2 (MMP-2) and the MMP-2 promoter-driven luciferase assay, we showed that the new synthetic bichalcone analog TSWU-CD4 inhibits the invasion of human cancer cells by down-regulating MMP-2 expression. Treatment with TSWU-CD4 inhibited MMP-2 expression and cell invasion, which were restored by ectopic wild type (wt) p85α or a constitutively active form of MAPK kinase 3 (CA MKK3), CA MKK6, or CA p38α mitogen-activated protein kinase (MAPK). The attenuated formation of lipid raft-associated phospho (p)-p85α-GTP-Rac1 complexes, protein kinase B (Akt) Ser 473 phosphorylation, and cell invasion by TSWU-CD4 was reversed by overexpression of wt p85α or the p85α Brc-homology (BH) domain. The ectopic expression of CA Rac1 L61 (but not wt Rac1) could overcome the suppression of Ser 473 phosphorylation, lipid raft association of Akt, the interaction between GTP-bound Rac1 and p85α in lipid rafts, and cell invasion by TSWU-CD4. The involvement of Akt activity in the functions of NF-κB-mediated MMP-2 was further confirmed through the attenuation of Akt phosphorylation signaling using the Akt-specific inhibitor MK-2206 and ectopic expression of NF-κB p65. Collectively, the inhibitory effect of TSWU-CD4 on cancer cell invasion was likely to suppress the p-p85α-GTP-Rac1 interaction in lipid rafts by targeting the p85α BH domain, which resulted in the suppression of MMP-2 expression via the PI3K-Akt-mediated ERK-MKK3/MKK6-p38 MAPK-NF-κB signaling pathway. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

ESD analog circuits and design

CERN Document Server

Voldman, Steven H

2014-01-01

A comprehensive and in-depth review of analog circuit layout, schematic architecture, device, power network and ESD design This book will provide a balanced overview of analog circuit design layout, analog circuit schematic development, architecture of chips, and ESD design.  It will start at an introductory level and will bring the reader right up to the state-of-the-art. Two critical design aspects for analog and power integrated circuits are combined. The first design aspect covers analog circuit design techniques to achieve the desired circuit performance. The second and main aspect pres

Agonist properties of a stable hexapeptide analog of neurotensin, N alpha MeArg-Lys-Pro-Trp-tLeu-Leu (NT1).

Science.gov (United States)

Akunne, H C; Demattos, S B; Whetzel, S Z; Wustrow, D J; Davis, D M; Wise, L D; Cody, W L; Pugsley, T A; Heffner, T G

1995-04-18

The major signal transduction pathway for neurotensin (NT) receptors is the G-protein-dependent stimulation of phospholipase C, leading to the mobilization of intracellular free Ca2+ ([Ca2+]i) and the stimulation of cyclic GMP. We investigated the functional actions of an analog of NT(8-13), N alpha MeArg-Lys-Pro-Trp-tLeu-Leu (NT1), and other NT related analogs by quantitative measurement of the cytosolic free Ca2+ concentration in HT-29 (human colonic adenocarcinoma) cells using the Ca(2+)-sensitive dye fura-2/AM and by effects on cyclic GMP levels in rat cerebellar slices. The NT receptor binding affinities for these analogs to HT-29 cell membranes and newborn (10-day-old) mouse brain membranes were also investigated. Data obtained from HT-29 cell and mouse brain membrane preparations showed saturable single high-affinity sites and binding densities (Bmax) of 130.2 and 87.5 fmol/mg protein, respectively. The respective KD values were 0.47 and 0.39 nM, and the Hill coefficients were 0.99 and 0.92. The low-affinity levocabastine-sensitive site was not present (K1 > 10,000) in either membrane preparation. Although the correlation of binding between HT-29 cell membranes and mouse brain membranes was quite significant (r = 0.92), some of the reference agents had lower binding affinities in the HT-29 cell membranes. The metabolically stable compound NT1 plus other NT analogs and related peptides [NT, NT(8-13), xenopsin, neuromedin N, NT(9-13), kinetensin and (D-Trp11)-NT] increased intracellular Ca2+ levels in HT-29 cells, indicating NT receptor agonist properties. The effect of NT1 in mobilizing [Ca2+]i blocked by SR 48692, a non-peptide NT antagonist. Receptor binding affinities of NT analogs to HT-29 cell membranes were positively correlated with potencies for mobilizing intracellular calcium in the same cells. In addition, NT1 increased cyclic GMP levels in rat cerebellar slices, confirming the latter findings of its NT agonist action. These results substantiate

Hydraulic Capacitor Analogy

Science.gov (United States)

Baser, Mustafa

2007-01-01

Students have difficulties in physics because of the abstract nature of concepts and principles. One of the effective methods for overcoming students' difficulties is the use of analogies to visualize abstract concepts to promote conceptual understanding. According to Iding, analogies are consistent with the tenets of constructivist learning…

Analog fourier transform channelizer and OFDM receiver

OpenAIRE

2007-01-01

An OFDM receiver having an analog multiplier based I-Q channelizing filter, samples and holds consecutive analog I-Q samples of an I-Q baseband, the I-Q basebands having OFDM sub-channels. A lattice of analog I-Q multipliers and analog I-Q summers concurrently receives the held analog I-Q samples, performs analog I-Q multiplications and analog I-Q additions to concurrently generate a plurality of analog I-Q output signals, representing an N-point discrete Fourier transform of the held analog ...

26 CFR 1.267(b)-1 - Relationships.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 3 2010-04-01 2010-04-01 false Relationships. 1.267(b)-1 Section 1.267(b)-1...) INCOME TAXES Items Not Deductible § 1.267(b)-1 Relationships. (a) In general. (1) The persons referred to... partnership separately. Therefore, if the other person and a partner are within any one of the relationships...

B-L mediated SUSY breaking with radiative B-L symmetry breaking

International Nuclear Information System (INIS)

Kikuchi, Tatsuru; Kubo, Takayuki

2008-01-01

We explore a mechanism of radiative B-L symmetry breaking in analogous to the radiative electroweak symmetry breaking. The breaking scale of B-L symmetry is related to the neutrino masses through the see-saw mechanism. Once we incorporate the U(1) B-L gauge symmetry in SUSY models, the U(1) B-L gaugino, Z-tilde B-L appears, and it can mediate the SUSY breaking (Z-prime mediated SUSY breaking) at around the scale of 10 6 GeV. Then we find a links between the neutrino mass (more precisly the see-saw or B-L scale of order 10 6 GeV) and the Z-prime mediated SUSY breaking scale. It is also very interesting that the gluino at the weak scale becomes relatively light, and almost compressed mass spectra for the gaugino sector can be realized in this scenario, which is very interesting in scope of the LHC.

Synthesis and Anti-HBV Activity of Novel 3′-N-phenylsulfonyl Docetaxel Analogs

Directory of Open Access Journals (Sweden)

Xun Sun

2013-08-01

Full Text Available Nine new 3′-N-phenylsulfonyl docetaxel analogs were synthesized in good yields from the key intermediate N-phenylsulfonyl oxazolidine via a six-step route. These analogs were tested for anti-hepatitis B virus (HBV activity in vitro. Compounds 3e, 3g and 3j showed more potent inhibitory activity against HBeAg secretion than the positive control lamivudine. Further extensive SAR and mechanistic studies will be reported in due course.

5'Azido-N-1-napthylphthalamic acid, a photolabile analog of N-1-naphthylphthalamic acid

International Nuclear Information System (INIS)

Voet, J.G.; Howley, K.S.; Shumsky, J.S.

1987-01-01

A photolabile analog of N-1-naphthylphthalamic acid (NPA), 5'-azido-N-1-naphthylphthalamic acid (Az-NPA), has been synthesized and characterized. This potential photoaffinity label for the plasma membrane NPA binding protein competes with [ 3 H]NPA for binding sites on Curcurbita pepo L. (zucchini) hypocotyl cell membranes with K/sub 0.5/ = 2.8 x 10 -7 molar. The K/sub 0.5/ for NPA under these conditions is 2 x 10 -8 molar, indicating that the affinity of Az-NPA for the membranes is only 14-fold lower than NPA. While the binding of Az-NPA to NPA binding sites is reversible in the dark, exposure of the Az-NPA treated membranes to light results in a 30% loss in [ 3 H]NPA binding ability. Pretreatment of the membranes with NPA protects the membranes against photodestruction of [ 3 H]NPA binding sites by Az-NPA supporting the conclusion that Az-NPA destroys these sites by specific covalent attachment

Enantiospecific Synthesis of Trisubstituted Butyrolactone Natural Products and Their Analogs.

Science.gov (United States)

Sibi, Mukund P.; Lu, Jianliang; Talbacka, Chelsy L.

1996-11-01

A general methodology for the synthesis of highly substituted butyrolactones in enantiomerically pure form has been developed. The application of this process in a highly efficient synthesis of lactone natural products blastmycinone (1), NFX-2 (2), antimycinone (3), and NFX-4 (4) and two lipid metabolites (5, 6) are described. Additionally, the total synthesis of 5-epi-blastmycinone (22), 5-epi-NFX-2 (21b), 5-epi-NFX-4 (21c), and lipid metabolite analogs (19, 20) are also described. The overall yields for the target molecules are the highest reported so far in the literature.

An Experimentation Platform for On-Chip Integration of Analog Neural Networks: A Pathway to Trusted and Robust Analog/RF ICs.

Science.gov (United States)

Maliuk, Dzmitry; Makris, Yiorgos

2015-08-01

We discuss the design of an experimentation platform intended for prototyping low-cost analog neural networks for on-chip integration with analog/RF circuits. The objective of such integration is to support various tasks, such as self-test, self-tuning, and trust/aging monitoring, which require classification of analog measurements obtained from on-chip sensors. Particular emphasis is given to cost-efficient implementation reflected in: 1) low energy and area budgets of circuits dedicated to neural networks; 2) robust learning in presence of analog inaccuracies; and 3) long-term retention of learned functionality. Our chip consists of a reconfigurable array of synapses and neurons operating below threshold and featuring sub-μW power consumption. The synapse circuits employ dual-mode weight storage: 1) a dynamic mode, for fast bidirectional weight updates during training and 2) a nonvolatile mode, for permanent storage of learned functionality. We discuss a robust learning strategy, and we evaluate the system performance on several benchmark problems, such as the XOR2-6 and two-spirals classification tasks.

Source selection for analogical reasoning an empirical approach

Energy Technology Data Exchange (ETDEWEB)

Stubblefield, W.A. [Sandia National Labs., Albuquerque, NM (United States); Luger, G.F. [Univ. of New Mexico, Albuquerque, NM (United States)

1996-12-31

The effectiveness of an analogical reasoner depends upon its ability to select a relevant analogical source. In many problem domains, however, too little is known about target problems to support effective source selection. This paper describes the design and evaluation of SCAVENGER, an analogical reasoner that applies two techniques to this problem: (1) An assumption-based approach to matching that allows properties of candidate sources to match unknown target properties in the absence of evidence to the contrary. (2) The use of empirical learning to improve memory organization based on problem solving experience.

Polycyclic phloroglucinols as PTP1B inhibitors from Hypericum longistylum: Structures, PTP1B inhibitory activities, and interactions with PTP1B.

Science.gov (United States)

Cao, Xiangrong; Yang, Xueyuan; Wang, Peixia; Liang, Yue; Liu, Feng; Tuerhong, Muhetaer; Jin, Da-Qing; Xu, Jing; Lee, Dongho; Ohizumi, Yasushi; Guo, Yuanqiang

2017-12-01

Protein tyrosine phosphatase 1B (PTP1B) has been regarded asa target for the research and development of new drugs to treat type II diabetes and PTP1B inhibitors are potential lead compounds for this type of new drugs. A phytochemical investigation to obtain new PTP1B inhibitors resulted in the isolation of four new phloroglucinols, longistyliones A-D (1-4) from the aerial parts of Hypericum longistylum. The structures of 1-4 were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analysis, and the absolute configurations of these compounds were established by comparing their experimental electronic circular dichroism (ECD) spectra with those calculated by the time-dependent density functional theory method. Compounds 1-4 possess a rare polycyclic phloroglucinol skeleton. The following biological evaluation revealed that all of the compounds showed PTP1B inhibitory effects. The further molecular docking studies indicated the strong interactions between these bioactive compounds with the PTP1B protein, which revealed the possible mechanism of PTP1B inhibition of bioactive compounds. All of the results implied that these compounds are potentially useful for the treatment of type II diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

Further evaluation of the tropane analogs of haloperidol.

Science.gov (United States)

Sampson, Dinithia; Bricker, Barbara; Zhu, Xue Y; Peprah, Kwakye; Lamango, Nazarius S; Setola, Vincent; Roth, Bryan L; Ablordeppey, Seth Y

2014-09-01

Previous work from our labs has indicated that a tropane analog of haloperidol with potent D2 binding but designed to avoid the formation of MPP(+)-like metabolites, such as 4-(4-chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridin-1-ium (BCPP(+)) still produced catalepsy, suggesting a strong role for the D2 receptor in the production of catalepsy in rats, and hence EPS in humans. This study tested the hypothesis that further modifications of the tropane analog to produce compounds with less potent binding to the D2 receptor than haloperidol, would produce less catalepsy. These tests have now revealed that while haloperidol produced maximum catalepsy, these compounds produced moderate to low levels of catalepsy. Compound 9, with the least binding affinity to the D2R, produced the least catalepsy and highest Minimum Adverse Effective Dose (MAED) of the analogs tested regardless of their affinities at other receptors including the 5-HT1AR. These observations support the hypothesis that moderation of the D2 binding of the tropane analogs could reduce catalepsy potential in rats and consequently EPS in man. Published by Elsevier Ltd.

Synthesis, biological evaluation, and live cell imaging of novel fluorescent duocarmycin analogs.

Science.gov (United States)

Tietze, Lutz F; Behrendt, Frank; Pestel, Galina F; Schuberth, Ingrid; Mitkovski, Mišo

2012-11-01

For a better understanding of the mode of action of duocarmycin and its analogs, the novel fluorescent duocarmycin derivatives 13-15 and 17b-19b were synthesized, and their bioactivity as well as their cellular uptake investigated using confocal laser scanning microscopy (CLSM) in live-cell imaging experiments. Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich.

Inductive, Analogical, and Communicative Generalization

Directory of Open Access Journals (Sweden)

Adri Smaling

2003-03-01

Full Text Available Three forms of inductive generalization - statistical generalization, variation-based generalization and theory-carried generalization - are insufficient concerning case-to-case generalization, which is a form of analogical generalization. The quality of case-to-case generalization needs to be reinforced by setting up explicit analogical argumentation. To evaluate analogical argumentation six criteria are discussed. Good analogical reasoning is an indispensable support to forms of communicative generalization - receptive and responsive (participative generalization — as well as exemplary generalization.

Resolvin E1 analog RX-10045 0.1% reduces corneal stromal haze in rabbits when applied topically after PRK.

Science.gov (United States)

Torricelli, Andre A M; Santhanam, Abirami; Agrawal, Vandana; Wilson, Steven E

2014-01-01

To perform a masked study to determine whether resolvin E1 (RvE1), a lipid-derived immunomodulator, could regulate the development of corneal haze and opacity-related myofibroblasts after opacity-generating high correction photorefractive keratectomy (PRK) in rabbits. Three groups of eight rabbits each were included in the study. Nine diopter (D) PRK for myopia was performed in each test cornea, and the eyes were treated with 30 µl of topical solution every 4 h (six times a day) for 5 days starting immediately after PRK. Group 1 was treated with 0.1% RX-10045, a prodrug of an RvE1 analog; group 2 was treated with 0.01% RX-10045; and group 3 was treated with vehicle control solution. At 1 month after PRK, haze was graded at the slit-lamp by a masked observer. Immunohistochemistry for α-smooth muscle actin (SMA) was performed on the central cornea of each test eye to determine the anterior stromal myofibroblast density. Corneal opacity was significantly lower in the 0.1% RX-10045 group, but not the 0.01% RX-10045 group, compared to the vehicle control group (p=0.029), at 1 month after -9.0D PRK. At 1 month after -9.0D PRK, SMA+ myofibroblast densities in the anterior stroma were not statistically significantly different among the three groups, although a trend toward lower myofibroblast generation was noted in the 0.1% RX-10045 group. Topical 0.1% RX-10045, a prodrug of an RvE1 analog, reduces corneal opacity after haze-generating PRK in rabbits. Further studies are needed to determine the precise points at which RvE1 decreases corneal opacity after injury.

On Lovelock analogs of the Riemann tensor

Science.gov (United States)

Camanho, Xián O.; Dadhich, Naresh

2016-03-01

It is possible to define an analog of the Riemann tensor for Nth order Lovelock gravity, its characterizing property being that the trace of its Bianchi derivative yields the corresponding analog of the Einstein tensor. Interestingly there exist two parallel but distinct such analogs and the main purpose of this note is to reconcile both formulations. In addition we will introduce a simple tensor identity and use it to show that any pure Lovelock vacuum in odd d=2N+1 dimensions is Lovelock flat, i.e. any vacuum solution of the theory has vanishing Lovelock-Riemann tensor. Further, in the presence of cosmological constant it is the Lovelock-Weyl tensor that vanishes.

Abnormal thiamine-dependent processes in Alzheimer's Disease. Lessons from diabetes.

Science.gov (United States)

Gibson, Gary E; Hirsch, Joseph A; Cirio, Rosanna T; Jordan, Barry D; Fonzetti, Pasquale; Elder, Jessica

2013-07-01

Reduced glucose metabolism is an invariant feature of Alzheimer's Disease (AD) and an outstanding biomarker of disease progression. Glucose metabolism may be an attractive therapeutic target, whether the decline initiates AD pathophysiology or is a critical component of a cascade. The cause of cerebral regional glucose hypometabolism remains unclear. Thiamine-dependent processes are critical in glucose metabolism and are diminished in brains of AD patients at autopsy. Further, the reductions in thiamine-dependent processes are highly correlated to the decline in clinical dementia rating scales. In animal models, thiamine deficiency exacerbates plaque formation, promotes phosphorylation of tau and impairs memory. In contrast, treatment of mouse models of AD with the thiamine derivative benfotiamine diminishes plaques, decreases phosphorylation of tau and reverses memory deficits. Diabetes predisposes to AD, which suggests they may share some common mechanisms. Benfotiamine diminishes peripheral neuropathy in diabetic humans and animals. In diabetes, benfotiamine induces key thiamine-dependent enzymes of the pentose shunt to reduce accumulation of toxic metabolites including advanced glycation end products (AGE). Related mechanisms may lead to reversal of plaque formation by benfotiamine in animals. If so, the use of benfotiamine could provide a safe intervention to reverse biological and clinical processes of AD progression. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'. Copyright © 2012 Elsevier Inc. All rights reserved.

26 CFR 1.367(b)-1 - Other transfers.

Science.gov (United States)

2010-04-01

... its successor in interest) that the shareholder is making the election described in § 1.367(b)-3(c)(3... paragraph (c)(2)— (i) A shareholder described in § 1.367(b)-3(b)(1) that realizes income in a transaction described in § 1.367(b)-3(a); (ii) A shareholder that makes the election described in § 1.367(b)-3(c)(3...

10 K gate I(2)L and 1 K component analog compatible bipolar VLSI technology - HIT-2

Science.gov (United States)

Washio, K.; Watanabe, T.; Okabe, T.; Horie, N.

1985-02-01

An advanced analog/digital bipolar VLSI technology that combines on the same chip 2-ns 10 K I(2)L gates with 1 K analog devices is proposed. The new technology, called high-density integration technology-2, is based on a new structure concept that consists of three major techniques: shallow grooved-isolation, I(2)L active layer etching, and I(2)L current gain increase. I(2)L circuits with 80-MHz maximum toggle frequency have developed compatibly with n-p-n transistors having a BV(CE0) of more than 10 V and an f(T) of 5 GHz, and lateral p-n-p transistors having an f(T) of 150 MHz.

Design and evaluation of novel interferon lambda analogs with enhanced antiviral activity and improved drug attributes

Directory of Open Access Journals (Sweden)

Yu D

2016-01-01

expression of the antiviral genes MxA and OAS and two of them, analog-6 and -7, displayed an unexpected high potency that is higher than that of type I IFN (IFN-α2a in activating the IFN-stimulated response element (ISRE-luciferase reporter. Importantly, both analog-6 and -7 effectively inhibited replication of hepatitis C virus in Huh-7.5.1 cells, with an IC50 that is comparable to that of IFN-α2a; and consistent with the roles of IFN-λ in mucosal epithelia, both analogs potently inhibited replication of H3N2 influenza A virus in A549 cells. Together, these studies identified two IFN-λ analogs as candidates to be developed as novel antiviral biologics. Keywords: type III interferon, IFN-λ, IL-29, IL-28B, analog, antiviral

Analogical Reasoning and Computer Programming.

Science.gov (United States)

Clement, Catherine A.; And Others

1986-01-01

A study of correlations between analogical reasoning and Logo programming mastery among female high school students related the results of pretests of analogical reasoning to posttests of programming mastery. A significant correlation was found between analogical reasoning and the ability to write subprocedures for use in several different…

SSERVI Analog Regolith Simulant Testbed Facility

Science.gov (United States)

Minafra, J.; Schmidt, G. K.

2016-12-01

SSERVI's goals include supporting planetary researchers within NASA, other government agencies; private sector and hardware developers; competitors in focused prize design competitions; and academic sector researchers. The SSERVI Analog Regolith Simulant Testbed provides opportunities for research scientists and engineers to study the effects of regolith analog testbed research in the planetary exploration field. This capability is essential to help to understand the basic effects of continued long-term exposure to a simulated analog test environment. The current facility houses approximately eight tons of JSC-1A lunar regolith simulant in a test bin consisting of a 4 meter by 4 meter area. SSERVI provides a bridge between several groups, joining together researchers from: 1) scientific and exploration communities, 2) multiple disciplines across a wide range of planetary sciences, and 3) domestic and international communities and partnerships. This testbed provides a means of consolidating the tasks of acquisition, storage and safety mitigation in handling large quantities of regolith simulant Facility hardware and environment testing scenarios include, but are not limited to the following; Lunar surface mobility, Dust exposure and mitigation, Regolith handling and excavation, Solar-like illumination, Lunar surface compaction profile, Lofted dust, Mechanical properties of lunar regolith, and Surface features (i.e. grades and rocks) Numerous benefits vary from easy access to a controlled analog regolith simulant testbed, and planetary exploration activities at NASA Research Park, to academia and expanded commercial opportunities in California's Silicon Valley, as well as public outreach and education opportunities.

4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol}, 1 a novel resveratrol analog, differentially regulates estrogen receptors α and β in breast cancer cells

Energy Technology Data Exchange (ETDEWEB)

Ronghe, Amruta; Chatterjee, Anwesha [Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108 (United States); Singh, Bhupendra [Department of Genetics, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Dandawate, Prasad [ISTRA, Department of Chemistry, Abeda Inamdar Senior College, University of Pune (India); Abdalla, Fatma; Bhat, Nimee K. [Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108 (United States); Padhye, Subhash [ISTRA, Department of Chemistry, Abeda Inamdar Senior College, University of Pune (India); Bhat, Hari K., E-mail: bhath@umkc.edu [Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108 (United States)

2016-06-15

Breast cancer is a public health concern worldwide. Prolonged exposure to estrogens has been implicated in the development of breast neoplasms. Epidemiologic and experimental evidence suggest a chemopreventive role of phytoestrogens in breast cancers. Resveratrol, a naturally occurring phytoestrogen, has been shown to have potent anti-cancer properties. However, poor efficacy and bioavailability have prevented the use of resveratrol in clinics. In order to address these problems, we have synthesized a combinatorial library of azaresveratrol analogs and tested them for their ability to inhibit the proliferation of breast cancer cells. We have recently shown that 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD), has better anti-cancer properties than resveratrol and any other resveratrol analog we have synthesized so far. The objective of this study was to investigate the regulation of estrogen receptors (ERs) α and β by TIMBD in breast cancer cell lines. We demonstrate that TIMBD significantly induces the mRNA and protein expression levels of ERβ and inhibits that of ERα. TIMBD inhibits mRNA and protein expression levels of oncogene c-Myc, and cell cycle protein cyclin D1, which are important regulators of cellular proliferation. TIMBD significantly induces protein expression levels of tumor suppressor genes p53 and p21 in MCF-7 cells. TIMBD inhibits c-Myc in an ERβ-dependent fashion in MCF-10 A and ERβ1-transfected MDA-MB-231 cells, suggesting regulation of ERs as an important upstream mechanism of this analog. ERβ plays a partial role in inhibition of proliferation by TIMBD while ERα overexpression does not significantly affect TIMBD's inhibition. - Highlights: • Resveratrol analog TIMBD inhibits growth of breast cancer cells. • TIMBD induces protein expression levels of ERβ and inhibits that of ERα. • TIMBD inhibits c-Myc and cyclin D1, and induces p53 and p21. • TIMBD suppresses c-Myc in an ER-dependent fashion.

4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol}, 1 a novel resveratrol analog, differentially regulates estrogen receptors α and β in breast cancer cells

International Nuclear Information System (INIS)

Ronghe, Amruta; Chatterjee, Anwesha; Singh, Bhupendra; Dandawate, Prasad; Abdalla, Fatma; Bhat, Nimee K.; Padhye, Subhash; Bhat, Hari K.

2016-01-01

Breast cancer is a public health concern worldwide. Prolonged exposure to estrogens has been implicated in the development of breast neoplasms. Epidemiologic and experimental evidence suggest a chemopreventive role of phytoestrogens in breast cancers. Resveratrol, a naturally occurring phytoestrogen, has been shown to have potent anti-cancer properties. However, poor efficacy and bioavailability have prevented the use of resveratrol in clinics. In order to address these problems, we have synthesized a combinatorial library of azaresveratrol analogs and tested them for their ability to inhibit the proliferation of breast cancer cells. We have recently shown that 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD), has better anti-cancer properties than resveratrol and any other resveratrol analog we have synthesized so far. The objective of this study was to investigate the regulation of estrogen receptors (ERs) α and β by TIMBD in breast cancer cell lines. We demonstrate that TIMBD significantly induces the mRNA and protein expression levels of ERβ and inhibits that of ERα. TIMBD inhibits mRNA and protein expression levels of oncogene c-Myc, and cell cycle protein cyclin D1, which are important regulators of cellular proliferation. TIMBD significantly induces protein expression levels of tumor suppressor genes p53 and p21 in MCF-7 cells. TIMBD inhibits c-Myc in an ERβ-dependent fashion in MCF-10 A and ERβ1-transfected MDA-MB-231 cells, suggesting regulation of ERs as an important upstream mechanism of this analog. ERβ plays a partial role in inhibition of proliferation by TIMBD while ERα overexpression does not significantly affect TIMBD's inhibition. - Highlights: • Resveratrol analog TIMBD inhibits growth of breast cancer cells. • TIMBD induces protein expression levels of ERβ and inhibits that of ERα. • TIMBD inhibits c-Myc and cyclin D1, and induces p53 and p21. • TIMBD suppresses c-Myc in an ER-dependent fashion.

Studies towards the synthesis of ATP analogs as potential glutamine synthetase inhibitors

CSIR Research Space (South Africa)

Salisu, S

2011-05-01

Full Text Available and Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown, South Africa b CSIR BIO/CHEMTEK, Modderfontein, South Africa ABSTRACT In research directed at the development of adenine triphosphate (ATP) analogs as potential...

NaturAnalogs for the Unsaturated Zone

Energy Technology Data Exchange (ETDEWEB)

A. Simmons; A. Unger; M. Murrell

2000-03-08

The purpose of this Analysis/Model Report (AMR) is to document natural and anthropogenic (human-induced) analog sites and processes that are applicable to flow and transport processes expected to occur at the potential Yucca Mountain repository in order to build increased confidence in modeling processes of Unsaturated Zone (UZ) flow and transport. This AMR was prepared in accordance with ''AMR Development Plan for U0135, Natural Analogs for the UZ'' (CRWMS 1999a). Knowledge from analog sites and processes is used as corroborating information to test and build confidence in flow and transport models of Yucca Mountain, Nevada. This AMR supports the Unsaturated Zone (UZ) Flow and Transport Process Model Report (PMR) and the Yucca Mountain Site Description. The objectives of this AMR are to test and build confidence in the representation of UZ processes in numerical models utilized in the UZ Flow and Transport Model. This is accomplished by: (1) applying data from Boxy Canyon, Idaho in simulations of UZ flow using the same methodologies incorporated in the Yucca Mountain UZ Flow and Transport Model to assess the fracture-matrix interaction conceptual model; (2) Providing a preliminary basis for analysis of radionuclide transport at Pena Blanca, Mexico as an analog of radionuclide transport at Yucca Mountain; and (3) Synthesizing existing information from natural analog studies to provide corroborating evidence for representation of ambient and thermally coupled UZ flow and transport processes in the UZ Model.

Natural Analogs for the Unsaturated Zone

International Nuclear Information System (INIS)

Simmons, A.; Unger, A.; Murrell, M.

2000-01-01

The purpose of this Analysis/Model Report (AMR) is to document natural and anthropogenic (human-induced) analog sites and processes that are applicable to flow and transport processes expected to occur at the potential Yucca Mountain repository in order to build increased confidence in modeling processes of Unsaturated Zone (UZ) flow and transport. This AMR was prepared in accordance with ''AMR Development Plan for U0135, Natural Analogs for the UZ'' (CRWMS 1999a). Knowledge from analog sites and processes is used as corroborating information to test and build confidence in flow and transport models of Yucca Mountain, Nevada. This AMR supports the Unsaturated Zone (UZ) Flow and Transport Process Model Report (PMR) and the Yucca Mountain Site Description. The objectives of this AMR are to test and build confidence in the representation of UZ processes in numerical models utilized in the UZ Flow and Transport Model. This is accomplished by: (1) applying data from Boxy Canyon, Idaho in simulations of UZ flow using the same methodologies incorporated in the Yucca Mountain UZ Flow and Transport Model to assess the fracture-matrix interaction conceptual model; (2) Providing a preliminary basis for analysis of radionuclide transport at Pena Blanca, Mexico as an analog of radionuclide transport at Yucca Mountain; and (3) Synthesizing existing information from natural analog studies to provide corroborating evidence for representation of ambient and thermally coupled UZ flow and transport processes in the UZ Model

Analogical reasoning in children with specific language impairment: Evidence from a scene analogy task.

Science.gov (United States)

Krzemien, Magali; Jemel, Boutheina; Maillart, Christelle

2017-01-01

Analogical reasoning is a human ability that maps systems of relations. It develops along with relational knowledge, working memory and executive functions such as inhibition. It also maintains a mutual influence on language development. Some authors have taken a greater interest in the analogical reasoning ability of children with language disorders, specifically those with specific language impairment (SLI). These children apparently have weaker analogical reasoning abilities than their aged-matched peers without language disorders. Following cognitive theories of language acquisition, this deficit could be one of the causes of language disorders in SLI, especially those concerning productivity. To confirm this deficit and its link to language disorders, we use a scene analogy task to evaluate the analogical performance of SLI children and compare them to controls of the same age and linguistic abilities. Results show that children with SLI perform worse than age-matched peers, but similar to language-matched peers. They are more influenced by increased task difficulty. The association between language disorders and analogical reasoning in SLI can be confirmed. The hypothesis of limited processing capacity in SLI is also being considered.

PEMETAAN ANALOGI PADA KONSEP ABSTRAK FISIKA

Directory of Open Access Journals (Sweden)

Nyoto Suseno

2014-11-01

Full Text Available The research of any where founded majority students have common difficulties in abstract physics concept. The result of observation, lecturers have problem  in teaching implementation of abstract concepts on physics learning. The objective of this research is to find out the ways how to overcome this problem. The research place of  physics education programs and senior high school. The data are colected by quetionere, observation and interview. The lecturer behavior to making out this case is use of analogy to make concrete a abstract concept. This action is true, because the analogies are dynamic tools that facilitate understanding, rather than representations of the correct and static explanations. Using analogies not only promoted profound understanding of abstract concept, but also helped students overcome their misconceptions. However used analogy in teaching not yet planed with seriousness, analogy used spontanously with the result that less optimal. By planing and selecting right analogy, the role of analogy can be achieved the optimal result. Therefore, it is important to maping analogies of abstract consepts on physics learning.

Association of Neuropeptide Y (NPY), Interleukin-1B (IL1B) Genetic Variants and Correlation of IL1B Transcript Levels with Vitiligo Susceptibility

Science.gov (United States)

Laddha, Naresh C.; Dwivedi, Mitesh; Mansuri, Mohmmad Shoab; Singh, Mala; Patel, Hetanshi H.; Agarwal, Nishtha; Shah, Anish M.; Begum, Rasheedunnisa

2014-01-01

Background Vitiligo is a depigmenting disorder resulting from loss of functional melanocytes in the skin. NPY plays an important role in induction of immune response by acting on a variety of immune cells. NPY synthesis and release is governed by IL1B. Moreover, genetic variability in IL1B is reported to be associated with elevated NPY levels. Objectives Aim of the present study was to explore NPY promoter −399T/C (rs16147) and exon2 +1128T/C (rs16139) polymorphisms as well as IL1B promoter −511C/T (rs16944) polymorphism and to correlate IL1B transcript levels with vitiligo. Methods PCR-RFLP method was used to genotype NPY -399T/C SNP in 454 patients and 1226 controls; +1128T/C SNP in 575 patients and 1279 controls and IL1B −511C/T SNP in 448 patients and 785 controls from Gujarat. IL1B transcript levels in blood were also assessed in 105 controls and 95 patients using real-time PCR. Results Genotype and allele frequencies for NPY −399T/C, +1128T/C and IL1B −511C/T SNPs differed significantly (pvitiligo by 2.3 fold (pvitiligo (p = 0.015), also in female patients than male patients (p = 0.026). Genotype-phenotype correlation showed moderate association of IL1B -511C/T polymorphism with higher IL1B transcript levels. Trend analysis revealed significant difference between patients and controls for IL1B transcript levels with respect to different genotypes. Conclusion Our results suggest that NPY −399T/C, +1128T/C and IL1B −511C/T polymorphisms are associated with vitiligo and IL1B −511C/T SNP influences its transcript levels leading to increased risk for vitiligo in Gujarat population. Up-regulation of IL1B transcript in patients advocates its possible role in autoimmune pathogenesis of vitiligo. PMID:25221996

An analog silicon retina with multichip configuration.

Science.gov (United States)

Kameda, Seiji; Yagi, Tetsuya

2006-01-01

The neuromorphic silicon retina is a novel analog very large scale integrated circuit that emulates the structure and the function of the retinal neuronal circuit. We fabricated a neuromorphic silicon retina, in which sample/hold circuits were embedded to generate fluctuation-suppressed outputs in the previous study [1]. The applications of this silicon retina, however, are limited because of a low spatial resolution and computational variability. In this paper, we have fabricated a multichip silicon retina in which the functional network circuits are divided into two chips: the photoreceptor network chip (P chip) and the horizontal cell network chip (H chip). The output images of the P chip are transferred to the H chip with analog voltages through the line-parallel transfer bus. The sample/hold circuits embedded in the P and H chips compensate for the pattern noise generated on the circuits, including the analog communication pathway. Using the multichip silicon retina together with an off-chip differential amplifier, spatial filtering of the image with an odd- and an even-symmetric orientation selective receptive fields was carried out in real time. The analog data transfer method in the present multichip silicon retina is useful to design analog neuromorphic multichip systems that mimic the hierarchical structure of neuronal networks in the visual system.

Color balancing in CCD color cameras using analog signal processors made by Kodak

Science.gov (United States)

Kannegundla, Ram

1995-03-01

The green, red, and blue color filters used for CCD sensors generally have different responses. It is often necessary to balance these three colors for displaying a high-quality image on the monitor. The color filter arrays on sensors have different architectures. A CCD with standard G R G B pattern is considered for the present discussion. A simple method of separating the colors using CDS/H that is a part of KASPs (Analog Signal Processors made by Kodak) and using the gain control, which is also a part of KASPs for color balance, is presented. The colors are separated from the video output of sensor by using three KASPs, one each for green, red, and blue colors and by using alternate sample pulses for green and 1 in 4 pulses for red and blue. The separated colors gain is adjusted either automatically or manually and sent to the monitor for direct display in the analog mode or through an A/D converter digitally to the memory. This method of color balancing demands high-quality ASPs. Kodak has designed four different chips with varying levels of power consumption and speed for analog signal processing of video output of CCD sensors. The analog ASICs have been characterized for noise, clock feedthrough, acquisition time, linearity, variable gain, line rate clamp, black muxing, affect of temperature variations on chip performance, and droop. The ASP chips have met their design specifications.

Science Teachers' Analogical Reasoning

Science.gov (United States)

Mozzer, Nilmara Braga; Justi, Rosária

2013-01-01

Analogies can play a relevant role in students' learning. However, for the effective use of analogies, teachers should not only have a well-prepared repertoire of validated analogies, which could serve as bridges between the students' prior knowledge and the scientific knowledge they desire them to understand, but also know how to…

Analog circuits cookbook

CERN Document Server

Hickman, Ian

2013-01-01

Analog Circuits Cookbook presents articles about advanced circuit techniques, components and concepts, useful IC for analog signal processing in the audio range, direct digital synthesis, and ingenious video op-amp. The book also includes articles about amplitude measurements on RF signals, linear optical imager, power supplies and devices, and RF circuits and techniques. Professionals and students of electrical engineering will find the book informative and useful.

Eye movements provide insight into individual differences in children's analogical reasoning strategies.

Science.gov (United States)

Starr, Ariel; Vendetti, Michael S; Bunge, Silvia A

2018-05-01

Analogical reasoning is considered a key driver of cognitive development and is a strong predictor of academic achievement. However, it is difficult for young children, who are prone to focusing on perceptual and semantic similarities among items rather than relational commonalities. For example, in a classic A:B::C:? propositional analogy task, children must inhibit attention towards items that are visually or semantically similar to C, and instead focus on finding a relational match to the A:B pair. Competing theories of reasoning development attribute improvements in children's performance to gains in either executive functioning or semantic knowledge. Here, we sought to identify key drivers of the development of analogical reasoning ability by using eye gaze patterns to infer problem-solving strategies used by six-year-old children and adults. Children had a greater tendency than adults to focus on the immediate task goal and constrain their search based on the C item. However, large individual differences existed within children, and more successful reasoners were able to maintain the broader goal in mind and constrain their search by initially focusing on the A:B pair before turning to C and the response choices. When children adopted this strategy, their attention was drawn more readily to the correct response option. Individual differences in children's reasoning ability were also related to rule-guided behavior but not to semantic knowledge. These findings suggest that both developmental improvements and individual differences in performance are driven by the use of more efficient reasoning strategies regarding which information is prioritized from the start, rather than the ability to disengage from attractive lure items. Copyright © 2018 Elsevier B.V. All rights reserved.

Advances in Analog Circuit Design 2015

CERN Document Server

Baschirotto, Andrea; Harpe, Pieter

2016-01-01

This book is based on the 18 tutorials presented during the 24th workshop on Advances in Analog Circuit Design. Expert designers present readers with information about a variety of topics at the frontier of analog circuit design, including low-power and energy-efficient analog electronics, with specific contributions focusing on the design of efficient sensor interfaces and low-power RF systems. This book serves as a valuable reference to the state-of-the-art, for anyone involved in analog circuit research and development. ·         Provides a state-of-the-art reference in analog circuit design, written by experts from industry and academia; ·         Presents material in a tutorial-based format; ·         Includes coverage of high-performance analog-to-digital and digital to analog converters, integrated circuit design in scaled technologies, and time-domain signal processing.

Command Interface ASIC - Analog Interface ASIC Chip Set

Science.gov (United States)

Ruiz, Baldes; Jaffe, Burton; Burke, Gary; Lung, Gerald; Pixler, Gregory; Plummer, Joe; Katanyoutanant,, Sunant; Whitaker, William

2003-01-01

A command interface application-specific integrated circuit (ASIC) and an analog interface ASIC have been developed as a chip set for remote actuation and monitoring of a collection of switches, which can be used to control generic loads, pyrotechnic devices, and valves in a high-radiation environment. The command interface ASIC (CIA) can be used alone or in combination with the analog interface ASIC (AIA). Designed primarily for incorporation into spacecraft control systems, they are also suitable for use in high-radiation terrestrial environments (e.g., in nuclear power plants and facilities that process radioactive materials). The primary role of the CIA within a spacecraft or other power system is to provide a reconfigurable means of regulating the power bus, actuating all valves, firing all pyrotechnic devices, and controlling the switching of power to all switchable loads. The CIA is a mixed-signal (analog and digital) ASIC that includes an embedded microcontroller with supporting fault-tolerant switch control and monitoring circuitry that is capable of connecting to a redundant set of interintegrated circuit (I(sup 2)C) buses. Commands and telemetry requests are communicated to the CIA. Adherence to the I(sup 2)C bus standard helps to reduce development costs by facilitating the use of previously developed, commercially available components. The AIA is a mixed-signal ASIC that includes the analog circuitry needed to connect the CIA to a custom higher powered version of the I(sup 2)C bus. The higher-powered version is designed to enable operation with bus cables longer than those contemplated in the I(sup 2)C standard. If there are multiple higher-power I(sup 2)C-like buses, then there must an AIA between the CIA and each such bus. The AIA includes two identical interface blocks: one for the side-A I(sup 2)C clock and data buses and the other for the side B buses. All the AIAs on each side are powered from a common power converter module (PCM). Sides A and B

Association of neuropeptide Y (NPY, interleukin-1B (IL1B genetic variants and correlation of IL1B transcript levels with vitiligo susceptibility.

Directory of Open Access Journals (Sweden)

Naresh C Laddha

Full Text Available BACKGROUND: Vitiligo is a depigmenting disorder resulting from loss of functional melanocytes in the skin. NPY plays an important role in induction of immune response by acting on a variety of immune cells. NPY synthesis and release is governed by IL1B. Moreover, genetic variability in IL1B is reported to be associated with elevated NPY levels. OBJECTIVES: Aim of the present study was to explore NPY promoter -399T/C (rs16147 and exon2 +1128T/C (rs16139 polymorphisms as well as IL1B promoter -511C/T (rs16944 polymorphism and to correlate IL1B transcript levels with vitiligo. METHODS: PCR-RFLP method was used to genotype NPY -399T/C SNP in 454 patients and 1226 controls; +1128T/C SNP in 575 patients and 1279 controls and IL1B -511C/T SNP in 448 patients and 785 controls from Gujarat. IL1B transcript levels in blood were also assessed in 105 controls and 95 patients using real-time PCR. RESULTS: Genotype and allele frequencies for NPY -399T/C, +1128T/C and IL1B -511C/T SNPs differed significantly (p<0.0001, p<0.0001; p = 0.0161, p = 0.0035 and p<0.0001, p<0.0001 between patients and controls. 'TC' haplotype containing minor alleles of NPY polymorphisms was significantly higher in patients and increased the risk of vitiligo by 2.3 fold (p<0.0001. Transcript levels of IL1B were significantly higher, in patients compared to controls (p = 0.0029, in patients with active than stable vitiligo (p = 0.015, also in female patients than male patients (p = 0.026. Genotype-phenotype correlation showed moderate association of IL1B -511C/T polymorphism with higher IL1B transcript levels. Trend analysis revealed significant difference between patients and controls for IL1B transcript levels with respect to different genotypes. CONCLUSION: Our results suggest that NPY -399T/C, +1128T/C and IL1B -511C/T polymorphisms are associated with vitiligo and IL1B -511C/T SNP influences its transcript levels leading to increased risk for vitiligo in

Analogical reasoning and prefrontal cortex: evidence for separable retrieval and integration mechanisms.

Science.gov (United States)

Bunge, Silvia A; Wendelken, Carter; Badre, David; Wagner, Anthony D

2005-03-01

The present study examined the contributions of prefrontal cortex (PFC) subregions to two component processes underlying verbal analogical reasoning: semantic retrieval and integration. Event-related functional magnetic resonance imaging data were acquired while subjects performed propositional analogy and semantic decision tasks. On each trial, subjects viewed a pair of words (pair 1), followed by an instructional cue and a second word pair (pair 2). On analogy trials, subjects evaluated whether pair 2 was semantically analogous to pair 1. On semantic trials, subjects indicated whether the pair 2 words were semantically related to each other. Thus, analogy--but not semantic--trials required integration across multiple retrieved relations. To identify regions involved in semantic retrieval, we manipulated the associative strength of pair 1 words in both tasks. Anterior left inferior PFC (aLIPC) was modulated by associative strength, consistent with a role in controlled semantic retrieval. Left frontopolar cortex was insensitive to associative strength, but was more sensitive to integration demands than was aLIPC, consistent with a role in integrating the products of semantic retrieval to evaluate whether distinct representations are analogous. Right dorsolateral PFC exhibited a profile consistent with a role in response selection rather than retrieval or integration. These findings indicate that verbal analogical reasoning depends on multiple, PFC-mediated computations.

Students' Pre- and Post-Teaching Analogical Reasoning when They Draw Their Analogies

Science.gov (United States)

Mozzer, Nilmara Braga; Justi, Rosaria

2012-01-01

Analogies are parts of human thought. From them, we can acquire new knowledge or change that which already exists in our cognitive structure. In this sense, understanding the analogical reasoning process becomes an essential condition to understand how we learn. Despite the importance of such an understanding, there is no general agreement in…

Analog and digital dividers for mass spectrometers

International Nuclear Information System (INIS)

Osipov, A.K.

1980-01-01

Errors of four different types of stress dividers used in statical mass-spectrometers for determination of mass number by accelerating stress are analyzed. The simplest flowsheet of the analog divider comprises operation amplifier, in the chain of the negative feedback of which a multiplication device on differential cascade is switched- in. This analog divider has high sensitivity to temperature and high error approximately 5%. Application of the multiplier on differential cascade with normalization permits to increase temperature stability and decrease the error up to 1%. Another type of the analog divider is a logarithmic divider the error of which is constant within the whole operation range and it constitutes 1-5%. The digital divider with a digital-analog transformer (DAT) has the error of +-0.015% which is determined by the error of detectors and resistance of keys in the locked state. Considered is the design of a divider based on transformation of the inlet stress into the time period. The error of the divider is determined in this case mainly by stress of the zero shift of the operation amplifier (it should be compensated) and relative threshold stability of the comparator triggering which equals (2-3)x10 -4 . It is noted that the divider with DAT application and the divider with the use of stress transformation within the time period are most perspective ones for statical mass-spectrometers [ru

Measurement of the $\\chi_b(3P)$ mass and of the relative rate of $\\chi_{b1}(1P)$ and $\\chi_{b2}(1P)$ production

CERN Document Server

Aaij, Roel; Adinolfi, Marco; Affolder, Anthony; Ajaltouni, Ziad; Akar, Simon; Albrecht, Johannes; Alessio, Federico; Alexander, Michael; Ali, Suvayu; Alkhazov, Georgy; Alvarez Cartelle, Paula; Alves Jr, Antonio Augusto; Amato, Sandra; Amerio, Silvia; Amhis, Yasmine; An, Liupan; Anderlini, Lucio; Anderson, Jonathan; Andreassen, Rolf; Andreotti, Mirco; Andrews, Jason; Appleby, Robert; Aquines Gutierrez, Osvaldo; Archilli, Flavio; Artamonov, Alexander; Artuso, Marina; Aslanides, Elie; Auriemma, Giulio; Baalouch, Marouen; Bachmann, Sebastian; Back, John; Badalov, Alexey; Baesso, Clarissa; Baldini, Wander; Barlow, Roger; Barschel, Colin; Barsuk, Sergey; Barter, William; Batozskaya, Varvara; Battista, Vincenzo; Bay, Aurelio; Beaucourt, Leo; Beddow, John; Bedeschi, Franco; Bediaga, Ignacio; Belogurov, Sergey; Belous, Konstantin; Belyaev, Ivan; Ben-Haim, Eli; Bencivenni, Giovanni; Benson, Sean; Benton, Jack; Berezhnoy, Alexander; Bernet, Roland; Bettler, Marc-Olivier; van Beuzekom, Martinus; Bien, Alexander; Bifani, Simone; Bird, Thomas; Bizzeti, Andrea; Bjørnstad, Pål Marius; Blake, Thomas; Blanc, Frédéric; Blouw, Johan; Blusk, Steven; Bocci, Valerio; Bondar, Alexander; Bondar, Nikolay; Bonivento, Walter; Borghi, Silvia; Borgia, Alessandra; Borsato, Martino; Bowcock, Themistocles; Bowen, Espen Eie; Bozzi, Concezio; Brambach, Tobias; van den Brand, Johannes; Bressieux, Joël; Brett, David; Britsch, Markward; Britton, Thomas; Brodzicka, Jolanta; Brook, Nicholas; Brown, Henry; Bursche, Albert; Busetto, Giovanni; Buytaert, Jan; Cadeddu, Sandro; Calabrese, Roberto; Calvi, Marta; Calvo Gomez, Miriam; Campana, Pierluigi; Campora Perez, Daniel; Carbone, Angelo; Carboni, Giovanni; Cardinale, Roberta; Cardini, Alessandro; Carson, Laurence; Carvalho Akiba, Kazuyoshi; Casse, Gianluigi; Cassina, Lorenzo; Castillo Garcia, Lucia; Cattaneo, Marco; Cauet, Christophe; Cenci, Riccardo; Charles, Matthew; Charpentier, Philippe; Chefdeville, Maximilien; Chen, Shanzhen; Cheung, Shu-Faye; Chiapolini, Nicola; Chrzaszcz, Marcin; Ciba, Krzystof; Cid Vidal, Xabier; Ciezarek, Gregory; Clarke, Peter; Clemencic, Marco; Cliff, Harry; Closier, Joel; Coco, Victor; Cogan, Julien; Cogneras, Eric; Cojocariu, Lucian; Collins, Paula; Comerma-Montells, Albert; Contu, Andrea; Cook, Andrew; Coombes, Matthew; Coquereau, Samuel; Corti, Gloria; Corvo, Marco; Counts, Ian; Couturier, Benjamin; Cowan, Greig; Craik, Daniel Charles; Cruz Torres, Melissa Maria; Cunliffe, Samuel; Currie, Robert; D'Ambrosio, Carmelo; Dalseno, Jeremy; David, Pascal; David, Pieter; Davis, Adam; De Bruyn, Kristof; De Capua, Stefano; De Cian, Michel; De Miranda, Jussara; De Paula, Leandro; De Silva, Weeraddana; De Simone, Patrizia; Decamp, Daniel; Deckenhoff, Mirko; Del Buono, Luigi; Déléage, Nicolas; Derkach, Denis; Deschamps, Olivier; Dettori, Francesco; Di Canto, Angelo; Dijkstra, Hans; Donleavy, Stephanie; Dordei, Francesca; Dorigo, Mirco; Dosil Suárez, Alvaro; Dossett, David; Dovbnya, Anatoliy; Dreimanis, Karlis; Dujany, Giulio; Dupertuis, Frederic; Durante, Paolo; Dzhelyadin, Rustem; Dziurda, Agnieszka; Dzyuba, Alexey; Easo, Sajan; Egede, Ulrik; Egorychev, Victor; Eidelman, Semen; Eisenhardt, Stephan; Eitschberger, Ulrich; Ekelhof, Robert; Eklund, Lars; El Rifai, Ibrahim; Elsasser, Christian; Ely, Scott; Esen, Sevda; Evans, Hannah Mary; Evans, Timothy; Falabella, Antonio; Färber, Christian; Farinelli, Chiara; Farley, Nathanael; Farry, Stephen; Fay, Robert; Ferguson, Dianne; Fernandez Albor, Victor; Ferreira Rodrigues, Fernando; Ferro-Luzzi, Massimiliano; Filippov, Sergey; Fiore, Marco; Fiorini, Massimiliano; Firlej, Miroslaw; Fitzpatrick, Conor; Fiutowski, Tomasz; Fontana, Marianna; Fontanelli, Flavio; Forty, Roger; Francisco, Oscar; Frank, Markus; Frei, Christoph; Frosini, Maddalena; Fu, Jinlin; Furfaro, Emiliano; Gallas Torreira, Abraham; Galli, Domenico; Gallorini, Stefano; Gambetta, Silvia; Gandelman, Miriam; Gandini, Paolo; Gao, Yuanning; García Pardiñas, Julián; Garofoli, Justin; Garra Tico, Jordi; Garrido, Lluis; Gaspar, Clara; Gauld, Rhorry; Gavardi, Laura; Gavrilov, Gennadii; Geraci, Angelo; Gersabeck, Evelina; Gersabeck, Marco; Gershon, Timothy; Ghez, Philippe; Gianelle, Alessio; Gianì, Sebastiana; Gibson, Valerie; Giubega, Lavinia-Helena; Gligorov, V.V.; Göbel, Carla; Golubkov, Dmitry; Golutvin, Andrey; Gomes, Alvaro; Gotti, Claudio; Grabalosa Gándara, Marc; Graciani Diaz, Ricardo; Granado Cardoso, Luis Alberto; Graugés, Eugeni; Graziani, Giacomo; Grecu, Alexandru; Greening, Edward; Gregson, Sam; Griffith, Peter; Grillo, Lucia; Grünberg, Oliver; Gui, Bin; Gushchin, Evgeny; Guz, Yury; Gys, Thierry; Hadjivasiliou, Christos; Haefeli, Guido; Haen, Christophe; Haines, Susan; Hall, Samuel; Hamilton, Brian; Hampson, Thomas; Han, Xiaoxue; Hansmann-Menzemer, Stephanie; Harnew, Neville; Harnew, Samuel; Harrison, Jonathan; He, Jibo; Head, Timothy; Heijne, Veerle; Hennessy, Karol; Henrard, Pierre; Henry, Louis; Hernando Morata, Jose Angel; van Herwijnen, Eric; Heß, Miriam; Hicheur, Adlène; Hill, Donal; Hoballah, Mostafa; Hombach, Christoph; Hulsbergen, Wouter; Hunt, Philip; Hussain, Nazim; Hutchcroft, David; Hynds, Daniel; Idzik, Marek; Ilten, Philip; Jacobsson, Richard; Jaeger, Andreas; Jalocha, Pawel; Jans, Eddy; Jaton, Pierre; Jawahery, Abolhassan; Jing, Fanfan; John, Malcolm; Johnson, Daniel; Jones, Christopher; Joram, Christian; Jost, Beat; Jurik, Nathan; Kandybei, Sergii; Kanso, Walaa; Karacson, Matthias; Karbach, Moritz; Karodia, Sarah; Kelsey, Matthew; Kenyon, Ian; Ketel, Tjeerd; Khanji, Basem; Khurewathanakul, Chitsanu; Klaver, Suzanne; Klimaszewski, Konrad; Kochebina, Olga; Kolpin, Michael; Komarov, Ilya; Koopman, Rose; Koppenburg, Patrick; Korolev, Mikhail; Kozlinskiy, Alexandr; Kravchuk, Leonid; Kreplin, Katharina; Kreps, Michal; Krocker, Georg; Krokovny, Pavel; Kruse, Florian; Kucewicz, Wojciech; Kucharczyk, Marcin; Kudryavtsev, Vasily; Kurek, Krzysztof; Kvaratskheliya, Tengiz; La Thi, Viet Nga; Lacarrere, Daniel; Lafferty, George; Lai, Adriano; Lambert, Dean; Lambert, Robert W; Lanfranchi, Gaia; Langenbruch, Christoph; Langhans, Benedikt; Latham, Thomas; Lazzeroni, Cristina; Le Gac, Renaud; van Leerdam, Jeroen; Lees, Jean-Pierre; Lefèvre, Regis; Leflat, Alexander; Lefrançois, Jacques; Leo, Sabato; Leroy, Olivier; Lesiak, Tadeusz; Lespinasse, Mickael; Leverington, Blake; Li, Yiming; Likhomanenko, Tatiana; Liles, Myfanwy; Lindner, Rolf; Linn, Christian; Lionetto, Federica; Liu, Bo; Lohn, Stefan; Longstaff, Iain; Lopes, Jose; Lopez-March, Neus; Lowdon, Peter; Lu, Haiting; Lucchesi, Donatella; Luo, Haofei; Lupato, Anna; Luppi, Eleonora; Lupton, Oliver; Machefert, Frederic; Machikhiliyan, Irina V; Maciuc, Florin; Maev, Oleg; Malde, Sneha; Malinin, Alexander; Manca, Giulia; Mancinelli, Giampiero; Mapelli, Alessandro; Maratas, Jan; Marchand, Jean François; Marconi, Umberto; Marin Benito, Carla; Marino, Pietro; Märki, Raphael; Marks, Jörg; Martellotti, Giuseppe; Martens, Aurelien; Martín Sánchez, Alexandra; Martinelli, Maurizio; Martinez Santos, Diego; Martinez Vidal, Fernando; Martins Tostes, Danielle; Massafferri, André; Matev, Rosen; Mathe, Zoltan; Matteuzzi, Clara; Mazurov, Alexander; McCann, Michael; McCarthy, James; McNab, Andrew; McNulty, Ronan; McSkelly, Ben; Meadows, Brian; Meier, Frank; Meissner, Marco; Merk, Marcel; Milanes, Diego Alejandro; Minard, Marie-Noelle; Moggi, Niccolò; Molina Rodriguez, Josue; Monteil, Stephane; Morandin, Mauro; Morawski, Piotr; Mordà, Alessandro; Morello, Michael Joseph; Moron, Jakub; Morris, Adam Benjamin; Mountain, Raymond; Muheim, Franz; Müller, Katharina; Mussini, Manuel; Muster, Bastien; Naik, Paras; Nakada, Tatsuya; Nandakumar, Raja; Nasteva, Irina; Needham, Matthew; Neri, Nicola; Neubert, Sebastian; Neufeld, Niko; Neuner, Max; Nguyen, Anh Duc; Nguyen, Thi-Dung; Nguyen-Mau, Chung; Nicol, Michelle; Niess, Valentin; Niet, Ramon; Nikitin, Nikolay; Nikodem, Thomas; Novoselov, Alexey; O'Hanlon, Daniel Patrick; Oblakowska-Mucha, Agnieszka; Obraztsov, Vladimir; Oggero, Serena; Ogilvy, Stephen; Okhrimenko, Oleksandr; Oldeman, Rudolf; Onderwater, Gerco; Orlandea, Marius; Otalora Goicochea, Juan Martin; Owen, Patrick; Oyanguren, Maria Arantza; Pal, Bilas Kanti; Palano, Antimo; Palombo, Fernando; Palutan, Matteo; Panman, Jacob; Papanestis, Antonios; Pappagallo, Marco; Pappalardo, Luciano; Parkes, Christopher; Parkinson, Christopher John; Passaleva, Giovanni; Patel, Girish; Patel, Mitesh; Patrignani, Claudia; Pearce, Alex; Pellegrino, Antonio; Pepe Altarelli, Monica; Perazzini, Stefano; Perret, Pascal; Perrin-Terrin, Mathieu; Pescatore, Luca; Pesen, Erhan; Petridis, Konstantin; Petrolini, Alessandro; Picatoste Olloqui, Eduardo; Pietrzyk, Boleslaw; Pilař, Tomas; Pinci, Davide; Pistone, Alessandro; Playfer, Stephen; Plo Casasus, Maximo; Polci, Francesco; Poluektov, Anton; Polycarpo, Erica; Popov, Alexander; Popov, Dmitry; Popovici, Bogdan; Potterat, Cédric; Price, Eugenia; Prisciandaro, Jessica; Pritchard, Adrian; Prouve, Claire; Pugatch, Valery; Puig Navarro, Albert; Punzi, Giovanni; Qian, Wenbin; Rachwal, Bartolomiej; Rademacker, Jonas; Rakotomiaramanana, Barinjaka; Rama, Matteo; Rangel, Murilo; Raniuk, Iurii; Rauschmayr, Nathalie; Raven, Gerhard; Reichert, Stefanie; Reid, Matthew; dos Reis, Alberto; Ricciardi, Stefania; Richards, Sophie; Rihl, Mariana; Rinnert, Kurt; Rives Molina, Vincente; Roa Romero, Diego; Robbe, Patrick; Rodrigues, Ana Barbara; Rodrigues, Eduardo; Rodriguez Perez, Pablo; Roiser, Stefan; Romanovsky, Vladimir; Romero Vidal, Antonio; Rotondo, Marcello; Rouvinet, Julien; Ruf, Thomas; Ruiz, Hugo; Ruiz Valls, Pablo; Saborido Silva, Juan Jose; Sagidova, Naylya; Sail, Paul; Saitta, Biagio; Salustino Guimaraes, Valdir; Sanchez Mayordomo, Carlos; Sanmartin Sedes, Brais; Santacesaria, Roberta; Santamarina Rios, Cibran; Santovetti, Emanuele; Sarti, Alessio; Satriano, Celestina; Satta, Alessia; Saunders, Daniel Martin; Savrina, Darya; Schiller, Manuel; Schindler, Heinrich; Schlupp, Maximilian; Schmelling, Michael; Schmidt, Burkhard; Schneider, Olivier; Schopper, Andreas; Schune, Marie Helene; Schwemmer, Rainer; Sciascia, Barbara; Sciubba, Adalberto; Semennikov, Alexander; Sepp, Indrek; Serra, Nicola; Serrano, Justine; Sestini, Lorenzo; Seyfert, Paul; Shapkin, Mikhail; Shapoval, Illya; Shcheglov, Yury; Shears, Tara; Shekhtman, Lev; Shevchenko, Vladimir; Shires, Alexander; Silva Coutinho, Rafael; Simi, Gabriele; Sirendi, Marek; Skidmore, Nicola; Skwarnicki, Tomasz; Smith, Anthony; Smith, Edmund; Smith, Eluned; Smith, Jackson; Smith, Mark; Snoek, Hella; Sokoloff, Michael; Soler, Paul; Soomro, Fatima; Souza, Daniel; Souza De Paula, Bruno; Spaan, Bernhard; Sparkes, Ailsa; Spradlin, Patrick; Sridharan, Srikanth; Stagni, Federico; Stahl, Marian; Stahl, Sascha; Steinkamp, Olaf; Stenyakin, Oleg; Stevenson, Scott; Stoica, Sabin; Stone, Sheldon; Storaci, Barbara; Stracka, Simone; Straticiuc, Mihai; Straumann, Ulrich; Stroili, Roberto; Subbiah, Vijay Kartik; Sun, Liang; Sutcliffe, William; Swientek, Krzysztof; Swientek, Stefan; Syropoulos, Vasileios; Szczekowski, Marek; Szczypka, Paul; Szumlak, Tomasz; T'Jampens, Stephane; Teklishyn, Maksym; Tellarini, Giulia; Teubert, Frederic; Thomas, Christopher; Thomas, Eric; van Tilburg, Jeroen; Tisserand, Vincent; Tobin, Mark; Tolk, Siim; Tomassetti, Luca; Tonelli, Diego; Topp-Joergensen, Stig; Torr, Nicholas; Tournefier, Edwige; Tourneur, Stephane; Tran, Minh Tâm; Tresch, Marco; Trisovic, Ana; Tsaregorodtsev, Andrei; Tsopelas, Panagiotis; Tuning, Niels; Ubeda Garcia, Mario; Ukleja, Artur; Ustyuzhanin, Andrey; Uwer, Ulrich; Vagnoni, Vincenzo; Valenti, Giovanni; Vallier, Alexis; Vazquez Gomez, Ricardo; Vazquez Regueiro, Pablo; Vázquez Sierra, Carlos; Vecchi, Stefania; Velthuis, Jaap; Veltri, Michele; Veneziano, Giovanni; Vesterinen, Mika; Viaud, Benoit; Vieira, Daniel; Vieites Diaz, Maria; Vilasis-Cardona, Xavier; Vollhardt, Achim; Volyanskyy, Dmytro; Voong, David; Vorobyev, Alexey; Vorobyev, Vitaly; Voß, Christian; de Vries, Jacco; Waldi, Roland; Wallace, Charlotte; Wallace, Ronan; Walsh, John; Wandernoth, Sebastian; Wang, Jianchun; Ward, David; Watson, Nigel; Websdale, David; Whitehead, Mark; Wicht, Jean; Wiedner, Dirk; Wilkinson, Guy; Williams, Matthew; Williams, Mike; Wilson, Fergus; Wimberley, Jack; Wishahi, Julian; Wislicki, Wojciech; Witek, Mariusz; Wormser, Guy; Wotton, Stephen; Wright, Simon; Wu, Suzhi; Wyllie, Kenneth; Xie, Yuehong; Xing, Zhou; Xu, Zhirui; Yang, Zhenwei; Yuan, Xuhao; Yushchenko, Oleg; Zangoli, Maria; Zavertyaev, Mikhail; Zhang, Liming; Zhang, Wen Chao; Zhang, Yanxi; Zhelezov, Alexey; Zhokhov, Anatoly; Zhong, Liang; Zvyagin, Alexander

2014-10-14

The production of $\\chi_b$ mesons in proton-proton collisions is studied using a data sample collected by the LHCb detector, at centre-of-mass energies of $\\sqrt{s}=7$ and $8$ TeV and corresponding to an integrated luminosity of 3.0 fb$^{-1}$. The $\\chi_b$ mesons are identified through their decays to $\\Upsilon(1S)\\gamma$ and $\\Upsilon(2S)\\gamma$ using photons that converted to $e^+e^-$ pairs in the detector. The $\\chi_b(3P)$ meson mass, and the relative prompt production rate of $\\chi_{b1}(1P)$ and $\\chi_{b2}(1P)$ mesons as a function of the $\\Upsilon(1S)$ transverse momentum in the $\\chi_b$ rapidity range 2.0< $y$<4.5, are measured. Assuming a mass splitting between the $\\chi_{b1}(3P)$ and the $\\chi_{b2}(3P)$ states of 10.5 MeV/$c^2$, the mass of the $\\chi_{b1}(3P)$ meson is \\begin{equation*} m(\\chi_{b1}(3P))= 10515.7^{+2.2}_{-3.9}(stat) ^{+1.5}_{-2.1}(syst) MeV/c^2. \\end{equation*}

Treating Type 1 Diabetes Mellitus with a Rapid-Acting Analog Insulin Regimen vs. Regular Human Insulin in Germany: A Long-Term Cost-Effectiveness Evaluation.

Science.gov (United States)

Valentine, William J; Van Brunt, Kate; Boye, Kristina S; Pollock, Richard F

2018-06-01

The aim of the present study was to evaluate the cost effectiveness of rapid-acting analog insulin relative to regular human insulin in adults with type 1 diabetes mellitus in Germany. The PRIME Diabetes Model, a patient-level, discrete event simulation model, was used to project long-term clinical and cost outcomes for patients with type 1 diabetes from the perspective of a German healthcare payer. Simulated patients had a mean age of 21.5 years, duration of diabetes of 8.6 years, and baseline glycosylated hemoglobin of 7.39%. Regular human insulin and rapid-acting analog insulin regimens reduced glycosylated hemoglobin by 0.312 and 0.402%, respectively. Compared with human insulin, hypoglycemia rate ratios with rapid-acting analog insulin were 0.51 (non-severe nocturnal) and 0.80 (severe). No differences in non-severe diurnal hypoglycemia were modeled. Discount rates of 3% were applied to future costs and clinical benefits accrued over the 50-year time horizon. In the base-case analysis, rapid-acting analog insulin was associated with an improvement in quality-adjusted life expectancy of 1.01 quality-adjusted life-years per patient (12.54 vs. 11.53 quality-adjusted life-years). Rapid-acting analog insulin was also associated with an increase in direct costs of €4490, resulting in an incremental cost-effectiveness ratio of €4427 per quality-adjusted life-year gained vs. human insulin. Sensitivity analyses showed that the base case was driven predominantly by differences in hypoglycemia; abolishing these differences reduced incremental quality-adjusted life expectancy to 0.07 quality-adjusted life-years, yielding an incremental cost-effectiveness ratio of €74,622 per quality-adjusted life-year gained. Rapid-acting analog insulin is associated with beneficial outcomes in patients with type 1 diabetes and is likely to be considered cost effective in the German setting vs. regular human insulin.

Seasonal behaviour of B0 and B1

International Nuclear Information System (INIS)

Mosert Gonzalez, M. de; Radicella, S.M.

1997-01-01

A preliminary analysis of the thickness parameter B0 and the shape parameter B1 is presented. Noon electron density profiles recorded at five ionospheric stations during different seasonal and solar activity conditions are used in the study. The results show that both parameters present a seasonal trend with minimum value for B0 during the local winter and maximum during the local summer. This behaviour is inverted for B1. Discrepancies with IRI-90 model are found. (author). 8 refs, 4 figs, 2 tabs

Iterative Chemical Engineering of Vancomycin Leads to Novel Vancomycin Analogs With a High in Vitro Therapeutic Index

Directory of Open Access Journals (Sweden)

Nigam M. Mishra

2018-06-01

Full Text Available Vancomycin is a glycopeptide antibiotic that inhibits transpeptidation during cell wall synthesis by binding to the D-Ala-D-Ala termini of lipid II. For long, it has been used as a last resort antibiotic. However, since the emergence of the first vancomycin-resistant enterococci in 1987, vancomycin resistance has become widespread, especially in hospitals. We have synthesized and evaluated 110 vancomycin analogs modified at the C-terminal carboxyl group of the heptapeptide moiety with R2NHR1NH2 substituents. Through iterative optimizations of the substituents, we identified vancomycin analogs that fully restore (or even exceed the original inhibitory activity against vancomycin-resistant enterococci (VRE, vancomycin-intermediate (VISA and vancomycin-resistant Staphylococcus aureus (VRSA strains. The best analogs have improved growth inhibitory activity and in vitro therapeutic indices against a broad set of VRE and methicillin-resistant S. aureus (MRSA isolates. They also exceed the activity of vancomycin against Clostridium difficile ribotypes. Vanc-39 and Vanc-42 have a low probability to provoke antibiotic resistance, and overcome different vancomycin resistance mechanisms (VanA, VanB, and VanC1.

The use of analogies in forecasting ecological and societal responses to global warming

Energy Technology Data Exchange (ETDEWEB)

Glantz, M.H. (National Center for Atmospheric Research, Boulder CO (USA). Environmental Research and Societal Impacts Group)

1991-06-01

Due to the limitations of general circulation models, researchers use analogies to look at future climatic change and its effects. Analogies used include the greenhouse, the Altithermal period, regional climates and summertime. Analogical reasoning is a prominent part of general circulation modeling of the atmosphere. Analogies are useful for generating hypotheses and improving understanding, but not as forecasts. The use of an analogy to develop specific policies related to global warming is risky. Historical analogies can provide a first approach to ascertaining the level of societal preparedness for the impacts of a global warming. Each analogy provides additional information about the target problem. 63 refs., 3 figs., 1 tab.

The use of analogies in forecasting ecological and societal responses to global warming

International Nuclear Information System (INIS)

Glantz, M.H.

1991-01-01

Due to the limitations of general circulation models, researchers use analogies to look at future climatic change and its effects. Analogies used include the greenhouse, the Altithermal period, regional climates and summertime. Analogical reasoning is a prominent part of general circulation modeling of the atmosphere. Analogies are useful for generating hypotheses and improving understanding, but not as forecasts. The use of an analogy to develop specific policies related to global warming is risky. Historical analogies can provide a first approach to ascertaining the level of societal preparedness for the impacts of a global warming. Each analogy provides additional information about the target problem. 63 refs., 3 figs., 1 tab

Analog circuit design art, science and personalities

CERN Document Server

Williams, Jim

1991-01-01

This book is far more than just another tutorial or reference guide - it's a tour through the world of analog design, combining theory and applications with the philosophies behind the design process. Readers will learn how leading analog circuit designers approach problems and how they think about solutions to those problems. They'll also learn about the `analog way' - a broad, flexible method of thinking about analog design tasks.A comprehensive and useful guide to analog theory and applications. Covers visualizing the operation of analog circuits. Looks at how to rap

Resistive RAMs as analog trimming elements

Science.gov (United States)

Aziza, H.; Perez, A.; Portal, J. M.

2018-04-01

This work investigates the use of Resistive Random Access Memory (RRAM) as an analog trimming device. The analog storage feature of the RRAM cell is evaluated and the ability of the RRAM to hold several resistance states is exploited to propose analog trim elements. To modulate the memory cell resistance, a series of short programming pulses are applied across the RRAM cell allowing a fine calibration of the RRAM resistance. The RRAM non volatility feature makes the analog device powers up already calibrated for the system in which the analog trimmed structure is embedded. To validate the concept, a test structure consisting of a voltage reference is evaluated.

A flexible analog memory address list manager for PHENIX

International Nuclear Information System (INIS)

Ericson, M.N.; Musrock, M.S.; Britton, C.L. Jr.; Walker, J.W.; Wintenberg, A.L.; Young, G.R.; Allen, M.D.

1996-01-01

A programmable analog memory address list manager has been developed for use with all analog memory-based detector subsystems of PHENIX. The unit provides simultaneous read/write control, cell write-over protection for both a Level-1 trigger decision delay and digitization latency, and re-ordering of AMU addresses following conversion, at a beam crossing rate of 105 ns. Addresses are handled such that up to 5 Level-1 (LVL-1) events can be maintained in the AMU without write-over. Data tagging is implemented for handling overlapping and shared beam-event data packets. Full usage in all PHENIX analog memory-based detector subsystems is accomplished by the use of detector-specific programmable parameters--the number of data samples per valid LVL-1 trigger and the sample spacing. Architectural candidates for the system are discussed with emphasis on implementation implications. Details of the design are presented including application specifics, timing information, and test results from a full implementation using field programmable gate arrays (FPGAs)

Bootstrapped Low-Voltage Analog Switches

DEFF Research Database (Denmark)

Steensgaard-Madsen, Jesper

1999-01-01

Novel low-voltage constant-impedance analog switch circuits are proposed. The switch element is a single MOSFET, and constant-impedance operation is obtained using simple circuits to adjust the gate and bulk voltages relative to the switched signal. Low-voltage (1-volt) operation is made feasible...

Organic anion transporter 3- and organic anion transporting polypeptides 1B1- and 1B3-mediated transport of catalposide

Directory of Open Access Journals (Sweden)

Jeong HU

2015-01-01

Full Text Available Hyeon-Uk Jeong,1 Mihwa Kwon,2 Yongnam Lee,3 Ji Seok Yoo,3 Dae Hee Shin,3 Im-Sook Song,2 Hye Suk Lee1 1College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea; 2College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Korea; 3Central R&D Institute, Yungjin Pharm Co., Ltd., Suwon 443-270, Korea Abstract: We investigated the in vitro transport characteristics of catalposide in HEK293 cells overexpressing organic anion transporter 1 (OAT1, OAT3, organic anion transporting polypeptide 1B1 (OATP1B1, OATP1B3, organic cation transporter 1 (OCT1, OCT2, P-glycoprotein (P-gp, and breast cancer resistance protein (BCRP. The transport mechanism of catalposide was investigated in HEK293 and LLC-PK1 cells overexpressing the relevant transporters. The uptake of catalposide was 319-, 13.6-, and 9.3-fold greater in HEK293 cells overexpressing OAT3, OATP1B1, and OATP1B3 transporters, respectively, than in HEK293 control cells. The increased uptake of catalposide via the OAT3, OATP1B1, and OATP1B3 transporters was decreased to basal levels in the presence of representative inhibitors such as probenecid, furosemide, and cimetidine (for OAT3 and cyclosporin A, gemfibrozil, and rifampin (for OATP1B1 and OATP1B3. The concentration-dependent OAT3-mediated uptake of catalposide revealed the following kinetic parameters: Michaelis constant (Km =41.5 µM, maximum uptake rate (Vmax =46.2 pmol/minute, and intrinsic clearance (CLint =1.11 µL/minute. OATP1B1- and OATP1B3-mediated catalposide uptake also showed concentration dependency, with low CLint values of 0.035 and 0.034 µL/minute, respectively. However, the OCT1, OCT2, OAT1, P-gp, and BCRP transporters were apparently not involved in the uptake of catalposide into cells. In addition, catalposide inhibited the transport activities of OAT3, OATP1B1, and OATP1B3 with half-maximal inhibitory concentration values of 83, 200, and 235 µ

Electrical Circuits and Water Analogies

Science.gov (United States)

Smith, Frederick A.; Wilson, Jerry D.

1974-01-01

Briefly describes water analogies for electrical circuits and presents plans for the construction of apparatus to demonstrate these analogies. Demonstrations include series circuits, parallel circuits, and capacitors. (GS)

Analog Multilayer Perceptron Circuit with On-chip Learning: Portable Electronic Nose

Science.gov (United States)

Pan, Chih-Heng; Tang, Kea-Tiong

2011-09-01

This article presents an analog multilayer perceptron (MLP) neural network circuit with on-chip back propagation learning. This low power and small area analog MLP circuit is proposed to implement as a classifier in an electronic nose (E-nose). Comparing with the E-nose using microprocessor or FPGA as a classifier, the E-nose applying analog circuit as a classifier can be faster and much smaller, demonstrate greater power efficiency and be capable of developing a portable E-nose [1]. The system contains four inputs, four hidden neurons, and only one output neuron; this simple structure allows the circuit to have a smaller area and less power consumption. The circuit is fabricated using TSMC 0.18 μm 1P6M CMOS process with 1.8 V supply voltage. The area of this chip is 1.353×1.353 mm2 and the power consumption is 0.54 mW. Post-layout simulations show that the proposed analog MLP circuit can be successively trained to identify three kinds of fruit odors.

Caffeic acid phenethyl ester downregulates phospholipase D1 via direct binding and inhibition of NFκB transactivation

Energy Technology Data Exchange (ETDEWEB)

Park, Mi Hee; Kang, Dong Woo [Department of Molecular Biology, Pusan National University, Busan 609-735 (Korea, Republic of); Jung, Yunjin [College of Pharmacy, Pusan National University, Busan 609-735 (Korea, Republic of); Choi, Kang-Yell [Translational Research Center for Protein Function Control, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul (Korea, Republic of); Min, Do Sik, E-mail: minds@pusan.ac.kr [Department of Molecular Biology, Pusan National University, Busan 609-735 (Korea, Republic of)

2013-12-06

Highlights: •We found CAFÉ, a natural product that suppresses expression and activity of PLD1. •CAPE decreased PLD1 expression by inhibiting NFκB transactivation. •CAPE rapidly inhibited PLD activity via its binding to a Cys837 of PLD1. •PLD1 downregulation by CAPE inhibited invasion and proliferation of glioma cells. -- Abstract: Upregulation of phospholipase D (PLD) is functionally linked with oncogenic signals and tumorigenesis. Caffeic acid phenethyl ester (CAPE) is an active compound of propolis extract that exhibits anti-proliferative, anti-inflammatory, anti-oxidant, and antineoplastic properties. In this study, we demonstrated that CAPE suppressed the expression of PLD1 at the transcriptional level via inhibition of binding of NFκB to PLD1 promoter. Moreover, CAPE, but not its analogs, bound to a Cys837 residue of PLD1 and inhibited enzymatic activity of PLD. CAPE also decreased activation of matrix metalloproteinases-2 induced by phosphatidic acid, a product of PLD activity. Ultimately, CAPE-induced downregulation of PLD1 suppressed invasion and proliferation of glioma cells. Taken together, the results of this study indicate that CAPE might contribute to anti-neoplastic effect by targeting PLD1.

Comparison of genetic variations of the SLCO1B1, SLCO1B3, and SLCO2B1 genes among five ethnic groups.

Science.gov (United States)

Namgoong, Suhg; Cheong, Hyun Sub; Kim, Ji On; Kim, Lyoung Hyo; Na, Han Sung; Koh, In Song; Chung, Myeon Woo; Shin, Hyoung Doo

2015-11-01

Organic anion-transporting polypeptide (OATP; gene symbol, SLCO) transporters are generally involved in the uptake of multiple drugs and their metabolites at most epithelial barriers. The pattern of single-nucleotide polymorphisms (SNPs) in these transporters may be determinants of interindividual variability in drug disposition and response. The objective of this study was to define the distribution of SNPs of three SLCO genes, SLCO1B1, SLCO1B3, and SLCO2B1, in a Korean population and other ethnic groups. The study was screened using the Illumina GoldenGate assay for genomic DNA from 450 interethnic subjects, including 11 pharmacogenetic core variants and 76 HapMap tagging SNPs. The genotype distribution of the Korean population was similar to East Asian populations, but significantly different from African American and European American cohorts. These interethnic differences will be useful information for prospective studies, including genetic association and pharmacogenetic studies of drug metabolism by SLCO families. Copyright © 2015 Elsevier B.V. All rights reserved.

Design of a 12-bit 80MS/s pipeline analog-to-digital converter for PLC-VDSL applications

Science.gov (United States)

Ruiz-Amaya, Jesus; Delgado-Restituto, Manuel; Fernandez-Bootello, Juan F.; de la Rosa, Jose M.

2005-06-01

This paper describes the design of a 12-bit 80MS/s pipeline Analog-to-Digital converter implemented in 0.13mm CMOS logic technology. The design has been computer-aided by a developed toolbox for the simulation, synthesis and verification of Nyquist-Rate Analog-to-Digital and Digital-to-Analog Converters in MATLAB. The embedded simulator uses SIMULINK C-coded S-functions to model all required subcircuits including their main error mechanisms. This approach allows to drastically speed up the simulation CPU-time and makes the proposed tool an advantageous alternative for fast exploration of requirements and as a design validation tool. The converter is based on a 10-stage pipeline preceded by a sample/hold with bootstrapping technique. Each stage gives 1.5 effective bits, except for the first one which provides 2.5 effective bits to improve linearity. The Analog-to-Digital architecture uses redundant bits for digital correction, it is planned to be implemented without using calibration and employs a subranging pipeline look-ahead technique to increase speed. Substrate biased MOSFETs in the depletion region are used as capacitors, linearized by a series compensation. Simulation results show that the Multi-Tone Power Ratio is higher than 56dB for several DMT test signals and the estimated Signal-to-Noise Ratio yield is supposed to be better than 62 dB from DC to Nyquist frequency. The converter dissipates less than 150mW from a 3.3V supply and occupies less than 4 mm2 die area. The results have been checked with all process corners from -40° to 85° and power supply from 3V to 3.6V.

Cross-Domain Analogies as Relating Derived Relations among Two Separate Relational Networks

Science.gov (United States)

Ruiz, Francisco J; Luciano, Carmen

2011-01-01

Contemporary behavior analytic research is making headway in analyzing analogy as the establishment of a relation of coordination among common types of trained or derived relations. Previous studies have been focused on within-domain analogy. The current study expands previous research by analyzing cross-domain analogy as relating relations among separate relational networks and by correlating participants' performance with a standard measure of analogical reasoning. In two experiments, adult participants first completed general intelligence and analogical reasoning tests. Subsequently, they were exposed to a computerized conditional discrimination training procedure designed to create two relational networks, each consisting of two 3-member equivalence classes. The critical test was a two-part analogical test in which participants had to relate combinatorial relations of coordination and distinction between the two relational networks. In Experiment 1, combinatorial relations for each network were individually tested prior to analogical testing, but in Experiment 2 they were not. Across both experiments, 65% of participants passed the analogical test on the first attempt. Moreover, results from the training procedure were strongly correlated with the standard measure of analogical reasoning. PMID:21547072

Challenges in Using Analogies

Science.gov (United States)

Lin, Shih-Yin; Singh, Chandralekha

2011-01-01

Learning physics requires understanding the applicability of fundamental principles in a variety of contexts that share deep features. One way to help students learn physics is via analogical reasoning. Students can be taught to make an analogy between situations that are more familiar or easier to understand and another situation where the same…

Analogical reasoning abilities of recovering alcoholics.

Science.gov (United States)

Gardner, M K; Clark, E; Bowman, M A; Miller, P J

1989-08-01

This study investigated analogical reasoning abilities of alcoholics who had been abstinent from alcohol for at least 1 year. Their performance was compared to that of nonalcoholic controls matched as a group for education, age, and gender. Solution times and error rates were modeled using a regression model. Results showed a nonsignificant trend for alcoholics to be faster, but more error prone, than controls. The same componential model applied to both groups, and fit them equally well. Although differences have been found in analogical reasoning ability between controls and alcoholics immediately following detoxification, we find no evidence of differences after extended periods of sobriety.

The Micro-Category Account of Analogy

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Green, Adam E.; Fugelsang, Jonathan A.; Kraemer, David J. M.; Dunbar, Kevin N.

2008-01-01

Here, we investigate how activation of mental representations of categories during analogical reasoning influences subsequent cognitive processing. Specifically, we present and test the central predictions of the "Micro-Category" account of analogy. This account emphasizes the role of categories in aligning terms for analogical mapping. In a…

Jumonji/Arid1b (Jarid1b) protein modulates human esophageal cancer cell growth

Science.gov (United States)

KANO, YOSHIHIRO; KONNO, MASAMITSU; OHTA, KATSUYA; HARAGUCHI, NAOTSUGU; NISHIKAWA, SHIMPEI; KAGAWA, YOSHINORI; HAMABE, ATSUSHI; HASEGAWA, SHINICHIRO; OGAWA, HISATAKA; FUKUSUMI, TAKAHITO; NOGUCHI, YUKO; OZAKI, MIYUKI; KUDO, TOSHIHIRO; SAKAI, DAISUKE; SATOH, TAROH; ISHII, MASARU; MIZOHATA, EIICHI; INOUE, TAKESHI; MORI, MASAKI; DOKI, YUICHIRO; ISHII, HIDESHI

2013-01-01

Although esophageal cancer is highly heterogeneous and the involvement of epigenetic regulation of cancer stem cells is highly suspected, the biological significance of epigenetically modified molecules that regulate different subpopulations remains to be firmly established. Using esophageal cancer cells, we investigated the functional roles of the H3K4 demethylase Jumonji/Arid1b (Jarid1b) (Kdm5b/Plu-1/Rbp2-h1), an epigenetic factor that is required for continuous cell growth in melanoma. JARID1B knockdown resulted in the suppression of esophageal cancer cell growth, sphere formation and invasion ability and was associated with loss of epithelial marker expression. However, these inhibitory effects observed on tumor formation were reverted subsequent to subcutaneous inoculation of these cells into immune-deficient mice. These results indicated that JARID1B plays a role in maintaining cancer stem cells in the esophagus and justifies the rationale for studying the effects of continuous inhibition of this epigenetic factor in esophageal cancer. PMID:24649241

An emergent approach to analogical inference

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Thibodeau, Paul H.; Flusberg, Stephen J.; Glick, Jeremy J.; Sternberg, Daniel A.

2013-03-01

In recent years, a growing number of researchers have proposed that analogy is a core component of human cognition. According to the dominant theoretical viewpoint, analogical reasoning requires a specific suite of cognitive machinery, including explicitly coded symbolic representations and a mapping or binding mechanism that operates over these representations. Here we offer an alternative approach: we find that analogical inference can emerge naturally and spontaneously from a relatively simple, error-driven learning mechanism without the need to posit any additional analogy-specific machinery. The results also parallel findings from the developmental literature on analogy, demonstrating a shift from an initial reliance on surface feature similarity to the use of relational similarity later in training. Variants of the model allow us to consider and rule out alternative accounts of its performance. We conclude by discussing how these findings can potentially refine our understanding of the processes that are required to perform analogical inference.

Working memory predicts children's analogical reasoning.

Science.gov (United States)

Simms, Nina K; Frausel, Rebecca R; Richland, Lindsey E

2018-02-01

Analogical reasoning is the cognitive skill of drawing relationships between representations, often between prior knowledge and new representations, that allows for bootstrapping cognitive and language development. Analogical reasoning proficiency develops substantially during childhood, although the mechanisms underlying this development have been debated, with developing cognitive resources as one proposed mechanism. We explored the role of executive function (EF) in supporting children's analogical reasoning development, with the goal of determining whether predicted aspects of EF were related to analogical development at the level of individual differences. We assessed 5- to 11-year-old children's working memory, inhibitory control, and cognitive flexibility using measures from the National Institutes of Health Toolbox Cognition battery. Individual differences in children's working memory best predicted performance on an analogical mapping task, even when controlling for age, suggesting a fundamental interrelationship between analogical reasoning and working memory development. These findings underscore the need to consider cognitive capacities in comprehensive theories of children's reasoning development. Copyright © 2017 Elsevier Inc. All rights reserved.

Selection and characterization of single stranded DNA aptamers recognizing fumonisin B1

International Nuclear Information System (INIS)

Chen, Xiujuan; Huang, Yukun; Duan, Nuo; Wu, Shijia; Xia, Yu; Ma, Xiaoyuan; Ding, Zhansheng; Wang, Zhouping; Zhu, Changqing; Jiang, Yuan

2014-01-01

We present an improved method for the selection of single-stranded DNA aptamers that can recognize fumonisin B 1 (FB 1 ). FB 1 is a carcinogenic mycotoxin mainly found in corn and corn-based food products worldwide, posing a global threat to feed and food safety. Selection was based on the mag-SELEX (magnetic bead systematic evolution of ligands by exponential enrichment) technology modified by adopting free analogs of targets rather than immobilized targets for counter selections. Firstly, aptamer candidates for FB 1 were selected from an 80 nt random DNA library after 13 rounds of selection. Next, binding assays were performed for affinity evaluation, and circular dichroism spectroscopy was used to investigate their conformation. A high-affinity aptamer designated as F10 (with a dissociation constant of 62 ± 5 nM) was identified and tested for its specificity by competitive binding assays. The results demonstrate that this improved mag-SELEX technology facilitates aptamer screening because it avoids the tedious immobilization of counter-selection molecules on magnetic beads. The aptamers obtained by this technique open new possibilities for the detection of FB 1 via aptasensors. (author)

Process and circuiting arrangement for the conversion of analog signals to digital signals and digital signals to analog signals

International Nuclear Information System (INIS)

Wintzer, K.

1977-01-01

Process for analog-to-digital and digital-to-analog conversion in telecommunication systems whose outstations each have an analog transmitter and an analog receiver. The invention illustrates a method of reducing the power demand of the converters at times when no conversion processes take place. (RW) [de

Karakteristik Cumi-Cumi Analog dari Surimi Ikan Patin (Pangasius hypopthalmus dengan Menggunakan berbagai Jenis Pati

Directory of Open Access Journals (Sweden)

Theresia Dwi Suryaningrum

2017-05-01

Full Text Available Cumi-cumi analog merupakan produk olahan tiruan dari surimi yang memiliki tekstur elastis, warna putih dan rasa khas cumi-cumi. Penelitian pembuatan cumi-cumi analog dari surimi ikan patin (Pangasius hypopthalmus dengan menggunakan berbagai jenis pati telah dilakukan.Penelitian ini dibagi menjadi 2 tahap, yaitu tahap 1 berupa optimasi formula cumi-cumi analoguntuk mendapatkan tekstur dan warna seperti produk yang ditiru. Formulasi cumi-cumi analog didasarkan pada formulasi kamaboko dengan perlakuan penambahan karaginan (1% dan 5%, konjak (1,5% dan 2% dan pewarna putih (cloudy (1% dan 2%. Penelitian tahap ke 2 dilakukan untuk mempelajari pengaruh jenis pati yaitu tapioka, kentang dan sagu terhadap karakteristik cumi-cumi analog yang dihasilkan. Pengamatan dilakukan terhadap nilai gizi, sifat fisik dan sensoricumi-cumi analog yang dihasilkan. Hasil penelitian menunjukkan penggunaan kombinasi karaginan 1%, konjak 1,5% dan pewarna putih 2% menghasilkan tekstur produk yang elastisitasdan warnanya mendekati produk yang ditiru. Penggunaan berbagai jenis pati tidak berpengaruhterhadap nilai gizi dan pH, namun berpengaruh nyata terhadap sifat fisik cumi-cumi analog yang dihasilkan. Cumi-cumi analog yang diolah dengan pati sagu menghasilkan tingkat kekerasan dan elastisitas paling tinggi, namun derajat putih paling rendah dibandingkan dengan tepung lainnya. Sedangkan cumi-cumi analog yang diolah dengan pati kentang menghasilkan kekerasan,elastisitas dan daya menahan air yang paling rendah dibandingkan dengan perlakuan lainnya. Uji sensori menunjukkan bahwa cumi-cumi analog yang diolah dengan menggunakan pati tapioka menghasilkan warna, rasa dan tekstur yang lebih disukai panelis dibandingkan dengan tepunglainnya. Sedangk an cumi-cumi analog yang diolah dengan pati kentang menghasilkan kenampakan dan bau yang lebih disukai panelis, namun mempunyai tekstur dengan nilai kesukaan yang paling rendah.

Analogies and the 5E Model

Science.gov (United States)

Orgill, Mary Kay; Thomas, Megan

2007-01-01

Science classes are full of abstract or challenging concepts that are easier to understand if an analogy is used to illustrate the points. Effective analogies motivate students, clarify students' thinking, help students overcome misconceptions, and give students ways to visualize abstract concepts. When they are used appropriately, analogies can…

How Analogy Drives Physics

International Nuclear Information System (INIS)

Hofstadter, Doug

2004-01-01

Many new ideas in theoretical physics come from analogies to older ideas in physics. For instance, the abstract notion of 'isospin' (or isotopic spin) originated in the prior concept of 'spin' (quantized angular momentum); likewise, the concept of 'phonon' (quantum of sound, or quantized collective excitation of a crystal) was based on the prior concept of 'photon' (quantum of light, or quantized element of the electromagnetic field). But these two examples, far from being exceptions, in fact represent the bread and butter of inventive thinking in physics. In a nutshell, intraphysics analogy-making -- borrowing by analogy with something already known in another area of physics -- is central to the progress of physics. The aim of this talk is to reveal the pervasiveness -- indeed, the indispensability -- of this kind of semi-irrational, wholly intuitive type of thinking (as opposed to more deductive mathematical inference) in the mental activity known as 'doing physics'. Speculations as to why wild analogical leaps are so crucial to the act of discovery in physics (as opposed to other disciplines) will be offered.

Data of evolutionary structure change: 1BT8B-1EN5B [Confc[Archive

Lifescience Database Archive (English)

Full Text Available e>KGLKK----GTTLQ >H ---- > ATOM ...bChain>B 1BT8B KNMAPKGSAPERPT cture>H ...DChain> LVLKG--DKLAV >EEEE -- EEEE...ence>LVWDPLGKRINT >EEEE EEEEe> AT...re> ATOM 2237 CA LYS B 80 12.251 15.102 18.409 1.00 11.94 C

Is the link from working memory to analogy causal? No analogy improvements following working memory training gains.

Directory of Open Access Journals (Sweden)

J Elizabeth Richey

Full Text Available Analogical reasoning has been hypothesized to critically depend upon working memory through correlational data, but less work has tested this relationship through experimental manipulation. An opportunity for examining the connection between working memory and analogical reasoning has emerged from the growing, although somewhat controversial, body of literature suggests complex working memory training can sometimes lead to working memory improvements that transfer to novel working memory tasks. This study investigated whether working memory improvements, if replicated, would increase analogical reasoning ability. We assessed participants' performance on verbal and visual analogy tasks after a complex working memory training program incorporating verbal and spatial tasks. Participants' improvements on the working memory training tasks transferred to other short-term and working memory tasks, supporting the possibility of broad effects of working memory training. However, we found no effects on analogical reasoning. We propose several possible explanations for the lack of an impact of working memory improvements on analogical reasoning.

Is the link from working memory to analogy causal? No analogy improvements following working memory training gains.

Science.gov (United States)

Richey, J Elizabeth; Phillips, Jeffrey S; Schunn, Christian D; Schneider, Walter

2014-01-01

Analogical reasoning has been hypothesized to critically depend upon working memory through correlational data, but less work has tested this relationship through experimental manipulation. An opportunity for examining the connection between working memory and analogical reasoning has emerged from the growing, although somewhat controversial, body of literature suggests complex working memory training can sometimes lead to working memory improvements that transfer to novel working memory tasks. This study investigated whether working memory improvements, if replicated, would increase analogical reasoning ability. We assessed participants' performance on verbal and visual analogy tasks after a complex working memory training program incorporating verbal and spatial tasks. Participants' improvements on the working memory training tasks transferred to other short-term and working memory tasks, supporting the possibility of broad effects of working memory training. However, we found no effects on analogical reasoning. We propose several possible explanations for the lack of an impact of working memory improvements on analogical reasoning.

Metabolomic Discovery of Novel Urinary Galabiosylceramide Analogs as Fabry Disease Biomarkers

Science.gov (United States)

Boutin, Michel; Auray-Blais, Christiane

2015-03-01

Fabry disease is an X-linked, complex, multisystemic lysosomal storage disorder presenting marked phenotypic and genotypic variability among affected male and female patients. Glycosphingolipids, mainly globotriaosylceramide (Gb3) isoforms/analogs, globotriaosylsphingosine (lyso-Gb3) and analogs, as well as galabiosylceramide (Ga2) isoforms/analogs accumulate in the vascular endothelium, nerves, cardiomyocytes, renal glomerular and tubular epithelial cells, and biological fluids. The search for biomarkers reflecting disease severity and progression is still on-going. A metabolomic study using quadrupole time-of-flight mass spectrometry has revealed 22 galabiosylceramide isoforms/analogs in urine of untreated Fabry patients classified in seven groups according to their chemical structure: (1) Saturated fatty acid; (2) one extra double bond; (3) two extra double bonds; (4) hydroxylated saturated fatty acid; (5) hydroxylated fatty acid and one extra double bond; (6) hydrated sphingosine and hydroxylated fatty acid; (7) methylated amide linkage. Relative quantification of both Ga2 and Gb3 isoforms/analogs was performed. All these biomarkers are significantly more abundant in urine samples from untreated Fabry males compared with healthy male controls. A significant amount of Ga2 isoforms/analogs, accounting for 18% of all glycosphingolipids analyzed (Ga2 + Gb3 and respective isoforms/analogs), were present in urine of Fabry patients. Gb3 isoforms containing saturated fatty acids are the most abundant (60.9%) compared with 26.3% for Ga2. A comparison between Ga2 isoforms/analogs and their Gb3 counterparts also showed that the proportion of analogs with hydroxylated fatty acids is significantly greater for Ga2 (35.8%) compared with Gb3 (1.9%). These results suggest different biological pathways involved in the synthesis and/or degradation of Gb3 and Ga2 metabolites.

Beginning analog electronics through projects

CERN Document Server

Singmin, Andrew

2001-01-01

Analog electronics is the simplest way to start a fun, informative, learning program. Beginning Analog Electronics Through Projects, Second Edition was written with the needs of beginning hobbyists and students in mind. This revision of Andrew Singmin's popular Beginning Electronics Through Projects provides practical exercises, building techniques, and ideas for useful electronics projects. Additionally, it features new material on analog and digital electronics, and new projects for troubleshooting test equipment.Published in the tradition of Beginning Electronics Through Projects an

GABAA receptor activity modulating piperine analogs: In vitro metabolic stability, metabolite identification, CYP450 reaction phenotyping, and protein binding.

Science.gov (United States)

Zabela, Volha; Hettich, Timm; Schlotterbeck, Götz; Wimmer, Laurin; Mihovilovic, Marko D; Guillet, Fabrice; Bouaita, Belkacem; Shevchenko, Bénédicte; Hamburger, Matthias; Oufir, Mouhssin

2018-01-01

In a screening of natural products for allosteric modulators of GABA A receptors (γ-aminobutyric acid type A receptor), piperine was identified as a compound targeting a benzodiazepine-independent binding site. Given that piperine is also an activator of TRPV1 (transient receptor potential vanilloid type 1) receptors involved in pain signaling and thermoregulation, a series of piperine analogs were prepared in several cycles of structural optimization, with the aim of separating GABA A and TRPV1 activating properties. We here investigated the metabolism of piperine and selected analogs in view of further cycles of lead optimization. Metabolic stability of the compounds was evaluated by incubation with pooled human liver microsomes, and metabolites were analyzed by UHPLC-Q-TOF-MS. CYP450 isoenzymes involved in metabolism of compounds were identified by reaction phenotyping with Silensomes™. Unbound fraction in whole blood was determined by rapid equilibrium dialysis. Piperine was the metabolically most stable compound. Aliphatic hydroxylation, and N- and O-dealkylation were the major routes of oxidative metabolism. Piperine was exclusively metabolized by CYP1A2, whereas CYP2C9 contributed significantly in the oxidative metabolism of all analogs. Extensive binding to blood constituents was observed for all compounds. Copyright © 2017 Elsevier B.V. All rights reserved.

Dynamic problems of power reactors and analogic devices

International Nuclear Information System (INIS)

Braffort, P.

1955-01-01

The raise of the nuclear physics came with heavy mathematical developments. The analogical installations became especially useful for precise calculations of parameters which depend the running of a reactor. They permit between other to study of kinetic problems and especially ''cybernetics'' of nuclear reactors. It doesn't make a doubt that their use will become widespread, not only in the calculations laboratories, in services for servo-mechanisms study, but also in the control panels of the reactors themselves. (M.B.) [fr

Analog circuit design art, science, and personalities

CERN Document Server

Williams, Jim

1991-01-01

Analog Circuit Design: Art, Science, and Personalities discusses the many approaches and styles in the practice of analog circuit design. The book is written in an informal yet informative manner, making it easily understandable to those new in the field. The selection covers the definition, history, current practice, and future direction of analog design; the practice proper; and the styles in analog circuit design. The book also includes the problems usually encountered in analog circuit design; approach to feedback loop design; and other different techniques and applications. The text is

Variability in equatorial B0 and B1

International Nuclear Information System (INIS)

Adeniyi, J.O.; Radicella, S.M.

2002-01-01

Variability of ionospheric profile parameters B0 and B1, below the F2 peak is investigated for an equatorial station at two levels of solar activities. The whole 24 hours of the day and the four seasons of the year are covered. Absolute and relative variability indices were utilized in the study. Some evidences of correlations of variability index and profiles parameters were observed. Daytime values of relative variability in B1 at solar minimum were found to be greater than those of solar maximum. (author)

Analogy as a strategy for supporting complex problem solving under uncertainty.

Science.gov (United States)

Chan, Joel; Paletz, Susannah B F; Schunn, Christian D

2012-11-01

Complex problem solving in naturalistic environments is fraught with uncertainty, which has significant impacts on problem-solving behavior. Thus, theories of human problem solving should include accounts of the cognitive strategies people bring to bear to deal with uncertainty during problem solving. In this article, we present evidence that analogy is one such strategy. Using statistical analyses of the temporal dynamics between analogy and expressed uncertainty in the naturalistic problem-solving conversations among scientists on the Mars Rover Mission, we show that spikes in expressed uncertainty reliably predict analogy use (Study 1) and that expressed uncertainty reduces to baseline levels following analogy use (Study 2). In addition, in Study 3, we show with qualitative analyses that this relationship between uncertainty and analogy is not due to miscommunication-related uncertainty but, rather, is primarily concentrated on substantive problem-solving issues. Finally, we discuss a hypothesis about how analogy might serve as an uncertainty reduction strategy in naturalistic complex problem solving.

Targeting (cellular) lysosomal acid ceramidase by B13: design, synthesis and evaluation of novel DMG-B13 ester prodrugs.

Science.gov (United States)

Bai, Aiping; Szulc, Zdzislaw M; Bielawski, Jacek; Pierce, Jason S; Rembiesa, Barbara; Terzieva, Silva; Mao, Cungui; Xu, Ruijuan; Wu, Bill; Clarke, Christopher J; Newcomb, Benjamin; Liu, Xiang; Norris, James; Hannun, Yusuf A; Bielawska, Alicja

2014-12-15

Acid ceramidase (ACDase) is being recognized as a therapeutic target for cancer. B13 represents a moderate inhibitor of ACDase. The present study concentrates on the lysosomal targeting of B13 via its N,N-dimethylglycine (DMG) esters (DMG-B13 prodrugs). Novel analogs, the isomeric mono-DMG-B13, LCL522 (3-O-DMG-B13·HCl) and LCL596 (1-O-DMG-B13·HCl) and di-DMG-B13, LCL521 (1,3-O, O-DMG-B13·2HCl) conjugates, were designed and synthesized through N,N-dimethyl glycine (DMG) esterification of the hydroxyl groups of B13. In MCF7 cells, DMG-B13 prodrugs were efficiently metabolized to B13. The early inhibitory effect of DMG-B13 prodrugs on cellular ceramidases was ACDase specific by their lysosomal targeting. The corresponding dramatic decrease of cellular Sph (80-97% Control/1h) by DMG-B13 prodrugs was mainly from the inhibition of the lysosomal ACDase. Copyright © 2014 Elsevier Ltd. All rights reserved.

Characterization of a novel telomerase-immortalized human endometrial stromal cell line, St-T1b

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Brosens Jan J

2009-07-01

Full Text Available Abstract Background Coordinated differentiation of the endometrial compartments in the second half of the menstrual cycle is a prerequisite for the establishment of pregnancy. Endometrial stromal cells (ESC decidualize under the influence of ovarian progesterone to accommodate implantation of the blastocyst and support establishment of the placenta. Studies into the mechanisms of decidualization are often hampered by the lack of primary ESC. Here we describe a novel immortalized human ESC line. Methods Primary ESC were immortalized by the transduction of telomerase. The resultant cell line, termed St-T1b, was characterized for its morphological and biochemical properties by immunocytochemistry, RT-PCR and immunoblotting. Its progestational response was tested using progesterone and medroxyprogesterone acetate with and without 8-Br-cAMP, an established inducer of decidualization in vitro. Results St-T1b were positive for the fibroblast markers vimentin and CD90 and negative for the epithelial marker cytokeratin-7. They acquired a decidual phenotype indistinguishable from primary ESC in response to cAMP stimulation. The decidual response was characterized by transcriptional activation of marker genes, such as PRL, IGFBP1, and FOXO1, and enhanced protein levels of the tumor suppressor p53 and the metastasis suppressor KAI1 (CD82. Progestins alone had no effect on St-T1b cells, but medroxyprogesterone acetate greatly enhanced the cAMP-stimulated expression of IGFBP-1 after 3 and 7 days. Progesterone, albeit more weakly, also augmented the cAMP-induced IGFBP-1 production but only after 7 days of treatment. The cell line remained stable in continuous culture for more than 150 passages. Conclusion St-T1b express the appropriate phenotypic ESC markers and their decidual response closely mimics that of primary cultures. Decidualization is efficiently induced by cAMP analog and enhanced by medroxyprogesterone acetate, and, to a lesser extent, by natural

Synthetic Analogs of Phospholipid Metabolites as Antimalarials.

Science.gov (United States)

1979-07-01

phosphatidic acid analogs containing ether and phosphonate groups; completely non- hydrolyzable lecithin analogs containing phosphinate and ether groups...substance is a completely non- hydrolyzable analog of lecithin containing ether and phosphonate moieties instead of the normally labile carboxylic and...and also ant-i-phospholipase C (clostridial enzyme) activity. This substance Is a completely non- hydrolyzable analog of lecithin containing ether

BPM ANALOG FRONT-END ELECTRONICS BASED ON THE AD8307 LOG AMPLIFIER

International Nuclear Information System (INIS)

R. SHURTER; ET AL

2000-01-01

Beam position monitor (BPM) signal-processing electronics utilizing the Analog Devices AD8307 logarithmic amplifier has been developed for the Low Energy Demonstration Accelerator (LEDA), part of the Accelerator Production of Tritium (APT) project at Los Alamos. The low-pass filtered 350 MHz fundamental signal from each of the four microstrip electrodes in a BPM is ''detected'' by an AD8307 log amp, amplified and scaled to accommodate the 0 to +5V input of an analog-to-digital (A/D) converter. The resultant four digitized signals represent a linear power relationship to the electrode signals, which are in turn related to beam current and position. As the AD8307 has a potential dynamic range of approximately 92 dB, much attention must be given to noise reduction, sources of which can be digital signals on the same board, power supplies, inter-channel coupling, stray RF and others. This paper will describe the operational experience of this particular analog front-end electronic circuit design

Analogical reasoning in a capuchin monkey (Cebus apella).

Science.gov (United States)

Kennedy, Erica Hoy; Fragaszy, Dorothy M

2008-05-01

Previous evidence has suggested that analogical reasoning (recognizing similarities among object relations when the objects themselves are dissimilar) is limited to humans and apes. This study investigated whether capuchin monkeys (Cebus apella) can use analogical reasoning to solve a 3-dimensional search task. The task involved hiding a food item under 1 of 2 or 3 plastic cups of different sizes and then allowing subjects to search for food hidden under the cup of analogous size in their own set of cups. Four monkeys were exposed to a series of relational matching tasks. If subjects reached criterion on these tasks, they were exposed to relational transfer tasks involving novel stimuli. Three of the monkeys failed to reach criterion on the basic relational matching tasks and therefore were not tested further. One monkey, however, revealed above-chance performance on a series of transfer tasks with 3 novel stimuli. This evidence suggests that contrary to previous arguments, a member of a New World monkey species can solve an analogical problem. PsycINFO Database Record (c) 2008 APA, all rights reserved.

Community Decadal Panel for Terrestrial Analogs to Mars

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Barlow, N. G.; Farr, T.; Baker, V. R.; Bridges, N.; Carsey, F.; Duxbury, N.; Gilmore, M. S.; Green, J. R.; Grin, E.; Hansen, V.; Keszthelyi, L.; Lanagan, P.; Lentz, R.; Marinangeli, L.; Morris, P. A.; Ori, G. G.; Paillou, P.; Robinson, C.; Thomson, B.

2001-11-01

It is well recognized that interpretations of Mars must begin with the Earth as a reference. The most successful comparisons have focused on understanding geologic processes on the Earth well enough to extrapolate to Mars' environment. Several facets of terrestrial analog studies have been pursued and are continuing. These studies include field workshops, characterization of terrestrial analog sites for Mars, instrument tests, laboratory measurements (including analysis of martian meteorites), and computer and laboratory modeling. The combination of all these activities allows scientists to constrain the processes operating in specific terrestrial environments and extrapolate how similar processes could affect Mars. The Terrestrial Analogs for Mars Community Panel is considering the following two key questions: (1) How do terrestrial analog studies tie in to the MEPAG science questions about life, past climate, and geologic evolution of Mars, and (2) How can future instrumentation be used to address these questions. The panel is considering the issues of data collection, value of field workshops, data archiving, laboratory measurements and modeling, human exploration issues, association with other areas of solar system exploration, and education and public outreach activities.

Towards a category theory approach to analogy: Analyzing re-representation and acquisition of numerical knowledge.

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Jairo A Navarrete

2017-08-01

Full Text Available Category Theory, a branch of mathematics, has shown promise as a modeling framework for higher-level cognition. We introduce an algebraic model for analogy that uses the language of category theory to explore analogy-related cognitive phenomena. To illustrate the potential of this approach, we use this model to explore three objects of study in cognitive literature. First, (a we use commutative diagrams to analyze an effect of playing particular educational board games on the learning of numbers. Second, (b we employ a notion called coequalizer as a formal model of re-representation that explains a property of computational models of analogy called "flexibility" whereby non-similar representational elements are considered matches and placed in structural correspondence. Finally, (c we build a formal learning model which shows that re-representation, language processing and analogy making can explain the acquisition of knowledge of rational numbers. These objects of study provide a picture of acquisition of numerical knowledge that is compatible with empirical evidence and offers insights on possible connections between notions such as relational knowledge, analogy, learning, conceptual knowledge, re-representation and procedural knowledge. This suggests that the approach presented here facilitates mathematical modeling of cognition and provides novel ways to think about analogy-related cognitive phenomena.

Towards a category theory approach to analogy: Analyzing re-representation and acquisition of numerical knowledge.

Science.gov (United States)

Navarrete, Jairo A; Dartnell, Pablo

2017-08-01

Category Theory, a branch of mathematics, has shown promise as a modeling framework for higher-level cognition. We introduce an algebraic model for analogy that uses the language of category theory to explore analogy-related cognitive phenomena. To illustrate the potential of this approach, we use this model to explore three objects of study in cognitive literature. First, (a) we use commutative diagrams to analyze an effect of playing particular educational board games on the learning of numbers. Second, (b) we employ a notion called coequalizer as a formal model of re-representation that explains a property of computational models of analogy called "flexibility" whereby non-similar representational elements are considered matches and placed in structural correspondence. Finally, (c) we build a formal learning model which shows that re-representation, language processing and analogy making can explain the acquisition of knowledge of rational numbers. These objects of study provide a picture of acquisition of numerical knowledge that is compatible with empirical evidence and offers insights on possible connections between notions such as relational knowledge, analogy, learning, conceptual knowledge, re-representation and procedural knowledge. This suggests that the approach presented here facilitates mathematical modeling of cognition and provides novel ways to think about analogy-related cognitive phenomena.

Structure problems in the analog computation

International Nuclear Information System (INIS)

Braffort, P.L.

1957-01-01

The recent mathematical development showed the importance of elementary structures (algebraic, topological, etc.) in abeyance under the great domains of classical analysis. Such structures in analog computation are put in evidence and possible development of applied mathematics are discussed. It also studied the topological structures of the standard representation of analog schemes such as additional triangles, integrators, phase inverters and functions generators. The analog method gives only the function of the variable: time, as results of its computations. But the course of computation, for systems including reactive circuits, introduces order structures which are called 'chronological'. Finally, it showed that the approximation methods of ordinary numerical and digital computation present the same structure as these analog computation. The structure analysis permits fruitful comparisons between the several domains of applied mathematics and suggests new important domains of application for analog method. (M.P.)

DockoMatic: automated peptide analog creation for high throughput virtual screening.

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Jacob, Reed B; Bullock, Casey W; Andersen, Tim; McDougal, Owen M

2011-10-01

The purpose of this manuscript is threefold: (1) to describe an update to DockoMatic that allows the user to generate cyclic peptide analog structure files based on protein database (pdb) files, (2) to test the accuracy of the peptide analog structure generation utility, and (3) to evaluate the high throughput capacity of DockoMatic. The DockoMatic graphical user interface interfaces with the software program Treepack to create user defined peptide analogs. To validate this approach, DockoMatic produced cyclic peptide analogs were tested for three-dimensional structure consistency and binding affinity against four experimentally determined peptide structure files available in the Research Collaboratory for Structural Bioinformatics database. The peptides used to evaluate this new functionality were alpha-conotoxins ImI, PnIA, and their published analogs. Peptide analogs were generated by DockoMatic and tested for their ability to bind to X-ray crystal structure models of the acetylcholine binding protein originating from Aplysia californica. The results, consisting of more than 300 simulations, demonstrate that DockoMatic predicts the binding energy of peptide structures to within 3.5 kcal mol(-1), and the orientation of bound ligand compares to within 1.8 Å root mean square deviation for ligand structures as compared to experimental data. Evaluation of high throughput virtual screening capacity demonstrated that Dockomatic can collect, evaluate, and summarize the output of 10,000 AutoDock jobs in less than 2 hours of computational time, while 100,000 jobs requires approximately 15 hours and 1,000,000 jobs is estimated to take up to a week. Copyright © 2011 Wiley Periodicals, Inc.

The development of analogical reasoning in deaf children and their parents' communication mode.

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Bandurski, Marcin; Galkowski, Tadeusz

2004-01-01

The purpose of this article is to analyze the results of a study of the development of analogical reasoning in deaf children coming from two different linguistic environments (deaf children of deaf parents--sign language, deaf children of hearing parents--spoken language) and in hearing children, as well as to compare two groups of deaf children to a group of hearing children. In order to estimate the development of children's analogical reasoning, especially the development of their understanding of different logical relations, two age groups were singled out in each population of children: younger (9- and 10-year-olds) and older (12- and 13-year-olds). In this way it is possible to assess the influence of early and consistent sign-language communication on the development of the conceptual system in deaf children and to establish whether early and consistent sign-language communication with deaf children affects their mental development to the same extent as early and consistent spoken-language communication with hearing children. The children were given three series of analogy tasks based on different logical relations: (a) a series of verbal analogy tasks (the relations of opposite, part-whole, and causality); (b) a series of numerical analogy tasks (the relations of class membership, opposite, and part-whole); and (c) a series of figural-geometric analogy tasks (the relations of opposite and part-whole). It was found that early and consistent sign-language communication with deaf children plays an almost equivalent role in the development of verbal, numerical, and spatial reasoning by analogy as early and consistent spoken-language communication with hearing children.

An integrated multichannel neural recording analog front-end ASIC with area-efficient driven right leg circuit.

Science.gov (United States)

Tao Tang; Wang Ling Goh; Lei Yao; Jia Hao Cheong; Yuan Gao

2017-07-01

This paper describes an integrated multichannel neural recording analog front end (AFE) with a novel area-efficient driven right leg (DRL) circuit to improve the system common mode rejection ratio (CMRR). The proposed AFE consists of an AC-coupled low-noise programmable-gain amplifier, an area-efficient DRL block and a 10-bit SAR ADC. Compared to conventional DRL circuit, the proposed capacitor-less DRL design achieves 90% chip area reduction with enhanced CMRR performance, making it ideal for multichannel biomedical recording applications. The AFE circuit has been designed in a standard 0.18-μm CMOS process. Post-layout simulation results show that the AFE provides two gain settings of 54dB/60dB while consuming 1 μA per channel under a supply voltage of 1 V. The input-referred noise of the AFE integrated from 1 Hz to 10k Hz is only 4 μVrms and the CMRR is 110 dB.

Molecular modeling of fentanyl analogs

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LJILJANA DOSEN-MICOVIC

2004-11-01

Full Text Available Fentanyl is a highly potent and clinically widely used narcotic analgesic. A large number of its analogs have been synthesized, some of which (sufentanil and alfentanyl are also in clinical use. Theoretical studies, in recent years, afforded a better understanding of the structure-activity relationships of this class of opiates and allowed insight into the molecular mechanism of the interactions of fentanyl analogs with their receptors. An overview of the current computational techniques for modeling fentanyl analogs, their receptors and ligand-receptor interactions is presented in this paper.

Expert analogy use in a naturalistic setting

Science.gov (United States)

Kretz, Donald R.; Krawczyk, Daniel C.

2014-01-01

The use of analogy is an important component of human cognition. The type of analogy we produce and communicate depends heavily on a number of factors, such as the setting, the level of domain expertise present, and the speaker's goal or intent. In this observational study, we recorded economics experts during scientific discussion and examined the categorical distance and structural depth of the analogies they produced. We also sought to characterize the purpose of the analogies that were generated. Our results supported previous conclusions about the infrequency of superficial similarity in subject-generated analogs, but also showed that distance and depth characteristics were more evenly balanced than in previous observational studies. This finding was likely due to the nature of the goals of the participants, as well as the broader nature of their expertise. An analysis of analogical purpose indicated that the generation of concrete source examples of more general target concepts was most prevalent. We also noted frequent instances of analogies intended to form visual images of source concepts. Other common purposes for analogies were the addition of colorful speech, inclusion (i.e., subsumption) of a target into a source concept, or differentiation between source and target concepts. We found no association between depth and either of the other two characteristics, but our findings suggest a relationship between purpose and distance; i.e., that visual imagery typically entailed an outside-domain source whereas exemplification was most frequently accomplished using within-domain analogies. Overall, we observed a rich and diverse set of spontaneously produced analogical comparisons. The high degree of expertise within the observed group along with the richly comparative nature of the economics discipline likely contributed to this analogical abundance. PMID:25505437

Expert Analogy Use in a Naturalistic Setting

Directory of Open Access Journals (Sweden)

Donald R Kretz

2014-11-01

Full Text Available The use of analogy is an important component of human cognition. The type of analogy we produce and communicate depends heavily on a number of factors, such as the setting, the level of domain expertise present, and the speaker’s goal or intent. In this observational study, we recorded economics experts during scientific discussion and examined the categorical distance and structural depth of the analogies they produced. We also sought to characterize the purpose of the analogies that were generated. Our results supported previous conclusions about the infrequency of superficial similarity in subject-generated analogs, but also showed that distance and depth characteristics were more evenly balanced than in previous observational studies. This finding was likely due to the nature of the goals of the participants, as well as the broader nature of their expertise. An analysis of analogical purpose indicated that the generation of concrete source examples of more general target concepts was most prevalent. We also noted frequent instances of analogies intended to form visual images of source concepts. Other common purposes for analogies were the addition of colorful speech, inclusion (i.e., subsumption of a target into a source concept, or differentiation between source and target concepts. We found no association between depth and either of the other two characteristics, but our findings suggest a relationship between purpose and distance; i.e., that visual imagery typically entailed an outside-domain source whereas exemplification was most frequently accomplished using within-domain analogies. Overall, we observed a rich and diverse set of spontaneously produced analogical comparisons. The high degree of expertise within the observed group along with the richly comparative nature of the economics discipline likely contributed to this analogical abundance.

A potent, selective, and orally bioavailable inhibitor of the protein-tyrosine phosphatase PTP1B improves insulin and leptin signaling in animal models.