Drug effects on drug targets: inhibition of enzymes by neuroleptics, antimycotics, antibiotics and other drugs on human pathogenic amoebas and their anti-proliferative effects.

PubMed

Ondarza, Raúl N

2007-11-01

This paper reviews the inhibition of various enzymes by neuroleptics, anti-mycotics, antibiotics and other drugs on three species of human pathogenic amoebas, mainly Entamoeba histolytica, Acanthamoeba polyphaga and Naegleria fowleri, and their antiproliferative effects. A recent patent registered by Philip relates to the combination of an antibacterial formulation and antifungal agent for producing a therapeutically effective quantity of an antimicrobial that is suitable for suppressing or treating fungal growth. The rationale behind this patent focused on essential and valid targets with a description of the main pathogenic characteristics of these amoebas. The study of new targets, such as trypanothione and trypanothione reductase, and the drug effects of selected agents were arranged into six main groups: A) Inhibition of disulfide reducing enzymes by neuroleptics, antimycotics and antibiotics; B) Comparative evaluation of the efficacies of several drugs with antiproliferative activities; C) Inhibition of the enzymes for the synthesis of trypanothione, such as ornithine decarboxylase, spermidine synthase and trypanothione synthetase; D) Inhibition of the glycolytic enzyme PPi-dependent phosphofructokinase (PFK) from Entamoeba and Naegleria by pyrophosphate analogues, different from the host enzyme; E) Inhibition of enzymes secreted by these parasites to invade the human host, for example cysteine proteinases; and F) Inhibition of encystment pathways and cyst-wall assembly proteins.

Drug-nutrient interactions: inhibition of amino acid intestinal absorption by fluoxetine.

PubMed

Urdaneta, E; Idoate, I; Larralde, J

1998-05-01

Fluoxetine is one of the most widely used antidepressants and nowadays it is also being used to manage obesity problems. In our laboratory we demonstrated that the drug inhibited sugar absorption (Monteiro et al. 1993). The aim of the present work was to determine the effect of fluoxetine on intestinal leucine absorption. Using a procedure of successive absorptions in vivo the drug diminished amino acid absorption by 30% (P < 0.001). Experiments in vitro in isolated jejunum also revealed a reduction in leucine uptake of 37% (P < 0.001). In both cases fluoxetine only affected mediated transport without altering diffusion. In a preparation enriched in basolateral membrane, fluoxetine inhibited the Na+,K(+)-ATPase (EC 3.6.1.37) activity (55%; P < 0.001) in a non-competitive manner with an inhibition constant (Ki) value of 0.92 mM. Leucine uptake by brush-border membrane vesicles was diminished by the drug (a reduction of 48% was observed at 30s, P < 0.001); only the apical Na(+)-dependent transport system of the amino acid was modified and the inhibition was non-competitive. Leucine uptake in the presence of lysine indicated that transporter B was involved. These results suggest that fluoxetine reduces leucine absorption by its action on the basolateral and apical membrane of the enterocyte; the nutritional status of the patients under drug treatment may be affected as neutral amino acid absorption is decreased.

Statin Drugs Markedly Inhibit Testosterone Production by Rat Leydig Cells In Vitro: Implications for Men

EPA Science Inventory

Statin drugs lower blood cholesterol by inhibiting hepatic 3-hydroxy-3-methylglutaryl-Coenzyme-A reductase. During drug development it was shown that statins inhibit production of cholesterol in the testis. We evaluated testosterone production in vitro, using highly purified rat ...

Sulfa drugs inhibit sepiapterin reduction and chemical redox cycling by sepiapterin reductase.

PubMed

Yang, Shaojun; Jan, Yi-Hua; Mishin, Vladimir; Richardson, Jason R; Hossain, Muhammad M; Heindel, Ned D; Heck, Diane E; Laskin, Debra L; Laskin, Jeffrey D

2015-03-01

Sepiapterin reductase (SPR) catalyzes the reduction of sepiapterin to dihydrobiopterin (BH2), the precursor for tetrahydrobiopterin (BH4), a cofactor critical for nitric oxide biosynthesis and alkylglycerol and aromatic amino acid metabolism. SPR also mediates chemical redox cycling, catalyzing one-electron reduction of redox-active chemicals, including quinones and bipyridinium herbicides (e.g., menadione, 9,10-phenanthrenequinone, and diquat); rapid reaction of the reduced radicals with molecular oxygen generates reactive oxygen species (ROS). Using recombinant human SPR, sulfonamide- and sulfonylurea-based sulfa drugs were found to be potent noncompetitive inhibitors of both sepiapterin reduction and redox cycling. The most potent inhibitors of sepiapterin reduction (IC50s = 31-180 nM) were sulfasalazine, sulfathiazole, sulfapyridine, sulfamethoxazole, and chlorpropamide. Higher concentrations of the sulfa drugs (IC50s = 0.37-19.4 μM) were required to inhibit redox cycling, presumably because of distinct mechanisms of sepiapterin reduction and redox cycling. In PC12 cells, which generate catecholamine and monoamine neurotransmitters via BH4-dependent amino acid hydroxylases, sulfa drugs inhibited both BH2/BH4 biosynthesis and redox cycling mediated by SPR. Inhibition of BH2/BH4 resulted in decreased production of dopamine and dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 5-hydroxytryptamine. Sulfathiazole (200 μM) markedly suppressed neurotransmitter production, an effect reversed by BH4. These data suggest that SPR and BH4-dependent enzymes, are "off-targets" of sulfa drugs, which may underlie their untoward effects. The ability of the sulfa drugs to inhibit redox cycling may ameliorate ROS-mediated toxicity generated by redox active drugs and chemicals, contributing to their anti-inflammatory activity. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Mechanisms of hematin crystallization and inhibition by the antimalarial drug chloroquine.

PubMed

Olafson, Katy N; Ketchum, Megan A; Rimer, Jeffrey D; Vekilov, Peter G

2015-04-21

Hematin crystallization is the primary mechanism of heme detoxification in malaria parasites and the target of the quinoline class of antimalarials. Despite numerous studies of malaria pathophysiology, fundamental questions regarding hematin growth and inhibition remain. Among them are the identity of the crystallization medium in vivo, aqueous or organic; the mechanism of crystallization, classical or nonclassical; and whether quinoline antimalarials inhibit crystallization by sequestering hematin in the solution, or by blocking surface sites crucial for growth. Here we use time-resolved in situ atomic force microscopy (AFM) and show that the lipid subphase in the parasite may be a preferred growth medium. We provide, to our knowledge, the first evidence of the molecular mechanisms of hematin crystallization and inhibition by chloroquine, a common quinoline antimalarial drug. AFM observations demonstrate that crystallization strictly follows a classical mechanism wherein new crystal layers are generated by 2D nucleation and grow by the attachment of solute molecules. We identify four classes of surface sites available for binding of potential drugs and propose respective mechanisms of drug action. Further studies reveal that chloroquine inhibits hematin crystallization by binding to molecularly flat {100} surfaces. A 2-μM concentration of chloroquine fully arrests layer generation and step advancement, which is ∼10(4)× less than hematin's physiological concentration. Our results suggest that adsorption at specific growth sites may be a general mode of hemozoin growth inhibition for the quinoline antimalarials. Because the atomic structures of the identified sites are known, this insight could advance the future design and/or optimization of new antimalarials.

The mutual extraction industry: drug use and the normative structure of social capital in the Russian far north.

PubMed

Pilkington, Hilary; Sharifullina, El'vira

2009-05-01

The article contributes to the literature on the role of social networks and social capital in young people's drug use. It considers the structural and cultural dimensions of the 'risk environment' of post-Soviet Russia, the micro risk-environment of a de-industrializing city in the far north of the country and the kind of social capital that circulates in young people's social networks there. Its focus is thus on social capital at the micro-level, the 'bridging' networks of peer friendship groups and the norms that govern them. The research is based on a small ethnographic study of the friendship groups and social networks of young people in the city of Vorkuta in 2006-2007. It draws on data from 32 respondents aged 17-27 in the form of 17 semi-structured audio and video interviews and field diaries. Respondents were selected from friendship groups in which drug use was a regular and symbolically significant practice. The risk environment of the Russian far north is characterised by major de-industrialization, poor health indicators, low life expectancy and limited educational and employment opportunities. It is also marked by a 'work hard, play hard' cultural ethos inherited from the Soviet period when risk-laden manual labour was well-rewarded materially and symbolically. However, young people today often rely on informal economic practices to generate the resource needed to fulfil their expectations. This is evident from the social networks among respondents which were found to be focused around a daily routine of generating and spending income, central to which is the purchase, sale and use of drugs. These practices are governed by norms that often invert those normally ascribed to social networks: reciprocity is replaced by mutual exploitation and trust by cheating. Social networks are central to young people's management of the risk environment associated with post-Soviet economic transformation. However, such networks are culturally as well as structurally

Mutual Impact of Diabetes Mellitus and Tuberculosis in China.

PubMed

Cheng, Jun; Zhang, Hui; Zhao, Yan Lin; Wang, Li Xia; Chen, Ming Ting

2017-05-01

China has a double burden of diabetes mellitus and tuberculosis, and many studies have been carried out on the mutual impact of these two diseases. This paper systematically reviewed studies conducted in China covering the mutual impact of epidemics of diabetes and tuberculosis, the impact of diabetes on multi-drug resistant tuberculosis and on the tuberculosis clinical manifestation and treatment outcome, the yields of bi-directional screening, and economic evaluation for tuberculosis screening among diabetes patients. Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Mechanisms Underlying Food-Drug Interactions: Inhibition of Intestinal Metabolism and Transport

PubMed Central

Won, Christina S.; Oberlies, Nicholas H.; Paine, Mary F.

2012-01-01

Food-drug interaction studies are critical to evaluate appropriate dosing, timing, and formulation of new drug candidates. These interactions often reflect prandial-associated changes in the extent and/or rate of systemic drug exposure. Physiologic and physicochemical mechanisms underlying food effects on drug disposition are well-characterized. However, biochemical mechanisms involving drug metabolizing enzymes and transport proteins remain underexplored. Several plant-derived beverages have been shown to modulate enzymes and transporters in the intestine, leading to altered pharmacokinetic (PK) and potentially negative pharmacodynamic (PD) outcomes. Commonly consumed fruit juices, teas, and alcoholic drinks contain phytochemicals that inhibit intestinal cytochrome P450 and phase II conjugation enzymes, as well as uptake and efflux transport proteins. Whereas myriad phytochemicals have been shown to inhibit these processes in vitro, translation to the clinic has been deemed insignificant or undetermined. An overlooked prerequisite for elucidating food effects on drug PK is thorough knowledge of causative bioactive ingredients. Substantial variability in bioactive ingredient composition and activity of a given dietary substance poses a challenge in conducting robust food-drug interaction studies. This confounding factor can be addressed by identifying and characterizing specific components, which could be used as marker compounds to improve clinical trial design and quantitatively predict food effects. Interpretation and integration of data from in vitro, in vivo, and in silico studies require collaborative expertise from multiple disciplines, from botany to clinical pharmacology (i.e., plant to patient). Development of more systematic methods and guidelines is needed to address the general lack of information on examining drug-dietary substance interactions prospectively. PMID:22884524

26 CFR 1.831-3 - Tax on insurance companies (other than life or mutual), mutual marine insurance companies, mutual...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Tax on insurance companies (other than life or mutual), mutual marine insurance companies, mutual fire insurance companies issuing perpetual policies, and mutual fire or flood insurance companies operating on the basis of premium deposits; taxable years...

26 CFR 1.831-3 - Tax on insurance companies (other than life or mutual), mutual marine insurance companies, mutual...

Code of Federal Regulations, 2012 CFR

2012-04-01

... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Tax on insurance companies (other than life or mutual), mutual marine insurance companies, mutual fire insurance companies issuing perpetual policies, and mutual fire or flood insurance companies operating on the basis of premium deposits; taxable years...

26 CFR 1.831-3 - Tax on insurance companies (other than life or mutual), mutual marine insurance companies, mutual...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Tax on insurance companies (other than life or mutual), mutual marine insurance companies, mutual fire insurance companies issuing perpetual policies, and mutual fire or flood insurance companies operating on the basis of premium deposits; taxable years...

26 CFR 1.831-3 - Tax on insurance companies (other than life or mutual), mutual marine insurance companies, mutual...

Code of Federal Regulations, 2011 CFR

2011-04-01

... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Tax on insurance companies (other than life or mutual), mutual marine insurance companies, mutual fire insurance companies issuing perpetual policies, and mutual fire or flood insurance companies operating on the basis of premium deposits; taxable years...

Modeling Synergistic Drug Inhibition of Mycobacterium tuberculosis Growth in Murine Macrophages

DTIC Science & Technology

2011-01-01

important application of metabolic network modeling is the ability to quantitatively model metabolic enzyme inhibition and predict bacterial growth...describe the extensions of this framework to model drug- induced growth inhibition of M. tuberculosis in macrophages.39 Mathematical framework Fig. 1 shows...starting point, we used the previously developed iNJ661v model to represent the metabolic Fig. 1 Mathematical framework: a set of coupled models used to

Lack of association between parental alcohol or drug addiction and behavioral inhibition in children.

PubMed

Biederman, J; Hirshfeld-Becker, D R; Rosenbaum, J F; Perenick, S G; Wood, J; Faraone, S V

2001-10-01

"Behavioral inhibition to the unfamiliar" has been proposed as a precursor to anxiety. A recent study proposed that it may also be a precursor to alcoholism. The authors sought to replicate the latter finding through a secondary analysis of data from a large study of young children (age 2-6 years)-offspring of parents with panic and depressive disorders-who had been assessed for behavioral inhibition through laboratory-based observations. The offspring were stratified on the basis of presence or absence of parental lifetime history of DSM-III-R alcohol dependence (N=115 versus N=166, respectively) or drug dependence (N=78 versus N=203). The rates of behavioral inhibition were then compared between groups. Despite adequate power to detect associations, neither parental alcohol dependence nor drug dependence was associated with a higher risk for behavioral inhibition in the offspring. These results are not consistent with the hypothesis linking behavioral inhibition to addictions.

Effect of drug-related cues on response inhibition through abstinence: A pilot study in male heroin abstainers.

PubMed

Su, Bobo; Yang, Ling; Wang, Grace Y; Wang, Sha; Li, Shaomei; Cao, Hua; Zhang, Yan

2017-11-01

Chronic heroin use can cause a deficit of inhibitory function, leading to a loss of control over drug use. Exposure to drug-related cues is considered as one of the contributing factors. However, it is unclear whether there are dynamic changes on the effect of drug-related cues on response inhibition following prolonged abstinence. The present study investigated the effect of drug-related cues on response inhibition in heroin abstainers at different abstinent phases. 26 shorter-term (2-6 months) and 26 longer-term (19-24 months) male heroin abstainers performed on a modified two-choice Oddball task, which included two conditions: in the cued condition, neutral pictures served as the background of standard stimuli (yellow frame) and heroin-related pictures served as the background of deviant stimuli (blue frame), reversed in the controlled conditions. Compared to longer-term abstainers, mean reaction time (RT) for drug deviants in shorter-term abstainers was significantly longer. Shorter-term abstainers also showed markedly slower response to neutral deviants relative to drug deviants, but this tendency was not observed in longer-term abstainers. Nevertheless, both groups had similar RT for standard stimuli regardless of their paired background pictures. Effect of drug-related cues on response inhibition remains at the early stage of abstinence; however, this effect may be reduced following a longer period of drug abstinence. Our findings highlight the importance of assessing and improving the ability of inhibiting drug-related cue reactivity during treatment.

Neuroimaging Impaired Response Inhibition and Salience Attribution in Human Drug Addiction: A Systematic Review.

PubMed

Zilverstand, Anna; Huang, Anna S; Alia-Klein, Nelly; Goldstein, Rita Z

2018-06-06

The impaired response inhibition and salience attribution (iRISA) model proposes that impaired response inhibition and salience attribution underlie drug seeking and taking. To update this model, we systematically reviewed 105 task-related neuroimaging studies (n > 15/group) published since 2010. Results demonstrate specific impairments within six large-scale brain networks (reward, habit, salience, executive, memory, and self-directed networks) during drug cue exposure, decision making, inhibitory control, and social-emotional processing. Addicted individuals demonstrated increased recruitment of these networks during drug-related processing but a blunted response during non-drug-related processing, with the same networks also being implicated during resting state. Associations with real-life drug use, relapse, therapeutic interventions, and the relevance to initiation of drug use during adolescence support the clinical relevance of the results. Whereas the salience and executive networks showed impairments throughout the addiction cycle, the reward network was dysregulated at later stages of abuse. Effects were similar in alcohol, cannabis, and stimulant addiction. Copyright © 2018 Elsevier Inc. All rights reserved.

Herb–drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Hai-Ying, E-mail: cmu4h-mhy@126.com; Sun, Dong-Xue; Cao, Yun-Feng

2014-05-15

Herb–drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP-glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4)-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives' inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (K{sub i}) were determined for themore » compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (K{sub i}) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb–drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolide derivatives as potential candidates for the selective inhibitors of UGT2B7. - Highlights: • Specific inhibition of andrographolide derivatives towards UGT2B7. • Herb-drug interaction related withAndrographis paniculata. • Guidance for design of UGT2B7 specific inhibitors.« less

Permutation auto-mutual information of electroencephalogram in anesthesia

NASA Astrophysics Data System (ADS)

Liang, Zhenhu; Wang, Yinghua; Ouyang, Gaoxiang; Voss, Logan J.; Sleigh, Jamie W.; Li, Xiaoli

2013-04-01

Objective. The dynamic change of brain activity in anesthesia is an interesting topic for clinical doctors and drug designers. To explore the dynamical features of brain activity in anesthesia, a permutation auto-mutual information (PAMI) method is proposed to measure the information coupling of electroencephalogram (EEG) time series obtained in anesthesia. Approach. The PAMI is developed and applied on EEG data collected from 19 patients under sevoflurane anesthesia. The results are compared with the traditional auto-mutual information (AMI), SynchFastSlow (SFS, derived from the BIS index), permutation entropy (PE), composite PE (CPE), response entropy (RE) and state entropy (SE). Performance of all indices is assessed by pharmacokinetic/pharmacodynamic (PK/PD) modeling and prediction probability. Main results. The PK/PD modeling and prediction probability analysis show that the PAMI index correlates closely with the anesthetic effect. The coefficient of determination R2 between PAMI values and the sevoflurane effect site concentrations, and the prediction probability Pk are higher in comparison with other indices. The information coupling in EEG series can be applied to indicate the effect of the anesthetic drug sevoflurane on the brain activity as well as other indices. The PAMI of the EEG signals is suggested as a new index to track drug concentration change. Significance. The PAMI is a useful index for analyzing the EEG dynamics during general anesthesia.

Inhibition of bile salt transport by drugs associated with liver injury in primary hepatocytes from human, monkey, dog, rat, and mouse

PubMed Central

Zhang, Jie; He, Kan; Cai, Lining; Chen, Yu-Chuan; Yang, Yifan; Shi, Qin; Woolf, Thomas F.; Ge, Weigong; Guo, Lei; Borlak, Jürgen; Tong, Weida

2018-01-01

Interference of bile salt transport is one of the underlying mechanisms for drug-induced liver injury (DILI). We developed a novel bile salt transport activity assay involving in situ biosynthesis of bile salts from their precursors in primary human, monkey, dog, rat, and mouse hepatocytes in suspension as well as LC-MS/MS determination of extracellular bile salts transported out of hepatocytes. Glycine- and taurine-conjugated bile acids were rapidly formed in hepatocytes and effectively transported into the extracellular medium. The bile salt formation and transport activities were time– and bile-acid-concentration–dependent in primary human hepatocytes. The transport activity was inhibited by the bile salt export pump (BSEP) inhibitors ketoconazole, saquinavir, cyclosporine, and troglitazone. The assay was used to test 86 drugs for their potential to inhibit bile salt transport activity in human hepatocytes, which included 35 drugs associated with severe DILI (sDILI) and 51 with non-severe DILI (non-sDILI). Approximately 60% of the sDILI drugs showed potent inhibition (with IC50 values <50 μM), but only about 20% of the non-sDILI drugs showed this strength of inhibition in primary human hepatocytes and these drugs are associated only with cholestatic and mixed hepatocellular cholestatic (mixed) injuries. The sDILI drugs, which did not show substantial inhibition of bile salt transport activity, are likely to be associated with immune-mediated liver injury. Twenty-four drugs were also tested in monkey, dog, rat and mouse hepatocytes. Species differences in potency were observed with mouse being less sensitive than other species to inhibition of bile salt transport. In summary, a novel assay has been developed using hepatocytes in suspension from human and animal species that can be used to assess the potential for drugs and/or drug-derived metabolites to inhibit bile salt transport and/or formation activity. Drugs causing sDILI, except those by immune

Inhibition of bile salt transport by drugs associated with liver injury in primary hepatocytes from human, monkey, dog, rat, and mouse.

PubMed

Zhang, Jie; He, Kan; Cai, Lining; Chen, Yu-Chuan; Yang, Yifan; Shi, Qin; Woolf, Thomas F; Ge, Weigong; Guo, Lei; Borlak, Jürgen; Tong, Weida

2016-08-05

Interference of bile salt transport is one of the underlying mechanisms for drug-induced liver injury (DILI). We developed a novel bile salt transport activity assay involving in situ biosynthesis of bile salts from their precursors in primary human, monkey, dog, rat, and mouse hepatocytes in suspension as well as LC-MS/MS determination of extracellular bile salts transported out of hepatocytes. Glycine- and taurine-conjugated bile acids were rapidly formed in hepatocytes and effectively transported into the extracellular medium. The bile salt formation and transport activities were time‒ and bile-acid-concentration‒dependent in primary human hepatocytes. The transport activity was inhibited by the bile salt export pump (BSEP) inhibitors ketoconazole, saquinavir, cyclosporine, and troglitazone. The assay was used to test 86 drugs for their potential to inhibit bile salt transport activity in human hepatocytes, which included 35 drugs associated with severe DILI (sDILI) and 51 with non-severe DILI (non-sDILI). Approximately 60% of the sDILI drugs showed potent inhibition (with IC50 values <50 μM), but only about 20% of the non-sDILI drugs showed this strength of inhibition in primary human hepatocytes and these drugs are associated only with cholestatic and mixed hepatocellular cholestatic (mixed) injuries. The sDILI drugs, which did not show substantial inhibition of bile salt transport activity, are likely to be associated with immune-mediated liver injury. Twenty-four drugs were also tested in monkey, dog, rat and mouse hepatocytes. Species differences in potency were observed with mouse being less sensitive than other species to inhibition of bile salt transport. In summary, a novel assay has been developed using hepatocytes in suspension from human and animal species that can be used to assess the potential for drugs and/or drug-derived metabolites to inhibit bile salt transport and/or formation activity. Drugs causing sDILI, except those by immune

Structure and Inhibition of Microbiome β-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wallace, Bret D.; Roberts, Adam B.; Pollet, Rebecca M.

The selective inhibition of bacterial β-glucuronidases was recently shown to alleviate drug-induced gastrointestinal toxicity in mice, including the damage caused by the widely used anticancer drug irinotecan. Here, we report crystal structures of representative β-glucuronidases from the Firmicutes Streptococcus agalactiae and Clostridium perfringens and the Proteobacterium Escherichia coli, and the characterization of a β-glucuronidase from the Bacteroidetes Bacteroides fragilis. While largely similar in structure, these enzymes exhibit marked differences in catalytic properties and propensities for inhibition, indicating that the microbiome maintains functional diversity in orthologous enzymes. Small changes in the structure of designed inhibitors can induce significant conformational changes inmore » the β-glucuronidase active site. Finally, we establish that β-glucuronidase inhibition does not alter the serum pharmacokinetics of irinotecan or its metabolites in mice. Together, the data presented advance our in vitro and in vivo understanding of the microbial β-glucuronidases, a promising new set of targets for controlling drug-induced gastrointestinal toxicity.« less

Inhibition mechanism of hydroxypropyl methylcellulose acetate succinate on drug crystallization in gastrointestinal fluid and drug permeability from a supersaturated solution.

PubMed

Ueda, Keisuke; Higashi, Kenjirou; Kataoka, Makoto; Yamashita, Shinji; Yamamoto, Keiji; Moribe, Kunikazu

2014-10-01

The effects of drug-crystallization inhibitor in bile acid/lipid micelles solution on drug permeation was evaluated during the drug crystallization process. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was used as a drug-crystallization inhibitor, which efficiently suppressed dexamethasone (DEX) crystallization in a gastrointestinal fluid model containing sodium taurocholate (NaTC) and egg-phosphatidylcholine (egg-PC). Changes of molecular state of supersaturated DEX during the DEX crystallization process was monitored in real time using proton nuclear magnetic resonance (1H NMR). It revealed that DEX distribution to bulk water and micellar phases formed by NaTC and egg-PC was not changed during the DEX crystallization process even in the presence of HPMC-AS. DEX permeation during DEX crystallization was evaluated using dissolution/permeability system. The combination of crystallization inhibition by HPMC-AS and micellar encapsulation by NaTC and egg-PC led to considerably higher DEX concentrations and improvement of DEX permeation at the beginning of the DEX crystallization process. Crystallization inhibition by HPMC-AS can efficiently work even in the micellar solution, where NaTC/egg-PC micelles encapsulates some DEX. It was concluded that a crystallization inhibitor contributed to improvement of permeation of a poorly water-soluble drug in gastrointestinal fluid. Copyright © 2014 Elsevier B.V. All rights reserved.

Common theme for drugs effective in overactive bladder treatment: Inhibition of afferent signaling from the bladder

PubMed Central

Hood, Brandy; Andersson, Karl-Erik

2013-01-01

The overactive bladder syndrome and detrusor overactivity are conditions that can have major effects on quality of life and social functioning. Antimuscarinic drugs are still first-line treatment. These drugs often have good initial response rates, but adverse effects and decreasing efficacy cause long-term compliance problems, and alternatives are needed. The recognition of the functional contribution of the urothelium/suburothelium, the autonomous detrusor muscle activity during bladder filling and the diversity of nerve transmitters involved has sparked interest in both peripheral and central modulation of overactive bladder syndrome/detrusor overactivity pathophysiology. Three drugs recently approved for treatment of overactive bladder syndrome/detrusor overactivity (mirabegron, tadalafil and onabotulinum toxin A), representing different pharmacological mechanisms; that is, β-adrenoceptor agonism, phosphodiesterase type 5 inhibition, and inhibition of nerve release of efferent and afferent transmitters, all seem to have one effect in common: inhibition of the afferent nervous activity generated by the bladder during filling. In the present review, the different mechanisms forming the pharmacological basis for the use of these drugs are discussed. PMID:23072271

Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile☆

PubMed Central

Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes; Hilber, Karlheinz; Sandtner, Walter

2013-01-01

The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Nav1.5 sodium and Cav1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. PMID:23707769

Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: a study to assess the drug's cardiac ion channel profile.

PubMed

Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K; Lukacs, Peter; Gawali, Vaibhavkumar S; Todt, Hannes; Hilber, Karlheinz; Sandtner, Walter

2013-12-01

The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licensed as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Nav1.5 sodium and Cav1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Gemfibrozil, a Lipid-lowering Drug, Inhibits the Induction of Nitric-oxide Synthase in Human Astrocytes*

PubMed Central

Pahan, Kalipada; Jana, Malabendu; Liu, Xiaojuan; Taylor, Bradley S.; Wood, Charles; Fischer, Susan M.

2007-01-01

Gemfibrozil, a lipid-lowering drug, inhibited cytokine-induced production of NO and the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astrocytes. Similar to gemfibrozil, clofibrate, another fibrate drug, also inhibited the expression of iNOS. Inhibition of human iNOS promoter-driven luciferase activity by gemfibrozil in cytokine-stimulated U373MG astroglial cells suggests that this compound inhibits the transcription of iNOS. Since gemfibrozil is known to activate peroxisome proliferator-activated receptor-α (PPAR-α), we investigated the role of PPAR-α in gemfibrozil-mediated inhibition of iNOS. Gemfibrozil induced peroxisome proliferator-responsive element (PPRE)-dependent luciferase activity, which was inhibited by the expression of ΔhPPAR-α, the dominant-negative mutant of human PPAR-α. However, ΔhPPAR-α was unable to abrogate gemfibrozil-mediated inhibition of iNOS suggesting that gemfibrozil inhibits iNOS independent of PPAR-α. The human iNOS promoter contains consensus sequences for the binding of transcription factors, including interferon-γ (IFN-γ) regulatory factor-1 (IRF-1) binding to interferon-stimulated responsive element (ISRE), signal transducer and activator of transcription (STAT) binding to γ-activation site (GAS), nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and CCAAT/enhancer-binding protein β (C/EBPβ); therefore, we investigated the effect of gemfibrozil on the activation of these transcription factors. The combination of interleukin (IL)-1β and IFN-γ induced the activation of NF-κB, AP-1, C/EBPβ, and GAS but not that of ISRE, suggesting that IRF-1 may not be involved in cytokine-induced expression of iNOS in human astrocytes. Interestingly, gemfibrozil strongly inhibited the activation of NF-κB, AP-1, and C/EBPβ but not that of GAS in cytokine-stimulated astroglial cells. These results suggest that gemfibrozil inhibits the induction of iNOS probably by

42 CFR 423.508 - Modification or termination of contract by mutual consent.

Code of Federal Regulations, 2011 CFR

2011-10-01

...) Prohibition against Part D program participation by organizations whose owners, directors, or management employees served in a similar capacity with another organization that mutually terminated its Medicare... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICARE PROGRAM VOLUNTARY MEDICARE PRESCRIPTION DRUG BENEFIT...

42 CFR 423.508 - Modification or termination of contract by mutual consent.

Code of Federal Regulations, 2013 CFR

2013-10-01

...) Prohibition against Part D program participation by organizations whose owners, directors, or management employees served in a similar capacity with another organization that mutually terminated its Medicare... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICARE PROGRAM (CONTINUED) VOLUNTARY MEDICARE PRESCRIPTION DRUG...

42 CFR 423.508 - Modification or termination of contract by mutual consent.

Code of Federal Regulations, 2014 CFR

2014-10-01

...) Prohibition against Part D program participation by organizations whose owners, directors, or management employees served in a similar capacity with another organization that mutually terminated its Medicare... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICARE PROGRAM (CONTINUED) VOLUNTARY MEDICARE PRESCRIPTION DRUG...

42 CFR 423.508 - Modification or termination of contract by mutual consent.

Code of Federal Regulations, 2012 CFR

2012-10-01

...) Prohibition against Part D program participation by organizations whose owners, directors, or management employees served in a similar capacity with another organization that mutually terminated its Medicare... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICARE PROGRAM (CONTINUED) VOLUNTARY MEDICARE PRESCRIPTION DRUG...

Role of Molecular Interactions for Synergistic Precipitation Inhibition of Poorly Soluble Drug in Supersaturated Drug-Polymer-Polymer Ternary Solution.

PubMed

Prasad, Dev; Chauhan, Harsh; Atef, Eman

2016-03-07

We are reporting a synergistic effect of combined Eudragit E100 and PVP K90 in precipitation inhibition of indomethacin (IND) in solutions at low polymer concentration, a phenomenon that has significant implications on the usefulness of developing novel ternary solid dispersion of poorly soluble drugs. The IND supersaturation was created by cosolvent technique, and the precipitation studies were performed in the absence and the presence of individual and combined PVP K90 and Eudragit E100. The studies were also done with PEG 8000 as a noninteracting control polymer. A continuous UV recording of the IND absorption was used to observe changes in the drug concentration over time. The polymorphic form and morphology of precipitated IND were characterized by Raman spectroscopy and scanning electron microscopy. The change in the chemical shift in solution (1)H NMR was used as novel approach to probe IND-polymer interactions. Molecular modeling was used for calculating binding energy between IND-polymer as another indication of IND-polymer interaction. Spontaneous IND precipitation was observed in the absence of polymers. Eudragit E100 showed significant inhibitory effect on nuclei formation due to stronger interaction as reflected in higher binding energy and greater change in chemical shift by NMR. PVP K90 led to significant crystal growth inhibition due to adsorption on growing IND crystals as confirmed by modified crystal habit of precipitate in the presence of PVP K90. Combination of polymers resulted in a synergistic precipitation inhibition and extended supersaturation. The NMR confirmed interaction between IND-Eudragit E100 and IND-PVP K90 in solution. The combination of polymers showed similar peak shift albeit using lower polymer concentration indicating stronger interactions. The results established the significant synergistic precipitation inhibition effect upon combining Eudragit E100 and PVP K90 due to drug-polymer interaction.

DMSO inhibits human platelet activation through cyclooxygenase-1 inhibition. A novel agent for drug eluting stents?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asmis, Lars; Tanner, Felix C.; Center for Integrative Human Physiology, University of Zuerich, Zuerich

2010-01-22

Background: DMSO is routinely infused together with hematopoietic cells in patients undergoing myeloablative therapy and was recently found to inhibit smooth muscle cells proliferation and arterial thrombus formation in the mouse by preventing tissue factor (TF), a key activator of the coagulation cascade. This study was designed to investigate whether DMSO prevents platelet activation and thus, whether it may represent an interesting agent to be used on drug eluting stents. Methods and results: Human venous blood from healthy volunteers was collected in citrated tubes and platelet activation was studied by cone and platelet analyzer (CPA) and rapid-platelet-function-assay (RPFA). CPA analysismore » showed that DMSO-treated platelets exhibit a lower adherence in response to shear stress (-15.54 {+-} 0.9427%, n = 5, P < 0.0001 versus control). Additionally, aggregometry studies revealed that DMSO-treated, arachidonate-stimulated platelets had an increased lag phase (18.0% {+-} 4.031, n = 9, P = 0.0004 versus control) as well as a decreased maximal aggregation (-6.388 {+-} 2.212%, n = 6, P = 0.0162 versus control). Inhibitory action of DMSO could be rescued by exogenous thromboxane A2 and was mediated, at least in part, by COX-1 inhibition. Conclusions: Clinically relevant concentrations of DMSO impair platelet activation by a thromboxane A2-dependent, COX-1-mediated effect. This finding may be crucial for the previously reported anti-thrombotic property displayed by DMSO. Our findings support a role for DMSO as a novel drug to prevent not only proliferation, but also thrombotic complications of drug eluting stents.« less

Role of mutual punishment in the snowdrift game

NASA Astrophysics Data System (ADS)

Yang, Han-Xin; Wang, Zhen

2015-09-01

The effects of punishment on cooperation have drawn increasing attention. In this paper, we propose a new mechanism of punishment, in which an individual will punish each neighbor if their strategies are different, and vice versa. We incorporate the mutual punishment into the snowdrift game. Results for well-mixed and structured populations have shown that, for no punishment or small values of punishment fine, the fraction of cooperators continuously decreases with the temptation to defect. However, for large values of punishment fine, there exists an abrupt transition point, at which the fraction of cooperators suddenly drops from 1 to 0. Compared to no punishment, mutual punishment promotes cooperation when the temptation to defect is small but inhibits cooperation when the temptation to defect is large. For weak (strong) temptation to defect, the cooperation level increases (decreases) with the punishment fine. For moderate temptation to defect, there exists an optimal value of the punishment fine that leads to the highest cooperation level.

Targeting Drug-Sensitive and -Resistant Strains of Mycobacterium tuberculosis by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology.

PubMed

Chandra, Pallavi; Rajmani, R S; Verma, Garima; Bhavesh, Neel Sarovar; Kumar, Dhiraj

2016-01-01

In view of emerging drug resistance among bacterial pathogens, including Mycobacterium tuberculosis, the development of novel therapeutic strategies is increasingly being sought. A recent paradigm in antituberculosis (anti-TB) drug development is to target the host molecules that are crucial for intracellular survival of the pathogen. We previously showed the importance of Src tyrosine kinases in mycobacterial pathogenesis. Here, we report that inhibition of Src significantly reduced survival of H37Rv as well as multidrug-resistant (MDR) and extremely drug-resistant (XDR) strains of M. tuberculosis in THP-1 macrophages. Src inhibition was also effective in controlling M. tuberculosis infection in guinea pigs. In guinea pigs, reduced M. tuberculosis burden due to Src inhibition also led to a marked decline in the disease pathology. In agreement with the theoretical framework of host-directed approaches against the pathogen, Src inhibition was equally effective against an XDR strain in controlling infection in guinea pigs. We propose that Src inhibitors could be developed into effective host-directed anti-TB drugs, which could be indiscriminately used against both drug-sensitive and drug-resistant strains of M. tuberculosis. IMPORTANCE The existing treatment regimen for tuberculosis (TB) suffers from deficiencies like high doses of antibiotics, long treatment duration, and inability to kill persistent populations in an efficient manner. Together, these contribute to the emergence of drug-resistant tuberculosis. Recently, several host factors were identified which help intracellular survival of Mycobacterium tuberculosis within the macrophage. These factors serve as attractive targets for developing alternate therapeutic strategies against M. tuberculosis. This strategy promises to be effective against drug-resistant strains. The approach also has potential to considerably lower the risk of emergence of new drug-resistant strains. We explored tyrosine kinase Src as a

The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation

PubMed Central

Senarathna, S M D K Ganga; Page-Sharp, Madhu; Crowe, Andrew

2016-01-01

The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10−6 cm/sec, followed by amodiaquine around 20 x 10−6 cm/sec; both mefloquine and artesunate were around 10 x 10−6 cm/sec. Methylene blue was between 2 and 6 x 10−6 cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine. PMID:27045516

Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wallace, Bret D.; Wang, Hongwei; Lane, Kimberly T.

2011-08-12

The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial {beta}-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial {beta}-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial {beta}-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally,more » oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.« less

Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme

PubMed Central

Wallace, Bret D.; Wang, Hongwei; Lane, Kimberly T.; Scott, John E.; Orans, Jillian; Koo, Ja Seol; Venkatesh, Madhukumar; Jobin, Christian; Yeh, Li-An; Mani, Sridhar; Redinbo, Matthew R.

2011-01-01

The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11–induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy. PMID:21051639

Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.

PubMed

Wallace, Bret D; Wang, Hongwei; Lane, Kimberly T; Scott, John E; Orans, Jillian; Koo, Ja Seol; Venkatesh, Madhukumar; Jobin, Christian; Yeh, Li-An; Mani, Sridhar; Redinbo, Matthew R

2010-11-05

The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.

Building a Morbidostat: An automated continuous-culture device for studying bacterial drug resistance under dynamically sustained drug inhibition

PubMed Central

Toprak, Erdal; Veres, Adrian; Yildiz, Sadik; Pedraza, Juan M.; Chait, Remy; Paulsson, Johan; Kishony, Roy

2013-01-01

We present a protocol for building and operating an automated fluidic system for continuous culture that we call the “morbidostat”. The morbidostat is used to follow evolution of microbial drug resistance in real time. Instead of exposing bacteria to predetermined drug environments, the morbidostat constantly measures the growth rates of evolving microbial populations and dynamically adjusts drug concentrations inside culture vials in order to maintain a constant drug induced inhibition. The growth rate measurements are done using an optical detection system that is based on measuring the intensity of back-scattered light from bacterial cells suspended in the liquid culture. The morbidostat can additionally be used as a chemostat or a turbidostat. The whole system can be built from readily available components within two to three weeks, by biologists with some electronics experience or engineers familiar with basic microbiology. PMID:23429717

Mutual Information between Discrete Variables with Many Categories using Recursive Adaptive Partitioning

PubMed Central

Seok, Junhee; Seon Kang, Yeong

2015-01-01

Mutual information, a general measure of the relatedness between two random variables, has been actively used in the analysis of biomedical data. The mutual information between two discrete variables is conventionally calculated by their joint probabilities estimated from the frequency of observed samples in each combination of variable categories. However, this conventional approach is no longer efficient for discrete variables with many categories, which can be easily found in large-scale biomedical data such as diagnosis codes, drug compounds, and genotypes. Here, we propose a method to provide stable estimations for the mutual information between discrete variables with many categories. Simulation studies showed that the proposed method reduced the estimation errors by 45 folds and improved the correlation coefficients with true values by 99 folds, compared with the conventional calculation of mutual information. The proposed method was also demonstrated through a case study for diagnostic data in electronic health records. This method is expected to be useful in the analysis of various biomedical data with discrete variables. PMID:26046461

Drug packaging and delivery using perfluorocarbon nanoparticles for targeted inhibition of vascular smooth muscle cells

PubMed Central

Zhou, Zhao-xiong; Zhang, Bai-gen; Zhang, Hao; Huang, Xiao-zhong; Hu, Ya-li; Sun, Li; Wang, Xiao-min; Zhang, Ji-wei

2009-01-01

Aim: To investigate the in vitro release profile of drugs encapsulated within perfluorocarbon (PFC) nanoparticles (NPs) and their ability to inhibit the activity of vascular smooth muscle cells (SMCs). Methods: Dexamethasone phosphate (DxP) or dexamethasone acetate (DxA) was encapsulated into PFC nanoparticles using a high-pressure homogenous method. The morphology and size of the NPs were examined using scanning electron microscopy (SEM) and a laser particle size analyzer. Drug loading and in vitro release were assessed by high-performance liquid chromatography (HPLC). The impact of NP capsules on SMC proliferation, migration and apoptosis in vitro was assessed using cell counting kit-8, transwell cell migration and flow cytometry assays. Results: The sizes of DxP-NPs and DxA-NPs were 224±6 nm and 236±9 nm, respectively. The encapsulation efficiency (EE) of DxP-NPs was 66.4%±1.0%, with an initial release rate of 77.2%, whereas the EE of DxA-NPs was 95.3%±1.3%, with an initial release rate of 23.6%. Both of the NP-coated drugs could be released over 7 d. Human umbilical artery SMCs were harvested and cultured for four to six passages. Compared to free DxP, SMCs treated with tissue factor (TF)-directed DxP-NPs showed significant differences in the inhibition of proliferation, migration and apoptosis (P<0.05). Conclusion: The results collectively suggest that PFC nanoparticles will be beneficial for targeted drug delivery because of the sustained drug release and effective inhibition of SMC proliferation and migration. PMID:19890365

Fluoxetine and norfluoxetine mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19 and CYP3A4

PubMed Central

Sager, Jennifer E; Lutz, Justin D; Foti, Robert S; Davis, Connie; Kunze, Kent L; Isoherranen, Nina

2014-01-01

Fluoxetine and its circulating metabolite norfluoxetine present a complex multiple inhibitor system that causes reversible or time-dependent inhibition of CYP2D6, CYP3A4, and CYP2C19 in vitro. While significant inhibition of all three enzymes in vivo is predicted, midazolam and lovastatin AUCs were unaffected by two week dosing of fluoxetine whereas dextromethorphan AUC was increased by 27-fold and omeprazole AUC by 7.1-fold. This observed discrepancy between in vitro risk assessment and in vivo DDI profile was rationalized by time-varying dynamic pharmacokinetic models that incorporated circulating concentrations of fluoxetine and norfluoxetine enantiomers, mutual inhibitor-inhibitor interactions and CYP3A4 induction. The dynamic models predicted all DDIs with less than 2-fold error. This study demonstrates that complex drug-drug interactions that involve multiple mechanisms, pathways and inhibitors with their metabolites can be predicted and rationalized via characterization of all the inhibitory species in vitro. PMID:24569517

The selenazal drug ebselen potently inhibits indoleamine 2,3-dioxygenase by targeting enzyme cysteine residues.

PubMed

Terentis, Andrew C; Freewan, Mohammed; Sempértegui Plaza, Tito S; Raftery, Mark J; Stocker, Roland; Thomas, Shane R

2010-01-26

The heme enzyme indoleamine 2,3-dioxygenase (IDO) plays an important immune regulatory role by catalyzing the oxidative degradation of l-tryptophan. Here we show that the selenezal drug ebselen is a potent IDO inhibitor. Exposure of human macrophages to ebselen inhibited IDO activity in a manner independent of changes in protein expression. Ebselen inhibited the activity of recombinant human IDO (rIDO) with an apparent inhibition constant of 94 +/- 17 nM. Optical and resonance Raman spectroscopy showed that ebselen altered the active site heme of rIDO by inducing a transition of the ferric heme iron from the predominantly high- to low-spin form and by lowering the vibrational frequency of the Fe-CO stretch of the CO complex, indicating an opening of the distal heme pocket. Substrate binding studies showed that ebselen enhanced nonproductive l-tryptophan binding, while circular dichroism indicated that the drug reduced the helical content and protein stability of rIDO. Thiol labeling and mass spectrometry revealed that ebselen reacted with multiple cysteine residues of IDO. Removal of cysteine-bound ebselen with dithiothreitol reversed the effects of the drug on the heme environment and significantly restored enzyme activity. These findings indicate that ebselen inhibits IDO activity by reacting with the enzyme's cysteine residues that result in changes to protein conformation and active site heme, leading to an increase in the level of nonproductive substrate binding. This study highlights that modification of cysteine residues is a novel and effective means of inhibiting IDO activity. It also suggests that IDO is under redox control and that the enzyme represents a previously unrecognized in vivo target of ebselen.

Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and molecular evidence.

PubMed

Merlo, Emiliano; Milton, Amy L; Goozée, Zara Y; Theobald, David E; Everitt, Barry J

2014-02-12

Memory persistence is critically influenced by retrieval. In rats, a single presentation of a conditioned fear stimulus induces memory reconsolidation and fear memory persistence, while repeated fear cue presentations result in loss of fear through extinction. These two opposite behavioral outcomes are operationally linked by the number of cue presentations at memory retrieval. However, the behavioral properties and mechanistic determinants of the transition have not yet been explored; in particular, whether reconsolidation and extinction processes coexist or are mutually exclusive, depending on the exposure to non-reinforced retrieval events. We characterized both behaviorally and molecularly the transition from reconsolidation to extinction of conditioned fear and showed that an increase in calcineurin (CaN) in the basolateral amygdala (BLA) supports the shift from fear maintenance to fear inhibition. Gradually increasing the extent of retrieval induces a gradual decrease in freezing responses to the conditioned stimulus and a gradual increase in amygdala CaN level. This newly synthesized CaN is required for the extinction, but not the reconsolidation, of conditioned fear. During the transition from reconsolidation to extinction, we have revealed an insensitive state of the fear memory where NMDA-type glutamate receptor agonist and antagonist drugs are unable either to modulate CaN levels in the BLA or alter the reconsolidation or extinction processes. Together, our data indicate both that reconsolidation and extinction are mutually exclusive processes and also reveal the presence of a transitional, or "limbo," state of the original memory between these two alternative outcomes of fear memory retrieval, when neither process is engaged.

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug-drug and drug-herb interaction by LC-ESI/MS/MS.

PubMed

Borkar, Roshan M; Bhandi, Murali Mohan; Dubey, Ajay P; Ganga Reddy, V; Komirishetty, Prashanth; Nandekar, Prajwal P; Sangamwar, Abhay T; Kamal, Ahmed; Banerjee, Sanjay K; Srinivas, R

2016-10-01

The aim of the present study was to evaluate the contribution of metabolites to drug-drug interaction and drug-herb interaction using the inhibition of CYP2D6 and CYP3A4 by metoprolol (MET) and its metabolites. The peak concentrations of unbound plasma concentration of MET, α-hydroxy metoprolol (HM), O-desmethyl metoprolol (ODM) and N-desisopropyl metoprolol (DIM) were 90.37 ± 2.69, 33.32 ± 1.92, 16.93 ± 1.70 and 7.96 ± 0.94 ng/mL, respectively. The metabolites identified, HM and ODM, had a ratio of metabolic area under the concentration-time curve (AUC) to parent AUC of ≥0.25 when either total or unbound concentration of metabolite was considered. In vitro CYP2D6 and CYP3A4 inhibition by MET, HM and ODM study revealed that MET, HM and ODM were not inhibitors of CYP3A4-catalyzed midazolam metabolism and CYP2D6-catalyzed dextromethorphan metabolism. However, DIM only met the criteria of >10% of the total drug related material and <25% of the parent using unbound concentrations. If CYP inhibition testing is solely based on metabolite exposure, DIM metabolite would probably not be considered. However, the present study has demonstrated that DIM contributes significantly to in vitro drug-drug interaction. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Inhibition of the high affinity myo-inositol transport system: a common mechanism of action of antibipolar drugs?

PubMed

Lubrich, B; van Calker, D

1999-10-01

The mechanism of action of antibipolar drugs like lithium, carbamazepine, and valproate that are used in the treatment of manic-depressive illness, is unknown. Lithium is believed to act through uncompetitive inhibition of inositolmonophosphatase, which results in a depletion of neural cells of inositol and a concomitant modulation of phosphoinositol signaling. Here, we show that lithium ions, carbamazepine, and valproate, but not the tricyclic antidepressant amitriptyline, inhibit at therapeutically relevant concentrations and with a time course similar to their clinical actions the high affinity myo-inositol transport in astrocyte-like cells and downregulate the level of the respective mRNA. Inhibition of inositol uptake could thus represent an additional pathway for inositol depletion, which might be relevant in the mechanism of action of all three antibipolar drugs.

Therapeutic effects of antibiotic drug tigecycline against cervical squamous cell carcinoma by inhibiting Wnt/β-catenin signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Hui; Jiao, Shun; Li, Xin

Aberrant activation of the Wnt/β-catenin signaling pathway is common in human cervical cancers and has great potential therapeutic value. We show that tigecycline, a FDA-approved antibiotic drug, targets cervical squamous cell carcinoma through inhibiting Wnt/β-catenin signaling pathway. Tigecycline is effective in inducing apoptosis, inhibiting proliferation and anchorage-independent colony formation of Hela cells. The inhibitory effects of tigecycline are further enhanced upon combination with paclitaxel, a most commonly used chemotherapeutic drug for cervical cancer. In a cervical xenograft model, tigecycline inhibits tumor growth as a single agent and its combination with paclitaxel significantly inhibits more tumor growth throughout the duration ofmore » treatment. We further show that tigecycline decreases level of both cytoplasmic and nuclear β-catenin and suppressed Wnt/β-catenin-mediated transcription through increasing levels of Axin 1 in Hela cells. In addition, stabilization or overexpression of β-catenin using pharmacological and genetic approaches abolished the effects of tigecycline in inhibiting proliferation and inducing apoptosis of Hela cells. Our study suggests that tigecycline is a useful addition to the treatment armamentarium for cervical cancer and targeting Wnt/β-catenin represents a potential therapeutic strategy in cervical cancer. - Highlights: • We repurposed the antibiotic drug tigecycline for cervical cancer treatment. • Tigecycline is effectively against cervical cancer cells in vitro and in vivo. • Combination of tigecycline and paclitaxel is synergistic in targeting Hela cells. • Tigecycline acts on Hela cells through inhibiting Wnt/β-catenin signaling.« less

The drug ornidazole inhibits photosynthesis in a different mechanism described for protozoa and anaerobic bacteria.

PubMed

Marcus, Yehouda; Tal, Noam; Ronen, Mordechai; Carmieli, Raanan; Gurevitz, Michael

2016-12-01

Ornidazole of the 5-nitroimidazole drug family is used to treat protozoan and anaerobic bacterial infections via a mechanism that involves preactivation by reduction of the nitro group, and production of toxic derivatives and radicals. Metronidazole, another drug family member, has been suggested to affect photosynthesis by draining electrons from the electron carrier ferredoxin, thus inhibiting NADP + reduction and stimulating radical and peroxide production. Here we show, however, that ornidazole inhibits photosynthesis via a different mechanism. While having a minute effect on the photosynthetic electron transport and oxygen photoreduction, ornidazole hinders the activity of two Calvin cycle enzymes, triose-phosphate isomerase (TPI) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Modeling of ornidazole's interaction with ferredoxin of the protozoan Trichomonas suggests efficient electron tunneling from the iron-sulfur cluster to the nitro group of the drug. A similar docking site of ornidazole at the plant-type ferredoxin does not exist, and the best simulated alternative does not support such efficient tunneling. Notably, TPI was inhibited by ornidazole in the dark or when electron transport was blocked by dichloromethyl diphenylurea, indicating that this inhibition was unrelated to the electron transport machinery. Although TPI and GAPDH isoenzymes are involved in glycolysis and gluconeogenesis, ornidazole's effect on respiration of photoautotrophs is moderate, thus raising its value as an efficient inhibitor of photosynthesis. The scarcity of Calvin cycle inhibitors capable of penetrating cell membranes emphasizes on the value of ornidazole for studying the regulation of this cycle. © 2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions.

PubMed

Zetterberg, Craig; Maltais, Francois; Laitinen, Leena; Liao, Shengkai; Tsao, Hong; Chakilam, Ananthsrinivas; Hariparsad, Niresh

2016-08-01

(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (VX-509, decernotinib) is an oral Janus kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis. Patients with rheumatoid arthritis often receive multiple medications, such as statins and steroids, to manage the signs and symptoms of comorbidities, which increases the chances of drug-drug interactions (DDIs). Mechanism-based inhibition is a subset of time-dependent inhibition (TDI) and occurs when a molecule forms a reactive metabolite which irreversibly binds and inactivates drug-metabolizing enzymes, potentially increasing the systemic load to toxic concentrations. Traditionally, perpetrating compounds are screened using human liver microsomes (HLMs); however, this system may be inadequate when the precipitant is activated by a non-cytochrome P450 (P450)-mediated pathway. Even though studies assessing competitive inhibition and TDI using HLM suggested a low risk for CYP3A4-mediated DDI in the clinic, VX-509 increased the area under the curve of midazolam, atorvastatin, and methyl-prednisolone by approximately 12.0-, 2.7-, and 4.3-fold, respectively. Metabolite identification studies using human liver cytosol indicated that VX-509 is converted to an oxidative metabolite, which is the perpetrator of the DDIs observed in the clinic. As opposed to HLM, hepatocytes contain the full complement of drug-metabolizing enzymes and transporters and can be used to assess TDI arising from non-P450-mediated metabolic pathways. In the current study, we highlight the role of aldehyde oxidase in the formation of the hydroxyl-metabolite of VX-509, which is involved in clinically significant TDI-based DDIs and represents an additional example in which a system-dependent prediction of TDI would be evident. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Gap Junction Inhibition Prevents Drug-induced Liver Toxicity and Fulminant Hepatic Failure

PubMed Central

Patel, Suraj J; Milwid, Jack M; King, Kevin R; Bohr, Stefan; Iracheta, Arvin; Li, Matthew; Vitalo, Antonia; Parekkadan, Biju; Jindal, Rohit; Yarmush, Martin L

2013-01-01

Drug-induced liver injury (DILI) limits the development and utilization of numerous therapeutic compounds, and consequently presents major challenges to the pharmaceutical industry and clinical medicine1, 2. Acetaminophen (APAP) containing compounds are among the most frequently prescribed drugs, and also the most common cause of DILI3. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and APAP-induced hepatotoxicity. We report that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of DILI by showing that mice deficient in Cx32 are protected against liver damage, acute inflammation, and death. We identified a small molecule inhibitor of Cx32 as a novel hepatoprotectant that achieves the same result in wildtype mice when coadministered with known hepatotoxic drugs. These findings demonstrate that gap junction inhibition is an effective therapy for limiting DILI, and suggest a novel pharmaceutical strategy to improve drug safety. PMID:22252509

Gamma-vinyl GABA inhibits cocaine-triggered reinstatement of drug-seeking behavior in rats by a non-dopaminergic mechanism

PubMed Central

Peng, Xiao-Qing; Li, Xia; Gilbert, Jeremy G.; Pak, Arlene C.; Ashby, Charles R.; Brodie, Jonathan D.; Dewey, Stephen L.; Gardner, Eliot L.; Xi, Zheng-Xiong

2008-01-01

Relapse to drug use is a core feature of addiction. Previous studies demonstrate that γ-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, attenuates the acute rewarding effects of cocaine and other addictive drugs. We here report that systemic administration of GVG (25–300 mg/kg) dose-dependently inhibits cocaine- or sucrose-induced reinstatement of reward-seeking behavior in rats. In vivo microdialysis data indicated that the same doses of GVG dose-dependently elevate extracellular GABA levels in the nucleus accumbens (NAc). However, GVG, when administered systemically or locally into the NAc, failed to inhibit either basal or cocaine-priming enhanced NAc dopamine in either naïve rats or cocaine extinction rats. These data suggest that: (1) GVG significantly inhibits cocaine- or sucrose-triggered reinstatement of reward-seeking behavior; and (2) a GABAergic-, but not dopaminergic-, dependent mechanism may underlie the antagonism by GVG of cocaine-triggered reinstatement of drug-seeking behavior, at least with respect to GVG's action on the NAc. PMID:18063319

Drug-protein hydrogen bonds govern the inhibition of the ATP hydrolysis of the multidrug transporter P-glycoprotein.

PubMed

Chufan, Eduardo E; Kapoor, Khyati; Ambudkar, Suresh V

2016-02-01

P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter superfamily. This multidrug transporter utilizes energy from ATP hydrolysis for the efflux of a variety of hydrophobic and amphipathic compounds including anticancer drugs. Most of the substrates and modulators of P-gp stimulate its basal ATPase activity, although some inhibit it. The molecular mechanisms that are in play in either case are unknown. In this report, mutagenesis and molecular modeling studies of P-gp led to the identification of a pair of phenylalanine-tyrosine structural motifs in the transmembrane region that mediate the inhibition of ATP hydrolysis by certain drugs (zosuquidar, elacridar and tariquidar), with high affinity (IC50's ranging from 10 to 30nM). Upon mutation of any of these residues, drugs that inhibit the ATPase activity of P-gp switch to stimulation of the activity. Molecular modeling revealed that the phenylalanine residues F978 and F728 interact with tyrosine residues Y953 and Y310, respectively, in an edge-to-face conformation, which orients the tyrosines in such a way that they establish hydrogen-bond contacts with the inhibitor. Biochemical investigations along with transport studies in intact cells showed that the inhibitors bind at a high affinity site to produce inhibition of ATP hydrolysis and transport function. Upon mutation, they bind at lower affinity sites, stimulating ATP hydrolysis and only poorly inhibiting transport. These results also reveal that screening chemical compounds for their ability to inhibit the basal ATP hydrolysis can be a reliable tool to identify modulators with high affinity for P-gp. Published by Elsevier Inc.

Kinetic studies of the inhibition of a human liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isozyme by bile acids and anti-inflammatory drugs.

PubMed

Miyabe, Y; Amano, T; Deyashiki, Y; Hara, A; Tsukada, F

1995-01-01

We have investigated the steady-state kinetics for a cytosolic 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isozyme of human liver and its inhibition by several bile acids and anti-inflammatory drugs such as indomethacin, flufemanic acid and naproxen. Initial velocity and product inhibition studies performed in the NADP(+)-linked (S)-1-indanol oxidation at pH 7.4 were consistent with a sequential ordered mechanism in which NADP+ binds first and leaves last. The bile acids and drugs, competitive inhibitors with respect to the alcohol substrate, exhibited uncompetitive inhibition with respect to the coenzyme, with Ki values less than 1 microM, whereas indomethacin exhibited noncompetitive inhibition (Ki < 24 microM). The kinetics of the inhibition by a mixture of the two inhibitors suggests that bile acids and drugs, except indomethacin, bind to overlapping sites at the active center of the enzyme-coenzyme binary complex.

Growth-independent cross-feeding modifies boundaries for coexistence in a bacterial mutualism.

PubMed

McCully, Alexandra L; LaSarre, Breah; McKinlay, James B

2017-09-01

Nutrient cross-feeding can stabilize microbial mutualisms, including those important for carbon cycling in nutrient-limited anaerobic environments. It remains poorly understood how nutrient limitation within natural environments impacts mutualist growth, cross-feeding levels and ultimately mutualism dynamics. We examined the effects of nutrient limitation within a mutualism using theoretical and experimental approaches with a synthetic anaerobic coculture pairing fermentative Escherichia coli and phototrophic Rhodopseudomonas palustris. In this coculture, E. coli and R. palustris resemble an anaerobic food web by cross-feeding essential carbon (organic acids) and nitrogen (ammonium) respectively. Organic acid cross-feeding stemming from E. coli fermentation can continue in a growth-independent manner during nitrogen limitation, while ammonium cross-feeding by R. palustris is growth-dependent. When ammonium cross-feeding was limited, coculture trends changed yet coexistence persisted under both homogenous and heterogenous conditions. Theoretical modelling indicated that growth-independent fermentation was crucial to sustain cooperative growth under conditions of low nutrient exchange. In contrast to stabilization at most cell densities, growth-independent fermentation inhibited mutualistic growth when the E. coli cell density was adequately high relative to that of R. palustris. Thus, growth-independent fermentation can conditionally stabilize or destabilize a mutualism, indicating the potential importance of growth-independent metabolism for nutrient-limited mutualistic communities. © 2017 Society for Applied Microbiology and John Wiley & Sons Ltd.

The relationship between the pharmacokinetics, cholinesterase inhibition and facilitation of twitch tension of the quaternary ammonium anticholinesterase drugs, neostigmine, pyridostigmine, edrophonium and 3-hydroxyphenyltrimethylammonium.

PubMed Central

Barber, H. E.; Calvey, T. N.; Muir, K. T.

1979-01-01

1 The relationship between the concentration of drug in plasma, the inhibition of erythrocyte acetylcholinesterase and the facilitation of neuromuscular transmission has been studied in the rat after the administration of neostigmine, pyridostigmine, edrophonium and 3-hydroxyphenyltrimethyl-ammonium (3-OH PTMA). 2 After the administration of neostigmine or pyridostigmine, acetylcholinesterase activity recovered only slowly due to the covalent nature of the inhibition. In contrast, recovery from the reversible inhibition caused by edrophonium or 3-OH PTMA was rapid and showed a direct relationship to the plasma concentration of these drugs. 3 There was a statistically significant linear correlation between the logarithm of the plasma concentration of the drugs and the increase in the tibialis twitch tension. 4 The relationship between the inhibition of acetylcholinesterase and the facilitation of neuromuscular transmission was complex. When the enzyme was less than 85% inhibited no facilitation occurred. Between 85% and 98% inhibition, facilitation was linearly related to enzyme inhibition. Above 98% inhibition, facilitation was unrelated to inhibition of the enzyme. PMID:223706

Toxicity of xanthene food dyes by inhibition of human drug-metabolizing enzymes in a noncompetitive manner.

PubMed

Mizutani, Takaharu

2009-01-01

The synthetic food dyes studied were rose bengal (RB), phroxine (PL), amaranth, erythrosine B (ET), allura red, new coccine, acid red (AR), tartrazine, sunset yellow FCF, brilliant blue FCF, and indigo carmine. First, data confirmed that these dyes were not substrates for CYP2A6, UGT1A6, and UGT2B7. ET inhibited UGT1A6 (glucuronidation of p-nitrophenol) and UGT2B7 (glucuronidation of androsterone). We showed the inhibitory effect of xanthene dye on human UGT1A6 activity. Basic ET, PL, and RB in those food dyes strongly inhibited UGT1A6 activity, with IC(50) values = 0.05, 0.04, and 0.015 mM, respectively. Meanwhile, AR of an acidic xanthene food dye showed no inhibition. Next, we studied the inhibition of CYP3A4 of a major phase I drug-metabolizing enzyme and P-glycoprotein of a major transporter by synthetic food dyes. Human CYP3A4 and P-glycoprotein were also inhibited by basic xanthene food dyes. The IC(50) values of these dyes to inhibit CYP3A4 and P-glycoprotein were the same as the inhibition level of UGT1A6 by three halogenated xanthene food dyes (ET, PL, and RB) described above, except AR, like the results with UGT1A6 and UGT2B7. We also confirmed the noninhibition of CYP3A4 and P-gp by other synthetic food dyes. Part of this inhibition depended upon the reaction of (1)O(2) originating on xanthene dyes by light irradiation, because inhibition was prevented by (1)O(2) quenchers. We studied the influence of superoxide dismutase and catalase on this inhibition by dyes and we found prevention of inhibition by superoxide dismutase but not catalase. This result suggests that superoxide anions, originating on dyes by light irradiation, must attack drug-metabolizing enzymes. It is possible that red cosmetics containing phloxine, erythrosine, or rose bengal react with proteins on skin under lighting and may lead to rough skin.

Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit Toxoplasma gondii Growth

PubMed Central

Dittmar, Ashley J.; Drozda, Allison A.

2016-01-01

ABSTRACT The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are tested for potential off-label uses. As a proof-of-principle screen to identify compounds effective against Toxoplasma gondii, we screened a collection of 1,120 compounds for the ability to significantly reduce Toxoplasma replication. A total of 94 compounds blocked parasite replication with 50% inhibitory concentrations of <5 µM. A significant number of these compounds are established inhibitors of dopamine or estrogen signaling. Follow-up experiments with the dopamine receptor inhibitor pimozide revealed that the drug impacted both parasite invasion and replication but did so independently of inhibition of dopamine or other neurotransmitter receptor signaling. Tamoxifen, which is an established inhibitor of the estrogen receptor, also reduced parasite invasion and replication. Even though Toxoplasma can activate the estrogen receptor, tamoxifen inhibits parasite growth independently of this transcription factor. Tamoxifen is also a potent inducer of autophagy, and we find that the drug stimulates recruitment of the autophagy marker light chain 3-green fluorescent protein onto the membrane of the vacuolar compartment in which the parasite resides and replicates. In contrast to other antiparasitic drugs, including pimozide, tamoxifen treatment of infected cells leads to a time-dependent elimination of intracellular parasites. Taken together, these data suggest that tamoxifen restricts Toxoplasma growth by inducing xenophagy or autophagic destruction of this obligate intracellular parasite. IMPORTANCE There is an urgent need to develop new therapies to treat microbial infections, and the repurposing of well-characterized compounds is emerging as one approach to achieving this goal. Using the protozoan parasite Toxoplasma gondii, we screened a library of 1,120 compounds and identified several

Oxidative stress-induced protein damage inhibits DNA repair and determines mutation risk and anticancer drug effectiveness

PubMed Central

McAdam, Elizabeth; Brem, Reto; Karran, Peter

2016-01-01

The relationship between sun exposure and non-melanoma skin cancer risk is well established. Solar ultraviolet radiation (UV; wavelengths 280-400 nm) is firmly implicated in skin cancer development. Nucleotide excision repair (NER) protects against cancer by removing potentially mutagenic DNA lesions induced by UVB (280-320 nm). How the 20-fold more abundant UVA (320-400 mn) component of solar UV radiation increases skin cancer risk is not understood. We demonstrate here that the contribution of UVA to the effects of UV radiation on cultured human cells is largely independent of its ability to damage DNA. Instead, the effects of UVA reflect the induction of oxidative stress that causes extensive protein oxidation. Because NER proteins are among those damaged, UVA irradiation inhibits NER and increases the cells’ susceptibility to mutation by UVB. NER inhibition is a common consequence of oxidative stress. Exposure to chemical oxidants, treatment with drugs that deplete cellular antioxidants, and interventions that interfere with glucose metabolism to disrupt the supply of cellular reducing power all inhibit NER. Tumor cells are often in a condition of oxidative stress and one effect of the NER inhibition that results from stress-induced protein oxidation is an increased sensitivity to the anticancer drug cisplatin. Statement of implication: Since NER is both a defence against cancer a significant determinant of cell survival after treatment with anticancer drugs, its attenuation by protein damage under conditions of oxidative-stress has implications for both cancer risk and for the effectiveness of anticancer therapy. PMID:27106867

Mutuality in the provision of Scottish healthcare.

PubMed

Howieson, Brian

2015-11-01

The backdrop to this article is provided by the Better Health, Better Care Action Plan (Scottish Government, 2007), Section 1 of which is entitled 'Towards a Mutual NHS'. According to Better Health, Better Care (Scottish Government, 2007: 5): 'Mutual organisations are designed to serve their members. They are designed to gather people around a common sense of purpose. They are designed to bring the organisation together in what people often call "co-production."' The aim of this article is to précis the current knowledge of mutuality in the provision of Scottish healthcare. In detail, it will: introduce the 'mutual' organisation; offer a historical perspective of mutuality; suggest why healthcare mutuality is important; and briefly, detail the differences in mutual health-care policy in England and Scotland. It is hoped that this analysis will help researchers and practitioners alike appreciate further the philosophy of mutuality in the provision of Scottish healthcare. © The Author(s) 2015.

MSN anti-cancer nanomedicines: chemotherapy enhancement, overcoming of drug resistance, and metastasis inhibition.

PubMed

He, Qianjun; Shi, Jianlin

2014-01-22

In the anti-cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti-cancer drugs to normal tissues due to the lack of tumor-selectivity, the multi-drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state-of-art nanomedicines based on mesoporous silica nanoparticles (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti-cancer strategy, this review highlights the most recent advances of MSN anti-cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs-based anti-cancer nanomedicines, and propose several innovative and forward-looking anti-cancer strategies, including tumor tissue-cell-nuclear successionally targeted drug delivery strategy, tumor cell-selective nuclear-targeted drug delivery strategy, multi-targeting and multi-drug strategy, chemo-/radio-/photodynamic-/ultrasound-/thermo-combined multi-modal therapy by virtue of functionalized hollow/rattle-structured MSNs. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The evolution of plant-insect mutualisms.

PubMed

Bronstein, Judith L; Alarcón, Ruben; Geber, Monica

2006-01-01

Mutualisms (cooperative interactions between species) have had a central role in the generation and maintenance of life on earth. Insects and plants are involved in diverse forms of mutualism. Here we review evolutionary features of three prominent insect-plant mutualisms: pollination, protection and seed dispersal. We focus on addressing five central phenomena: evolutionary origins and maintenance of mutualism; the evolution of mutualistic traits; the evolution of specialization and generalization; coevolutionary processes; and the existence of cheating. Several features uniting very diverse insect-plant mutualisms are identified and their evolutionary implications are discussed: the involvement of one mobile and one sedentary partner; natural selection on plant rewards; the existence of a continuum from specialization to generalization; and the ubiquity of cheating, particularly on the part of insects. Plant-insect mutualisms have apparently both arisen and been lost repeatedly. Many adaptive hypotheses have been proposed to explain these transitions, and it is unlikely that any one of them dominates across interactions differing so widely in natural history. Evolutionary theory has a potentially important, but as yet largely unfilled, role to play in explaining the origins, maintenance, breakdown and evolution of insect-plant mutualisms.

Reciprocal inhibition between motor neurons of the tibialis anterior and triceps surae in humans.

PubMed

Yavuz, Utku Ş; Negro, Francesco; Diedrichs, Robin; Farina, Dario

2018-05-01

Motor neurons innervating antagonist muscles receive reciprocal inhibitory afferent inputs to facilitate the joint movement in the two directions. The present study investigates the mutual transmission of reciprocal inhibitory afferent inputs between the tibialis anterior (TA) and triceps surae (soleus and medial gastrocnemius) motor units. We assessed this mutual mechanism in large populations of motor units for building a statistical distribution of the inhibition amplitudes during standardized input to the motor neuron pools to minimize the effect of modulatory pathways. Single motor unit activities were identified using high-density surface electromyography (HDsEMG) recorded from the TA, soleus (Sol), and medial gastrocnemius (GM) muscles during isometric dorsi- and plantarflexion. Reciprocal inhibition on the antagonist muscle was elicited by electrical stimulation of the tibial (TN) or common peroneal nerves (CPN). The probability density distributions of reflex strength for each muscle were estimated to examine the strength of mutual transmission of reciprocal inhibitory input. The results showed that the strength of reciprocal inhibition in the TA motor units was fourfold greater than for the GM and the Sol motor units. This suggests an asymmetric transmission of reciprocal inhibition between ankle extensor and flexor muscles. This asymmetry cannot be explained by differences in motor unit type composition between the investigated muscles since we sampled low-threshold motor units in all cases. Therefore, the differences observed for the strength of inhibition are presumably due to a differential reciprocal spindle afferent input and the relative contribution of nonreciprocal inhibitory pathways. NEW & NOTEWORTHY We investigated the mutual transmission of reciprocal inhibition in large samples of motor units using a standardized input (electrical stimulation) to the motor neurons. The results demonstrated that the disynaptic reciprocal inhibition exerted

Human cytosolic glutathione-S-transferases: quantitative analysis of expression, comparative analysis of structures and inhibition strategies of isozymes involved in drug resistance.

PubMed

Mohana, Krishnamoorthy; Achary, Anant

2017-08-01

Glutathione-S-transferase (GST) inhibition is a strategy to overcome drug resistance. Several isoforms of human GSTs are present and they are expressed in almost all the organs. Specific expression levels of GSTs in various organs are collected from the human transcriptome data and analysis of the organ-specific expression of GST isoforms is carried out. The variations in the level of expressions of GST isoforms are statistically significant. The GST expression differs in diseased conditions as reported by many investigators and some of the isoforms of GSTs are disease markers or drug targets. Structure analysis of various isoforms is carried out and literature mining has been performed to identify the differences in the active sites of the GSTs. The xenobiotic binding H site is classified into H1, H2, and H3 and the differences in the amino acid composition, the hydrophobicity and other structural features of H site of GSTs are discussed. The existing inhibition strategies are compared. The advent of rational drug design, mechanism-based inhibition strategies, availability of high-throughput screening, target specific, and selective inhibition of GST isoforms involved in drug resistance could be achieved for the reversal of drug resistance and aid in the treatment of diseases.

Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals.

PubMed

Aleo, Michael D; Shah, Falgun; He, Kan; Bonin, Paul D; Rodrigues, A David

2017-05-15

The role of bile salt export protein (BSEP) inhibition in drug-induced liver injury (DILI) has been investigated widely, while inhibition of the canalicular multidrug resistant protein 3 (MDR3) has received less attention. This transporter plays a pivotal role in secretion of phospholipids into bile and functions coordinately with BSEP to mediate the formation of bile acid-containing biliary micelles. Therefore, inhibition of MDR3 in human hepatocytes was examined across 125 drugs (70 of Most-DILI-concern and 55 of No-DILI-concern). Of these tested, 41% of Most-DILI-concern and 47% of No-DILI-concern drugs had MDR3 IC 50 values of <50 μM. A better distinction across DILI classifications occurred when systemic exposure was considered where safety margins of 50-fold had low sensitivity (0.29), but high specificity (0.96). Analysis of physical chemical property space showed that basic compounds were twice as likely to be MDR3 inhibitors as acids, neutrals, and zwitterions and that inhibitors were more likely to have polar surface area (PSA) values of <100 Å 2 and cPFLogD values between 1.5 and 5. These descriptors, with different cutoffs, also highlighted a group of compounds that shared dual potency as MDR3 and BSEP inhibitors. Nine drugs classified as Most-DILI-concern compounds (four withdrawn, four boxed warning, and one liver injury warning in their approved label) had intrinsic potency features of <20 μM in both assays, thereby reinforcing the notion that multiple inhibitory mechanisms governing bile formation (bile acid and phospholipid efflux) may confer additional risk factors that play into more severe forms of DILI as shown by others for BSEP inhibitors combined with multidrug resistance-associated protein (MRP2, MRP3, MRP4) inhibitory properties. Avoiding physical property descriptors that highlight dual BSEP and MDR3 inhibition or testing drug candidates for inhibition of multiple efflux transporters (e.g., BSEP, MDR3, and MRPs) may be an effective

Genipin-induced inhibition of uncoupling protein-2 sensitizes drug-resistant cancer cells to cytotoxic agents.

PubMed

Mailloux, Ryan J; Adjeitey, Cyril Nii-Klu; Harper, Mary-Ellen

2010-10-13

Uncoupling protein-2 (UCP2) is known to suppress mitochondrial reactive oxygen species (ROS) production and is employed by drug-resistant cancer cells to mitigate oxidative stress. Using the drug-sensitive HL-60 cells and the drug-resistant MX2 subline as model systems, we show that genipin, a UCP2 inhibitor, sensitizes drug-resistant cells to cytotoxic agents. Increased MX2 cell death was observed upon co-treatment with genipin and different doses of menadione, doxorubicin, and epirubicin. DCFH-DA fluorimetry revealed that the increase in MX2 cell death was accompanied by enhanced cellular ROS levels. The drug-induced increase in ROS was linked to genipin-mediated inhibition of mitochondrial proton leak. State 4 and resting cellular respiratory rates were higher in the MX2 cells in comparison to the HL-60 cells, and the increased respiration was readily suppressed by genipin in the MX2 cells. UCP2 accounted for a remarkable 37% of the resting cellular oxygen consumption indicating that the MX2 cells are functionally reliant on this protein. Higher amounts of UCP2 protein were detected in the MX2 versus the HL-60 mitochondria. The observed effects of genipin were absent in the HL-60 cells pointing to the selectivity of this natural product for drug-resistant cells. The specificity of genipin for UCP2 was confirmed using CHO cells stably expressing UCP2 in which genipin induced an ∼22% decrease in state 4 respiration. These effects were absent in empty vector CHO cells expressing no UCP2. Thus, the chemical inhibition of UCP2 with genipin sensitizes multidrug-resistant cancer cells to cytotoxic agents.

Mutually unbiased product bases for multiple qudits

DOE Office of Scientific and Technical Information (OSTI.GOV)

McNulty, Daniel; Pammer, Bogdan; Weigert, Stefan

We investigate the interplay between mutual unbiasedness and product bases for multiple qudits of possibly different dimensions. A product state of such a system is shown to be mutually unbiased to a product basis only if each of its factors is mutually unbiased to all the states which occur in the corresponding factors of the product basis. This result implies both a tight limit on the number of mutually unbiased product bases which the system can support and a complete classification of mutually unbiased product bases for multiple qubits or qutrits. In addition, only maximally entangled states can be mutuallymore » unbiased to a maximal set of mutually unbiased product bases.« less

[Maintaining solidarity: is mutuality the solution?].

PubMed

Gevers, J K M; Ploem, M C

2013-01-01

Solidarity is essentially the willingness to contribute to the community and its demands, which may even involve contributing more than one is expecting to receive. Another principle is mutuality: this refers to a balance between rights and obligations or between mutual obligations. In its advisory document 'The importance of mutuality......solidarity takes work!', The Dutch Council for Public Health and Health Care underlines the importance of ensuring solidarity within the Dutch health care system, e.g. by encouraging patients to take responsibility for their own health, possibly by introducing elements of mutuality. In our contribution, we comment on the Council's advice. Although we fully agree with the overall conclusion that solidarity should be maintained within the system, we do not see how the introduction of increased mutuality will contribute to this goal.

Toxicity of Xanthene Food Dyes by Inhibition of Human Drug-Metabolizing Enzymes in a Noncompetitive Manner

PubMed Central

Mizutani, Takaharu

2009-01-01

The synthetic food dyes studied were rose bengal (RB), phroxine (PL), amaranth, erythrosine B (ET), allura red, new coccine, acid red (AR), tartrazine, sunset yellow FCF, brilliant blue FCF, and indigo carmine. First, data confirmed that these dyes were not substrates for CYP2A6, UGT1A6, and UGT2B7. ET inhibited UGT1A6 (glucuronidation of p-nitrophenol) and UGT2B7 (glucuronidation of androsterone). We showed the inhibitory effect of xanthene dye on human UGT1A6 activity. Basic ET, PL, and RB in those food dyes strongly inhibited UGT1A6 activity, with IC50 values = 0.05, 0.04, and 0.015 mM, respectively. Meanwhile, AR of an acidic xanthene food dye showed no inhibition. Next, we studied the inhibition of CYP3A4 of a major phase I drug-metabolizing enzyme and P-glycoprotein of a major transporter by synthetic food dyes. Human CYP3A4 and P-glycoprotein were also inhibited by basic xanthene food dyes. The IC50 values of these dyes to inhibit CYP3A4 and P-glycoprotein were the same as the inhibition level of UGT1A6 by three halogenated xanthene food dyes (ET, PL, and RB) described above, except AR, like the results with UGT1A6 and UGT2B7. We also confirmed the noninhibition of CYP3A4 and P-gp by other synthetic food dyes. Part of this inhibition depended upon the reaction of 1O2 originating on xanthene dyes by light irradiation, because inhibition was prevented by 1O2 quenchers. We studied the influence of superoxide dismutase and catalase on this inhibition by dyes and we found prevention of inhibition by superoxide dismutase but not catalase. This result suggests that superoxide anions, originating on dyes by light irradiation, must attack drug-metabolizing enzymes. It is possible that red cosmetics containing phloxine, erythrosine, or rose bengal react with proteins on skin under lighting and may lead to rough skin. PMID:20041016

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

PubMed Central

Shedlofsky, S I; Israel, B C; McClain, C J; Hill, D B; Blouin, R A

1994-01-01

In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance study with saline injections. In the first experiment, six subjects received the drug cocktail 0.5 h after the first dose of LPS. In the second experiment, another six subjects received the drug cocktail 0.5 h after the second dose of LPS. In both experiments, LPS caused the expected physiologic responses of inflammation including fever with increases in serum concentrations of TNF alpha, IL-1 beta, IL-6, and acute phase reactants. In the first experiment, only minor decreases in clearances of the probe drugs were observed (7-12%). However in the second experiment, marked decreases in the clearances of AP (35, 95% CI 18-48%), HB (27, 95% CI 14-34%), and TH (22, 95% CI 12-32%) were seen. The decreases in AP clearance correlated with initial peak values of TNF alpha (r = 0.82) and IL-6 (r = 0.86). These data show that in humans the inflammatory response to even a very low dose of LPS significantly decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients with much higher exposures to LPS have more profound inhibition of drug metabolism. PMID:7989576

Antibiotic drug tigecycline inhibited cell proliferation and induced autophagy in gastric cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tang, Chunling; Yang, Liqun; Jiang, Xiaolan

Highlights: • Tigecycline inhibited cell growth and proliferation in human gastric cancer cells. • Tigecycline induced autophagy not apoptosis in human gastric cancer cells. • AMPK/mTOR/p70S6K pathway was activated after tigecycline treatment. • Tigecycline inhibited tumor growth in xenograft model of human gastric cancer cells. - Abstract: Tigecycline acts as a glycylcycline class bacteriostatic agent, and actively resists a series of bacteria, specifically drug fast bacteria. However, accumulating evidence showed that tetracycline and their derivatives such as doxycycline and minocycline have anti-cancer properties, which are out of their broader antimicrobial activity. We found that tigecycline dramatically inhibited gastric cancer cellmore » proliferation and provided an evidence that tigecycline induced autophagy but not apoptosis in human gastric cancer cells. Further experiments demonstrated that AMPK pathway was activated accompanied with the suppression of its downstream targets including mTOR and p70S6K, and ultimately induced cell autophagy and inhibited cell growth. So our data suggested that tigecycline might act as a candidate agent for pre-clinical evaluation in treatment of patients suffering from gastric cancer.« less

Generation of Bayesian prediction models for OATP-mediated drug-drug interactions based on inhibition screen of OATP1B1, OATP1B1∗15 and OATP1B3.

PubMed

van de Steeg, E; Venhorst, J; Jansen, H T; Nooijen, I H G; DeGroot, J; Wortelboer, H M; Vlaming, M L H

2015-04-05

Human organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3 are important hepatic uptake transporters. Early assessment of OATP1B1/1B3-mediated drug-drug interactions (DDIs) is therefore important for successful drug development. A promising approach for early screening and prediction of DDIs is computational modeling. In this study we aimed to generate a rapid, single Bayesian prediction model for OATP1B1, OATP1B1∗15 and OATP1B3 inhibition. Besides our previously generated HEK-OATP1B1 and HEK-OATP1B1∗15 cells, we now generated and characterized HEK-OATP1B3 cells. Using these cell lines we investigated the inhibitory potential of 640 FDA-approved drugs from a commercial library (10μM) on the uptake of [(3)H]-estradiol-17β-d-glucuronide (1μM) by OATP1B1, OATP1B1∗15, and OATP1B3. Using a cut-off of ⩾60% inhibition, 8% and 7% of the 640 drugs were potent OATP1B1 and OATP1B1∗15 inhibitors, respectively. Only 1% of the tested drugs significantly inhibited OATP1B3, which was not sufficient for Bayesian modeling. Modeling of OATP1B1 and OATP1B1∗15 inhibition revealed that presence of conjugated systems and (hetero)cycles with acceptor/donor atoms in- or outside the ring enhance the probability of a molecule binding these transporters. The overall performance of the model for OATP1B1 and OATP1B1∗15 was ⩾80%, including evaluation with a true external test set. Our Bayesian classification model thus represents a fast, inexpensive and robust means of assessing potential binding of new chemical entities to OATP1B1 and OATP1B1∗15. As such, this model may be used to rank compounds early in the drug development process, helping to avoid adverse effects in a later stage due to inhibition of OATP1B1 and/or OATP1B1∗15. Copyright © 2015 Elsevier B.V. All rights reserved.

New use of an old drug: inhibition of breast cancer stem cells by benztropine mesylate.

PubMed

Cui, Jihong; Hollmén, Maija; Li, Lina; Chen, Yong; Proulx, Steven T; Reker, Daniel; Schneider, Gisbert; Detmar, Michael

2017-01-03

Cancer stem cells (CSCs) play major roles in cancer initiation, metastasis, recurrence and therapeutic resistance. Targeting CSCs represents a promising strategy for cancer treatment. The purpose of this study was to identify selective inhibitors of breast CSCs (BCSCs). We carried out a cell-based phenotypic screening with cell viability as a primary endpoint, using a collection of 2,546 FDA-approved drugs and drug-like molecules in spheres formed by malignant human breast gland-derived cells (HMLER-shEcad cells, representing BCSCs) and control immortalized non-tumorigenic human mammary cells (HMLE cells, representing normal stem cells). 19 compounds were identified from screening. The chemically related molecules benztropine mesylate and deptropine citrate were selected for further validation and both potently inhibited sphere formation and self-renewal of BCSCs in vitro. Benztropine mesylate treatment decreased cell subpopulations with high ALDH activity and with a CD44+/CD24- phenotype. In vivo, benztropine mesylate inhibited tumor-initiating potential in a 4T1 mouse model. Functional studies indicated that benztropine mesylate inhibits functions of CSCs via the acetylcholine receptors, dopamine transporters/receptors, and/or histamine receptors. In summary, our findings identify benztropine mesylate as an inhibitor of BCSCs in vitro and in vivo. This study also provides a screening platform for identification of additional anti-CSC agents.

Exposure time independent summary statistics for assessment of drug dependent cell line growth inhibition.

PubMed

Falgreen, Steffen; Laursen, Maria Bach; Bødker, Julie Støve; Kjeldsen, Malene Krag; Schmitz, Alexander; Nyegaard, Mette; Johnsen, Hans Erik; Dybkær, Karen; Bøgsted, Martin

2014-06-05

In vitro generated dose-response curves of human cancer cell lines are widely used to develop new therapeutics. The curves are summarised by simplified statistics that ignore the conventionally used dose-response curves' dependency on drug exposure time and growth kinetics. This may lead to suboptimal exploitation of data and biased conclusions on the potential of the drug in question. Therefore we set out to improve the dose-response assessments by eliminating the impact of time dependency. First, a mathematical model for drug induced cell growth inhibition was formulated and used to derive novel dose-response curves and improved summary statistics that are independent of time under the proposed model. Next, a statistical analysis workflow for estimating the improved statistics was suggested consisting of 1) nonlinear regression models for estimation of cell counts and doubling times, 2) isotonic regression for modelling the suggested dose-response curves, and 3) resampling based method for assessing variation of the novel summary statistics. We document that conventionally used summary statistics for dose-response experiments depend on time so that fast growing cell lines compared to slowly growing ones are considered overly sensitive. The adequacy of the mathematical model is tested for doxorubicin and found to fit real data to an acceptable degree. Dose-response data from the NCI60 drug screen were used to illustrate the time dependency and demonstrate an adjustment correcting for it. The applicability of the workflow was illustrated by simulation and application on a doxorubicin growth inhibition screen. The simulations show that under the proposed mathematical model the suggested statistical workflow results in unbiased estimates of the time independent summary statistics. Variance estimates of the novel summary statistics are used to conclude that the doxorubicin screen covers a significant diverse range of responses ensuring it is useful for biological

Mutualisms and Population Regulation: Mechanism Matters

PubMed Central

Jha, Shalene; Allen, David; Liere, Heidi; Perfecto, Ivette; Vandermeer, John

2012-01-01

For both applied and theoretical ecological science, the mutualism between ants and their hemipteran partners is iconic. In this well-studied interaction, ants are assumed to provide hemipterans protection from natural enemies in exchange for nutritive honeydew. Despite decades of research and the potential importance in pest control, the precise mechanism producing this mutualism remains contested. By analyzing maximum likelihood parameter estimates of a hemipteran population model, we show that the mechanism of the mutualism is direct, via improved hemipteran growth rates, as opposed to the frequently assumed indirect mechanism, via harassment of the specialist parasites and predators of the hemipterans. Broadly, this study demonstrates that the management of mutualism-based ecosystem services requires a mechanistic understanding of mutualistic interactions. A consequence of this finding is the counter intuitive demonstration that preserving ant participation in the ant-hemipteran mutualism may be the best way of insuring pest control. PMID:22927978

Economic contract theory tests models of mutualism.

PubMed

Weyl, E Glen; Frederickson, Megan E; Yu, Douglas W; Pierce, Naomi E

2010-09-07

Although mutualisms are common in all ecological communities and have played key roles in the diversification of life, our current understanding of the evolution of cooperation applies mostly to social behavior within a species. A central question is whether mutualisms persist because hosts have evolved costly punishment of cheaters. Here, we use the economic theory of employment contracts to formulate and distinguish between two mechanisms that have been proposed to prevent cheating in host-symbiont mutualisms, partner fidelity feedback (PFF) and host sanctions (HS). Under PFF, positive feedback between host fitness and symbiont fitness is sufficient to prevent cheating; in contrast, HS posits the necessity of costly punishment to maintain mutualism. A coevolutionary model of mutualism finds that HS are unlikely to evolve de novo, and published data on legume-rhizobia and yucca-moth mutualisms are consistent with PFF and not with HS. Thus, in systems considered to be textbook cases of HS, we find poor support for the theory that hosts have evolved to punish cheating symbionts; instead, we show that even horizontally transmitted mutualisms can be stabilized via PFF. PFF theory may place previously underappreciated constraints on the evolution of mutualism and explain why punishment is far from ubiquitous in nature.

Economic contract theory tests models of mutualism

PubMed Central

Weyl, E. Glen; Frederickson, Megan E.; Yu, Douglas W.; Pierce, Naomi E.

2010-01-01

Although mutualisms are common in all ecological communities and have played key roles in the diversification of life, our current understanding of the evolution of cooperation applies mostly to social behavior within a species. A central question is whether mutualisms persist because hosts have evolved costly punishment of cheaters. Here, we use the economic theory of employment contracts to formulate and distinguish between two mechanisms that have been proposed to prevent cheating in host–symbiont mutualisms, partner fidelity feedback (PFF) and host sanctions (HS). Under PFF, positive feedback between host fitness and symbiont fitness is sufficient to prevent cheating; in contrast, HS posits the necessity of costly punishment to maintain mutualism. A coevolutionary model of mutualism finds that HS are unlikely to evolve de novo, and published data on legume–rhizobia and yucca–moth mutualisms are consistent with PFF and not with HS. Thus, in systems considered to be textbook cases of HS, we find poor support for the theory that hosts have evolved to punish cheating symbionts; instead, we show that even horizontally transmitted mutualisms can be stabilized via PFF. PFF theory may place previously underappreciated constraints on the evolution of mutualism and explain why punishment is far from ubiquitous in nature. PMID:20733067

Inhibition of cardiac inward rectifier currents by cationic amphiphilic drugs.

PubMed

van der Heyden, M A G; Stary-Weinzinger, A; Sanchez-Chapula, J A

2013-09-01

Cardiac inward rectifier channels belong to three different classes of the KIR channel protein family. The KIR2.x proteins generate the classical inward rectifier current, IK1, while KIR3 and KIR6 members are responsible for the acetylcholine responsive and ATP sensitive inward rectifier currents IKAch and IKATP, respectively. Aberrant function of these channels has been correlated with severe cardiac arrhythmias, indicating their significant contribution to normal cardiac electrophysiology. A common feature of inward rectifier channels is their dependence on the lipid phosphatidyl-4,5-bisphospate (PIP2) interaction for functional activity. Cationic amphiphilic drugs (CADs) are one of the largest classes of pharmaceutical compounds. Several widely used CADs have been associated with inward rectifier current disturbances, and recent evidence points to interference of the channel-PIP2 interaction as the underlying mechanism of action. Here, we will review how six of these well known drugs, used for treatment in various different conditions, interfere in cardiac inward rectifier functioning. In contrast, KIR channel inhibition by the anionic anesthetic thiopental is achieved by a different mechanism of channel-PIP2 interference. We will discuss the latest basic science insights of functional inward rectifier current characteristics, recently derived KIR channel structures and specific PIP2-receptor interactions at the molecular level and provide insight in how these drugs interfere in the structure-function relationships.

Grief and Palliative Care: Mutuality

PubMed Central

Moon, Paul J

2013-01-01

Grief and palliative care are interrelated and perhaps mutually inclusive. Conceptually and practically, grief intimately relates to palliative care, as both domains regard the phenomena of loss, suffering, and a desire for abatement of pain burden. Moreover, the notions of palliative care and grief may be construed as being mutually inclusive in terms of one cueing the other. As such, the discussions in this article will center on the conceptualizations of the mutuality between grief and palliative care related to end-of-life circumstances. Specifically, the complementarity of grief and palliative care, as well as a controvertible view thereof, will be considered. PMID:25278758

Design of a Drug-in-Adhesive Transdermal Patch for Risperidone: Effect of Drug-Additive Interactions on the Crystallization Inhibition and In Vitro/In Vivo Correlation Study.

PubMed

Weng, Wei; Quan, Peng; Liu, Chao; Zhao, Hanqing; Fang, Liang

2016-10-01

The purpose of this work was to develop and design an appropriate drug-in-adhesive patch for transdermal delivery of risperidone (RISP). Various formulation factors were investigated by in vitro permeation study using excised rabbit skin. Increasing the drug concentration in the pressure sensitive adhesive (PSA) was used to enhance the drug permeation. To overcome the high crystallization tendency of the patch, several crystallization inhibitors such as PVP, PEG, and surfactants and fatty acids were evaluated by microscopy study. The mechanism of crystallization inhibition was investigated by differential scanning calorimetry, nuclear magnetic resonance spectrometer, and FT-IR studies. RISP and its active metabolite were determined after topical application of the optimized transdermal patch, and the in vivo pharmacokinetic parameters were compared with the intravenous administration group. The microscopy study indicated that fatty acid greatly inhibited the crystallization of RISP in PSA. The inhibition was attributed to the drug-additive interaction between amino group of RISP and the carboxyl group of fatty acid which was further confirmed by (1)H-NMR and FT-IR studies. The optimal permeation profile was obtained with the patches containing 5% RISP and 5% oleic acid in Duro-Tak(®) 87-2287. The in vivo pharmacokinetic study exhibited a sustained absorption and metabolism profile and well correlated with the in vitro permeation data. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

26 CFR 1.831-1 - Tax on insurance companies (other than life or mutual), mutual marine insurance companies, and...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Tax on insurance companies (other than life or mutual), mutual marine insurance companies, and mutual fire insurance companies issuing perpetual... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Other Insurance Companies § 1.831-1 Tax on...

26 CFR 1.831-1 - Tax on insurance companies (other than life or mutual), mutual marine insurance companies, and...

Code of Federal Regulations, 2010 CFR

2010-04-01

... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Tax on insurance companies (other than life or mutual), mutual marine insurance companies, and mutual fire insurance companies issuing perpetual... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Other Insurance Companies § 1.831-1 Tax on insurance...

26 CFR 1.831-1 - Tax on insurance companies (other than life or mutual), mutual marine insurance companies, and...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Tax on insurance companies (other than life or mutual), mutual marine insurance companies, and mutual fire insurance companies issuing perpetual... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Other Insurance Companies § 1.831-1 Tax on...

26 CFR 1.831-1 - Tax on insurance companies (other than life or mutual), mutual marine insurance companies, and...

Code of Federal Regulations, 2011 CFR

2011-04-01

... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Tax on insurance companies (other than life or mutual), mutual marine insurance companies, and mutual fire insurance companies issuing perpetual... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Other Insurance Companies § 1.831-1 Tax on...

26 CFR 1.831-1 - Tax on insurance companies (other than life or mutual), mutual marine insurance companies, and...

Code of Federal Regulations, 2012 CFR

2012-04-01

... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Tax on insurance companies (other than life or mutual), mutual marine insurance companies, and mutual fire insurance companies issuing perpetual... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Other Insurance Companies § 1.831-1 Tax on...

Multitarget drug design strategy in Alzheimer's disease: focus on cholinergic transmission and amyloid-β aggregation.

PubMed

Simoni, Elena; Bartolini, Manuela; Abu, Izuddin F; Blockley, Alix; Gotti, Cecilia; Bottegoni, Giovanni; Caporaso, Roberta; Bergamini, Christian; Andrisano, Vincenza; Cavalli, Andrea; Mellor, Ian R; Minarini, Anna; Rosini, Michela

2017-06-01

Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network. By exploiting the multitarget approach, hybrid compounds have been synthesized and studied in vitro and in silico toward selected targets of the cholinergic and amyloidogenic pathways. The new molecules were able to target the cholinergic system, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit amyloid-β aggregation. The compounds emerged as a suitable starting point for a further optimization process.

New use of an old drug: inhibition of breast cancer stem cells by benztropine mesylate

PubMed Central

Cui, Jihong; Hollmén, Maija; Li, Lina; Chen, Yong; Proulx, Steven T.; Reker, Daniel; Schneider, Gisbert; Detmar, Michael

2017-01-01

Cancer stem cells (CSCs) play major roles in cancer initiation, metastasis, recurrence and therapeutic resistance. Targeting CSCs represents a promising strategy for cancer treatment. The purpose of this study was to identify selective inhibitors of breast CSCs (BCSCs). We carried out a cell-based phenotypic screening with cell viability as a primary endpoint, using a collection of 2,546 FDA-approved drugs and drug-like molecules in spheres formed by malignant human breast gland-derived cells (HMLER-shEcad cells, representing BCSCs) and control immortalized non-tumorigenic human mammary cells (HMLE cells, representing normal stem cells). 19 compounds were identified from screening. The chemically related molecules benztropine mesylate and deptropine citrate were selected for further validation and both potently inhibited sphere formation and self-renewal of BCSCs in vitro. Benztropine mesylate treatment decreased cell subpopulations with high ALDH activity and with a CD44+/CD24− phenotype. In vivo, benztropine mesylate inhibited tumor-initiating potential in a 4T1 mouse model. Functional studies indicated that benztropine mesylate inhibits functions of CSCs via the acetylcholine receptors, dopamine transporters/receptors, and/or histamine receptors. In summary, our findings identify benztropine mesylate as an inhibitor of BCSCs in vitro and in vivo. This study also provides a screening platform for identification of additional anti-CSC agents. PMID:27894093

Structural basis for non-competitive product inhibition in human thymidine phosphorylase: implications for drug design

PubMed Central

Omari, Kamel EL; Bronckaers, Annelies; Liekens, Sandra; Pérez-Pérez, Maria-Jésus; Balzarini, Jan; Stammers, David K.

2006-01-01

HTP (human thymidine phosphorylase), also known as PD-ECGF (platelet-derived endothelial cell growth factor) or gliostatin, has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis and therefore is a prime target for drug design, including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose phosphate and product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end com-plex. Thus thymine appears to be able to reassociate with HTP after its initial ordered release before ribose phosphate and induces the closed conformation, hence explaining the mechanism of non-competitive product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase and it defines a subsite that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406–415), disordered in the previous HTP structure. This loop extends across the active-site cleft and appears to stabilize the dimer interface and the closed conformation by hydrogen-bonding. The present study will assist in the design of HTP inhibitors that could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs. PMID:16803458

Synthesis of biocompatible nanoparticle drug complexes for inhibition of mycobacteria

NASA Astrophysics Data System (ADS)

Bhave, Tejashree; Ghoderao, Prachi; Sanghavi, Sonali; Babrekar, Harshada; Bhoraskar, S. V.; Ganesan, V.; Kulkarni, Anjali

2013-12-01

Tuberculosis (TB) is one of the most critical infectious diseases affecting the world today. Current TB treatment involves six months long daily administration of four oral doses of antibiotics. Due to severe side effects and the long treatment, a patient's adherence is low and this results in relapse of symptoms causing an alarming increase in the prevalence of multi-drug resistant (MDR) TB. Hence, it is imperative to develop a new drug delivery technology wherein these effects can be reduced. Rifampicin (RIF) is one of the widely used anti-tubercular drugs (ATD). The present study discusses the development of biocompatible nanoparticle-RIF complexes with superior inhibitory activity against both Mycobacterium smegmatis (M. smegmatis) and Mycobacterium tuberculosis (M. tuberculosis). Iron oxide nanoparticles (NPs) synthesized by gas phase condensation and NP-RIF complexes were tested against M. smegmatis SN2 strain as well as M. tuberculosis H37Rv laboratory strain. These complexes showed significantly better inhibition of M. smegmatis SN2 strain at a much lower effective concentration (27.5 μg ml-1) as compared to neat RIF (125 μg ml-1). Similarly M. tuberculosis H37Rv laboratory strain was susceptible to both nanoparticle-RIF complex and neat RIF at a minimum inhibitory concentration of 0.22 and 1 μg ml-1, respectively. Further studies are underway to determine the efficacy of NPs-RIF complexes in clinical isolates of M. tuberculosis as well as MDR isolates.

Population Density Modulates Drug Inhibition and Gives Rise to Potential Bistability of Treatment Outcomes for Bacterial Infections.

PubMed

Karslake, Jason; Maltas, Jeff; Brumm, Peter; Wood, Kevin B

2016-10-01

The inoculum effect (IE) is an increase in the minimum inhibitory concentration (MIC) of an antibiotic as a function of the initial size of a microbial population. The IE has been observed in a wide range of bacteria, implying that antibiotic efficacy may depend on population density. Such density dependence could have dramatic effects on bacterial population dynamics and potential treatment strategies, but explicit measures of per capita growth as a function of density are generally not available. Instead, the IE measures MIC as a function of initial population size, and population density changes by many orders of magnitude on the timescale of the experiment. Therefore, the functional relationship between population density and antibiotic inhibition is generally not known, leaving many questions about the impact of the IE on different treatment strategies unanswered. To address these questions, here we directly measured real-time per capita growth of Enterococcus faecalis populations exposed to antibiotic at fixed population densities using multiplexed computer-automated culture devices. We show that density-dependent growth inhibition is pervasive for commonly used antibiotics, with some drugs showing increased inhibition and others decreased inhibition at high densities. For several drugs, the density dependence is mediated by changes in extracellular pH, a community-level phenomenon not previously linked with the IE. Using a simple mathematical model, we demonstrate how this density dependence can modulate population dynamics in constant drug environments. Then, we illustrate how time-dependent dosing strategies can mitigate the negative effects of density-dependence. Finally, we show that these density effects lead to bistable treatment outcomes for a wide range of antibiotic concentrations in a pharmacological model of antibiotic treatment. As a result, infections exceeding a critical density often survive otherwise effective treatments.

Population Density Modulates Drug Inhibition and Gives Rise to Potential Bistability of Treatment Outcomes for Bacterial Infections

PubMed Central

Maltas, Jeff; Brumm, Peter; Wood, Kevin B.

2016-01-01

The inoculum effect (IE) is an increase in the minimum inhibitory concentration (MIC) of an antibiotic as a function of the initial size of a microbial population. The IE has been observed in a wide range of bacteria, implying that antibiotic efficacy may depend on population density. Such density dependence could have dramatic effects on bacterial population dynamics and potential treatment strategies, but explicit measures of per capita growth as a function of density are generally not available. Instead, the IE measures MIC as a function of initial population size, and population density changes by many orders of magnitude on the timescale of the experiment. Therefore, the functional relationship between population density and antibiotic inhibition is generally not known, leaving many questions about the impact of the IE on different treatment strategies unanswered. To address these questions, here we directly measured real-time per capita growth of Enterococcus faecalis populations exposed to antibiotic at fixed population densities using multiplexed computer-automated culture devices. We show that density-dependent growth inhibition is pervasive for commonly used antibiotics, with some drugs showing increased inhibition and others decreased inhibition at high densities. For several drugs, the density dependence is mediated by changes in extracellular pH, a community-level phenomenon not previously linked with the IE. Using a simple mathematical model, we demonstrate how this density dependence can modulate population dynamics in constant drug environments. Then, we illustrate how time-dependent dosing strategies can mitigate the negative effects of density-dependence. Finally, we show that these density effects lead to bistable treatment outcomes for a wide range of antibiotic concentrations in a pharmacological model of antibiotic treatment. As a result, infections exceeding a critical density often survive otherwise effective treatments. PMID:27764095

Exposure time independent summary statistics for assessment of drug dependent cell line growth inhibition

PubMed Central

2014-01-01

Background In vitro generated dose-response curves of human cancer cell lines are widely used to develop new therapeutics. The curves are summarised by simplified statistics that ignore the conventionally used dose-response curves’ dependency on drug exposure time and growth kinetics. This may lead to suboptimal exploitation of data and biased conclusions on the potential of the drug in question. Therefore we set out to improve the dose-response assessments by eliminating the impact of time dependency. Results First, a mathematical model for drug induced cell growth inhibition was formulated and used to derive novel dose-response curves and improved summary statistics that are independent of time under the proposed model. Next, a statistical analysis workflow for estimating the improved statistics was suggested consisting of 1) nonlinear regression models for estimation of cell counts and doubling times, 2) isotonic regression for modelling the suggested dose-response curves, and 3) resampling based method for assessing variation of the novel summary statistics. We document that conventionally used summary statistics for dose-response experiments depend on time so that fast growing cell lines compared to slowly growing ones are considered overly sensitive. The adequacy of the mathematical model is tested for doxorubicin and found to fit real data to an acceptable degree. Dose-response data from the NCI60 drug screen were used to illustrate the time dependency and demonstrate an adjustment correcting for it. The applicability of the workflow was illustrated by simulation and application on a doxorubicin growth inhibition screen. The simulations show that under the proposed mathematical model the suggested statistical workflow results in unbiased estimates of the time independent summary statistics. Variance estimates of the novel summary statistics are used to conclude that the doxorubicin screen covers a significant diverse range of responses ensuring it is

Inhibition of epithelial ovarian cancer by Minnelide, a water-soluble pro-drug.

PubMed

Rivard, Colleen; Geller, Melissa; Schnettler, Erica; Saluja, Manju; Vogel, Rachel Isaksson; Saluja, Ashok; Ramakrishnan, Sundaram

2014-11-01

Minnelide is a water-soluble pro-drug of triptolide, a natural product. The goal of this study was to evaluate the effectiveness of Minnelide on ovarian cancer growth in vitro and in vivo. The effect of Minnelide on ovarian cancer cell proliferation was determined by real time electrical impedance measurements. Multiple mouse models with C200 and A2780 epithelial ovarian cancer cell lines were used to assess the efficacy of Minnelide in inhibiting ovarian cancer growth. Minnelide decreased cell viability of both platinum sensitive and resistant epithelial ovarian cancer cells in vitro. Minnelide with carboplatin showed additive effects in vitro. Minnelide monotherapy increased the survival of mice bearing established ovarian tumors. Minnelide, in combination with carboplatin and paclitaxel, improved overall survival of mice. Minnelide is a promising pro-drug for the treatment of ovarian cancer, especially when combined with standard chemotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1

DOE PAGES

Szymańska, Paulina; Martin, Katie R.; MacKeigan, Jeffrey P.; ...

2015-03-11

We constructed a mechanistic, computational model for regulation of (macro)autophagy and protein synthesis (at the level of translation). The model was formulated to study the system-level consequences of interactions among the following proteins: two key components of MTOR complex 1 (MTORC1), namely the protein kinase MTOR (mechanistic target of rapamycin) and the scaffold protein RPTOR; the autophagy-initiating protein kinase ULK1; and the multimeric energy-sensing AMP-activated protein kinase (AMPK). Inputs of the model include intrinsic AMPK kinase activity, which is taken as an adjustable surrogate parameter for cellular energy level or AMP:ATP ratio, and rapamycin dose, which controls MTORC1 activity. Outputsmore » of the model include the phosphorylation level of the translational repressor EIF4EBP1, a substrate of MTORC1, and the phosphorylation level of AMBRA1 (activating molecule in BECN1-regulated autophagy), a substrate of ULK1 critical for autophagosome formation. The model incorporates reciprocal regulation of mTORC1 and ULK1 by AMPK, mutual inhibition of MTORC1 and ULK1, and ULK1-mediated negative feedback regulation of AMPK. Through analysis of the model, we find that these processes may be responsible, depending on conditions, for graded responses to stress inputs, for bistable switching between autophagy and protein synthesis, or relaxation oscillations, comprising alternating periods of autophagy and protein synthesis. A sensitivity analysis indicates that the prediction of oscillatory behavior is robust to changes of the parameter values of the model. The model provides testable predictions about the behavior of the AMPK-MTORC1-ULK1 network, which plays a central role in maintaining cellular energy and nutrient homeostasis.« less

Molecular Basis for Cyclooxygenase Inhibition by the Non-steroidal Anti-inflammatory Drug Naproxen

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duggan, Kelsey C.; Walters, Matthew J.; Musee, Joel

Naproxen ((S)-6-methoxy-{alpha}-methyl-2-naphthaleneacetic acid) is a powerful non-selective non-steroidal anti-inflammatory drug that is extensively used as a prescription and over-the-counter medication. Naproxen exhibits gastrointestinal toxicity, but its cardiovascular toxicity may be reduced compared with other drugs in its class. Despite the fact that naproxen has been marketed for many years, the molecular basis of its interaction with cyclooxygenase (COX) enzymes is unknown. We performed a detailed study of naproxen-COX-2 interactions using site-directed mutagenesis, structure-activity analysis, and x-ray crystallography. The results indicate that each of the pendant groups of the naphthyl scaffold are essential for COX inhibition, and only minimal substitutions aremore » tolerated. Mutation of Trp-387 to Phe significantly reduced inhibition by naproxen, a result that appears unique to this inhibitor. Substitution of S or CH2 for the O atom of the p-methoxy group yielded analogs that were not affected by the W387F substitution and that exhibited increased COX-2 selectivity relative to naproxen. Crystallization and x-ray analysis yielded structures of COX-2 complexed to naproxen and its methylthio analog at 1.7 and 2.3 {angstrom} resolution, respectively. The combination of mutagenesis, structure analysis, and x-ray crystallography provided comprehensive information on the unique interactions responsible for naproxen binding to COX-2.« less

Mutual benefits in academic-service partnership: An integrative review.

PubMed

Sadeghnezhad, Maliheh; Heshmati Nabavi, Fatemeh; Najafi, Fereshteh; Kareshki, Hossein; Esmaily, Habibollah

2018-05-30

Academic and service institutions involve with many challenges. Partnership programs are a golden opportunity to achieve mutual benefits to overcome these challenges. Identifying mutual benefits is the cornerstone of forming a successful partnership and guarantee to its continuity. There are definitions and instances of mutual benefits in the literature related to partnership programs, but there is no coherent evidence and clear picture of these benefits. This study is conducted to identify mutual benefits in academic-service partnership by analyzing the definitions and instances of it in the literature. An integrative review of key papers regarding mutual benefits in academic-service partnership was undertaken. This review was guided by the framework described by Whittemore and Knafl. Search of the following databases was conducted: MEDLINE, ERIC, Google Scholar, Emerald Insight and Science Direct. The search terms were mutual benefits, mutual gains, mutual interest, mutual expectations, mutual goals, mutual demand, partnership, collaboration, academic-service partnership and academic service collaboration. Cooper's five-stage integrative review method was used. Quality evaluation of articles was conducted. Data were abstracted from included articles. The analysis was conducted based on the qualitative content analysis of the literature suggested by Zhang and Wildemuth. 28 articles were included in this review. Mutual benefits are described in four categories include: synergy in training and empowerment of human resources, education improvement, access to shared resources, facilitate production and application of beneficial knowledge into practice. Mutual benefits in the academic-service partnership include a range of goals, interests, expectations, and needs of partner organizations that is achievable and measurable through joint planning and collaboration. We suggest academic and service policymakers to consider these benefits in the planning and evaluating

Cardiotoxicity of copper-based antineoplastic drugs casiopeinas is related to inhibition of energy metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hernandez-Esquivel, Luz; Marin-Hernandez, Alvaro; Pavon, Natalia

2006-04-01

Isolated rat hearts were perfused with glucose, octanoate or glucose + octanoate and different concentrations of the copper-based antineoplastic drugs casiopeina II-gly (CSII) or casiopeina III-i-a (CSIII). In isolated perfused hearts with glucose + octanoate, both casiopeinas induced diminution in cardiac work and O{sub 2} consumption with half-maximal inhibitory concentrations (IC{sub 5}) of 4 (CSII) and 4.6 (CSIII) {mu}M, after 1 h of perfusion. Strong inhibition of the pyruvate and 2-oxoglutarate dehydrogenases as well as total creatine kinase by casiopeinas suggested that ATP generation by oxidative phosphorylation and its transfer towards myofibrils were targets for these drugs. In consequence, themore » cellular contents of ATP and phosphocreatine were also lowered by casiopeinas. Remarkably, casiopeinas were less toxic than adriamycin (IC{sub 5} = 2.6 {mu}M), a well-known potent cardiotoxic and antineoplastic drug, which has a wide clinical use. In an open-chest animal, which is a more physiological model than the isolated heart, femoral administration of 1 {mu}M drug revealed that CSII was innocuous very likely due to strong binding to serum albumin, whereas adriamycin induced again a potent cardiotoxic effect (diminution in heart rate and severe depression of systolic blood pressure). Thus, it seems that casiopeinas are a group of new antineoplastic drugs with milder secondary toxic effects than proven drugs such as adriamycin.« less

The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry.

PubMed

Gehring, Gerrit; Rohrmann, Katrin; Atenchong, Nkacheh; Mittler, Eva; Becker, Stephan; Dahlmann, Franziska; Pöhlmann, Stefan; Vondran, Florian W R; David, Sascha; Manns, Michael P; Ciesek, Sandra; von Hahn, Thomas

2014-08-01

Filoviruses such as Ebola virus and Marburg virus cause a severe haemorrhagic fever syndrome in humans for which there is no specific treatment. Since filoviruses use a complex route of cell entry that depends on numerous cellular factors, we hypothesized that there may be drugs already approved for human use for other indications that interfere with signal transduction or other cellular processes required for their entry and hence have anti-filoviral properties. We used authentic filoviruses and lentiviral particles pseudotyped with filoviral glycoproteins to identify and characterize such compounds. We discovered that amiodarone, a multi-ion channel inhibitor and adrenoceptor antagonist, is a potent inhibitor of filovirus cell entry at concentrations that are routinely reached in human serum during anti-arrhythmic therapy. A similar effect was observed with the amiodarone-related agent dronedarone and the L-type calcium channel blocker verapamil. Inhibition by amiodarone was concentration dependent and similarly affected pseudoviruses as well as authentic filoviruses. Inhibition of filovirus entry was observed with most but not all cell types tested and was accentuated by the pre-treatment of cells, indicating a host cell-directed mechanism of action. The New World arenavirus Guanarito was also inhibited by amiodarone while the Old World arenavirus Lassa and members of the Rhabdoviridae (vesicular stomatitis virus) and Bunyaviridae (Hantaan) families were largely resistant. The ion channel blockers amiodarone, dronedarone and verapamil inhibit filoviral cell entry. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Generalized mutual information and Tsirelson's bound

NASA Astrophysics Data System (ADS)

Wakakuwa, Eyuri; Murao, Mio

2014-12-01

We introduce a generalization of the quantum mutual information between a classical system and a quantum system into the mutual information between a classical system and a system described by general probabilistic theories. We apply this generalized mutual information (GMI) to a derivation of Tsirelson's bound from information causality, and prove that Tsirelson's bound can be derived from the chain rule of the GMI. By using the GMI, we formulate the "no-supersignalling condition" (NSS), that the assistance of correlations does not enhance the capability of classical communication. We prove that NSS is never violated in any no-signalling theory.

Generalized mutual information and Tsirelson's bound

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wakakuwa, Eyuri; Murao, Mio

2014-12-04

We introduce a generalization of the quantum mutual information between a classical system and a quantum system into the mutual information between a classical system and a system described by general probabilistic theories. We apply this generalized mutual information (GMI) to a derivation of Tsirelson's bound from information causality, and prove that Tsirelson's bound can be derived from the chain rule of the GMI. By using the GMI, we formulate the 'no-supersignalling condition' (NSS), that the assistance of correlations does not enhance the capability of classical communication. We prove that NSS is never violated in any no-signalling theory.

12 CFR 239.3 - Mutual holding company reorganizations.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 12 Banks and Banking 4 2012-01-01 2012-01-01 false Mutual holding company reorganizations. 239.3 Section 239.3 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) MUTUAL HOLDING COMPANIES (REGULATION MM) Mutual Holding Companies § 239.3...

12 CFR 239.3 - Mutual holding company reorganizations.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 12 Banks and Banking 4 2014-01-01 2014-01-01 false Mutual holding company reorganizations. 239.3 Section 239.3 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) MUTUAL HOLDING COMPANIES (REGULATION MM) Mutual Holding Companies § 239.3...

12 CFR 239.3 - Mutual holding company reorganizations.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 12 Banks and Banking 4 2013-01-01 2013-01-01 false Mutual holding company reorganizations. 239.3 Section 239.3 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) MUTUAL HOLDING COMPANIES (REGULATION MM) Mutual Holding Companies § 239.3...

Cytochrome P450 3A4 in vivo ketoconazole competitive inhibition: determination of Ki and dangers associated with high clearance drugs in general.

PubMed

Boxenbaum, H

1999-01-01

Assuming complete hepatic substrate metabolism and system linearity, quantitative effects of in vivo competitive inhibition are investigated. Following oral administration of a substrate in the presence of a competitive inhibitor, determination of the inhibition constant (Ki) is possible when plasma concentration-time profiles of both substrate and inhibitor are available. When triazolam is the P450 3A4 substrate and ketoconazole the competitive inhibitor, Ki approximately 1.2 microg/mL in humans. The effects of competitive inhibition can be divided into two components: first-pass hepatic metabolism and systemic metabolism. For drugs with high hepatic extraction ratios, the impact of competitive inhibition on hepatic first-pass metabolism can be particularly dramatic. For example, human terfenadine hepatic extraction goes from 95% in the absence of a competitive inhibitor to 35% in the presence of one (ketoconazole, 200 mg po Q 12 h dosed to steady-state). First-pass extraction therefore goes from 5% in the absence of the inhibitor to 65% in its presence. The combined effect on first-pass and systemic metabolism produces an approximate 37 fold increase in terfenadine area under the plasma concentration-time curve. Assuming intact drug is active and/or toxic, development of metabolized drugs with extensive first-pass metabolism should be avoided if possible, since inhibition of metabolism may lead to profound increases in exposure.

Drug Repositioning for Effective Prostate Cancer Treatment.

PubMed

Turanli, Beste; Grøtli, Morten; Boren, Jan; Nielsen, Jens; Uhlen, Mathias; Arga, Kazim Y; Mardinoglu, Adil

2018-01-01

Drug repositioning has gained attention from both academia and pharmaceutical companies as an auxiliary process to conventional drug discovery. Chemotherapeutic agents have notorious adverse effects that drastically reduce the life quality of cancer patients so drug repositioning is a promising strategy to identify non-cancer drugs which have anti-cancer activity as well as tolerable adverse effects for human health. There are various strategies for discovery and validation of repurposed drugs. In this review, 25 repurposed drug candidates are presented as result of different strategies, 15 of which are already under clinical investigation for treatment of prostate cancer (PCa). To date, zoledronic acid is the only repurposed, clinically used, and approved non-cancer drug for PCa. Anti-cancer activities of existing drugs presented in this review cover diverse and also known mechanisms such as inhibition of mTOR and VEGFR2 signaling, inhibition of PI3K/Akt signaling, COX and selective COX-2 inhibition, NF-κB inhibition, Wnt/β-Catenin pathway inhibition, DNMT1 inhibition, and GSK-3β inhibition. In addition to monotherapy option, combination therapy with current anti-cancer drugs may also increase drug efficacy and reduce adverse effects. Thus, drug repositioning may become a key approach for drug discovery in terms of time- and cost-efficiency comparing to conventional drug discovery and development process.

Drug-induced in vitro inhibition of neutrophil-endothelial cell adhesion.

PubMed Central

Pellegatta, F.; Lu, Y.; Radaelli, A.; Zocchi, M. R.; Ferrero, E.; Chierchia, S.; Gaja, G.; Ferrero, M. E.

1996-01-01

1. Leukocyte-endothelial cell interactions play an important role during ischaemia-reperfusion events. Adhesion molecules are specifically implicated in this interaction process. 2. Since defibrotide has been shown to be an efficient drug in reducing damage due to ischaemia-reperfusion in many experimental models, we analysed the effect of defibrotide in vitro on leukocyte adhesion to endothelial cells in basal conditions and after their stimulation. 3. In basal conditions, defibrotide (1000 micrograms ml-1) partially inhibited leukocyte adhesion to endothelial cells by 17.3% +/- 3.6 (P < 0.05), and after endothelial cell stimulation (TNF-alpha, 500 u ml-1) or after leukocyte stimulation (fMLP, 10(-7) M), it inhibited leukocyte adhesion by 26.5% +/- 3.4 and 32.4% +/- 1.8, respectively (P < 0.05). 4. In adhesion blockage experiments, the use of the monoclonal antibody anti-CD31 (5 micrograms ml-1) did not demonstrate a significant inhibitory effect whereas use of the monoclonal antibody anti-LFA-1 (5 micrograms ml-1) significantly interfered with the effect of defibrotide. 5. This result was confirmed in NIH/3T3-ICAM-1 transfected cells. 6. We conclude that defibrotide is able to interfere with leukocyte adhesion to endothelial cells mainly in activated conditions and that the ICAM-1/LFA-1 adhesion system is involved in the defibrotide mechanism of action. PMID:8762067

PANC-1 pancreatic cancer cell growth inhibited by cucurmosin alone and in combination with an epidermal growth factor receptor-targeted drug.

PubMed

Wang, Congfei; Yang, Aiqin; Zhang, Baoming; Yin, Qiang; Huang, Heguang; Chen, Minghuang; Xie, Jieming

2014-03-01

To investigate the inhibition of PANC-1 pancreatic cancer cell growth by cucurmosin (CUS) and its possible mechanism. We observed the inhibition of PANC-1 cell growth by sulforhodamine B and colony-forming experiments in vitro and established nonobese diabetic/severe combined immunodeficiency mouse subcutaneous tumor models in vivo. We used Western blot to analyze protein levels related to apoptosis and epidermal growth factor receptor (EGFR) signaling pathways after drug intervention, whereas the messenger RNA expression of EGFR was analyzed by quantitative real-time polymerase chain reaction. Sulforhodamine B and colony-forming experiments indicated that CUS inhibited PANC-1 cell proliferation in a dose- and time-dependent manner. A stronger inhibitory effect was observed when CUS was combined with gefitinib. The subcutaneous tumor growth was also inhibited. Western blot showed that all the examined proteins decreased, except for 4E-BP1 and the active fragments of caspase 3 and caspase 9 increased. Epidermal growth factor receptor expression did not change significantly in quantitative real-time polymerase chain reaction. Cucurmosin can strongly inhibit the growth of PANC-1 cells in vitro and in vivo. Cucurmosin can down-regulate EGFR protein expression, but not at the messenger RNA level. Cucurmosin can also inhibit the ras/raf and phosphatidylinositol 3-kinase/Akt downstream signaling pathways and enhance the sensitivity of the EGFR-targeted drug gefitinib.

Choline Kinase, A Novel Drug Target for the Inhibition of Streptococcus pneumoniae.

PubMed

Zimmerman, Tahl; Ibrahim, Salam

2017-09-25

Gram-positive pathogens, such as S treptococcus pneumoniae , can have deleterious effects on both human and animal health. Antibiotics and antimicrobials have been developed to treat infections caused by such pathogens and to prevent food contamination. However, these strategies have been increasingly thwarted by the emergence of resistant bacteria strains. Thus, new methods for controlling Gram-positive pathogen growth need to be continuously developed. Choline analogs, such as Hemicholinium-3 (HC-3), have been shown to be useful in blocking cell division in eukaryotic cells through the inhibition of choline kinase, an enzyme which catalyzes the production of phosphocholine from choline and ATP. In some Gram-positive pathogens, choline kinase is an important enzyme in the production of the cell wall element, lipoteichoic acid. However, it is not known if inhibiting this enzyme has any effect on cell division in Gram-positive bacteria. Using the R6 strain as a model, we tested the ability of HC-3 to block the activity of choline kinase in S. pneumoniae and inhibit cell growth. Mass-spectrometry measurements of crude extracts revealed that HC-3 blocked choline kinase activity. Turbidity measurements and population counts showed that HC-3 inhibited cell growth. Competition assays with choline suggested that HC-3 also blocked choline transporters. Western blots showed that lipoteichoic acid production was blocked in the presence of HC-3, and autolytic assays showed that this decrease in lipoteichoic acids caused cells to be more resistant to autolysis. Scanning electron microscopy revealed that HC-3 distorted the cell wall. This study thus establishes choline kinase as a novel drug target for S. pneumoniae .

Structure–inhibition relationship of ginsenosides towards UDP-glucuronosyltransferases (UGTs)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fang, Zhong-Ze; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of Sciences and The first Affiliated Hospital of Liaoning Medical University, No.457, Zhongshan Road, Dalian 116023; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892

The wide utilization of ginseng provides the high risk of herb–drug interaction (HDI) with many clinical drugs. The inhibition of ginsenosides towards drug-metabolizing enzymes (DMEs) has been regarded as an important reason for herb–drug interaction (HDI). Compared with the deep studies on the ginsenosides' inhibition towards cytochrome P450 (CYP), the inhibition of ginsenosides towards the important phase II enzymes UDP-glucuronosyltransferases (UGTs) remains to be unclear. The present study aims to evaluate the inhibition behavior of ginsenosides towards important UGT isoforms located in the liver and intestine using in vitro methods. The recombinant UGT isoform-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employedmore » as in vitro probe reaction. The results showed that structure-dependent inhibition existed for the inhibition of ginsenosides towards UGT isoforms. To clarify the possibility of in vivo herb–drug interaction induced by this kind of inhibition, the ginsenoside Rg{sub 3} was selected as an example, and the inhibition kinetic type and parameters (K{sub i}) were determined. Rg{sub 3} competitively inhibited UGT1A7, 2B7 and 2B15-catalyzed 4-MU glucuronidation reaction, and exerted noncompetitive inhibition towards UGT1A8-catalyzed 4-MU glucuronidation. The inhibition parameters (K{sub i} values) were calculated to be 22.6, 7.9, 1.9, and 2.0 μM for UGT1A7, 1A8, 2B7 and 2B15. Using human maximum plasma concentration of Rg{sub 3} (400 ng/ml (0.5 μM)) after intramuscular injection of 60 mg Rg{sub 3}, the area under the plasma concentration-time curve (AUC) was extrapolated to increase by 2.2%, 6.3%, 26.3%, and 25% for the co-administered drugs completely undergoing the metabolism catalyzed by UGT1A7, 1A8, 2B7 and 2B15, respectively. All these results indicated that the ginsenosides' inhibition towards UGT isoforms might be an important reason for ginseng–drug interaction. - Highlights: ► Structure-dependent inhibition

Inhibition of Major Drug Metabolizing CYPs by Common Herbal Medicines used by HIV/AIDS Patients in Africa– Implications for Herb-Drug Interactions

PubMed Central

Awortwe, Charles; Bouic, Patrick J.; Masimirembwa, Collen M.; Rosenkranz, Bernd

2015-01-01

The purpose of this study was to evaluate the potential risk of common herbal medicines used by HIV-infected patients in Africa for herb-drug interactions (HDI). High throughput screening assays consisting of recombinant Cytochrome P450 enzymes (CYPs) and fluorescent probes, and parallel artificial membrane permeability assays (PAMPA) were used. The potential of herbal medicines to cause HDI was ranked according to FDA guidelines for reversible inhibition and categorization of time dependent inhibition was based on the normalized ratio. CYPs 1A2 and 3A4 were most inhibited by the herbal extracts. H. hemerocallidea (IC50 = 0.63 μg/mL and 58 μg/mL) and E. purpurea (IC50 = 20 μg/mL and 12 μg/mL) were the potent inhibitors of CYPs 1A2 and 3A4 respectively. L. frutescens and H. hemerocallidea showed clear time dependent inhibition on CYP3A4. Furthermore, the inhibitory effect of both H. hemerocallidea and L. frutescens before and after PAMPA were identical. The results indicate potential HDI of H. hemerocallidea, L. frutescens and E. purpurea with substrates of the affected enzymes if maximum in vivo concentration is achieved. PMID:24475926

Cyclodextrin-Modified Porous Silicon Nanoparticles for Efficient Sustained Drug Delivery and Proliferation Inhibition of Breast Cancer Cells.

PubMed

Correia, Alexandra; Shahbazi, Mohammad-Ali; Mäkilä, Ermei; Almeida, Sérgio; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A

2015-10-21

Over the past decade, the potential of polymeric structures has been investigated to overcome many limitations related to nanosized drug carriers by modulating their toxicity, cellular interactions, stability, and drug-release kinetics. In this study, we have developed a successful nanocomposite consisting of undecylenic acid modified thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs) loaded with an anticancer drug, sorafenib, and surface-conjugated with heptakis(6-amino-6-deoxy)-β-cyclodextrin (HABCD) to show the impact of the surface polymeric functionalization on the physical and biological properties of the drug-loaded nanoparticles. Cytocompatibility studies showed that the UnTHCPSi-HABCD NPs were not toxic to breast cancer cells. HABCD also enhanced the suspensibility and both the colloidal and plasma stabilities of the UnTHCPSi NPs. UnTHCPSi-HABCD NPs showed a significantly increased interaction with breast cancer cells compared to bare NPs and also sustained the drug release. Furthermore, the sorafenib-loaded UnTHCPSi-HABCD NPs efficiently inhibited cell proliferation of the breast cancer cells.

Nonsteroidal Anti-inflammatory Drugs (NSAIDS) Inhibit the Growth and Reproduction of Chaetomium globosum and Other Fungi Associated with Water-Damaged Buildings.

PubMed

Dalmont, Kelsey; Biles, Charles L; Konsure, Heather; Dahal, Sujita; Rowsey, Tyler; Broge, Matthew; Poudyal, Shubhra; Gurung, Tara; Shrestha, Sabina; Biles, Caleb L; Cluck, Terry; Howard, Alisha

2017-12-01

Indoor mold due to water damage causes serious human respiratory disorders, and the remediation to homes, schools, and businesses is a major expense. Prevention of mold infestation of building materials would reduce health problems and building remediation costs. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit yeasts and a limited number of filamentous fungi. The purpose of this research was to determine the possible inhibitory activity of nonsteroidal anti-inflammatory drugs (NSAIDs) on germination, fungal growth, and reproduction of Chaetomium globosum and other important filamentous fungi that occur in water-damaged buildings. Several NSAIDs were found to inhibit C. globosum germination, growth, and reproduction. The most effective NSAIDs inhibiting C. globosum were ibuprofen, diflunisal, and diclofenac. Fusarium oxysporum, Fusarium solani, Aspergillus niger, and Stachybotrys atra were also tested on the various media with similar results obtained. However, F. oxysporum and A. niger exhibited a higher level of resistance to aspirin and NaSAL when compared to the C. globosum isolates. The inhibition exhibited by NSAIDs was variable depending on growth media and stage of fungal development. These compounds have a great potential of inhibiting fungal growth on building materials such as gypsum board. Formulations of sprays or building materials with NSAID-like chemical treatments may hold promise in reducing mold in homes and buildings.

Mutual Mentoring Makes Better Mentors

NASA Astrophysics Data System (ADS)

Blaha, Cindy; Bug, Amy; Cox, Anne; Fritz, Linda; Whitten, Barbara

2011-03-01

In this talk we discuss one of the impacts of an NSF ADVANCE sponsored horizontal, mutual mentoring alliance. Our cohort of five women physicists at liberal arts colleges has found that mutual mentoring has had a profound impact on many aspects of our professional lives. In this talk we will describe how our peer-to-peer mentoring has enabled us to become better mentors for our undergraduate students, for recent graduates beginning their careers and for colleagues at local and neighboring institutions.

Elucidating rifampin's inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite.

PubMed

Zheng, H X; Huang, Y; Frassetto, L A; Benet, L Z

2009-01-01

The effects of single doses of intravenous (IV) ciprofloxacin and rifampin and of multiple doses of rifampin on glyburide exposure and blood glucose levels were investigated in nine healthy volunteers. A single IV dose of rifampin significantly increased the area under the concentration-time curve (AUC) of glyburide and its metabolite. Blood glucose levels were significantly lower than those observed after dosing with glyburide alone. Multiple doses of rifampin induced an increase in liver enzyme levels, leading to a marked decrease in glyburide exposure and blood glucose levels. When IV rifampin was administered after multiple doses of rifampin, the inhibition of hepatic uptake transporters masked the induction effect; however, the relative changes in AUC for glyburide and its hydroxyl metabolite were similar to those seen under noninduced conditions. The studies reported here demonstrate how measurements of the levels of both the parent drug and its primary metabolite are useful in unmasking simultaneous drug-drug induction and inhibition effects and in characterizing enzymatic vs. transporter mechanisms.

Evaluation of human D-amino acid oxidase inhibition by anti-psychotic drugs in vitro.

PubMed

Shishikura, Miho; Hakariya, Hitomi; Iwasa, Sumiko; Yoshio, Takashi; Ichiba, Hideaki; Yorita, Kazuko; Fukui, Kiyoshi; Fukushima, Takeshi

2014-06-01

It is of importance to determine whether antipsychotic drugs currently prescribed for schizophrenia exert D-amino acid oxidase (DAO)-inhibitory effects. We first investigated whether human (h)DAO can metabolize D-kynurenine (D-KYN) to produce the fluorescent compound kynurenic acid (KYNA) by using high-performance liquid chromatography with mass spectrometry, and fluorescence spectrometry. After confirmation of KYNA production from D-KYN by hDAO, 8 first- and second-generation antipsychotic drugs, and 6 drugs often prescribed concomitantly, were assayed for hDAO-inhibitory effects by using in vitro fluorometric methods with D-KYN as the substrate. DAO inhibitors 3-methylpyrazole-5-carboxylic acid and 4H-thieno[3,2-b]pyrrole-5-carboxylic acid inhibited KYNA production in a dose-dependent manner. Similarly, the second-generation antipsychotics blonanserin and risperidone were found to possess relatively strong hDAO-inhibitory effects in vitro (5.29 ± 0.47 μM and 4.70 ± 0.17 μM, respectively). With regard to blonanserin and risperidone, DAO-inhibitory effects should be taken into consideration in the context of their in vivo pharmacotherapeutic efficacy.

Construction of High Drug Loading and Enzymatic Degradable Multilayer Films for Self-Defense Drug Release and Long-Term Biofilm Inhibition.

PubMed

Wang, Bailiang; Liu, Huihua; Sun, Lin; Jin, Yingying; Ding, Xiaoxu; Li, Lingli; Ji, Jian; Chen, Hao

2018-01-08

Bacterial infections and biofilm formation on the surface of implants are important issues that greatly affect biomedical applications and even cause device failure. Construction of high drug loading systems on the surface and control of drug release on-demand is an efficient way to lower the development of resistant bacteria and biofilm formation. In the present study, (montmorillonite/hyaluronic acid-gentamicin) 10 ((MMT/HA-GS) 10 ) organic/inorganic hybrid multilayer films were alternately self-assembled on substrates. The loading dosage of GS was as high as 0.85 mg/cm 2 , which could be due the high specific surface area of MMT. The obtained multilayer film with high roughness gradually degraded in hyaluronidase (HAS) solutions or a bacterial infection microenvironment, which caused the responsive release of GS. The release of GS showed dual enzyme and bacterial infection responsiveness, which also indicated good drug retention and on-demand self-defense release properties of the multilayer films. Moreover, the GS release responsiveness to E. coli showed higher sensitivity than that to S. aureus. There was only ∼5 wt % GS release from the film in PBS after 48 h of immersion, and the amount quickly increased to 30 wt % in 10 5 CFU/mL of E. coli. Importantly, the high drug dosage, smart drug release, and film peeling from the surface contributed to the efficient antibacterial properties and long-term biofilm inhibition functions. Both in vitro and in vivo antibacterial tests indicated efficient sterilization function and good mammalian cell and tissue compatibility.

Inhibition of monoamine oxidase A and B activities by imidazol(ine)/guanidine drugs, nature of the interaction and distinction from I2-imidazoline receptors in rat liver

PubMed Central

Ozaita, Andrés; Olmos, Gabriel; Assumpció Boronat, M; Miguel Lizcano, José; Unzeta, Mercedes; García-Sevilla, Jesús A

1997-01-01

I2-Imidazoline sites ([3H]-idazoxan binding) have been identified on monoamine oxidase (MAO) and proposed to modulate the activity of the enzyme through an allosteric inhibitory mechanism (Tesson et al., 1995). The main aim of this study was to assess the inhibitory effects and nature of the inhibition of imidazol(ine)/guanidine drugs on rat liver MAO-A and MAO-B isoforms and to compare their inhibitory potencies with their affinities for the sites labelled by [3H]-clonidine in the same tissue. Competition for [3H]-clonidine binding in rat liver mitochondrial fractions by imidazol(ine)/guanidine compounds revealed that the pharmacological profile of the interaction (2 - styryl - 2 - imidazoline, LSL 61112>idazoxan>2 - benzofuranyl - 2 - imidazoline, 2-BFI=cirazoline>guanabenz>oxymetazoline>>clonidine) was typical of that for I2-sites. Clonidine inhibited rat liver MAO-A and MAO-B activities with very low potency (IC50s: 700 μM and 6 mM, respectively) and displayed the typical pattern of competitive enzyme inhibition (Lineweaver-Burk plots: increased Km and unchanged Vmax values). Other imidazol(ine)/guanidine drugs also were weak MAO inhibitors with the exception of guanabenz, 2-BFI and cirazoline on MAO-A (IC50s: 4–11 μM) and 2-benzofuranyl-2-imidazol (LSL 60101) on MAO-B (IC50: 16 μM). Idazoxan was a full inhibitor, although with rather low potency, on both MAO-A and MAO-B isoenzymes (IC50s: 280 μM and 624 μM, respectively). Kinetic analyses of MAO-A inhibition by these drugs revealed that the interactions were competitive. For the same drugs acting on MAO-B the interactions were of the mixed type inhibition (increased Km and decreased Vmax values), although the greater inhibitory effects on the apparent value of Vmax/Km than on the Vmax value indicated that the competitive element of the MAO-B inhibition predominated. Competition for [3H]-Ro 41-1049 binding to MAO-A or [3H]-Ro 19-6327 binding to MAO-B in rat liver

Inhibition of the NorA multi-drug transporter by oxygenated monoterpenes.

PubMed

Coêlho, Mayara Ladeira; Ferreira, Josie Haydée Lima; de Siqueira Júnior, José Pinto; Kaatz, Glenn W; Barreto, Humberto Medeiros; de Carvalho Melo Cavalcante, Ana Amélia

2016-10-01

The aim of this study was to investigate intrinsic antimicrobial activity of three monoterpenes nerol, dimethyl octanol and estragole, against bacteria and yeast strains, as well as, investigate if these compounds are able to inhibit the NorA efflux pump related to fluoroquinolone resistance in Staphylococcus aureus. Minimal inhibitory concentrations (MICs) of the monoterpenes against Staphylococcus aureus, Escherichia coli and Candida albicans strains were determined by micro-dilution assay. MICs of the norfloxacin against a S. aureus strain overexpressing the NorA protein were determined in the absence or in the presence of the monoterpenes at subinhibitory concentrations, aiming to verify the ability of this compounds act as efflux pump inhibitors. The monoterpenes were inactive against S. aureus however the nerol was active against E. coli and C. albicans. The addition of the compounds to growth media at sub-inhibitory concentrations enhanced the activity of norfloxacin against S. aureus SA1199-B. This result shows that bioactives tested, especially the nerol, are able to inhibit NorA efflux pump indicating a potential use as adjuvants of norfloxacin for therapy of infections caused by multi-drug resistant S. aureus strains. Copyright © 2016 Elsevier Ltd. All rights reserved.

Zika viral polymerase inhibition using anti-HCV drugs both in market and under clinical trials.

PubMed

Elfiky, Abdo A

2016-12-01

In the last few months, a new Zika virus (ZIKV) outbreak evolved in America. In accordance, World Health Organization (WHO) in February 2016 declared it as Public Health Emergency of International Concern (PHEIC). ZIKV infection was reported in more than 60 countries and the disease was spreading since 2007 but with little momentum. Many antiviral drugs are available in market or in laboratories under clinical trials, could affect ZIKV infection. In silico docking study were performed on the ZIKV polymerase to test some of Hepatitis C Virus (HCV) drugs (approved and in clinical trials). The results show potency of almost all of the studied compounds on ZIKV polymerase and hence inhibiting the propagation of the disease. In addition, the study suggested two nucleotide inhibitors (IDX-184 and MK0608) that may be tested as drugs against ZIKV infection. J. Med. Virol. 88:2044-2051, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Group Differences in the Mutual Gaze of Chimpanzees (Pan Troglodytes)

ERIC Educational Resources Information Center

Bard, Kim A.; Myowa-Yamakoshi, Masako; Tomonaga, Masaki; Tanaka, Masayuki; Costall, Alan; Matsuzawa, Tetsuro

2005-01-01

A comparative developmental framework was used to determine whether mutual gaze is unique to humans and, if not, whether common mechanisms support the development of mutual gaze in chimpanzees and humans. Mother-infant chimpanzees engaged in approximately 17 instances of mutual gaze per hour. Mutual gaze occurred in positive, nonagonistic…

TANKYRASE Inhibition Enhances the Antiproliferative Effect of PI3K and EGFR Inhibition, Mutually Affecting β-CATENIN and AKT Signaling in Colorectal Cancer.

PubMed

Solberg, Nina T; Waaler, Jo; Lund, Kaja; Mygland, Line; Olsen, Petter A; Krauss, Stefan

2018-03-01

Overactivation of the WNT/β-CATENIN signaling axis is a common denominator in colorectal cancer. Currently, there is no available WNT inhibitor in clinical practice. Although TANKYRASE (TNKS) inhibitors have been proposed as promising candidates, there are many colorectal cancer models that do not respond positively to TNKS inhibition in vitro and in vivo Therefore, a combinatorial therapeutic approach combining a TNKS inhibitor (G007-LK) with PI3K (BKM120) and EGFR (erlotinib) inhibitors in colorectal cancer was investigated. The data demonstrate that TNKS inhibition enhances the effect of PI3K and EGFR inhibition in the TNKS inhibitor-sensitive COLO320DM, and in the nonsensitive HCT-15 cell line. In both cell lines, combined TNKS/PI3K/EGFR inhibition is more effective at reducing growth than a dual TNKS/MEK inhibition. TNKS/PI3K/EGFR inhibition affected in a context-dependent manner components of the WNT/β-CATENIN, AKT/mTOR, EGFR, and RAS signaling pathways. TNKS/PI3K/EGFR inhibition also efficiently reduced growth of both COLO320DM and HCT-15 tumor xenografts in vivo At the highest doses, tumor xenograft growth was halted without affecting the body weight of the tested animals. Implications: Combining TNKS inhibitors with PI3K and EGFR inhibition may expand the therapeutic arsenal against colorectal cancers. Mol Cancer Res; 16(3); 543-53. ©2017 AACR . ©2017 American Association for Cancer Research.

12 CFR 575.12 - Conversion or liquidation of mutual holding companies.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Conversion or liquidation of mutual holding... MUTUAL HOLDING COMPANIES § 575.12 Conversion or liquidation of mutual holding companies. (a) Conversion... stock issued by the parent mutual holding company in connection with the conversion of the parent mutual...

Molecular Insights into Human Monoamine Oxidase B Inhibition by the Glitazone Antidiabetes Drugs

PubMed Central

2011-01-01

The widely employed antidiabetic drug pioglitazone (Actos) is shown to be a specific and reversible inhibitor of human monoamine oxidase B (MAO B). The crystal structure of the enzyme–inhibitor complex shows that the R-enantiomer is bound with the thiazolidinedione ring near the flavin. The molecule occupies both substrate and entrance cavities of the active site, establishing noncovalent interactions with the surrounding amino acids. These binding properties differentiate pioglitazone from the clinically used MAO inhibitors, which act through covalent inhibition mechanisms and do not exhibit a high degree of MAO A versus B selectivity. Rosiglitazone (Avandia) and troglitazone, other members of the glitazone class, are less selective in that they are weaker inhibitors of both MAO A and MAO B. These results suggest that pioglitazone may have utility as a “repurposed” neuroprotectant drug in retarding the progression of disease in Parkinson's patients. They also provide new insights for the development of reversible isoenzyme-specific MAO inhibitors. PMID:22282722

Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels

PubMed Central

Chauhan, Vikash P.; Martin, John D.; Liu, Hao; Lacorre, Delphine A.; Jain, Saloni R.; Kozin, Sergey V.; Stylianopoulos, Triantafyllos; Mousa, Ahmed S.; Han, Xiaoxing; Adstamongkonkul, Pichet; Popović, Zoran; Huang, Peigen; Bawendi, Moungi G.; Boucher, Yves; Jain, Rakesh K.

2013-01-01

Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors —inexpensive drugs with decades of safe use — could be rapidly repurposed as cancer therapeutics. PMID:24084631

Reducing Deviance Through Youths' Mutual Aid Group Dynamics.

PubMed

Cheung, Chau-kiu; Ngai, Steven Sek-yum

2016-01-01

The mutual aid group, as supported by the social worker, emerges to play a vital role in helping group members reduce their deviance or behavioral problem. However, how the collaboration of the group and social worker accomplishes the reduction has remained uncharted. Based on social capital theory, mutual aid and cohesion within the group and social workers' specific aid for the group are likely responsible for the reduction. The test of such hypotheses relies on a two-wave panel survey of the members of 60 mutual aid groups who had deviant behavioral problems, located in Hong Kong, China. These groups had 241 youths completing both initial and 1-year follow-up surveys. Results manifested the direct or unconditional contributions of mutual aid, group cohesion, and social workers' specific aid to reducing deviance. Hence, social workers can enhance the effectiveness of the mutual aid group in reducing youths' deviance. © The Author(s) 2014.

Multiple myeloma phosphotyrosine proteomic profile associated with FGFR3 expression, ligand activation, and drug inhibition

PubMed Central

St-Germain, Jonathan R.; Taylor, Paul; Tong, Jiefei; Jin, Lily L.; Nikolic, Ana; Stewart, Ian I.; Ewing, Robert M.; Dharsee, Moyez; Li, Zhihua; Trudel, Suzanne; Moran, Michael F.

2009-01-01

Signaling by growth factor receptor tyrosine kinases is manifest through networks of proteins that are substrates and/or bind to the activated receptors. FGF receptor-3 (FGFR3) is a drug target in a subset of human multiple myelomas (MM) and is mutationally activated in some cervical and colon and many bladder cancers and in certain skeletal dysplasias. To define the FGFR3 network in multiple myeloma, mass spectrometry was used to identify and quantify phosphotyrosine (pY) sites modulated by FGFR3 activation and inhibition in myeloma-derived KMS11 cells. Label-free quantification of peptide ion currents indicated the activation of FGFR3 by phosphorylation of tandem tyrosines in the kinase domain activation loop when cellular pY phosphatases were inhibited by pervanadate. Among the 175 proteins that accumulated pY in response to pervanadate was a subset of 52 including FGFR3 that contained a total of 61 pY sites that were sensitive to inhibition by the FGFR3 inhibitor PD173074. The FGFR3 isoform containing the tandem pY motif in its activation loop was targeted by PD173074. Forty of the drug-sensitive pY sites, including two located within the 35-residue cytoplasmic domain of the transmembrane growth factor binding proteoglycan (and multiple myeloma biomarker) Syndecan-1/CD138, were also stimulated in cells treated with the ligand FGF1, providing additional validation of their link to FGFR3. The identification of these overlapping sets of co-modulated tyrosine phosphorylations presents an outline of an FGFR3 network in the MM model and demonstrates the potential for pharmacodynamic monitoring by label-free quantitative phospho-proteomics. PMID:19901323

Benefit and cost curves for typical pollination mutualisms.

PubMed

Morris, William F; Vázquez, Diego P; Chacoff, Natacha P

2010-05-01

Mutualisms provide benefits to interacting species, but they also involve costs. If costs come to exceed benefits as population density or the frequency of encounters between species increases, the interaction will no longer be mutualistic. Thus curves that represent benefits and costs as functions of interaction frequency are important tools for predicting when a mutualism will tip over into antagonism. Currently, most of what we know about benefit and cost curves in pollination mutualisms comes from highly specialized pollinating seed-consumer mutualisms, such as the yucca moth-yucca interaction. There, benefits to female reproduction saturate as the number of visits to a flower increases (because the amount of pollen needed to fertilize all the flower's ovules is finite), but costs continue to increase (because pollinator offspring consume developing seeds), leading to a peak in seed production at an intermediate number of visits. But for most plant-pollinator mutualisms, costs to the plant are more subtle than consumption of seeds, and how such costs scale with interaction frequency remains largely unknown. Here, we present reasonable benefit and cost curves that are appropriate for typical pollinator-plant interactions, and we show how they can result in a wide diversity of relationships between net benefit (benefit minus cost) and interaction frequency. We then use maximum-likelihood methods to fit net-benefit curves to measures of female reproductive success for three typical pollination mutualisms from two continents, and for each system we chose the most parsimonious model using information-criterion statistics. We discuss the implications of the shape of the net-benefit curve for the ecology and evolution of plant-pollinator mutualisms, as well as the challenges that lie ahead for disentangling the underlying benefit and cost curves for typical pollination mutualisms.

Hypusine modification in eukaryotic initiation factor 5A in rodent cells selected for resistance to growth inhibition by ornithine decarboxylase-inhibiting drugs.

PubMed Central

Tome, M E; Gerner, E W

1996-01-01

Selection of HTC cells in drugs that inhibit ornithine decarboxylase (ODC) has produced two cell lines, HMOA and DH23A/b, that contain increased amounts of more stable ODC. In addition to alterations in ODC, these cells appear to produce modified eukaryotic initiation factor 5A (eIF-5A) at different rates, a reaction that both requires spermidine and is essential for proliferation. Alterations to the modification of eIF-5A by spermidine cannot be accounted for by changes in eIF-5A protein or modified eIF-5A turnover. Deoxyhypusine synthetase activity is similar in the parental and variant cell lines and is unaltered by growth into plateau phase or by spermidine depletion. The increased rate of eIF-5A modification in DH23A/b cells is due to an increased accumulation of the unmodified eIF-5A precursor. Increased precursor accumulation is not due to increased eIF-5A transcription, but rather it can be attributed to a metabolic accumulation caused by growth under conditions of chronically limiting spermidine. Selection using drugs that inhibit ODC apparently does not cause alterations in the eIF-5A modification pathway. These data support the hypothesis that one of the main effects of spermidine depletion is depletion of the modified eIF-5A pool, and that this is a critical factor in the cytostasis often observed after depletion of cellular polyamines. PMID:8947467

Mutually unbiased bases and semi-definite programming

NASA Astrophysics Data System (ADS)

Brierley, Stephen; Weigert, Stefan

2010-11-01

A complex Hilbert space of dimension six supports at least three but not more than seven mutually unbiased bases. Two computer-aided analytical methods to tighten these bounds are reviewed, based on a discretization of parameter space and on Gröbner bases. A third algorithmic approach is presented: the non-existence of more than three mutually unbiased bases in composite dimensions can be decided by a global optimization method known as semidefinite programming. The method is used to confirm that the spectral matrix cannot be part of a complete set of seven mutually unbiased bases in dimension six.

Correlation of cholinergic drug induced quenching of acetylcholinesterase bound thioflavin-T fluorescence with their inhibition activity

NASA Astrophysics Data System (ADS)

Islam, Mullah Muhaiminul; Rohman, Mostofa Ataur; Gurung, Arun Bahadur; Bhattacharjee, Atanu; Aguan, Kripamoy; Mitra, Sivaprasad

2018-01-01

The development of new acetylcholinesterase inhibitors (AChEIs) and subsequent assay of their inhibition efficiency is considered to be a key step for AD treatment. The fluorescence intensity of thioflavin-T (ThT) bound in the active site of acetylcholinesterase (AChE) quenches substantially in presence of standard AChEI drugs due to the dynamic replacement of the fluorophore from the AChE active site as confirmed from steady state emission as well as time-resolved fluorescence anisotropy measurement and molecular dynamics simulation in conjunction with docking calculation. The parametrized % quenching data for individual system shows excellent correlation with enzyme inhibition activity measured independently by standard Ellman AChE assay method in a high throughput plate reader system. The results are encouraging towards design of a fluorescence intensity based AChE inhibition assay method and may provide a better toolset to rapidly evaluate as well as develop newer AChE-inhibitors for AD treatment.

Anthelminthic drug niclosamide sensitizes the responsiveness of cervical cancer cells to paclitaxel via oxidative stress-mediated mTOR inhibition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Liping; Wang, Li; Shen, Haibin

Drug repurposing represents an alternative therapeutic strategy to cancer treatment. The potent anti-cancer activities of a FDA-approved anthelminthic drug niclosamide have been demonstrated in various cancers. However, whether niclosamide is active against cervical cancer is unknown. In this study, we investigated the effects of niclosamide alone and its combination with paclitaxel in cervical cancer in vitro and in vivo. We found that niclosamide significantly inhibited proliferation and induced apoptosis of a panel of cervical cancer cell lines, regardless of their cellular origin and genetic pattern. Niclosamide also inhibited tumor growth in cervical cancer xenograft mouse model. Importantly, niclosamide significantly enhanced the responsivenessmore » of cervical cancer cell to paclitaxel. We further found that niclosamide induced mitochondrial dysfunctions via inhibiting mitochondrial respiration, complex I activity and ATP generation, which led to oxidative stress. ROS scavenge agent N-acetyl-L-cysteine (NAC) completely reversed the effects of niclosamide in increasing cellular ROS, inhibiting proliferation and inducing apoptosis, suggesting that oxidative stress induction is the mechanism of action of niclosamide in cervical cancer cells. In addition, niclosamide significantly inhibited mammalian target of rapamycin (mTOR) signaling pathway in cervical cancer cells and its inhibitory effect on mTOR is modulated by oxidative stress. Our work suggests that niclosamide is a useful addition to the treatment armamentarium for cervical cancer and induction of oxidative stress may be a potential therapeutic strategy in cervical cancer. - Highlights: • Niclosamide is active against cervical cancer cells in vitro and in vivo. • Niclosamide sensitizes cervical cancer cell response to paclitaxel. • Niclosamide induces mitochondrial dysfunction and oxidative damage. • Niclosamide inhibits mTOR signaling in an oxidative stress-dependent manner.« less

Elucidating Rifampin’s Inducing and Inhibiting Effects on Glyburide Pharmacokinetics and Blood Glucose in Healthy Volunteers: Unmasking the Differential Effect of Enzyme Induction and Transporter Inhibition for a Drug and Its Primary Metabolite

PubMed Central

Zheng, HX; Huang, Y; Frassetto, LA; Benet, LZ

2013-01-01

The effects of single doses of intravenous ciprofloxacin and rifampin, multiple doses of rifampin, on glyburide exposure and effect on blood glucose levels in 9 healthy volunteers were investigated. The single intravenous dose of rifampin significantly increased the AUCs of glyburide and metabolite. Blood glucose levels dropped significantly in comparison to when glyburide was dosed alone. Multiple doses of rifampin induced liver enzymes leading to a marked decrease in glyburide exposure and in blood glucose measurements. When intravenous rifampin was given after multiple doses of rifampin, the inhibition of hepatic uptake transporters masked the induction effect, however, relative changes in AUC for glyburide and its hydroxyl metabolite were the same as that seen under non-induced conditions. The studies reported here demonstrate how measurements of both the parent drug and its primary metabolite are useful in unmasking simultaneous drug-drug induction and inhibition effects and characterizing enzymatic versus transporter mechanisms. PMID:18843263

7 CFR 550.13 - Mutuality of interest.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 6 2012-01-01 2012-01-01 false Mutuality of interest. 550.13 Section 550.13 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL RESEARCH SERVICE, DEPARTMENT.... Mutual interest exists when both parties benefit in the same qualitative way from the objectives of the...

7 CFR 550.13 - Mutuality of interest.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 6 2011-01-01 2011-01-01 false Mutuality of interest. 550.13 Section 550.13 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL RESEARCH SERVICE, DEPARTMENT.... Mutual interest exists when both parties benefit in the same qualitative way from the objectives of the...

7 CFR 550.13 - Mutuality of interest.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 6 2013-01-01 2013-01-01 false Mutuality of interest. 550.13 Section 550.13 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL RESEARCH SERVICE, DEPARTMENT.... Mutual interest exists when both parties benefit in the same qualitative way from the objectives of the...

7 CFR 550.13 - Mutuality of interest.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 6 2014-01-01 2014-01-01 false Mutuality of interest. 550.13 Section 550.13 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL RESEARCH SERVICE, DEPARTMENT.... Mutual interest exists when both parties benefit in the same qualitative way from the objectives of the...

7 CFR 550.13 - Mutuality of interest.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 6 2010-01-01 2010-01-01 false Mutuality of interest. 550.13 Section 550.13 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL RESEARCH SERVICE, DEPARTMENT.... Mutual interest exists when both parties benefit in the same qualitative way from the objectives of the...

Antihelminthic drug niclosamide inhibits CIP2A and reactivates tumor suppressor protein phosphatase 2A in non-small cell lung cancer cells.

PubMed

Kim, Myeong-Ok; Choe, Min Ho; Yoon, Yi Na; Ahn, Jiyeon; Yoo, Minjin; Jung, Kwan-Young; An, Sungkwan; Hwang, Sang-Gu; Oh, Jeong Su; Kim, Jae-Sung

2017-11-15

Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A reactivation has emerged asan anticancer strategy. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A, is upregulated in many cancer cells, including non-small cell lung cancer (NSCLC) cells. We demonstrated that the antihelminthic drug niclosamide inhibited the expression of CIP2A and reactivated the tumor suppressor PP2A in NSCLC cells. We performed a drug-repurposing screen and identified niclosamide asa CIP2A suppressor in NSCLC cells. Niclosamide inhibited cell proliferation, colony formation, and tumor sphere formation, and induced mitochondrial dysfunction through increased mitochondrial ROS production in NSCLC cells; however, these effects were rescued by CIP2A overexpression, which indicated that the antitumor activity of niclosamide was dependent on CIP2A. We found that niclosamide increased PP2A activity through CIP2A inhibition, which reduced the phosphorylation of several oncogenic proteins. Moreover, we found that a niclosamide analog inhibited CIP2A expression and increased PP2A activity in several types of NSCLC cells. Finally, we showed that other well-known PP2A activators, including forskolin and FTY720, did not inhibit CIP2A and that their activities were not dependent on CIP2A. Collectively, our data suggested that niclosamide effectively suppressed CIP2A expression and subsequently activated PP2A in NSCLC cells. This provided strong evidence for the potential use of niclosamide asa PP2A-activating drug in the clinical treatment of NSCLC. Copyright © 2017 Elsevier Inc. All rights reserved.

Quantitative Analysis of Complex Drug-Drug Interactions Between Repaglinide and Cyclosporin A/Gemfibrozil Using Physiologically Based Pharmacokinetic Models With In Vitro Transporter/Enzyme Inhibition Data.

PubMed

Kim, Soo-Jin; Toshimoto, Kota; Yao, Yoshiaki; Yoshikado, Takashi; Sugiyama, Yuichi

2017-09-01

Quantitative analysis of transporter- and enzyme-mediated complex drug-drug interactions (DDIs) is challenging. Repaglinide (RPG) is transported into the liver by OATP1B1 and then is metabolized by CYP2C8 and CYP3A4. The purpose of this study was to describe the complex DDIs of RPG quantitatively based on unified physiologically based pharmacokinetic (PBPK) models using in vitro K i values for OATP1B1, CYP3A4, and CYP2C8. Cyclosporin A (CsA) or gemfibrozil (GEM) increased the blood concentrations of RPG. The time profiles of RPG and the inhibitors were analyzed by PBPK models, considering the inhibition of OATP1B1 and CYP3A4 by CsA or OATP1B1 inhibition by GEM and its glucuronide and the mechanism-based inhibition of CYP2C8 by GEM glucuronide. RPG-CsA interaction was closely predicted using a reported in vitro K i,OATP1B1 value in the presence of CsA preincubation. RPG-GEM interaction was underestimated compared with observed data, but the simulation was improved with the increase of f m,CYP2C8 . These results based on in vitro K i values for transport and metabolism suggest the possibility of a bottom-up approach with in vitro inhibition data for the prediction of complex DDIs using unified PBPK models and in vitro f m value of a substrate for multiple enzymes should be considered carefully for the prediction. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Quantitative NTCP Pharmacophore and Lack of Association between DILI and NTCP Inhibition

PubMed Central

Dong, Zhongqi; Ekins, Sean; Polli, James E.

2014-01-01

The human sodium taurocholate cotransporting polypeptide (NTCP) is a hepatic bile acid transporter. Inhibition of NTCP uptake may potentially also prevent hepatitis B virus (HBV) infection. The first objective was to develop a quantitative pharmacophore for NTCP inhibition. Recent studies showed that hepatotoxic drugs could inhibit bile acid uptake into hepatocytes, without inhibiting canalicular efflux, and cause bile acid elevation in plasma. Hence, a second objective was to examine whether NTCP inhibition is associated with drug induced liver injury (DILI). Twenty-seven drugs from our previous study were used as the training set to develop a quantitative pharmacophore. From secondary screening from a drug database, six retrieved drugs and three drugs not retrieved by the model were tested for NTCP inhibition. Tertiary screening involved drugs known to cause DILI and not cause DILI. Overall, ninety-four drugs were assessed for hepatotoxicity and were assessed relative to NTCP inhibition. The quantitative pharmacophore possessed one hydrogen bond acceptor, one hydrogen bond donor, a hydrophobic feature, and excluded volumes. From 94 drugs, NTCP inhibitors and non-inhibitors were approximately equally distributed across the drugs of most DILI concern, less DILI concern, and no DILI concern, indicating no relationship between NTCP inhibition and DILI risk. Hence, an approach to treat HBV via NTCP inhibition is not expected to be associated with DILI. PMID:25220493

Quantitative NTCP pharmacophore and lack of association between DILI and NTCP Inhibition.

PubMed

Dong, Zhongqi; Ekins, Sean; Polli, James E

2015-01-23

The human sodium taurocholate cotransporting polypeptide (NTCP) is a hepatic bile acid transporter. Inhibition of NTCP uptake may potentially also prevent hepatitis B virus (HBV) infection. The first objective was to develop a quantitative pharmacophore for NTCP inhibition. Recent studies showed that hepatotoxic drugs could inhibit bile acid uptake into hepatocytes, without inhibiting canalicular efflux, and cause bile acid elevation in plasma. Hence, a second objective was to examine whether NTCP inhibition is associated with drug induced liver injury (DILI). Twenty-seven drugs from our previous study were used as the training set to develop a quantitative pharmacophore. From secondary screening from a drug database, six retrieved drugs and three drugs not retrieved by the model were tested for NTCP inhibition. Tertiary screening involved drugs known to cause DILI and not cause DILI. Overall, ninety-four drugs were assessed for hepatotoxicity and were assessed relative to NTCP inhibition. The quantitative pharmacophore possessed one hydrogen bond acceptor, one hydrogen bond donor, a hydrophobic feature, and excluded volumes. From 94 drugs, NTCP inhibitors and non-inhibitors were approximately equally distributed across the drugs of most DILI concern, less DILI concern, and no DILI concern, indicating no relationship between NTCP inhibition and DILI risk. Hence, an approach to treat HBV via NTCP inhibition is not expected to be associated with DILI. Copyright © 2014 Elsevier B.V. All rights reserved.

Combined use of drugs inhibiting the renin-angiotensin system: prescribing patterns and risk of acute kidney injury in German nursing home residents.

PubMed

Dörks, Michael; Herget-Rosenthal, Stefan; Hoffmann, Falk; Jobski, Kathrin

2018-01-01

In 2012, the European Medicines Agency reviewed the safety of dual renin-angiotensin system (RAS) blockade because of potentially increased risks for inter alia acute kidney injury (AKI). Since residents of nursing homes are particularly vulnerable to adverse drug outcomes, the aims of our study were to describe RAS-inhibiting drug use in German nursing home residents and examine the risk of AKI associated with dual RAS blockade. Based on claims data, a nested case-control study within a cohort of RAS-inhibiting drug users was conducted. Using conditional logistic regression, confounder-adjusted odds ratios (aORs) and 95% confidence intervals (CI) were obtained for the risk of AKI associated with dual RAS blockade. Subgroup analyses were performed in patients with diabetes or chronic kidney disease and both comorbidities. Of all 127,227 nursing home residents, the study cohort included 64,567 (50.7%) who were treated with at least one RAS-inhibiting drug. More than three quarters of the study population were female (77.1%). Mean age was 86.0 ± 6.8 years. Most residents were treated with angiotensin-converting enzyme inhibitors (77.8%), followed by angiotensin II receptor blockers (21.6%) and aliskiren (0.2%). Annual prevalence of dual RAS blockade declined from 9.6 (95% CI 7.8-11.8) in 2010 to 4.7 (95% CI 4.0-5.4) per 1,000 users in 2014. In the overall cohort, AKI was not significantly associated with dual RAS blockade (aOR 1.99; 0.77-5.17). However, significantly increased aORs were observed when considering patients with diabetes (3.47; 1.27-9.47), chronic kidney disease (4.74; 1.24-18.13) or both (11.17; 2.65-47.15). Prescribing of drugs inhibiting the RAS is common in German nursing homes. Though the prevalence of dual RAS blockade declined, our study showed an increased risk of AKI in patients with diabetes and/or chronic kidney disease. Therefore, cautious use is warranted in these vulnerable patients.

Evolution of plant–pollinator mutualisms in response to climate change

PubMed Central

Gilman, R Tucker; Fabina, Nicholas S; Abbott, Karen C; Rafferty, Nicole E

2012-01-01

Climate change has the potential to desynchronize the phenologies of interdependent species, with potentially catastrophic effects on mutualist populations. Phenologies can evolve, but the role of evolution in the response of mutualisms to climate change is poorly understood. We developed a model that explicitly considers both the evolution and the population dynamics of a plant–pollinator mutualism under climate change. How the populations evolve, and thus whether the populations and the mutualism persist, depends not only on the rate of climate change but also on the densities and phenologies of other species in the community. Abundant alternative mutualist partners with broad temporal distributions can make a mutualism more robust to climate change, while abundant alternative partners with narrow temporal distributions can make a mutualism less robust. How community composition and the rate of climate change affect the persistence of mutualisms is mediated by two-species Allee thresholds. Understanding these thresholds will help researchers to identify those mutualisms at highest risk owing to climate change. PMID:25568025

(Mutual Security Mutual Affluence) Negative Factors = Sustained Stability: A Framework for Establishing Stability Between Like States

DTIC Science & Technology

2017-03-31

160-163. 2 The Concept of Mutually Assured Destruction (MAD) dates back to the post-WWFI em and the Cold War where the United States and Soviet Unions...United States. Following its defeat in W\\VH, Japan was in shambles. The bombing campaigns left nine million Japanese homeless and three million more...the United States, the Charlie Hebdo attacks in Paris in 2015, and the bombings in Istanbul in 2016. Michael Bamier, “From Mutual Assistance to

26 CFR 1.1502-42 - Mutual savings banks, etc.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 26 Internal Revenue 12 2011-04-01 2011-04-01 false Mutual savings banks, etc. 1.1502-42 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Special Taxes and Taxpayers § 1.1502-42 Mutual savings banks, etc. (a) In general. This section applies to mutual s avings banks and other institutions described in section...

The Complexities of Interpreting Reversible Elevated Serum Creatinine Levels in Drug Development: Does a Correlation with Inhibition of Renal Transporters Exist?

PubMed

Chu, Xiaoyan; Bleasby, Kelly; Chan, Grace Hoyee; Nunes, Irene; Evers, Raymond

2016-09-01

In humans, creatinine is formed by a multistep process in liver and muscle and eliminated via the kidney by a combination of glomerular filtration and active transport. Based on current evidence, creatinine can be taken up into renal proximal tubule cells by the basolaterally localized organic cation transporter 2 (OCT2) and the organic anion transporter 2, and effluxed into the urine by the apically localized multidrug and toxin extrusion protein 1 (MATE1) and MATE2K. Drug-induced elevation of serum creatinine (SCr) and/or reduced creatinine renal clearance is routinely used as a marker for acute kidney injury. Interpretation of elevated SCr can be complex, because such increases can be reversible and explained by inhibition of renal transporters involved in active secretion of creatinine or other secondary factors, such as diet and disease state. Distinction between these possibilities is important from a drug development perspective, as increases in SCr can result in the termination of otherwise efficacious drug candidates. In this review, we discuss the challenges associated with using creatinine as a marker for kidney damage. Furthermore, to evaluate whether reversible changes in SCr can be predicted prospectively based on in vitro transporter inhibition data, an in-depth in vitro-in vivo correlation (IVIVC) analysis was conducted for 16 drugs with in-house and literature in vitro transporter inhibition data for OCT2, MATE1, and MATE2K, as well as total and unbound maximum plasma concentration (Cmax and Cmax,u) data measured in the clinic. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

12 CFR 563.74 - Mutual capital certificates.

Code of Federal Regulations, 2010 CFR

2010-01-01

... otherwise be required by applicable law. (e) Filing requirements. The application for issuance of mutual... of filing of the application are in accordance with the provisions of this section. (b) Eligibility... mutual capital certificates; (E) Action is sought to be authorized which would increase the number of a...

Mutual proximity graphs for improved reachability in music recommendation.

PubMed

Flexer, Arthur; Stevens, Jeff

2018-01-01

This paper is concerned with the impact of hubness, a general problem of machine learning in high-dimensional spaces, on a real-world music recommendation system based on visualisation of a k-nearest neighbour (knn) graph. Due to a problem of measuring distances in high dimensions, hub objects are recommended over and over again while anti-hubs are nonexistent in recommendation lists, resulting in poor reachability of the music catalogue. We present mutual proximity graphs, which are an alternative to knn and mutual knn graphs, and are able to avoid hub vertices having abnormally high connectivity. We show that mutual proximity graphs yield much better graph connectivity resulting in improved reachability compared to knn graphs, mutual knn graphs and mutual knn graphs enhanced with minimum spanning trees, while simultaneously reducing the negative effects of hubness.

26 CFR 1.1502-42 - Mutual savings banks, etc.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 26 Internal Revenue 12 2010-04-01 2010-04-01 false Mutual savings banks, etc. 1.1502-42 Section 1... (CONTINUED) INCOME TAXES Special Taxes and Taxpayers § 1.1502-42 Mutual savings banks, etc. (a) In general. This section applies to mutual s avings banks and other institutions described in section 593(a). (b...

Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions.

PubMed

Weiss, Johanna; Gajek, Thomas; Köhler, Bruno Christian; Haefeli, Walter Emil

2016-02-24

Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug-drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug-drug interactions.

Combinatorial drug screening and molecular profiling reveal diverse mechanisms of intrinsic and adaptive resistance to BRAF inhibition in V600E BRAF mutant melanomas

PubMed Central

Roller, Devin G.; Capaldo, Brian; Bekiranov, Stefan; Mackey, Aaron J.; Conaway, Mark R.; Petricoin, Emanuel F.; Gioeli, Daniel; Weber, Michael J.

2016-01-01

Over half of BRAFV600E melanomas display intrinsic resistance to BRAF inhibitors, in part due to adaptive signaling responses. In this communication we ask whether BRAFV600E melanomas share common adaptive responses to BRAF inhibition that can provide clinically relevant targets for drug combinations. We screened a panel of 12 treatment-naïve BRAFV600E melanoma cell lines with MAP Kinase pathway inhibitors in pairwise combination with 58 signaling inhibitors, assaying for synergistic cytotoxicity. We found enormous diversity in the drug combinations that showed synergy, with no two cell lines having an identical profile. Although the 6 lines most resistant to BRAF inhibition showed synergistic benefit from combination with lapatinib, the signaling mechanisms by which this combination generated synergistic cytotoxicity differed between the cell lines. We conclude that adaptive responses to inhibition of the primary oncogenic driver (BRAFV600E) are determined not only by the primary oncogenic driver but also by diverse secondary genetic and epigenetic changes (“back-seat drivers”) and hence optimal drug combinations will be variable. Because upregulation of receptor tyrosine kinases is a major source of drug resistance arising from diverse adaptive responses, we propose that inhibitors of these receptors may have substantial clinical utility in combination with inhibitors of the MAP Kinase pathway. PMID:26673621

Combinatorial drug screening and molecular profiling reveal diverse mechanisms of intrinsic and adaptive resistance to BRAF inhibition in V600E BRAF mutant melanomas.

PubMed

Roller, Devin G; Capaldo, Brian; Bekiranov, Stefan; Mackey, Aaron J; Conaway, Mark R; Petricoin, Emanuel F; Gioeli, Daniel; Weber, Michael J

2016-01-19

Over half of BRAFV600E melanomas display intrinsic resistance to BRAF inhibitors, in part due to adaptive signaling responses. In this communication we ask whether BRAFV600E melanomas share common adaptive responses to BRAF inhibition that can provide clinically relevant targets for drug combinations. We screened a panel of 12 treatment-naïve BRAFV600E melanoma cell lines with MAP Kinase pathway inhibitors in pairwise combination with 58 signaling inhibitors, assaying for synergistic cytotoxicity. We found enormous diversity in the drug combinations that showed synergy, with no two cell lines having an identical profile. Although the 6 lines most resistant to BRAF inhibition showed synergistic benefit from combination with lapatinib, the signaling mechanisms by which this combination generated synergistic cytotoxicity differed between the cell lines. We conclude that adaptive responses to inhibition of the primary oncogenic driver (BRAFV600E) are determined not only by the primary oncogenic driver but also by diverse secondary genetic and epigenetic changes ("back-seat drivers") and hence optimal drug combinations will be variable. Because upregulation of receptor tyrosine kinases is a major source of drug resistance arising from diverse adaptive responses, we propose that inhibitors of these receptors may have substantial clinical utility in combination with inhibitors of the MAP Kinase pathway.

[Mechanism of action of antiepileptic drugs].

PubMed

Saidón, Patricia

2003-01-01

Antiepileptic drugs (DAEs) act through different mechanisms of action: increase in central inhibition, inhibition of excitatorios mechanisms and modification of the excitability through their action on the ionic channels. Epilepsy is characterized by an abnormal and hypersynchronic unloading of a neuronal population. The activity of numerous drugs is associated to increase in gabaergic activity. Another group of drugs decreases excitatory mechanisms, through the inhibition of ionic channels, or through a decrease in the activity of the excitatory neurotransmitters. There are some of antiepileptic drugs, especially within the group of drugs of recent appearance, for wich the mechanism of action remains unknown.

Enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7.

PubMed

Fang, Zhong-Ze; Wang, Haina; Cao, Yun-Feng; Sun, Dong-Xue; Wang, Li-Xuan; Hong, Mo; Huang, Ting; Chen, Jian-Xing; Zeng, Jia

2015-03-01

UDP-glucuronosyltransferases (UGTs)-catalyzed glucuronidation conjugation reaction plays an important role in the elimination of many important clinical drugs and endogenous substances. The present study aims to investigate the enantioselective inhibition of carprofen towards UGT isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation mixture was used to screen the inhibition potential of (R)-carprofen and (S)-carprofen towards multiple UGT isoforms. The results showed that (S)-carprofen exhibited stronger inhibition potential than (R)-carprofen towards UGT2B7. However, no significant difference was observed for the inhibition of (R)-carprofen and (S)-carprofen towards other UGT isoforms. Furthermore, the inhibition kinetic behavior was compared for the inhibition of (S)-carprofen and (R)-carprofen towards UGT2B7. A Lineweaver-Burk plot showed that both (S)-carprofen and (R)-carprofen exhibited competitive inhibition towards UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameter (Ki ) was calculated to be 7.0 μM and 31.1 μM for (S)-carprofen and (R)-carprofen, respectively. Based on the standard for drug-drug interaction, the threshold for (S)-carprofen and (R)-carprofen to induce a drug-drug interaction is 0.7 μM and 3.1 μM, respectively. In conclusion, enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7 was demonstrated in the present study. Using the in vitro inhibition kinetic parameter, the concentration threshold of (S)-carprofen and (R)-carprofen to possibly induce the drug-drug interaction was obtained. Therefore, clinical monitoring of the plasma concentration of (S)-carprofen is more important than (R)-carprofen to avoid a possible drug-drug interaction between carprofen and the drugs mainly undergoing UGT2B7-catalyzed metabolism. © 2014 Wiley Periodicals, Inc.

Bright Lights and Questions: Using Mutual Interrogation

ERIC Educational Resources Information Center

Adam, Aishikin; Alangui, Willy; Barton, Bill

2010-01-01

Mutual Interrogation is a research methodology for ethnomathematics proposed by Alangui in 2006 in an attempt to avoid the potential inequality set up when a restricted cultural practice is viewed through the lens of the near-universal and highly developed research domain of mathematics. Using three significant examples of mutual interrogation in…

Parents Helping Parents: Mutual Parenting Network Handbook.

ERIC Educational Resources Information Center

Simkinson, Charles H.; Redmond, Robert F.

Guidelines for mutual parenting are provided in this handbook. "Mutual parenting" means that everyone in the community shares the responsibility for the safety and well-being of the community's youngsters. Several topics are discussed in the 15 brief chapters of the handbook. Chapters 1 through 3 focus on the formation of a mutual…

Circumvention of the multidrug-resistance protein (MRP-1) by an antitumor drug through specific inhibition of gene transcription in breast tumor cells.

PubMed

Mansilla, Sylvia; Rojas, Marta; Bataller, Marc; Priebe, Waldemar; Portugal, José

2007-04-01

Multidrug-resistance protein 1 (MRP-1) confers resistance to a number of clinically important chemotherapeutic agents. The promoter of the mrp-1 gene contains an Sp1-binding site, which we targeted using the antitumor bis-anthracycline WP631. When MCF-7/VP breast cancer cells, which overexpress MRP-1 protein, were incubated with WP631 the expression of the multidrug-resistance protein gene decreased. Conversely, doxorubicin did not alter mrp-1 gene expression. The inhibition of gene expression was followed by a decrease in the activity of the MRP-1 protein. The IC(75) for WP631 (drug concentration required to inhibit cell growth by 75%) circumvented the drug-efflux pump, without addition of resistant modifiers. After treatment with WP631, MCF-7/VP cells were committed to die after entering mitosis (mitotic catastrophe), while treatment with doxorubicin did not affect cell growth. This is the first report on an antitumor drug molecule inhibiting the mrp-1 gene directly, rather than being simply a poor substrate for the transporter-mediated efflux. However, both situations appeared to coexist, thereby a superior cytotoxic effect was attained. Ours results suggest that WP631 offers great potential for the clinical treatment of tumors displaying a multidrug-resistance phenotype.

Mutual proximity graphs for improved reachability in music recommendation

PubMed Central

Flexer, Arthur; Stevens, Jeff

2018-01-01

This paper is concerned with the impact of hubness, a general problem of machine learning in high-dimensional spaces, on a real-world music recommendation system based on visualisation of a k-nearest neighbour (knn) graph. Due to a problem of measuring distances in high dimensions, hub objects are recommended over and over again while anti-hubs are nonexistent in recommendation lists, resulting in poor reachability of the music catalogue. We present mutual proximity graphs, which are an alternative to knn and mutual knn graphs, and are able to avoid hub vertices having abnormally high connectivity. We show that mutual proximity graphs yield much better graph connectivity resulting in improved reachability compared to knn graphs, mutual knn graphs and mutual knn graphs enhanced with minimum spanning trees, while simultaneously reducing the negative effects of hubness. PMID:29348779

26 CFR 1.831-3 - Tax on insurance companies (other than life or mutual), mutual marine insurance companies, mutual...

Code of Federal Regulations, 2010 CFR

2010-04-01

... premium deposits not required for losses, expenses or reserves is returned or credited to the policyholder..., and mutual fire or flood insurance companies operating on the basis of premium deposits; taxable years... operating on the basis of premium deposits; taxable years beginning after December 31, 1962. (a) All...

Zoledronic Acid Inhibits Aromatase Activity and Phosphorylation: Potential Mechanism for Additive Zoledronic Acid and Letrozole Drug Interaction

PubMed Central

Schech, Amanda J.; Nemieboka, Brandon E.; Brodie, Angela H.

2012-01-01

Zoledronic acid (ZA), a bisphosphonate originally indicated for use in osteoporosis, has been reported to exert a direct effect on breast cancer cells, although the mechanism of this effect is currently unknown. Data from the ABCSG-12 and ZO-FAST clinical trials suggest that treatment with the combination of ZA and aromatase inhibitors (AI) result in increased disease free survival in breast cancer patients over AI alone. To determine whether the mechanism of this combination involved inhibition of aromatase, AC-1 cells (MCF-7 human breast cancer cells transfected with an aromatase construct) were treated simultaneously with combinations of ZA and AI letrozole for 72 hours. This combination significantly increased inhibition of aromatase activity of AC-1 cells by compared to letrozole alone. Combination treatment of 1nM letrozole and 1μM and 10μM zoledronic acid resulted in an additive drug interaction on inhibiting cell viability, as measured by MTT assay. Treatment with ZA was found to inhibit phosphorylation of aromatase on serine 473. Zoledronic acid was also shown to be more effective in inhibiting cell viability in aromatase transfected AC-1 cells when compared to inhibition of cell viability observed in non-transfected MCF-7. Estradiol was able to partially rescue the effect of 1μM and 10μM ZA on cell viability following treatment for 72 hours, as shown by a shift to the right in the estradiol dose response curve. In conclusion, these results indicate that the combination of ZA and letrozole results in an additive inhibition of cell viability. Furthermore, ZA alone can inhibit aromatase activity through inhibition of serine phosphorylation events important for aromatase enzymatic activity and contributes to inhibition of cell viability. PMID:22659283

Structural Insights into Drug Processing by Human Carboxylesterase 1: Tamoxifen, Mevastatin, and Inhibition by Benzil

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fleming, Christopher D.; Bencharit, Sompop; Edwards, Carol C.

2010-07-19

Human carboxylesterase 1 (hCE1) exhibits broad substrate specificity and is involved in xenobiotic processing and endobiotic metabolism. We present and analyze crystal structures of hCE1 in complexes with the cholesterol-lowering drug mevastatin, the breast cancer drug tamoxifen, the fatty acyl ethyl ester (FAEE) analogue ethyl acetate, and the novel hCE1 inhibitor benzil. We find that mevastatin does not appear to be a substrate for hCE1, and instead acts as a partially non-competitive inhibitor of the enzyme. Similarly, we show that tamoxifen is a low micromolar, partially non-competitive inhibitor of hCE1. Further, we describe the structural basis for the inhibition ofmore » hCE1 by the nanomolar-affinity dione benzil, which acts by forming both covalent and non-covalent complexes with the enzyme. Our results provide detailed insights into the catalytic and non-catalytic processing of small molecules by hCE1, and suggest that the efficacy of clinical drugs may be modulated by targeted hCE1 inhibitors.« less

Structural insights into drug processing by human carboxylesterase 1: tamoxifen, mevastatin, and inhibition by benzil.

PubMed

Fleming, Christopher D; Bencharit, Sompop; Edwards, Carol C; Hyatt, Janice L; Tsurkan, Lyudmila; Bai, Feng; Fraga, Charles; Morton, Christopher L; Howard-Williams, Escher L; Potter, Philip M; Redinbo, Matthew R

2005-09-09

Human carboxylesterase 1 (hCE1) exhibits broad substrate specificity and is involved in xenobiotic processing and endobiotic metabolism. We present and analyze crystal structures of hCE1 in complexes with the cholesterol-lowering drug mevastatin, the breast cancer drug tamoxifen, the fatty acyl ethyl ester (FAEE) analogue ethyl acetate, and the novel hCE1 inhibitor benzil. We find that mevastatin does not appear to be a substrate for hCE1, and instead acts as a partially non-competitive inhibitor of the enzyme. Similarly, we show that tamoxifen is a low micromolar, partially non-competitive inhibitor of hCE1. Further, we describe the structural basis for the inhibition of hCE1 by the nanomolar-affinity dione benzil, which acts by forming both covalent and non-covalent complexes with the enzyme. Our results provide detailed insights into the catalytic and non-catalytic processing of small molecules by hCE1, and suggest that the efficacy of clinical drugs may be modulated by targeted hCE1 inhibitors.

Optimization of drug-drug interaction study design: comparison of minimal physiologically based pharmacokinetic models on prediction of CYP3A inhibition by ketoconazole.

PubMed

Han, Bing; Mao, Jialin; Chien, Jenny Y; Hall, Stephen D

2013-07-01

Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (f(m)) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.

Multimodal registration via spatial-context mutual information.

PubMed

Yi, Zhao; Soatto, Stefano

2011-01-01

We propose a method to efficiently compute mutual information between high-dimensional distributions of image patches. This in turn is used to perform accurate registration of images captured under different modalities, while exploiting their local structure otherwise missed in traditional mutual information definition. We achieve this by organizing the space of image patches into orbits under the action of Euclidean transformations of the image plane, and estimating the modes of a distribution in such an orbit space using affinity propagation. This way, large collections of patches that are equivalent up to translations and rotations are mapped to the same representative, or "dictionary element". We then show analytically that computing mutual information for a joint distribution in this space reduces to computing mutual information between the (scalar) label maps, and between the transformations mapping each patch into its closest dictionary element. We show that our approach improves registration performance compared with the state of the art in multimodal registration, using both synthetic and real images with quantitative ground truth.

31 CFR 1024.320 - Reports by mutual funds of suspicious transactions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Reports by mutual funds of suspicious... (Continued) FINANCIAL CRIMES ENFORCEMENT NETWORK, DEPARTMENT OF THE TREASURY RULES FOR MUTUAL FUNDS Reports Required To Be Made By Mutual Funds § 1024.320 Reports by mutual funds of suspicious transactions. (a...

Mutuality and the social regulation of neural threat responding

PubMed Central

Coan, James A.; Kasle, Shelley; Jackson, Alice; Schaefer, Hillary S.; Davidson, Richard J.

2014-01-01

Recent studies have shown that the presence of a caring relational partner can attenuate neural responses to threat. Here we report reanalyzed data from Coan, Schaefer, and Davidson (2006), investigating the role of relational mutuality in the neural response to threat. Mutuality reflects the degree to which couple members show mutual interest in the sharing of internal feelings, thoughts, aspirations, and joys – a vital form of responsiveness in attachment relationships. We predicted that wives who were high (versus low) in perceived mutuality, and who attended the study session with their husbands, would show reduced neural threat reactivity in response to mild electric shocks. We also explored whether this effect would depend on physical contact (handholding). As predicted, we observed that higher mutuality scores corresponded with decreased neural threat responding in the right dorsolateral prefrontal cortex and supplementary motor cortex. These effects were independent of hand-holding condition. These findings suggest that higher perceived mutuality corresponds with decreased self-regulatory effort and attenuated preparatory motor activity in response to threat cues, even in the absence of direct physical contact with social resources. PMID:23547803

Mutual information against correlations in binary communication channels.

PubMed

Pregowska, Agnieszka; Szczepanski, Janusz; Wajnryb, Eligiusz

2015-05-19

Explaining how the brain processing is so fast remains an open problem (van Hemmen JL, Sejnowski T., 2004). Thus, the analysis of neural transmission (Shannon CE, Weaver W., 1963) processes basically focuses on searching for effective encoding and decoding schemes. According to the Shannon fundamental theorem, mutual information plays a crucial role in characterizing the efficiency of communication channels. It is well known that this efficiency is determined by the channel capacity that is already the maximal mutual information between input and output signals. On the other hand, intuitively speaking, when input and output signals are more correlated, the transmission should be more efficient. A natural question arises about the relation between mutual information and correlation. We analyze the relation between these quantities using the binary representation of signals, which is the most common approach taken in studying neuronal processes of the brain. We present binary communication channels for which mutual information and correlation coefficients behave differently both quantitatively and qualitatively. Despite this difference in behavior, we show that the noncorrelation of binary signals implies their independence, in contrast to the case for general types of signals. Our research shows that the mutual information cannot be replaced by sheer correlations. Our results indicate that neuronal encoding has more complicated nature which cannot be captured by straightforward correlations between input and output signals once the mutual information takes into account the structure and patterns of the signals.

Emetine inhibits replication of RNA and DNA viruses without generating drug-resistant virus variants.

PubMed

Khandelwal, Nitin; Chander, Yogesh; Rawat, Krishan Dutt; Riyesh, Thachamvally; Nishanth, Chikkahonnaiah; Sharma, Shalini; Jindal, Naresh; Tripathi, Bhupendra N; Barua, Sanjay; Kumar, Naveen

2017-08-01

At a noncytotoxic concentration, emetine was found to inhibit replication of DNA viruses [buffalopoxvirus (BPXV) and bovine herpesvirus 1 (BHV-1)] as well as RNA viruses [peste des petits ruminants virus (PPRV) and Newcastle disease virus (NDV)]. Using the time-of-addition and virus step-specific assays, we showed that emetine treatment resulted in reduced synthesis of viral RNA (PPRV and NDV) and DNA (BPXV and BHV-1) as well as inhibiting viral entry (NDV and BHV-1). In addition, emetine treatment also resulted in decreased synthesis of viral proteins. In a cell free endogenous viral polymerase assay, emetine was found to significantly inhibit replication of NDV, but not BPXV genome, suggesting that besides directly inhibiting specific viral polymerases, emetine may also target other factors essentially required for efficient replication of the viral genome. Moreover, emetine was found to significantly inhibit BPXV-induced pock lesions on chorioallantoic membrane (CAM) along with associated mortality of embryonated chicken eggs. At a lethal dose 50 (LD 50 ) of 126.49 ng/egg and at an effective concentration 50 (EC 50 ) of 3.03 ng/egg, the therapeutic index of the emetine against BPXV was determined to be 41.74. Emetine was also found to significantly delay NDV-induced mortality in chicken embryos associated with reduced viral titers. Further, emetine-resistant mutants were not observed upon long-term (P = 25) sequential passage of BPXV and NDV in cell culture. Collectively, we have extended the effective antiviral activity of emetine against diverse groups of DNA and RNA viruses and propose that emetine could provide significant therapeutic value against some of these viruses without inducing an antiviral drug-resistant phenotype. Copyright © 2017 Elsevier B.V. All rights reserved.

31 CFR 1024.220 - Customer identification programs for mutual funds.

Code of Federal Regulations, 2011 CFR

2011-07-01

... mutual funds. 1024.220 Section 1024.220 Money and Finance: Treasury Regulations Relating to Money and... FUNDS Programs § 1024.220 Customer identification programs for mutual funds. (a) Customer identification program: minimum requirements—(1) In general. A mutual fund must implement a written Customer...

Freedom and imperative: mutual care between older spouses with physical disabilities.

PubMed

Torgé, Cristina Joy

2014-05-01

This article explores mutual caregiving between older spouses aging with physical disabilities. Nine older couples, where both partners had lived long lives with physical disabilities, were interviewed as dyads about mutual caregiving. The couples not only had access to different kinds and degrees of formal support but also provided mutual care to each other in a variety of ways. Interview coding using grounded theory led to two overarching categories from which motivation for mutual caregiving could be understood. These categories were Mutual care as freedom and Mutual care as imperative. The results extend understanding about how older couples with disabilities attached meaning to their mutual caregiving, and why mutual care was sometimes preferable, despite the availability of other sources of help and despite practical difficulties of providing this help. These findings suggest that health care professionals need to be sensitive to the dynamics of the couple relationship and carefully explore the couple's preferences for how formal support can best be provided in ways that honor and sustain the integrity of the couple relationship.

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kadam, Rameshwar U.; Wilson, Ian A.

The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers. This cavity is distal to the conserved epitope targeted by broadly neutralizing stem antibodies and is ~16 Åmore » from the fusion peptide. Arbidol primarily makes hydrophobic interactions with the binding site but also induces some conformational rearrangements to form a network of inter- and intraprotomer salt bridges. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome. This unique binding mode compared with the small-molecule inhibitors of other class I fusion proteins enhances our understanding of how small molecules can function as fusion inhibitors and guides the development of broad-spectrum therapeutics against influenza virus.« less

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

PubMed Central

Mast, Natalia; Lin, Joseph B.

2015-01-01

Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6- and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification. PMID:26082378

Dopamine D3 receptor antagonist SB-277011A inhibits methamphetamine self-administration and methamphetamine-induced reinstatement of drug-seeking in rats

PubMed Central

Higley, Amanda E.; Kiefer, Stephen W.; Li, Xia; Gaál, József; Xi, Zheng-Xiong; Gardner, Eliot L.

2013-01-01

We have previously reported that selective blockade of brain dopamine D3 receptors by SB-277011A significantly attenuates cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior. In the present study, we investigated whether SB-277011A similarly inhibits methamphetamine self-administration and methamphetamine-induced reinstatement to drug-seeking behavior. Male Long–Evans rats were allowed to intravenously self-administer methamphetamine (0.05 mg/kg/infusion) under fixed-ratio 2 (FR2) or progressive-ratio (PR) reinforcement conditions, and some rats were tested for methamphetamine-induced reinstatement of drug-seeking behavior after extinction of self-administration. The effects of SB-277011A on each of these methamphetamine-supported behaviors were then tested. Acute intraperitoneal (i.p.) administration of SB-277011A failed to alter methamphetamine self-administration under FR2 reinforcement, but significantly lowered the break-point for methamphetamine self-administration under PR reinforcement. SB-277011A also significantly inhibited methamphetamine-triggered reinstatement of extinguished drug-seeking behavior. Overall, these data show that blockade of dopamine D3 receptors by SB-277011A attenuates the rewarding and incentive motivational effects of methamphetamine in rats, supporting the development of selective dopamine D3 antagonists for the treatment of methamphetamine addiction. PMID:21466803

Amino acid conjugated antimicrobial drugs: Synthesis, lipophilicity- activity relationship, antibacterial and urease inhibition activity.

PubMed

Ullah, Atta; Iftikhar, Fatima; Arfan, Muhammad; Batool Kazmi, Syeda Tayyaba; Anjum, Muhammad Naveed; Haq, Ihsan-Ul; Ayaz, Muhammad; Farooq, Sadia; Rashid, Umer

2018-02-10

Present work describes the in vitro antibacterial evaluation of some new amino acid conjugated antimicrobial drugs. Structural modification was attempted on the three existing antimicrobial pharmaceuticals namely trimethoprim, metronidazole, isoniazid. Twenty one compounds from seven series of conjugates of these drugs were synthesized by coupling with some selected Boc-protected amino acids. The effect of structural features and lipophilicity on the antibacterial activity was investigated. The synthesized compounds were evaluated against five standard American type culture collection (ATCC) i.e. Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi strains of bacteria. Our results identified a close relationship between the lipophilicity and the activity. Triazine skeleton proved beneficial for the increase in hydrophobicity and potency. Compounds with greater hydrophobicity have shown excellent activities against Gram-negative strains of bacteria than Gram-positive. 4-amino unsubstituted trimethoprim-triazine derivative 7b have shown superior activity with MIC = 3.4 μM (2 μg/mL) for S. aureus and 1.1 μM (0.66 μg/mL) for E. coli. The synthesized compounds were also evaluated for their urease inhibition study. Microbial urease from Bacillus pasteurii was chosen for this study. Triazine derivative 7a showed excellent inhibition with IC 50  = 6.23 ± 0.09 μM. Docking studies on the crystal structure of B. pasteurii urease (PDB ID 4UBP) were carried out. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

77 FR 48566 - The Hartford Mutual Funds, Inc., et al.;

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-14

...] The Hartford Mutual Funds, Inc., et al.; Notice of Application August 8, 2012. AGENCY: Securities and... to invest in certain financial instruments. Applicants: The Hartford Mutual Funds, Inc., The Hartford Mutual Funds II, Inc., Hartford Series Fund, Inc., Hartford HLS Series Fund II, Inc., Hartford Variable...

[Comparative observation on inhibition of hemozoin formation and their in vitro and in vivo anti-schistosome activity displayed by 7 antimalarial drugs].

PubMed

Xue, Jian; Jiang, Bin; Liu, Cong-Shan; Sun, Jun; Xiao, Shu-Hua

2013-06-01

To observe and compare the inhibition of hemozoin formation and the in vitro as well as in vivo antischistosomal activity induced by seven antimalarial drugs. Inhibition of hemozoin formation displayed by chloroquine phosphate, quinine hydrochloride, quinidine, mefloquine hydrochloride, pyronaridine phosphate and lumefantrine at 25 micromol/L, and artemether at 100 micromol/L was performed by assay of inhibition of beta-hematin formation in 1 mol/L sodium acetate buffers containing hematin with various pH of 4.0, 4.2, 4.4, 4.6, 4.8, and 5.0. In in vitro antischistosomal study, the medium of RPMI 1640 supplemented by 10% calf serum was used to maintain the adult Schistosoma japonicum, and the 50% and 95% lethal concentrations (LC50 and LC95) to kill the adult worms of each drug were then determined. Meanwhile, the interaction of quinine, pyronaridine and chloroquine combined with hemin against adult schistosomes was also undertaken. As to in vivo test, the efficacy of seven antimalarial drugs administered orally or intraperitoneally to mice infected with adult schistosomes was observed. In the acidic acetate-hematin solution, 25 micromol/L pyronaridine showed significant inhibition of beta-hematin formation at pH 4.4-5.0 with inhibition rates of 81.3%-97.0%. At pH 4.6, the inhibition rates of beta-hematin formation in acetate-hematin solution induced by mefloquine, chloroquine or quinine at concentration of 25 beta mol/L were 79.7%, 72.8% or 65.8%, respectively, and the beta-hematin formation was continually inhibited by these 3 antimalarial drugs at pH 4.8 and 5.0 with inhibition rates of 83.1%-90.6%, 41.9%-49.0% or 53.2-62.0%. The inhibition rates of beta-hematin formation at pH 4.6 and 4.8-5.0 induced by lumefantrine 25 micromol/L were 74.3% and 40.4%-40.5%, respectively. While under the same concentration of quinidine, 53.4% and 50.9% inhibition rates of beta-hematin formation were observed at pH 4.8 and 5.0. As to artemether, higher concentration of 100

Potential of the novel antiretroviral drug rilpivirine to modulate the expression and function of drug transporters and drug-metabolising enzymes in vitro.

PubMed

Weiss, Johanna; Haefeli, Walter Emil

2013-05-01

The objective of this study was to assess the drug-drug interaction potential of the new non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine in vitro. The following were evaluated: P-glycoprotein (P-gp/ABCB1) inhibition by calcein assay; breast cancer resistance protein (BCRP/ABCG2) inhibition by pheophorbide A efflux; and inhibition of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 by 8-fluorescein-cAMP uptake. Inhibition of cytochrome P450 enzymes was assessed using commercially available kits. Substrate characteristics were evaluated by growth inhibition assays in MDCKII cells overexpressing particular ABC transporters. Induction of drug-metabolising enzymes and transporters was quantified by real-time RT-PCR in LS180 cells, and activation of pregnane X receptor (PXR) by a reporter gene assay. Rilpivirine significantly inhibited P-gp (IC(50) = 13.1 ± 6.8 μmol/L), BCRP (IC(50) = 1.5 ± 0.3 μmol/L), OATP1B1 (IC(50) = 4.1 ± 1.8 μmol/L), OATP1B3 (IC(50) = 6.1 ± 0.9 μmol/L), CYP3A4 (IC(50) = 1.3 ± 0.6 μmol/L), CYP2C19 (IC(50) = 2.7 ± 0.3 μmol/L) and CYP2B6 (IC(50) = 4.2 ± 1.6 μmol/L). Growth inhibition assays indicate that rilpivirine is not a substrate of P-gp, BCRP, or multidrug resistance-associated proteins 1 and 2. In LS180 cells, rilpivirine induced mRNA expression of ABCB1, CYP3A4 and UGT1A3, whereas ABCC1, ABCC2, ABCG2, OATP1B1 and UGT1A9 were not induced. Moreover, rilpivirine was a PXR activator. In conclusion, rilpivirine inhibits and induces several relevant drug-metabolising enzymes and drug transporters, but owing to its low plasma concentrations it is most likely less prone to drug-drug interactions than older NNRTIs. Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Mutual information and spontaneous symmetry breaking

NASA Astrophysics Data System (ADS)

Hamma, A.; Giampaolo, S. M.; Illuminati, F.

2016-01-01

We show that the metastable, symmetry-breaking ground states of quantum many-body Hamiltonians have vanishing quantum mutual information between macroscopically separated regions and are thus the most classical ones among all possible quantum ground states. This statement is obvious only when the symmetry-breaking ground states are simple product states, e.g., at the factorization point. On the other hand, symmetry-breaking states are in general entangled along the entire ordered phase, and to show that they actually feature the least macroscopic correlations compared to their symmetric superpositions is highly nontrivial. We prove this result in general, by considering the quantum mutual information based on the two-Rényi entanglement entropy and using a locality result stemming from quasiadiabatic continuation. Moreover, in the paradigmatic case of the exactly solvable one-dimensional quantum X Y model, we further verify the general result by considering also the quantum mutual information based on the von Neumann entanglement entropy.

76 FR 35084 - Mutual to Stock Conversion Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-15

... DEPARTMENT OF THE TREASURY Office of Thrift Supervision Mutual to Stock Conversion Application... invite comments on the following information collection. Title of Proposal: Mutual to Stock Conversion... and soundness of the proposed stock conversion. The purpose of the information collection is to...

24 CFR 203.420 - Nature of Mutual Mortgage Insurance Fund.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 24 Housing and Urban Development 2 2013-04-01 2013-04-01 false Nature of Mutual Mortgage Insurance Fund. 203.420 Section 203.420 Housing and Urban Development Regulations Relating to Housing and Urban... and Distributive Shares § 203.420 Nature of Mutual Mortgage Insurance Fund. The Mutual Mortgage...

24 CFR 203.420 - Nature of Mutual Mortgage Insurance Fund.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 24 Housing and Urban Development 2 2010-04-01 2010-04-01 false Nature of Mutual Mortgage Insurance Fund. 203.420 Section 203.420 Housing and Urban Development Regulations Relating to Housing and Urban... and Distributive Shares § 203.420 Nature of Mutual Mortgage Insurance Fund. The Mutual Mortgage...

24 CFR 203.420 - Nature of Mutual Mortgage Insurance Fund.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 24 Housing and Urban Development 2 2014-04-01 2014-04-01 false Nature of Mutual Mortgage Insurance Fund. 203.420 Section 203.420 Housing and Urban Development Regulations Relating to Housing and Urban... and Distributive Shares § 203.420 Nature of Mutual Mortgage Insurance Fund. The Mutual Mortgage...

24 CFR 203.420 - Nature of Mutual Mortgage Insurance Fund.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 24 Housing and Urban Development 2 2012-04-01 2012-04-01 false Nature of Mutual Mortgage Insurance Fund. 203.420 Section 203.420 Housing and Urban Development Regulations Relating to Housing and Urban... and Distributive Shares § 203.420 Nature of Mutual Mortgage Insurance Fund. The Mutual Mortgage...

24 CFR 203.420 - Nature of Mutual Mortgage Insurance Fund.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 24 Housing and Urban Development 2 2011-04-01 2011-04-01 false Nature of Mutual Mortgage Insurance Fund. 203.420 Section 203.420 Housing and Urban Development Regulations Relating to Housing and Urban... and Distributive Shares § 203.420 Nature of Mutual Mortgage Insurance Fund. The Mutual Mortgage...

Drug-induced sexual dysfunction.

PubMed

Aldridge, S A

1982-01-01

Commonly used drugs that may cause sexual dysfunction are reviewed. The anatomy and physiology of the normal sexual response are reviewed. The influence of drugs on neurogenic, hormonal, and vascular mechanisms may result in diminished libido, impotence, ejaculatory and orgasmic difficulties, inhibited vaginal lubrication, menstrual irregularities, and gynecomastia in men or painful breast enlargement in women. Parasympatholytic agents, which interfere with cholinergic transmission, may affect erectile potency, while adrenergic inhibiting agents may interfere with ejaculatory control. Central nervous system depressants or sedating drugs, drugs producing hyperprolactinemia, and antiandrogenic drugs also may affect the normal sexual response. Drugs such as antihypertensive and antipsychotic agents may induce sexual dysfunction that can result in patient noncompliance. Usually, drug-induced side effects are reversible with discontinuation of the offending agent.

Chaetominine reduces MRP1-mediated drug resistance via inhibiting PI3K/Akt/Nrf2 signaling pathway in K562/Adr human leukemia cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yao, Jingyun; Wei, Xing; Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai

Drug resistance limits leukemia treatment and chaetominine, a cytotoxic alkaloid that promotes apoptosis in a K562 human leukemia cell line via the mitochondrial pathway was studied with respect to chemoresistance in a K562/Adr human resistant leukemia cell line. Cytotoxicity assays indicated that K562/Adr resistance to adriamycin (ADR) did not occur in the presence of chaetominine and that chaetominine increased chemosensitivity of K562/Adr to ADR. Data show that chaetominine enhanced ADR-induced apoptosis and intracellular ADR accumulation in K562/Adr cells. Accordingly, chaetominine induced apoptosis by upregulating ROS, pro-apoptotic Bax and downregulating anti-apoptotic Bcl-2. RT-PCR and western-blot confirmed that chaetominine suppressed highly expressedmore » MRP1 at mRNA and protein levels. But little obvious alternation of another drug transporter MDR1 mRNA was observed. Furthermore, inhibition of MRP1 by chaetominine relied on inhibiting Akt phosphorylation and nuclear Nrf2. In summary, chaetominine strongly reverses drug resistance by interfering with the PI3K/Akt/Nrf2 signaling, resulting in reduction of MRP1-mediated drug efflux and induction of Bax/Bcl-2-dependent apoptosis in an ADR-resistant K562/Adr leukemia cell line. - Highlights: • Chaetominine enhanced chemosensitivity of ADR against K562/Adr cells. • Chaetominine increased intracellular ADR levels via inhibiting MRP1. • Chaetominine induced apoptosis of K562/Adr cells through upregulation of ROS and modulation of Bax/Bcl-2. • Inhibition of MRP1 and Nrf2 by chaetominine treatment was correlative with blockade of PI3K/Akt signaling.« less

Co-treatment with grapefruit juice inhibits while chronic administration activates intestinal P-glycoprotein-mediated drug efflux.

PubMed

Panchagnula, R; Bansal, T; Varma, M V S; Kaul, C L

2005-12-01

P-Glycoprotein (P-gp) mediated efflux is recognized as a significant biochemical barrier affecting oral absorption for a number of drugs. Various conflicting reports have been published regarding the effects of grapefruit juice (GFJ) on P-gp-mediated drug efflux, in which GFJ has been shown both to inhibit and activate it. Hence, the present study adopted a two-way approach, involving both co-treatment and chronic administration. Bi-directional transport of paclitaxel (PCL) was carried out in the absence and presence of GFJ extract, in rat everted ileum sac. Further, the effect of chronic administration of GFJ to rats was characterized by permeability studies with indinavir (INDI). Co-treatment of GFJ extract at 100% concentration reduced the asymmetric transport of PCL (efflux ratio = 20.8) by increasing absorptive (A --> B) transport by 921% and reducing secretory (B --> A) transport by 41%. Further, GFJ showed a concentration dependent effect on PCL permeability. Imipramine, a passive permeability marker with absorptive permeability of 15.33 +/- 4.26 x 10(-6) cm/s showed no asymmetric transport and also no significant (P < 0.05) change in permeability in the presence of GFJ. Chronic administration of GFJ resulted in a significant decrease in absorptive transport of indinavir, which was even greater than that produced by rifampicin pretreatment. No change in permeability of propranolol, a passive permeability marker, was observed. Further, the decrease in absorptive transport of INDI was reversed by the P-gp inhibitor verapamil. In conclusion, GFJ extract inhibited P-gp-mediated efflux in co-treatment, whereas chronic administration led to increased levels of P-gp expression, thus having a profound effect on intestinal absorption and GFJ-drug interactions in vivo.

Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs

PubMed Central

Fox, Jennifer M.; Moynihan, James R.; Mott, Bryan T.; Mazzone, Jennifer R.; Anders, Nicole M.; Brown, Patrick A.; Rudek, Michelle A.; Liu, Jun O.; Arav-Boger, Ravit; Posner, Gary H.

2016-01-01

Artemisinins, endoperoxide-containing molecules, best known as antimalarials, have potent antineoplastic activity. The established antimalarial, artesunate (AS), and the novel artemisinin-derived trioxane diphenylphosphate dimer 838 (ART-838) inhibited growth of all 23 tested acute leukemia cell lines, reduced cell proliferation and clonogenicity, induced apoptosis, and increased intracellular levels of reactive oxygen species (ROS). ART-838 was 88-fold more potent that AS in vitro, inhibiting all leukemia cell lines at submicromolar concentrations. Both ART-838 and AS cooperated with several established antileukemic drugs and newer kinase inhibitors to inhibit leukemia cell growth. ART-838 had a longer plasma half-life than AS in immunodeficient NOD-SCID-IL2Rgnull (NSG) mice, remaining at effective antileukemic concentrations for >8h. Intermittent cycles of ART-838 inhibited growth of acute leukemia xenografts and primagrafts in NSG mice, at higher potency than AS. Based on these preclinical data, we propose that AS, with its established low toxicity and low cost, and ART-838, with its higher potency and longer persistence in vivo, should be further developed toward integration into antileukemic regimens. PMID:26771236

Modelling nutritional mutualisms: challenges and opportunities for data integration.

PubMed

Clark, Teresa J; Friel, Colleen A; Grman, Emily; Shachar-Hill, Yair; Friesen, Maren L

2017-09-01

Nutritional mutualisms are ancient, widespread, and profoundly influential in biological communities and ecosystems. Although much is known about these interactions, comprehensive answers to fundamental questions, such as how resource availability and structured interactions influence mutualism persistence, are still lacking. Mathematical modelling of nutritional mutualisms has great potential to facilitate the search for comprehensive answers to these and other fundamental questions by connecting the physiological and genomic underpinnings of mutualisms with ecological and evolutionary processes. In particular, when integrated with empirical data, models enable understanding of underlying mechanisms and generalisation of principles beyond the particulars of a given system. Here, we demonstrate how mathematical models can be integrated with data to address questions of mutualism persistence at four biological scales: cell, individual, population, and community. We highlight select studies where data has been or could be integrated with models to either inform model structure or test model predictions. We also point out opportunities to increase model rigour through tighter integration with data, and describe areas in which data is urgently needed. We focus on plant-microbe systems, for which a wealth of empirical data is available, but the principles and approaches can be generally applied to any nutritional mutualism. © 2017 John Wiley & Sons Ltd/CNRS.

Utilisation of the isobole methodology to study dietary peptide-drug and peptide-peptide interactive effects on dipeptidyl peptidase IV (DPP-IV) inhibition.

PubMed

Nongonierma, Alice B; FitzGerald, Richard J

2015-01-01

Inhibition of dipeptidyl peptidase-IV (DPP-IV) is used as a means to regulate post-prandial serum glucose in type 2 diabetics. The effect of drug (Sitagliptin®)/peptide and binary peptide mixtures on DPP-IV inhibition was studied using an isobole approach. Five peptides (Ile-Pro-Ile-Gln-Tyr, Trp-Lys, Trp-Pro, Trp-Arg and Trp-Leu), having DPP-IV half maximum inhibitory concentration values (IC₅₀)<60 μM and reported to act through different inhibition mechanisms, were investigated. The dose response relationship of Sitagliptin : peptide (1:0, 0:1, 1:852, 1:426 and 1:1704 on a molar basis) and binary Ile-Pro-Ile-Gln-Tyr : peptide (1:0, 0:1, 1:1, 1:2 and 2:1 on a molar basis) mixtures for DPP-IV inhibition was characterised. Isobolographic analysis showed, in most instances, an additive effect on DPP-IV inhibition. However, a synergistic effect was observed with two Sitagliptin:Ile-Pro-Ile-Gln-Tyr (1:426 and 1:852) mixtures and an antagonistic effect was seen with one Sitagliptin : Trp-Pro (1:852) mixture, and three binary peptide mixtures (Ile-Pro-Ile-Gln-Tyr : Trp-Lys (1:1 and 2:1) and Ile-Pro-Ile-Gln-Tyr:Trp-Leu (1:2)). The results show that Sitagliptin and food protein-derived peptides can interact, thereby enhancing overall DPP-IV inhibition. Combination of Sitagliptin with food protein-derived peptides may help in reducing drug dosage and possible associated side-effects.

Evidence That P-glycoprotein Inhibitor (Elacridar)-Loaded Nanocarriers Improve Epidermal Targeting of an Anticancer Drug via Absorptive Cutaneous Transporters Inhibition.

PubMed

Giacone, Daniela V; Carvalho, Vanessa F M; Costa, Soraia K P; Lopes, Luciana B

2018-02-01

Because P-glycoprotein (P-gp) plays an absorptive role in the skin, its pharmacological inhibition represents a strategy to promote cutaneous localization of anticancer agents that serve as its substrates, improving local efficacy while reducing systemic exposure. Here, we evaluated the ability of a nanoemulsion (NE) coencapsulating a P-gp inhibitor (elacridar) with the antitumor drug paclitaxel to promote epidermal targeting. Loaded NE displayed a nanometric size (45.2 ± 4.0 nm) and negative zeta potential (-4.2 ± 0.8 mV). Elacridar improved NE ability to inhibit verapamil-induced ATPase activity of P-gp; unloaded NE-inhibited P-gp when used at a concentration of 1500 μM, while elacridar encapsulation decreased this concentration by 3-fold (p <0.05). Elacridar-loaded NE reduced paclitaxel penetration into the dermis of freshly excised mice skin and its percutaneous permeation by 1.5- and 1.7-fold (p <0.05), respectively at 6 h, whereas larger drug amounts (1.4-fold, p <0.05) were obtained in viable epidermis. Assessment of cutaneous distribution of a fluorescent paclitaxel derivative confirmed the smaller delivery into the dermis at elacridar presence. In conclusion, we have provided novel evidence that NE containing elacridar exhibited a clear potential for P-gp inhibition and enabled epidermal targeting of paclitaxel, which in turn, can potentially reduce adverse effects associated with systemic exposure to anticancer therapy. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

76 FR 20459 - Mutual to Stock Conversion Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-12

... DEPARTMENT OF THE TREASURY Office of Thrift Supervision Mutual to Stock Conversion Application... collection. Title of Proposal: Mutual to Stock Conversion Application. OMB Number: 1550-0014. Form Numbers... furnished in the application in order to determine the safety and soundness of the proposed stock conversion...

Reconnection Dynamics and Mutual Friction in Quantum Turbulence

NASA Astrophysics Data System (ADS)

Laurie, Jason; Baggaley, Andrew W.

2015-07-01

We investigate the behaviour of the mutual friction force in finite temperature quantum turbulence in He, paying particular attention to the role of quantized vortex reconnections. Through the use of the vortex filament model, we produce three experimentally relevant types of vortex tangles in steady-state conditions, and examine through statistical analysis, how local properties of the tangle influence the mutual friction force. Finally, by monitoring reconnection events, we present evidence to indicate that vortex reconnections are the dominant mechanism for producing areas of high curvature and velocity leading to regions of high mutual friction, particularly for homogeneous and isotropic vortex tangles.

Limiting the cost of mutualism: the defensive role of elongated gynophore in the leafflower-moth mutualism.

PubMed

Furukawa, Saori; Kawakita, Atsushi

2017-08-01

Mutualisms are interactions from which both partners benefit but may collapse if mutualists' costs and benefits are not aligned. Host sanctions are one mechanism whereby hosts selectively allocate resources to the more cooperative partners and thereby reduce the fitness of overexploiters; however, many mutualisms lack apparent means of host sanctions. In mutualisms between plants and pollinating seed parasites, such as those between leafflowers and leafflower moths, pollinators consume subsets of the seeds as larval food in return for their pollination service. Plants may select against overexploiters by selectively aborting flowers with a heavy egg load, but in many leafflower species, seeds are fully eaten in some fruits, suggesting that such a mechanism is not present in all species. Instead, the fruits of Breynia vitis-idaea have stalk-like structures (gynophore) through which early-instar moth larvae must bore to reach seeds. Examination of moth mortality in fruits with different gynophore lengths suggested that fruits with longer gynophore had higher moth mortality and, therefore, less seed damage. Most moth mortality occurred at the egg stage or as early larval instar before moths reached the seeds, consistent with the view that gynophore functions to prevent moth access to seeds. Gynophore length was unaffected by plant size, extent of moth oviposition, or geography; thus, it is most likely genetically controlled. Because gynophores do not elongate in related species whose pollinators oviposit directly into the ovary, the gynophore in B. vitis-idaea may have evolved as a defense to limit the cost of the mutualism.

Hierarchical clustering using mutual information

NASA Astrophysics Data System (ADS)

Kraskov, A.; Stögbauer, H.; Andrzejak, R. G.; Grassberger, P.

2005-04-01

We present a conceptually simple method for hierarchical clustering of data called mutual information clustering (MIC) algorithm. It uses mutual information (MI) as a similarity measure and exploits its grouping property: The MI between three objects X, Y, and Z is equal to the sum of the MI between X and Y, plus the MI between Z and the combined object (XY). We use this both in the Shannon (probabilistic) version of information theory and in the Kolmogorov (algorithmic) version. We apply our method to the construction of phylogenetic trees from mitochondrial DNA sequences and to the output of independent components analysis (ICA) as illustrated with the ECG of a pregnant woman.

Pharmacokinetic interaction of diosmetin and silibinin with other drugs: Inhibition of CYP2C9-mediated biotransformation and displacement from serum albumin.

PubMed

Poór, Miklós; Boda, Gabriella; Mohos, Violetta; Kuzma, Mónika; Bálint, Mónika; Hetényi, Csaba; Bencsik, Tímea

2018-06-01

Diosmin and silibinin (SIL) are polyphenolic compounds which are the active components of several drugs and dietary supplements. After the oral administration of diosmin (flavonoid glycoside), only its aglycone diosmetin (DIO) reaches the systemic circulation. Both DIO and SIL form complexes with serum albumin and are able to inhibit several cytochrome P450 enzymes. Therefore, it is reasonable to hypothesize that these polyphenols may displace some drugs from serum albumin and inhibit their biotransformation, potentially leading to the disruption of drug therapy. In this study, the inhibitory action of DIO and SIL on CYP2C9-catalyzed metabolism of diclofenac to 4'-hydroxydiclofenac was examined, using warfarin as a positive control. Furthermore, interaction of DIO and SIL with human and bovine serum albumins as well as the displacement of warfarin from albumin by DIO and SIL were tested, employing steady-state fluorescence spectroscopy, fluorescence anisotropy, ultrafiltration, and molecular modeling. It is demonstrated that DIO and SIL are potent inhibitors of CYP2C9 enzyme and are able to displace the Site I ligand warfarin from human serum albumin. Because DIO and SIL may interfere with the pharmacokinetics of several drugs through both ways, we need to consider the potentially hazardous consequences of the consumption of diosmin or SIL together with other drugs. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

12 CFR 333.4 - Conversions from mutual to stock form.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Conversions from mutual to stock form. 333.4... GENERAL POLICY EXTENSION OF CORPORATE POWERS Regulations § 333.4 Conversions from mutual to stock form. (a) Scope. This section applies to the conversion of insured mutual state savings banks to the stock form of...

Impact of Mutual Mentoring on Research

NASA Astrophysics Data System (ADS)

Whitten, Barbara; Blaha, Cynthia; Bug, Amy; Cox, Anne; Fritz, Linda

2011-03-01

In this talk we discuss one of the impacts of an NSF ADVANCE sponsored horizontal, mutual mentoring alliance. Our cohort of five women physicists at liberal arts colleges has found that mutual mentoring has had a profound impact on many aspects of our professional lives. In this talk we will give some specific ways that we have supported and helped to expand each other's research. For some new areas of research were opened, for others new focus was brought to existing areas, and still others found acceptance for where they were.

Inhibition of recombinant Ca(v)3.1 (alpha(1G)) T-type calcium channels by the antipsychotic drug clozapine.

PubMed

Choi, Kee-Hyun; Rhim, Hyewhon

2010-01-25

Low voltage-activated T-type calcium channels are involved in the regulation of the neuronal excitability, and could be subject to many antipsychotic drugs. The effects of clozapine, an atypical antipsychotic drug, on recombinant Ca(v)3.1 T-type calcium channels heterologously expressed in human embryonic kidney 293 cells were examined using whole-cell patch-clamp recordings. At a standard holding potential of -100 mV, clozapine inhibited Ca(v)3.1 currents with an IC(50) value of 23.7+/-1.3 microM in a use-dependent manner. However, 10 microM clozapine inhibited more than 50% of the Ca(v)3.1 currents in recordings at a more physiologically relevant holding potential of -75 mV. Clozapine caused a significant hyperpolarizing shift in the steady-state inactivation curve of the Ca(v)3.1 channels, which is presumably the main mechanism accounting for the inhibition of the Ca(v)3.1 currents. In addition, clozapine slowed Ca(v)3.1 deactivation and inactivation kinetics but not activation kinetics. Clozapine-induced changes in deactivation and inactivation rates of the Ca(v)3.1 channel gating would likely facilitate calcium influx via Ca(v)3.1 T-type calcium channels. Thus, clozapine may exert its therapeutic and/or side effects by altering cell's excitability and firing properties through actions on T-type calcium channels.

The Development of Mutuality in Natural Small Groups.

ERIC Educational Resources Information Center

Baker, Paul Morgan

1983-01-01

Describes factors affecting the development of mutuality of attraction in natural small groups, and tests the hypothesis of the acquaintance process in 41 female residents of three floors of a university dormitory over the course of a year. Two floors showed definite increases in dyadic mutuality over time. (JAC)

Antiplatelet drug interactions with proton pump inhibitors

PubMed Central

Scott, Stuart A; Obeng, Aniwaa Owusu; Hulot, Jean-Sébastien

2014-01-01

Introduction Non-aspirin antiplatelet agents (e.g., clopidogrel, prasugrel, ticagrelor) are commonly prescribed for the prevention of recurrent cardiovascular events among patients with acute coronary syndromes (ACS) and/or those undergoing percutaneous coronary intervention (PCI). In addition, combination therapy with proton pump inhibitors (PPIs) is often recommended to attenuate gastrointestinal bleeding risk, particularly during dual antiplatelet therapy (DAPT) with clopidogrel and aspirin. Importantly, a pharmacological interaction between clopidogrel and some PPIs has been proposed based on mutual CYP450-dependent metabolism, but available evidence is inconsistent. Areas covered This article provides an overview of the currently approved antiplatelet agents and PPIs, including their metabolic pathways. Additionally, the CYP450 isoenzyme at the center of the drug interaction, CYP2C19, is described in detail, and the available evidence on both the potential pharmacological interaction and influence on clinical outcomes are summarized and evaluated. Expert opinion Although concomitant DAPT and PPI use reduces clopidogrel active metabolite levels and ex vivo-measured platelet inhibition, the influence of the drug interaction on clinical outcomes has been conflicting and largely reported from non-randomized observational studies. Despite this inconsistency, a clinically important interaction cannot be definitively excluded, particularly among patient subgroups with higher overall cardiovascular risk and potentially among CYP2C19 loss-of-function allele carriers. PMID:24205916

Nonsteroidal anti-inflammatory drug-induced fracture nonunion: an inhibition of angiogenesis?

PubMed

Murnaghan, Mark; Li, Gang; Marsh, David R

2006-11-01

Approximately 5% to 10% of fractures may result in delayed union or nonunion. The results of research done over the past three decades have shown that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) has an inhibitory effect on fracture repair, but the exact mechanism of action remains to be elucidated. Cancer research has identified that NSAIDs impede cell proliferation by inhibiting angiogenesis. It is proposed that a similar mechanism occurs in the induction of NSAID-induced nonunions. This hypothesis was investigated in a randomized placebo-controlled trial of the NSAID rofecoxib with use of a murine femoral fracture model. Two hundred and forty mice were randomized to receive either the nonsteroidal anti-inflammatory drug rofecoxib (5 mg/kg orally) in a 0.5% methylcellulose solution (the NSAID group) or the 0.5% methylcellulose solution only (the control group). Two hundred and thirty-five of the 240 mice underwent surgery to induce an open transverse middiaphyseal femoral fracture, which was then treated with use of a custom-made external fixator. Five additional animals underwent sham surgery with no fracture induced. Outcomes measures included radiographic assessment, histologic analysis, biomechanical testing, and use of laser Doppler flowmetry to assess blood flow across the fracture gap. Radiography revealed similar healing patterns in both groups; however, at the later stages (day 32), the NSAID group had poorer healing. Histological analysis demonstrated that the control animals healed quicker (at days 24 and 32) and had more callus and less fibrous tissue (at days 8 and 32) than the NSAID animals did. Biomechanical testing found that the control animals were stronger at day 32. Both groups exhibited a similar pattern of blood flow; however, the NSAID group exhibited a lower median flow from day 4 onward (significant at days 4, 16, and 24). Positive correlations were demonstrated between both histological and radiographic assessments of healing

24 CFR 203.422 - Right and liability under Mutual Mortgage Insurance Fund.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Mortgage Insurance Fund and Distributive Shares § 203.422 Right and liability under Mutual Mortgage... to any liability arising under the mutuality of the Mutual Mortgage Insurance Fund. ... 24 Housing and Urban Development 2 2010-04-01 2010-04-01 false Right and liability under Mutual...

24 CFR 203.422 - Right and liability under Mutual Mortgage Insurance Fund.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Mortgage Insurance Fund and Distributive Shares § 203.422 Right and liability under Mutual Mortgage... to any liability arising under the mutuality of the Mutual Mortgage Insurance Fund. ... 24 Housing and Urban Development 2 2011-04-01 2011-04-01 false Right and liability under Mutual...

Inhibition of Lactate Transport Erases Drug Memory and Prevents Drug Relapse.

PubMed

Zhang, Yan; Xue, Yanxue; Meng, Shiqiu; Luo, Yixiao; Liang, Jie; Li, Jiali; Ai, Sizhi; Sun, Chengyu; Shen, Haowei; Zhu, Weili; Wu, Ping; Lu, Lin; Shi, Jie

2016-06-01

Drug memories that associate drug-paired stimuli with the effects of abused drugs contribute to relapse. Exposure to drug-associated contexts causes consolidated drug memories to be in a labile state, during which manipulations can be given to impair drug memories. Although substantial evidence demonstrates the crucial role of neuronal signaling in addiction, little is known about the contribution of astrocyte-neuron communication. Rats were trained for cocaine-induced conditioned place preference (CPP) or self-administration and microinjected with the glycogen phosphorylation inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol into the basolateral amygdala (BLA) immediately after retrieval. The concentration of lactate was measured immediately after retrieval via microdialysis, and the CPP score and number of nosepokes were recorded 24 hours later. Furthermore, we used antisense oligodeoxynucleotides to disrupt the expression of astrocytic lactate transporters (monocarboxylate transporters 1 and 2) in the BLA after retrieval, tested the expression of CPP 1 day later, and injected L-lactate into the BLA 15 minutes before retrieval to rescue the effects of the oligodeoxynucleotides. Injection of 1,4-dideoxy-1,4-imino-D-arabinitol into the BLA immediately after retrieval prevented the subsequent expression of cocaine-induced CPP, decreased the concentration of lactate in the BLA, and reduced the number of nosepokes for cocaine self-administration. Disrupting the expression of monocarboxylate transporters 1 and 2 in the BLA also caused subsequent deficits in the expression of cocaine-induced CPP, which was rescued by pretreatment with L-lactate. Our results suggest that astrocyte-neuron lactate transport in the BLA is critical for the reconsolidation of cocaine memory. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Mutual Intelligibility between Closely Related Languages in Europe

ERIC Educational Resources Information Center

Gooskens, Charlotte; van Heuven, Vincent J.; Golubovic, Jelena; Schüppert, Anja; Swarte, Femke; Voigt, Stefanie

2018-01-01

By means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language families in Europe. We first present the results of a selection of 1833 listeners representing the mutual intelligibility between young, educated Europeans…

Equitability, mutual information, and the maximal information coefficient.

PubMed

Kinney, Justin B; Atwal, Gurinder S

2014-03-04

How should one quantify the strength of association between two random variables without bias for relationships of a specific form? Despite its conceptual simplicity, this notion of statistical "equitability" has yet to receive a definitive mathematical formalization. Here we argue that equitability is properly formalized by a self-consistency condition closely related to Data Processing Inequality. Mutual information, a fundamental quantity in information theory, is shown to satisfy this equitability criterion. These findings are at odds with the recent work of Reshef et al. [Reshef DN, et al. (2011) Science 334(6062):1518-1524], which proposed an alternative definition of equitability and introduced a new statistic, the "maximal information coefficient" (MIC), said to satisfy equitability in contradistinction to mutual information. These conclusions, however, were supported only with limited simulation evidence, not with mathematical arguments. Upon revisiting these claims, we prove that the mathematical definition of equitability proposed by Reshef et al. cannot be satisfied by any (nontrivial) dependence measure. We also identify artifacts in the reported simulation evidence. When these artifacts are removed, estimates of mutual information are found to be more equitable than estimates of MIC. Mutual information is also observed to have consistently higher statistical power than MIC. We conclude that estimating mutual information provides a natural (and often practical) way to equitably quantify statistical associations in large datasets.

Modified Metformin as a More Potent Anticancer Drug: Mitochondrial Inhibition, Redox Signaling, Antiproliferative Effects and Future EPR Studies.

PubMed

Kalyanaraman, Balaraman; Cheng, Gang; Hardy, Micael; Ouari, Olivier; Sikora, Adam; Zielonka, Jacek; Dwinell, Michael B

2017-12-01

Metformin, one of the most widely prescribed antidiabetic drugs in the world, is being repurposed as a potential drug in cancer treatment. Epidemiological studies suggest that metformin exerts anticancer effects in diabetic patients with pancreatic cancer. However, at typical antidiabetic doses the bioavailability of metformin is presumably too low to exert antitumor effects. Thus, more potent analogs of metformin are needed in order to increase its anticancer efficacy. To this end, a new class of mitochondria-targeted metformin analogs (or mito-metformins) containing a positively-charged lipophilic triphenylphosphonium group was synthesized and tested for their antitumor efficacy in pancreatic cancer cells. Results indicate that the lead compound, mito-metformin 10 , was nearly 1000-fold more potent than metformin in inhibiting mitochondrial complex I activity, inducing reactive oxygen species (superoxide and hydrogen peroxide) that stimulate redox signaling mechanisms, including the activation of adenosinemonophosphate kinase and inhibition of proliferation of pancreatic cancer cells. The potential use of the low-temperature electron paramagnetic resonance technique in assessing the role of mitochondrial complexes including complex I in tumor regression in response to metformin and mito-metformins in the in vivo setting is discussed.

Evolutionary origin of insect–Wolbachia nutritional mutualism

PubMed Central

Nikoh, Naruo; Hosokawa, Takahiro; Moriyama, Minoru; Oshima, Kenshiro; Hattori, Masahira; Fukatsu, Takema

2014-01-01

Obligate insect–bacterium nutritional mutualism is among the most sophisticated forms of symbiosis, wherein the host and the symbiont are integrated into a coherent biological entity and unable to survive without the partnership. Originally, however, such obligate symbiotic bacteria must have been derived from free-living bacteria. How highly specialized obligate mutualisms have arisen from less specialized associations is of interest. Here we address this evolutionary issue by focusing on an exceptional insect–Wolbachia nutritional mutualism. Although Wolbachia endosymbionts are ubiquitously found in diverse insects and generally regarded as facultative/parasitic associates for their insect hosts, a Wolbachia strain associated with the bedbug Cimex lectularius, designated as wCle, was shown to be essential for host’s growth and reproduction via provisioning of B vitamins. We determined the 1,250,060-bp genome of wCle, which was generally similar to the genomes of insect-associated facultative Wolbachia strains, except for the presence of an operon encoding the complete biotin synthetic pathway that was acquired via lateral gene transfer presumably from a coinfecting endosymbiont Cardinium or Rickettsia. Nutritional and physiological experiments, in which wCle-infected and wCle-cured bedbugs of the same genetic background were fed on B-vitamin–manipulated blood meals via an artificial feeding system, demonstrated that wCle certainly synthesizes biotin, and the wCle-provisioned biotin significantly contributes to the host fitness. These findings strongly suggest that acquisition of a single gene cluster consisting of biotin synthesis genes underlies the bedbug–Wolbachia nutritional mutualism, uncovering an evolutionary transition from facultative symbiosis to obligate mutualism facilitated by lateral gene transfer in an endosymbiont lineage. PMID:24982177

Public-channel cryptography based on mutual chaos pass filters.

PubMed

Klein, Einat; Gross, Noam; Kopelowitz, Evi; Rosenbluh, Michael; Khaykovich, Lev; Kinzel, Wolfgang; Kanter, Ido

2006-10-01

We study the mutual coupling of chaotic lasers and observe both experimentally and in numeric simulations that there exists a regime of parameters for which two mutually coupled chaotic lasers establish isochronal synchronization, while a third laser coupled unidirectionally to one of the pair does not synchronize. We then propose a cryptographic scheme, based on the advantage of mutual coupling over unidirectional coupling, where all the parameters of the system are public knowledge. We numerically demonstrate that in such a scheme the two communicating lasers can add a message signal (compressed binary message) to the transmitted coupling signal and recover the message in both directions with high fidelity by using a mutual chaos pass filter procedure. An attacker, however, fails to recover an errorless message even if he amplifies the coupling signal.

Chronic anti-inflammatory drug therapy inhibits gel-forming mucin production in a murine xenograft model of human pseudomyxoma peritonei.

PubMed

Choudry, Haroon Asif; Mavanur, Arun; O'Malley, Mark E; Zeh, Herbert J; Guo, Z Sheng; Bartlett, David L

2012-05-01

Intraperitoneal accumulation of mucinous ascites in pseudomyxoma peritonei (PMP) promotes an inflammatory/fibrotic reaction that progresses to bowel obstruction and eventual patient demise. Cytokines and inflammation-associated transcription factor binding sites, such as glucocorticoid response elements and COX-2, regulate secretory mucin, specifically MUC2, production. We hypothesized that anti-inflammatory drugs targeting inflammation-associated pathways may reduce mucin production and subsequent disease morbidity in PMP. The effects of dexamethasone and Celebrex were assessed in mucin-secreting human colon cancer LS174T cells in vitro and murine xenograft models of LS174T and human appendiceal PMP in vivo by serial parametric measurements, MUC2 transcripts via real-time RT-PCR, and MUC2 protein expression via immunofluorescence assays. Dexamethasone significantly inhibited basal MUC2 mRNA levels in LS174T cells, inhibited mucinous tumor accumulation in an intraperitoneal PMP xenograft model, and prolonged survival in a subcutaneous LS174T xenograft model. Celebrex significantly inhibited sodium butyrate-stimulated MUC2 mRNA levels in LS174T cells and demonstrated a statistically nonsignificant trend toward reduced mucinous tumor growth and prolonged survival in the xenograft models. MUC2 protein analysis by immunofluorescence demonstrated a dual effect of dexamethasone on mucin production and tumor cell count. Inflammatory mediators are known to regulate mucin production and may promote overexpression of MUC2 by neoplastic cells with goblet cell phenotype in PMP. Anti-inflammatory drugs, dexamethasone and Celebrex, could inhibit extracellular mucin production in PMP by targeting inflammatory cascades and, therefore, may decrease compressive symptoms, increase the disease-free interval, and reduce the extent or frequency of morbid cytoreductive surgeries.

Holographic mutual information of two disjoint spheres

NASA Astrophysics Data System (ADS)

Chen, Bin; Fan, Zhong-Ying; Li, Wen-Ming; Zhang, Cheng-Yong

2018-04-01

We study quantum corrections to holographic mutual information for two disjoint spheres at a large separation by using the operator product expansion of the twist field. In the large separation limit, the holographic mutual information is vanishing at the semiclassical order, but receive quantum corrections from the fluctuations. We show that the leading contributions from the quantum fluctuations take universal forms as suggested from the boundary CFT. We find the universal behavior for the scalar, the vector, the tensor and the fermionic fields by treating these fields as free fields propagating in the fixed background and by using the 1 /n prescription. In particular, for the fields with gauge symmetries, including the massless vector boson and massless graviton, we find that the gauge parts in the propagators play an indispensable role in reading the leading order corrections to the bulk mutual information.

(-)Ephedrine and caffeine mutually potentiate one another's amphetamine-like stimulus effects.

PubMed

Young, R; Gabryszuk, M; Glennon, R A

1998-10-01

Using rats trained to discriminate 1 mg/kg of (+)amphetamine (ED50 = 0.4 mg/kg) from saline vehicle in a two-lever drug discrimination procedure, it was shown that (-)ephedrine (ED50 = 4.5 mg/kg), but not (+)ephedrine, substitutes for the (+)AMPH stimulus. It was also shown that caffeine (ED50 = 12.9 mg/kg) can substitute for (+)amphetamine in a dose-related fashion. Doses of (-)ephedrine and caffeine, which produced < or = 1% drug-appropriate responding when administered alone, were able to enhance each other's stimulus effects when administered in combination such that there was a twofold leftward shift in their respective dose-response curves. Furthermore, stimulus generalization occurred when a dose of caffeine that produced saline-appropriate responding when administered alone was administered in combination with (+)ephedrine. It would appear that low doses of (-)ephedrine and caffeine may mutually potentiate one another's stimulus effects in (+)AMPH-trained rats, and that a combination of caffeine and (+)ephedrine result in altered stimulus character when compared to comparable doses of either agent administered alone.

Short- and long-term inhibition of cardiac inward-rectifier potassium channel current by an antiarrhythmic drug bepridil.

PubMed

Ma, Fangfang; Takanari, Hiroki; Masuda, Kimiko; Morishima, Masaki; Ono, Katsushige

2016-07-01

Bepridil is an effective antiarrhythmic drug on supraventricular and ventricular arrhythmias, and inhibitor of calmodulin. Recent investigations have been elucidating that bepridil exerts antiarrhythmic effects through its acute and chronic application for patients. The aim of this study was to identify the efficacy and the potential mechanism of bepridil on the inward-rectifier potassium channel in neonatal rat cardiomyocytes in acute- and long-term conditions. Bepridil inhibited inward-rectifier potassium current (I K1) as a short-term effect with IC50 of 17 μM. Bepridil also reduced I K1 of neonatal cardiomyocytes when applied for 24 h in the culture medium with IC50 of 2.7 μM. Both a calmodulin inhibitor (W-7) and an inhibitor of calmodulin-kinase II (KN93) reduced I K1 when applied for 24 h as a long-term effect in the same fashion, suggesting that the long-term application of bepridil inhibits I K1 more potently than that of the short-term application through the inhibition of calmodulin kinase II pathway in cardiomyocytes.

Analysis of high-frequency oscillations in mutually-coupled nano-lasers.

PubMed

Han, Hong; Shore, K Alan

2018-04-16

The dynamics of mutually coupled nano-lasers has been analyzed using rate equations which include the Purcell cavity-enhanced spontaneous emission factor F and the spontaneous emission coupling factor β. It is shown that in the mutually-coupled system, small-amplitude oscillations with frequencies of order 100 GHz are generated and are maintained with remarkable stability. The appearance of such high-frequency oscillations is associated with the effective reduction of the carrier lifetime for larger values of the Purcell factor, F, and spontaneous coupling factor, β. In mutually-coupled nano-lasers the oscillation frequency changes linearly with the frequency detuning between the lasers. For non-identical bias currents, the oscillation frequency of mutually-coupled nano-lasers also increases with bias current. The stability of the oscillations which appear in mutually coupled nano-lasers offers opportunities for their practical applications and notably in photonic integrated circuits.

78 FR 53175 - The Northwestern Mutual Life Insurance Company, et al.;

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-28

...] The Northwestern Mutual Life Insurance Company, et al.; Notice of Application Agency: Securities and... the Act from Section 17(a) of the Act. Applicants: The Northwestern Mutual Life Insurance Company (the... Account B, the ``Annuity Accounts'') and Northwestern Mutual Variable Life Account (``VL Account'') and...

12 CFR 543.9 - Application for conversion to Federal mutual charter.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Application for conversion to Federal mutual... FEDERAL MUTUAL SAVINGS ASSOCIATIONS-INCORPORATION, ORGANIZATION, AND CONVERSION Conversion § 543.9 Application for conversion to Federal mutual charter. (a)(1) Filing. Any depository institution that proposes...

12 CFR 543.9 - Application for conversion to Federal mutual charter.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 12 Banks and Banking 5 2011-01-01 2011-01-01 false Application for conversion to Federal mutual... FEDERAL MUTUAL SAVINGS ASSOCIATIONS-INCORPORATION, ORGANIZATION, AND CONVERSION Conversion § 543.9 Application for conversion to Federal mutual charter. (a)(1) Filing. Any depository institution that proposes...

Evolutionary dynamics of fluctuating populations with strong mutualism

NASA Astrophysics Data System (ADS)

Chotibut, Thiparat; Nelson, David

2013-03-01

Evolutionary game theory with finite interacting populations is receiving increased attention, including subtle phenomena associated with number fluctuations, i.e., ``genetic drift.'' Models of cooperation and competition often utilize a simplified Moran model, with a strictly fixed total population size. We explore a more general evolutionary model with independent fluctuations in the numbers of two distinct species, in a regime characterized by ``strong mutualism.'' The model has two absorbing states, each corresponding to fixation of one of the two species, and allows exploration of the interplay between growth, competition, and mutualism. When mutualism is favored, number fluctuations eventually drive the system away from a stable fixed point, characterized by cooperation, to one of the absorbing states. Well-mixed populations will thus be taken over by a single species in a finite time, despite the bias towards cooperation. We calculate both the fixation probability and the mean fixation time as a function of the initial conditions and carrying capacities in the strong mutualism regime, using the method of matched asymptotic expansions. Our results are compared to computer simulations.

Mutual information in the evolution of trajectories in discrete aiming movements.

PubMed

Lai, Shih-Chiung; Mayer-Kress, Gottfried; Newell, Karl M

2008-07-01

This study investigated the mutual information in the trajectories of discrete aiming movements on a computer controlled graphics tablet where movement time ( 300 - 2050 ms) was manipulated in a given distance (100 mm) and movement distance (15-240 mm) in 2 given movement times (300 ms and 800 ms ). For the distance-fixed conditions, there was higher mutual information in the slower movements in the 0 vs. 80-100% trajectory point comparisons, whereas the mutual information was higher for the faster movements when comparing within the 80 and 100% points of the movement trajectory. For the time-fixed conditions, the spatial constraints led to a decreasing pattern of the mutual information throughout the points of the trajectory, with the highest mutual information found in the 80 vs. 100% comparison. Overall, the pattern of mutual information reveals systematic modulation of the trajectories between the attractive fixed point of the target as a function of movement condition. These mutual information patterns are postulated to be the consequence of the different relative contributions of feedforward and feedback control processes in trajectory formation as a function of task constraints.

Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs.

PubMed

Ramsay, Rona R; Tipton, Keith F

2017-07-15

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC 50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.

77 FR 73700 - Mutual of America Life Insurance Company, et al;

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-11

... Life Insurance Company, et al; Notice of Application December 5, 2012. AGENCY: Securities and Exchange... Section 17(a) of the Act. APPLICANTS: Mutual of America Life Insurance Company (``Mutual of America''), Wilton Reassurance Life Company of New York (``Wilton,'' and, together with Mutual of America Life...

31 CFR 1024.210 - Anti-money laundering programs for mutual funds.

Code of Federal Regulations, 2011 CFR

2011-07-01

... mutual funds. 1024.210 Section 1024.210 Money and Finance: Treasury Regulations Relating to Money and... FUNDS Programs § 1024.210 Anti-money laundering programs for mutual funds. (a) Effective July 24, 2002, each mutual fund shall develop and implement a written anti-money laundering program reasonably...

12 CFR 239.9 - Conversion or liquidation of mutual holding companies.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 12 Banks and Banking 4 2013-01-01 2013-01-01 false Conversion or liquidation of mutual holding companies. 239.9 Section 239.9 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) MUTUAL HOLDING COMPANIES (REGULATION MM) Mutual Holding...

12 CFR 239.9 - Conversion or liquidation of mutual holding companies.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 12 Banks and Banking 4 2012-01-01 2012-01-01 false Conversion or liquidation of mutual holding companies. 239.9 Section 239.9 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) MUTUAL HOLDING COMPANIES (REGULATION MM) Mutual Holding...

12 CFR 239.9 - Conversion or liquidation of mutual holding companies.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 12 Banks and Banking 4 2014-01-01 2014-01-01 false Conversion or liquidation of mutual holding companies. 239.9 Section 239.9 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) MUTUAL HOLDING COMPANIES (REGULATION MM) Mutual Holding...

Mutual Coupling and Compensation in FMCW MIMO Radar Systems

NASA Astrophysics Data System (ADS)

Schmid, Christian M.; Feger, Reinhard; Wagner, Christoph; Stelzer, Andreas

2011-09-01

This paper deals with mutual coupling, its effects and the compensation thereof in frequency-modulated continuous-wave (FMCW) multiple-input multiple-output (MIMO) array radar systems. Starting with a signal model we introduce mutual coupling and its primary sources in FMCW MIMO systems. We also give a worst-case boundary of the effects that mutual coupling can have on the side lobe level of an array. A method of dealing with and compensating for these effects is covered in this paper and verified by measurements from a 77-GHz FMCW radar system.

47 CFR 90.165 - Procedures for mutually exclusive applications.

Code of Federal Regulations, 2010 CFR

2010-10-01

.... 90.165 Section 90.165 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND... Governing Facilities Used to Provide Commercial Mobile Radio Services § 90.165 Procedures for mutually exclusive applications. Mutually exclusive commercial mobile radio service applications are processed in...

Mutual Information Rate and Bounds for It

PubMed Central

Baptista, Murilo S.; Rubinger, Rero M.; Viana, Emilson R.; Sartorelli, José C.; Parlitz, Ulrich; Grebogi, Celso

2012-01-01

The amount of information exchanged per unit of time between two nodes in a dynamical network or between two data sets is a powerful concept for analysing complex systems. This quantity, known as the mutual information rate (MIR), is calculated from the mutual information, which is rigorously defined only for random systems. Moreover, the definition of mutual information is based on probabilities of significant events. This work offers a simple alternative way to calculate the MIR in dynamical (deterministic) networks or between two time series (not fully deterministic), and to calculate its upper and lower bounds without having to calculate probabilities, but rather in terms of well known and well defined quantities in dynamical systems. As possible applications of our bounds, we study the relationship between synchronisation and the exchange of information in a system of two coupled maps and in experimental networks of coupled oscillators. PMID:23112809

Local drug delivery - the early Berlin experience: single drug administration versus sustained release.

PubMed

Speck, Ulrich; Scheller, Bruno; Rutsch, Wolfgang; Laule, Michael; Stangl, Verena

2011-05-01

Our initial investigations into restenosis inhibition by local drug delivery were prompted by reports on an improved outcome of coronary interventions, including a lower rate of target lesion revascularisation, when the intervention was performed with an ionic instead of non-ionic contrast medium. Although this was not confirmed in an animal study, the short exposure of the vessel wall to paclitaxel dissolved in contrast agent or coated on balloons proved to be efficacious. A study comparing three methods of local drug delivery to the coronary artery in pigs indicated the following order of efficacy in inhibiting neointimal proliferation: paclitaxel-coated balloons > sirolimus-eluting stents, sustained drug release > paclitaxel in contrast medium. Cell culture experiments confirmed that cell proliferation can be inhibited by very short exposure to the drug. Shorter exposure times require higher drug concentrations. Effective paclitaxel concentrations in porcine arteries are achieved when the drug is dissolved in contrast medium or coated on balloons. Paclitaxel is an exceptional drug in that it stays in the treated tissue for a long time. This may explain the long-lasting efficacy of paclitaxel-coated balloons, but does not disprove the hypothesis that the agent blocks a process initiating long-lasting excessive neointimal proliferation, which occurs early after vessel injury.

Inhibition of the development of myringosclerosis by local administration of fenspiride, an anti-inflammatory drug.

PubMed

Mattsson, C; Hellström, S

1997-01-01

Earlier studies have revealed a relationship between the development of myringosclerosis and oxygen-derived free radicals. The latter can be blocked by the anti-inflammatory drug fenspiride. The present study was undertaken to test the ability of fenspiride to prevent myringosclerosis from developing during healing of the tympanic membrane. Myringotomized rats were treated with either topical applications or intraperitoneal injections of fenspiride for 12 days, after which the tympanic membranes were examined by otomicroscopy and studied histologically by light microscopy. Topically applied fenspiride was found to inhibit the development of sclerotic lesions, whereas intraperitoneal injections were ineffective.

United Nations Office on Drugs and Crime International Network of Drug Dependence Treatment and Rehabilitation Resource Centres: Treatnet

ERIC Educational Resources Information Center

Tomas-Rossello, Juana; Rawson, Richard A.; Zarza, Maria J.; Bellows, Anne; Busse, Anja; Saenz, Elizabeth; Freese, Thomas; Shawkey, Mansour; Carise, Deni; Ali, Robert; Ling, Walter

2010-01-01

Key to the dissemination of evidence-based addiction treatments is the exchange of experiences and mutual support among treatment practitioners, as well as the availability of accurate addiction training materials and effective trainers. To address the shortage of such resources, the United Nations Office on Drugs and Crime (UNODC) created…

Mutuality, empowerment and the health-wealth model: the Scottish context.

PubMed

Howieson, Brian

2013-06-01

This paper will offer an alternative paradigm to healthcare delivery by introducing the concept of mutuality and empowerment into the existing health-wealth model. The backdrop is provided by Better Health, Better Care (Scottish Government 2007), Section 1 of which is entitled 'Towards a Mutual NHS'. In detail, the paper will: revisit what is meant by mutuality; advance the meaning of the 'public interest'; explore empowerment and community empowerment and its relationship to health; and introduce a model, which tries to link these concepts and terms together. It is hoped that this analysis will help researchers and practitioners alike further appreciate the important concept of mutuality and empowerment into the existing health-wealth model.

47 CFR 22.131 - Procedures for mutually exclusive applications.

Code of Federal Regulations, 2010 CFR

2010-10-01

... SERVICES PUBLIC MOBILE SERVICES Licensing Requirements and Procedures Applications and Notifications § 22... procedures in this section for processing mutually exclusive applications in the Public Mobile Services... 47 Telecommunication 2 2010-10-01 2010-10-01 false Procedures for mutually exclusive applications...

The enriched fraction of Vernonia cinerea L. induces apoptosis and inhibits multi-drug resistance transporters in human epithelial cancer cells.

PubMed

Appadath Beeran, Asmy; Maliyakkal, Naseer; Rao, Chamallamudi Mallikarjuna; Udupa, Nayanabhirama

2014-12-02

Vernonia cinerea Less. (VC) of the family Asteraceaes is considered as the sacred plant; 'Dasapushpam' which is ethnopharmacologically significant to the people of Kerala in India. In fact, VC has been used in the traditional system of medicine (Ayurveda) for the treatment of various ailments including cancer. Cytotoxicity of the ethanolic extract of VC (VC-ET), petroleum ether fraction (VC-PET), dichloromethane fraction (VC-DCM), n-butyl alcohol fraction (VC-BT), and rest fraction (VC-R) was evaluated in cervical carcinoma (HeLa), lung adenocarcinoma (A549), breast cancer (MCF-7), and colon carcinoma (Caco-2) cells using Sulforhodamine B (SRB) assay. The apoptotic effects of VC-DCM were assessed in cancer cells using Annexin V assay. The effects of VC-DCM on multi-drug resistance (MDR) transporters in HeLa, A549, MCF-7, and Caco-2 cells were evaluated using flow cytometry based functional assays. Similarly, drug uptake in cancer cells and sensitization of cancer cells towards chemotherapeutic drugs in the presence of VC-DCM were studied using Daunorubicin (DNR) accumulation assay and SRB assay, respectively. Cytotoxicity assay revealed that the enriched fraction of VC (VC-DCM) possessed dose-dependent cytotoxic effects in human epithelial cancer cells (HeLa, A549, MCF-7, and Caco-2). Further, treatment of cancer cells (HeLa, A549, MCF-7, and Caco-2) with VC-DCM led to a significant increase in both early and late apoptosis, indicating the induction of apoptosis. Interestingly, VC-DCM significantly inhibited functional activity of MDR transporters (ABC-B1 and ABC-G2), enhanced DNR-uptake in cancer cells, and sensitized cancer cells towards chemotherapeutic drug-mediated cytotoxicity, thus indicating the ability of VC-DCM to reverse MDR in cancer and enhance the cytotoxic effects of anticancer drugs. A methodological investigation on the anti-cancer properties of Vernonia cinerea Less. (VC) revealed that an enriched fraction of VC (VC-DCM) possessed cytotoxic

Brand-name drug, generic drug, orphan drug. Pharmacological therapy with biosimilar drugs - provision of due diligence in the treatment process.

PubMed

Zajdel, Justyna; Zajdel, Radosław

2013-01-01

Due diligence in the process of provision of healthcare services refers, among other elements, to the application of pharmacological therapy at a time which offers the greatest chance for a successful outcome of treatment, i.e. for achieving the optimum expected effect understood as an improvement in the patient's health, reduction of health risks or elimination of the disease. However, due diligence may also refer to actions aimed at ensuring that neither the patient nor the healthcare payer is required to incur unreasonable costs in the process of treatment. The validity of that statement stems not only from normative acts but also from ethical standards laid down in the Medical Code of Ethics (Article 57 section 2). It often happens that the provision of optimal treatment calls for deviations from the formal provisions included in Summary Product Characteristics (SPCs), and the application of drugs that are bioequivalent to reference drugs, which translates into a significant reduction of costs. The present study addresses the problem of acceptability of a specific form of drug substitution consisting in the replacement of a reference drug with a generic drug. Also explored are legal aspects associated with the possibility of therapy based on "off-label use". The study reviews normative acts existing in the Polish and EU legislation. It also provides a clear definition of orphan drug, which has made it possible to make a distinction and investigate mutual relations between the concepts of brand-name (reference) drug, orphan drug and generic drug.

Chirality Influence of Zaltoprofen Towards UDP-Glucuronosyltransferases (UGTs) Inhibition Potential.

PubMed

Jia, Lin; Hu, Cuimin; Wang, Haina; Liu, Yongzhe; Liu, Xin; Zhang, Yan-Yan; Li, Wei; Wang, Li-Xuan; Cao, Yun-Feng; Fang, Zhong-Ze

2015-06-01

Zaltoprofen (ZLT) is a nonsteroidal antiinflammation drug, and has been clinically employed to treat rheumatoid arthritis, osteoarthritis, and other chronic inflammatory pain conditions. The present study aims to investigate the chirality influence of zaltoprofen towards the inhibition potential towards UDP-glucuronosyltransferases (UGTs) isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation system was employed to investigate the inhibition of (R)-zaltoprofen and (S)-zaltoprofen towards UGT isoforms. The inhibition difference capability was observed for the inhibition of (R)-zaltoprofen and (S)-zaltoprofen towards UGT1A8 and UGT2B7, but not for other tested UGT isoforms. (R)-zaltoprofen exhibited noncompetitive inhibition towards UGT1A8 and competitive inhibition towards UGT2B7. The inhibition kinetic parameters were calculated to be 35.3 μM and 19.2 μM for UGT1A8 and UGT2B7. (R)-zaltoprofen and (S)-zaltoprofen exhibited a different inhibition type towards UGT1A7. Based on the reported maximum plasma concentration of (R)-zaltoprofen in vivo, a high drug-drug interaction between (R)-zaltoprofen and the drugs mainly undergoing UGT1A7, UGT1A8, and UGT2B7-catalyzed glucuronidation was indicated. © 2015 Wiley Periodicals, Inc.

Liver proteomics for therapeutic drug discovery: inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure

PubMed Central

Dear, James W.; Leelahavanichkul, Asada; Aponte, Angel; Hu, Xuzhen; Constant, Stephanie L.; Hewitt, Stephen M.; Yuen, Peter S.T.; Star, Robert A.

2008-01-01

Objective Sepsis-induced multi-organ failure continues to have a high mortality. The liver is an organ central to the disease pathogenesis. The objective of this study was to identify the liver proteins that change in abundance with sepsis and, therefore, identify new drug targets. Design Proteomic discovery study and drug target validation Setting Research institute laboratory Subjects Three month old C57BL/6 mice Interventions We used a mouse model of sepsis based on cecal ligation and puncture (CLP) but with fluid and antibiotic resuscitation. Liver proteins that changed in abundance were identified by difference in-gel electrophoresis (DIGE). We compared liver proteins from 6 hr post-CLP to sham-operated mice (‘early proteins’) and 24 hr post-CLP with 6 hr post-CLP (‘late proteins’). Proteins that changed in abundance were identified by tandem mass spectrometry. We then inhibited the receptor for one protein and determined the effect on sepsis-induced organ dysfunction. Results The liver proteins that changed in abundance after sepsis had a range of functions such as acute phase proteins, coagulation, ER stress, oxidative stress, apoptosis, mitochondrial proteins and nitric oxide metabolism. We found that cyclophilin increased in abundance after CLP. When the receptor for this protein, CD147, was inhibited sepsis-induced renal dysfunction was reduced. There was also a significant reduction in serum cytokine production when CD147 was inhibited. Conclusion By applying proteomics to a clinically relevant mouse model of sepsis we identified a number of novel proteins that changed in abundance. The inhibition of the receptor for one of these proteins, cyclophilin, attenuated sepsis-induced acute renal failure. The application of proteomics to sepsis research can facilitate the discovery of new therapeutic targets. PMID:17944020

Dual-targeting Wnt and uPA receptors using peptide conjugated ultra-small nanoparticle drug carriers inhibited cancer stem-cell phenotype in chemo-resistant breast cancer.

PubMed

Miller-Kleinhenz, Jasmine; Guo, Xiangxue; Qian, Weiping; Zhou, Hongyu; Bozeman, Erica N; Zhu, Lei; Ji, Xin; Wang, Y Andrew; Styblo, Toncred; O'Regan, Ruth; Mao, Hui; Yang, Lily

2018-01-01

Heterogeneous tumor cells, high incidence of tumor recurrence, and decrease in overall survival are the major challenges for the treatment of chemo-resistant breast cancer. Results of our study showed differential chemotherapeutic responses among breast cancer patient derived xenograft (PDX) tumors established from the same patients. All doxorubicin (Dox)-resistant tumors expressed higher levels of cancer stem-like cell biomarkers, including CD44, Wnt and its receptor LRP5/6, relative to Dox-sensitive tumors. To effectively treat resistant tumors, we developed an ultra-small magnetic iron oxide nanoparticle (IONP) drug carrier conjugated with peptides that are dually targeted to Wnt/LRP5/6 and urokinase plasminogen activator receptor (uPAR). Our results showed that simultaneous binding to LRP5/6 and uPAR by the dual receptor targeted IONPs was required to inhibit breast cancer cell invasion. Molecular analysis revealed that the dual receptor targeted IONPs significantly inhibited Wnt/β-catenin signaling and cancer stem-like phenotype of tumor cells, with marked reduction of Wnt ligand, CD44 and uPAR. Systemic administration of the dual targeted IONPs led to nanoparticle-drug delivery into PDX tumors, resulting in stronger tumor growth inhibition compared to non-targeted or single-targeted IONP-Dox in a human breast cancer PDX model. Therefore, co-targeting Wnt/LRP and uPAR using IONP drug carriers is a promising therapeutic approach for effective drug delivery to chemo-resistant breast cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Supporting parent-child interactions: music therapy as an intervention for promoting mutually responsive orientation.

PubMed

Pasiali, Varvara

2012-01-01

Music therapists working with families address relationship and interpersonal communication issues. Few controlled studies exist in the literature but a growing body of documented practice is emerging. This study makes a contribution by documenting how music therapy supports mutuality and reciprocity in parent-child interactions. This study investigated mutually responsive orientation (MRO) behaviors of young children (aged 3-5) and their family members during music therapy. Participants were 4 families with low income and history of maternal depression as common risk factors. Data were collected by videotaping sessions, creating field notes and analytic memos, conducting parent interviews and reviewing parent journals. A cross-case analysis using MRO theory as a conceptualizing framework was used for the purpose of data reduction. Greeting and farewell rituals, and the flexibility of music-based therapeutic applications facilitated development of coordinated routines. Therapist's actions (e.g., encouraging and modeling musical interactions) and bidirectional parent-child actions (e.g., joint attention, turn-taking, being playful) facilitated harmonious communication. Behaviors promoting mutual cooperation were evident when adults attempted to scaffold a child's participation or when children sought comfort from parents, engaged in social referencing and made requests that shaped the direction of the session. The novelty of musical tasks captivated attention, increasing impulse inhibition. Parent actions (e.g., finding delight in watching their child participate, acting silly) and parent-child interactions (e.g., play exploration, shared excitement, cuddling) contributed to positive emotional ambiance. Music therapy assisted development of MRO within parent-child dyads by providing opportunities to rehearse adaptive ways of connecting with each other. Results of this study may serve as an archetypal model guiding clinical treatment planning.

Graph-state formalism for mutually unbiased bases

NASA Astrophysics Data System (ADS)

Spengler, Christoph; Kraus, Barbara

2013-11-01

A pair of orthonormal bases is called mutually unbiased if all mutual overlaps between any element of one basis and an arbitrary element of the other basis coincide. In case the dimension, d, of the considered Hilbert space is a power of a prime number, complete sets of d+1 mutually unbiased bases (MUBs) exist. Here we present a method based on the graph-state formalism to construct such sets of MUBs. We show that for n p-level systems, with p being prime, one particular graph suffices to easily construct a set of pn+1 MUBs. In fact, we show that a single n-dimensional vector, which is associated with this graph, can be used to generate a complete set of MUBs and demonstrate that this vector can be easily determined. Finally, we discuss some advantages of our formalism regarding the analysis of entanglement structures in MUBs, as well as experimental realizations.

Multiparty quantum mutual information: An alternative definition

NASA Astrophysics Data System (ADS)

Kumar, Asutosh

2017-07-01

Mutual information is the reciprocal information that is common to or shared by two or more parties. Quantum mutual information for bipartite quantum systems is non-negative, and bears the interpretation of total correlation between the two subsystems. This may, however, no longer be true for three or more party quantum systems. In this paper, we propose an alternative definition of multipartite information, taking into account the shared information between two and more parties. It is non-negative, observes monotonicity under partial trace as well as completely positive maps, and equals the multipartite information measure in literature for pure states. We then define multiparty quantum discord, and give some examples. Interestingly, we observe that quantum discord increases when a measurement is performed on a large number of subsystems. Consequently, the symmetric quantum discord, which involves a measurement on all parties, reveals the maximal quantumness. This raises a question on the interpretation of measured mutual information as a classical correlation.

A drug-like antagonist inhibits thyrotropin receptor-mediated stimulation of cAMP production in Graves' orbital fibroblasts.

PubMed

Neumann, Susanne; Pope, Arthur; Geras-Raaka, Elizabeth; Raaka, Bruce M; Bahn, Rebecca S; Gershengorn, Marvin C

2012-08-01

Fibroblasts (FIBs) within the retro-orbital space of patients with Graves' disease (GOFs) express thyrotropin receptors (TSHRs) and are thought to be an orbital target of TSHR-stimulating autoantibodies in Graves' ophthalmopathy (GO). Recently, we developed a low molecular weight, drug-like TSHR antagonist (NCGC00229600) that inhibited TSHR activation in a model cell system overexpressing TSHRs and in normal human thyrocytes expressing endogenous TSHRs. Herein, we test the hypothesis that NCGC00229600 will inhibit activation of TSHRs endogenously expressed in GOFs. Three strains of GOFs, previously obtained from patients with GO, were studied as undifferentiated FIBs and after differentiation into adipocytes (ADIPs), and another seven strains were studied only as FIBs. ADIP differentiation was monitored by morphology and measurement of adiponectin mRNA. FIBs and ADIPs were treated with the TSH- or TSHR-stimulating antibody M22 in the absence or presence of NCGC00229600 and TSHR activation was monitored by cAMP production. FIBs contained few if any lipid vesicles and undetectable levels of adiponectin mRNA, whereas ADIPs exhibited abundant lipid vesicles and levels of adiponectin mRNA more than 250,000 times greater than FIBs; TSHR mRNA levels were 10-fold higher in ADIPs than FIBs. FIBs exhibited higher absolute levels of basal and forskolin-stimulated cAMP production than ADIPs. Consistent with previous findings, TSH stimulated cAMP production in the majority of ADIP strains and less consistently in FIBs. Most importantly, NCGC00229600 reduced both TSH- and M22-stimulated cAMP production in GOFs. These data confirm previous findings that TSHR activation may cause increased cAMP production in GOFs and show that NCGC00229600 can inhibit TSHR activation in GOFs. These findings suggest that drug-like TSHR antagonists may have a role in treatment of GO.

Cyclosporine-inhibitable Cerebral Drug Transport Does not Influence Clinical Methadone Pharmacodynamics

PubMed Central

Meissner, Konrad; Blood, Jane; Francis, Amber M.; Yermolenka, Viktar; Kharasch, Evan D.

2015-01-01

Background Interindividual variability and drug interaction studies suggest that blood-brain barrier drug transporters mediate human methadone brain biodistribution. In vitro and animal studies suggest that methadone is a substrate for the efflux transporter P-glycoprotein, and that P-glycoprotein-mediated transport influences brain access and pharmacologic effect. This investigation tested whether methadone is a transporter substrate in humans. Methods Healthy volunteers received oral (N=16) or IV (N=12) methadone in different crossover protocols after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (4.5 mg/kg orally twice daily for 4 days, or 5 mg/kg IV over 2 hr). Plasma and urine methadone and metabolite concentrations were measured by mass spectrometry. Methadone effects were measured by miosis and thermal analgesia (maximally tolerated temperature and verbal analog scale rating of discreet temperatures). Results Cyclosporine marginally but significantly decreased methadone plasma concentrations and apparent oral clearance, but had no effect on methadone renal clearance or on hepatic N-demethylation. Cyclosporine had no effect on miosis, or on R-methadone concentration-miosis relationships after either oral or IV methadone. Peak miosis was similar in controls and cyclosporine-treated subjects after oral methadone (1.4 ± 0.4 and 1.3 ± 0.5 mm/mg, respectively) and IV methadone (3.1 ± 1.0 and 3.2 ± 0.8 mm respectively). Methadone increased maximally tolerated temperature, but analgesia testing was confounded by cyclosporine-related pain. Conclusions Cyclosporine did not affect methadone pharmacodynamics. This result does not support a role for cyclosporine-inhibitable transporters mediating methadone brain access and biodistribution. PMID:25072223

Identifying kinase dependency in cancer cells by integrating high-throughput drug screening and kinase inhibition data.

PubMed

Ryall, Karen A; Shin, Jimin; Yoo, Minjae; Hinz, Trista K; Kim, Jihye; Kang, Jaewoo; Heasley, Lynn E; Tan, Aik Choon

2015-12-01

Targeted kinase inhibitors have dramatically improved cancer treatment, but kinase dependency for an individual patient or cancer cell can be challenging to predict. Kinase dependency does not always correspond with gene expression and mutation status. High-throughput drug screens are powerful tools for determining kinase dependency, but drug polypharmacology can make results difficult to interpret. We developed Kinase Addiction Ranker (KAR), an algorithm that integrates high-throughput drug screening data, comprehensive kinase inhibition data and gene expression profiles to identify kinase dependency in cancer cells. We applied KAR to predict kinase dependency of 21 lung cancer cell lines and 151 leukemia patient samples using published datasets. We experimentally validated KAR predictions of FGFR and MTOR dependence in lung cancer cell line H1581, showing synergistic reduction in proliferation after combining ponatinib and AZD8055. KAR can be downloaded as a Python function or a MATLAB script along with example inputs and outputs at: http://tanlab.ucdenver.edu/KAR/. aikchoon.tan@ucdenver.edu. Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Mutually Exclusive, Complementary, or . . .

ERIC Educational Resources Information Center

Schloemer, Cathy G.

2016-01-01

Whether students are beginning their study of probability or are well into it, distinctions between complementary sets and mutually exclusive sets can be confusing. Cathy Schloemer writes in this article that for years she used typical classroom examples but was not happy with the student engagement or the level of understanding they produced.…

Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey.

PubMed

Kosa, Rachel E; Lazzaro, Sarah; Bi, Yi-An; Tierney, Brendan; Gates, Dana; Modi, Sweta; Costales, Chester; Rodrigues, A David; Tremaine, Larry M; Varma, Manthena V

2018-06-07

We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion transporting polypeptide (OATP)1B, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp) and organic anion transporter (OAT)3. Pharmacokinetics of substrate cocktail consisting of pitavastatin (OATP1B substrate), rosuvastatin (OATP1B/BCRP/OAT3), sulfasalazine (BCRP) and talinolol (P-gp) were obtained in cynomolgus monkey - alone or in combination with transporter inhibitors. Single dose rifampicin (30 mg/kg) significantly (p<0.01) increased the plasma exposure of all four drugs, with a marked effect on pitavastatin and rosuvastatin (AUC ratio ~21-39). Elacridar, BCRP/P-gp inhibitor, increased the AUC of sulfasalazine, talinolol, as well as rosuvastatin and pitavastatin. An OAT1/3 inhibitor (probenecid) significantly (p<0.05) impacted the renal clearance of rosuvastatin (~8-fold). In vitro, rifampicin (10μM) inhibited uptake of pitavastatin, rosuvastatin and sulfasalazine by monkey and human primary hepatocytes. Transport studies using membrane vesicles suggested that all probe substrates, except talinolol, are transported by cynoBCRP; while talinolol is a cynoP-gp substrate. Elacridar and rifampicin inhibited both cynoBCRP and cynoP-gp in vitro, indicating potential for in vivo intestinal efflux inhibition. In conclusion, a probe substrate cocktail was validated to simultaneously evaluate perpetrator impact on multiple clinically relevant transporters using the cynomolgus monkey. The results support the use of the cynomolgus monkey as a model that could enable drug-drug interaction risk assessment, before advancing a new molecular entity into clinical development, as well as providing mechanistic insights on transporter-mediated interactions. The American Society for Pharmacology and Experimental Therapeutics.

Lichen acids may be used as a potential drug for cancer therapy; by inhibiting mitochondrial thioredoxin reductase purified from rat lung.

PubMed

Ozgencli, Ilknur; Budak, Harun; Ciftci, Mehmet; Anar, Mustafa

2018-05-24

Thioredoxin reductase (E.C 1.6.4.5.; TrxR) is a widely distributed flavoprotein that catalyzes the NADPH-dependent reduction of thioredoxin (Trx) in many cellular events such as DNA synthesis, DNA repair, angiogenesis, antioxidative defense, and regulating apoptosis. Although TrxR is indispensible in protecting cells against oxidative stress, the overexpression of TrxR is seen in many aggressive tumors. Therefore, targeted inhibition of TrxR has been accepted as a new approach for chemotherapy. In this study, in vitro inhibition effect of the lichen acids (diffractaic, evernic, lobaric, lecanoric, and vulpinic acid) on mitochondrial TrxR purified from rat lung was investigated. It was the first time the enzyme was purified from rat lungs by using 2', 5'-ADP Sepharose 4B affinity chromatography. The purity of the enzyme was checked with SDS-PAGE. In vitro inhibition effect of the lichen acids was investigated spectrophotometrically. To emphasize the importance of the obtained data, the commercial anticancer drugs cisplatin and doxorubicin were used as positive controls. Molecular mass of the enzyme was calculated as approximately 52.4 kDa. The enzyme was purified with a 63.6% yield, 208.3 fold, and 0.5 EU/mg proteins specific activity. The IC50 values of five lichen acids were significantly lower than IC50 values of anticancer drugs. All of the lichen acids, especially lecanoric and vulpinic acid, exhibited much stronger inhibitory effect on TrxR than the anticancer drugs cisplatin and doxorubicin. These lichen acids have pharmacological potential as effective natural antioxidants, antimicrobials, and anticancer agents. . Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Assessment of mutual understanding of physician patient encounters: development and validation of a Mutual Understanding Scale (MUS) in a multicultural general practice setting.

PubMed

Harmsen, J A M; Bernsen, R M D; Meeuwesen, L; Pinto, D; Bruijnzeels, M A

2005-11-01

Mutual understanding between physician and patient is essential for good quality of care; however, both parties have different views on health complaints and treatment. This study aimed to develop and validate a measure of mutual understanding (MU) in a multicultural setting. The study included 986 patients from 38 general practices. GPs completed a questionnaire and patients were interviewed after the consultation. To assess mutual understanding the answers from GP and patient to questions about different consultation aspects were compared. An expert panel, using nominal group technique, developed criteria for mutual understanding on consultation aspects and secondly, established a ranking to combine all aspects into an overall consultation judgement. Regarding construct validity, patients' ethnicity, age and language proficiency were the most important predictors for MU. Regarding criterion validity, all GP-related criteria (the GPs perception of his ability to explain to the patient, the patient's ability to explain to the GP, and the patient's understanding of consultation aspects), were well-related to MU. The same can be said of patient's consultation satisfaction and feeling that the GP was considerate. We conclude that the Mutual Understanding Scale is regarded a reliable and valid measure to be used in large-scale quantitative studies.

Overexpression of uncoupling protein-2 in cancer: metabolic and heat changes, inhibition and effects on drug resistance.

PubMed

Pitt, Michael A

2015-12-01

This paper deals with the role of uncoupling protein-2 (UCP2) in cancer. UCP2 is overexpressed in cancer. This overexpression results in uncoupling of mitochondrial oxidative phosphorylation and a shift in production of ATP from mitochondrial oxidative phosphorylation to cytosolic aerobic glycolysis. UCP2 overexpression results in the following changes. Mitochondrial membrane potential (Δψ(m)) is decreased and lactate accumulates. There is a diminished production of reactive oxygen species and apoptosis is inhibited post-exposure to chemotherapeutic agents. There is an increase in heat and entropy production and a departure from the stationary state of non-cancerous tissue. Uncoupling of oxidative phosphorylation may also be caused by protonophores and non-steroidal anti-inflammatory drugs. UCP2 requires activation by superoxide and lipid peroxidation derivatives. As vitamin E inhibits lipid peroxidation, it might be expected that vitamin E would act as a chemotherapeutic agent against cancer. A recent study has shown that vitamin E and another anti-oxidant accelerate cancer progression. UCP2 is inhibited by genipin, chromane compounds and short interfering RNAs (siRNA). Genipin, chromanes and siRNA are taken up by both cancer and non-cancerous cells. Targeting the uptake of these agents by cancer cells by the enhanced permeability and retention effect is considered. Inhibition of UCP2 enhances the action of several anti-cancer agents.

Oleamide derivatives are prototypical anti-metastasis drugs that act by inhibiting Connexin 26.

PubMed

Nojima, Hiroshi; Ohba, Yusuke; Kita, Yasuyuki

2007-09-01

Despite considerable research, metastasis remains a major challenge in the clinical management of cancer. Recent reports show that abnormally augmented expression of Cx26 is responsible for the enhanced spontaneous metastasis of mouse BL6 melanoma cells. The function of Cx26 appears to be responsible for this phenotype since exogenous expression of a dominant-negative form of Cx26 and oleamide derivatives called MI-18 and MI-22 that specifically inhibit Cx26-mediated gap junction-mediated intercellular communications (GJIC) prevent the spontaneous metastasis of BL6 cells. As expected from their structural similarity to oleic acid (the major component of olive oil), both MI-18 and MI-22 are safe drugs; nonetheless, they are potent inhibitors of the spontaneous metastasis of BL6 mouse melanoma cells. Thus, they are a novel prototype of an anti-metastasis drug that has minimal side effects. While the primary tumors do not necessarily show strong Cx26-immunostaining signals, pronounced Cx26 expression is detected in the highly invasive tumor regions; it is also more frequently observed in metastasized tumors. Thus, Cx26 expression may be useful as a prognostic tool that can predict the existence of highly metastatic cancer cells in clinical samples.

Brand-name drug, generic drug, orphan drug. Pharmacological therapy with biosimilar drugs – provision of due diligence in the treatment process

PubMed Central

Zajdel, Justyna

2013-01-01

Due diligence in the process of provision of healthcare services refers, among other elements, to the application of pharmacological therapy at a time which offers the greatest chance for a successful outcome of treatment, i.e. for achieving the optimum expected effect understood as an improvement in the patient's health, reduction of health risks or elimination of the disease. However, due diligence may also refer to actions aimed at ensuring that neither the patient nor the healthcare payer is required to incur unreasonable costs in the process of treatment. The validity of that statement stems not only from normative acts but also from ethical standards laid down in the Medical Code of Ethics (Article 57 section 2). It often happens that the provision of optimal treatment calls for deviations from the formal provisions included in Summary Product Characteristics (SPCs), and the application of drugs that are bioequivalent to reference drugs, which translates into a significant reduction of costs. The present study addresses the problem of acceptability of a specific form of drug substitution consisting in the replacement of a reference drug with a generic drug. Also explored are legal aspects associated with the possibility of therapy based on “off-label use”. The study reviews normative acts existing in the Polish and EU legislation. It also provides a clear definition of orphan drug, which has made it possible to make a distinction and investigate mutual relations between the concepts of brand-name (reference) drug, orphan drug and generic drug. PMID:24592133

Entropic uncertainty relations and locking: Tight bounds for mutually unbiased bases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ballester, Manuel A.; Wehner, Stephanie

We prove tight entropic uncertainty relations for a large number of mutually unbiased measurements. In particular, we show that a bound derived from the result by Maassen and Uffink [Phys. Rev. Lett. 60, 1103 (1988)] for two such measurements can in fact be tight for up to {radical}(d) measurements in mutually unbiased bases. We then show that using more mutually unbiased bases does not always lead to a better locking effect. We prove that the optimal bound for the accessible information using up to {radical}(d) specific mutually unbiased bases is log d/2, which is the same as can be achievedmore » by using only two bases. Our result indicates that merely using mutually unbiased bases is not sufficient to achieve a strong locking effect and we need to look for additional properties.« less

Organotypic three-dimensional cancer cell cultures mirror drug responses in vivo: lessons learned from the inhibition of EGFR signaling

PubMed Central

Jacobi, Nico; Seeboeck, Rita; Hofmann, Elisabeth; Schweiger, Helmut; Smolinska, Veronika; Mohr, Thomas; Boyer, Alexandra; Sommergruber, Wolfgang; Lechner, Peter; Pichler-Huebschmann, Corina; Önder, Kamil; Hundsberger, Harald; Wiesner, Christoph; Eger, Andreas

2017-01-01

Complex three-dimensional (3D) in vitro models that recapitulate human tumor biology are essential to understand the pathophysiology of the disease and to aid in the discovery of novel anti-cancer therapies. 3D organotypic cultures exhibit intercellular communication, nutrient and oxygen gradients, and cell polarity that is lacking in two-dimensional (2D) monolayer cultures. In the present study, we demonstrate that 2D and 3D cancer models exhibit different drug sensitivities towards both targeted inhibitors of EGFR signaling and broad acting cytotoxic agents. Changes in the kinase activities of ErbB family members and differential expression of apoptosis- and survival-associated genes before and after drug treatment may account for the differential drug sensitivities. Importantly, EGFR oncoprotein addiction was evident only in the 3D cultures mirroring the effect of EGFR inhibition in the clinic. Furthermore, targeted drug efficacy was strongly increased when incorporating cancer-associated fibroblasts into the 3D cultures. Taken together, we provide conclusive evidence that complex 3D cultures are more predictive of the clinical outcome than their 2D counterparts. In the future, 3D cultures will be instrumental for understanding the mode of action of drugs, identifying genotype-drug response relationships and developing patient-specific and personalized cancer treatments. PMID:29296175

Mutuality, Self-Silencing, and Disordered Eating in College Women

ERIC Educational Resources Information Center

Wechsler, Lisa S.; Riggs, Shelley A.; Stabb, Sally D.; Marshall, David M.

2006-01-01

The current study examined patterns of association among mutuality, self-silencing, and disordered eating in an ethnically diverse sample of college women (N = 149). Partner mutuality and overall self-silencing were negatively correlated and together were associated with six disordered eating indices. All four self-silencing subscales were…

Mutual Adaptaion in Action

ERIC Educational Resources Information Center

Siskin, Leslie Santee

2016-01-01

Building on an expanded concept of mutual adaptation, this chapter explores a distinctive and successful aspect of International Baccalaureate's effort to scale up, as they moved to expand their programs and support services in Title I schools. Based on a three-year, mixed-methods study, it offers a case where we see not only local adaptations…

The mutuality metaphor: understanding healthcare provision in NHS Scotland.

PubMed

Howieson, Brian

2016-06-20

Purpose - Better Health, Better Care Action Plan (Scottish Government, 2007) sets out how the Scottish Government intends to strengthen public ownership of the National Health Service in Scotland. The purpose of this paper is to advance extant knowledge by understanding how a state-led mutual health policy may be interpreted, and importantly, communicated. Design/methodology/approach - The definitional problem of mutuality will be discussed and analysed in terms of how it is (or perhaps should be) communicated? will be offered. Findings - It actually may be more instructive to think of, and communicate, mutuality as a metaphor to aid understanding of the openness and fluidity found in NHS Scotland. Research limitations/implications - The existence of paradox and ambiguity does not, however, negate the usefulness of the term "mutuality". Quite the opposite in fact: it is precisely by examining healthcare and its delivery through the lens of mutuality (rather than rejecting its complexity as a failure) that this amorphousness can be better appreciated. Practical implications - There is a need for more public, professional, and academic debate to explore and clarify its implementation, and how it is to be led. This must be provided whilst recognising the daily imperatives that NHS leaders must face. This would suggest, therefore, that a dual development path may help. Originality/value - Although Better Health, Better Care Action Plan was published in 2007, some eight years on there is still confusion and misunderstanding as to what mutuality in healthcare is, not only in policy and theory, but also in practice. It is hoped that this analysis will help address, in part, some of this confusion and misunderstanding.

Spatial Mutual Information Based Hyperspectral Band Selection for Classification

PubMed Central

2015-01-01

The amount of information involved in hyperspectral imaging is large. Hyperspectral band selection is a popular method for reducing dimensionality. Several information based measures such as mutual information have been proposed to reduce information redundancy among spectral bands. Unfortunately, mutual information does not take into account the spatial dependency between adjacent pixels in images thus reducing its robustness as a similarity measure. In this paper, we propose a new band selection method based on spatial mutual information. As validation criteria, a supervised classification method using support vector machine (SVM) is used. Experimental results of the classification of hyperspectral datasets show that the proposed method can achieve more accurate results. PMID:25918742

Mutually unbiased coarse-grained measurements of two or more phase-space variables

NASA Astrophysics Data System (ADS)

Paul, E. C.; Walborn, S. P.; Tasca, D. S.; Rudnicki, Łukasz

2018-05-01

Mutual unbiasedness of the eigenstates of phase-space operators—such as position and momentum, or their standard coarse-grained versions—exists only in the limiting case of infinite squeezing. In Phys. Rev. Lett. 120, 040403 (2018), 10.1103/PhysRevLett.120.040403, it was shown that mutual unbiasedness can be recovered for periodic coarse graining of these two operators. Here we investigate mutual unbiasedness of coarse-grained measurements for more than two phase-space variables. We show that mutual unbiasedness can be recovered between periodic coarse graining of any two nonparallel phase-space operators. We illustrate these results through optics experiments, using the fractional Fourier transform to prepare and measure mutually unbiased phase-space variables. The differences between two and three mutually unbiased measurements is discussed. Our results contribute to bridging the gap between continuous and discrete quantum mechanics, and they could be useful in quantum-information protocols.

Hardware device binding and mutual authentication

DOEpatents

Hamlet, Jason R; Pierson, Lyndon G

2014-03-04

Detection and deterrence of device tampering and subversion by substitution may be achieved by including a cryptographic unit within a computing device for binding multiple hardware devices and mutually authenticating the devices. The cryptographic unit includes a physically unclonable function ("PUF") circuit disposed in or on the hardware device, which generates a binding PUF value. The cryptographic unit uses the binding PUF value during an enrollment phase and subsequent authentication phases. During a subsequent authentication phase, the cryptographic unit uses the binding PUF values of the multiple hardware devices to generate a challenge to send to the other device, and to verify a challenge received from the other device to mutually authenticate the hardware devices.

Persistence of pollination mutualisms in the presence of ants.

PubMed

Wang, Yuanshi; Wang, Shikun

2015-01-01

This paper considers plant-pollinator-ant systems in which the plant-pollinator interaction is mutualistic but ants have both positive and negative effects on plants. The ants also interfere with pollinators by preventing them from accessing plants. While a Beddington-DeAngelis (BD) formula can describe the plant-pollinator interaction, the formula is extended in this paper to characterize the pollination mutualism under the ant interference. Then, a plant-pollinator-ant system with the extended BD functional response is discussed, and global dynamics of the model demonstrate the mechanisms by which pollination mutualism can persist in the presence of ants. When the ant interference is strong, it can result in extinction of pollinators. Moreover, if the ants depend on pollination mutualism for survival, the strong interference could drive pollinators into extinction, which consequently lead to extinction of the ants themselves. When the ant interference is weak, a cooperation between plant-ant and plant-pollinator mutualisms could occur, which promotes survival of both ants and pollinators, especially in the case that ants (respectively, pollinators) cannot survive in the absence of pollinators (respectively, ants). Even when the level of ant interference remains invariant, varying ants' negative effect on plants can result in survival/extinction of both ants and pollinators. Therefore, our results provide an explanation for the persistence of pollination mutualism when there exist ants.

Inhibition of crystal nucleation and growth by water-soluble polymers and its impact on the supersaturation profiles of amorphous drugs.

PubMed

Ozaki, Shunsuke; Kushida, Ikuo; Yamashita, Taro; Hasebe, Takashi; Shirai, Osamu; Kano, Kenji

2013-07-01

The impact of water-soluble polymers on drug supersaturation behavior was investigated to elucidate the role of water-soluble polymers in enhancing the supersaturation levels of amorphous pharmaceuticals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and Eudragit L-100 (Eudragit) were used as representative polymers, and griseofulvin and danazol were used as model drugs. Supersaturation profiles of amorphous drugs were measured in biorelevant dissolution tests. Crystal growth rate was measured from the decrease in dissolved drug concentration in the presence of seed crystals. Nucleation kinetics was evaluated by measuring the induction time for nucleation. All experiments were performed in the presence and absence of polymers. The degree of supersaturation of the amorphous model drugs increased with an increase in the inhibitory efficiency of polymers against crystal nucleation and growth (HPMC > PVP > Eudragit). In the presence of HPMC, the addition of seed crystals diminished the supersaturation ratio dramatically for griseofulvin and moderately for danazol. The results demonstrated that the polymers contributed to drug supersaturation by inhibiting both nucleation and growth. The effect of the polymers was drug dependent. The detailed characterization of polymers would allow selection of appropriate crystallization inhibitors and a planned quality control strategy for the development of supersaturable formulations. Copyright © 2013 Wiley Periodicals, Inc.

Nonrigid mammogram registration using mutual information

NASA Astrophysics Data System (ADS)

Wirth, Michael A.; Narhan, Jay; Gray, Derek W. S.

2002-05-01

Of the papers dealing with the task of mammogram registration, the majority deal with the task by matching corresponding control-points derived from anatomical landmark points. One of the caveats encountered when using pure point-matching techniques is their reliance on accurately extracted anatomical features-points. This paper proposes an innovative approach to matching mammograms which combines the use of a similarity-measure and a point-based spatial transformation. Mutual information is a cost-function used to determine the degree of similarity between the two mammograms. An initial rigid registration is performed to remove global differences and bring the mammograms into approximate alignment. The mammograms are then subdivided into smaller regions and each of the corresponding subimages is matched independently using mutual information. The centroids of each of the matched subimages are then used as corresponding control-point pairs in association with the Thin-Plate Spline radial basis function. The resulting spatial transformation generates a nonrigid match of the mammograms. The technique is illustrated by matching mammograms from the MIAS mammogram database. An experimental comparison is made between mutual information incorporating purely rigid behavior, and that incorporating a more nonrigid behavior. The effectiveness of the registration process is evaluated using image differences.

Natural products inhibiting the ubiquitin-proteasome proteolytic pathway, a target for drug development.

PubMed

Tsukamoto, Sachiko; Yokosawa, Hideyoshi

2006-01-01

The ubiquitin-proteasome proteolytic pathway plays a major role in selective protein degradation and regulates various cellular events including cell cycle progression, transcription, DNA repair, signal transduction, and immune response. Ubiquitin, a highly conserved small protein in eukaryotes, attaches to a target protein prior to degradation. The polyubiquitin chain tagged to the target protein is recognized by the 26S proteasome, a high-molecular-mass protease subunit complex, and the protein portion is degraded by the 26S proteasome. The potential of specific proteasome inhibitors, which act as anti-cancer agents, is now under intensive investigation, and bortezomib (PS-341), a proteasome inhibitor, has been recently approved by FDA for multiple myeloma treatment. Since ubiquitination of proteins requires the sequential action of three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), and polyubiquitination is a prerequisite for proteasome-mediated protein degradation, inhibitors of E1, E2, and E3 are reasonably thought to be drug candidates for treatment of diseases related to ubiquitination. Recently, various compounds inhibiting the ubiquitin-proteasome pathway have been isolated from natural resources. We also succeeded in isolating inhibitors against the proteasome and E1 enzyme from marine natural resources. In this review, we summarize the structures and biological activities of natural products that inhibit the ubiquitin-proteasome proteolytic pathway.

Antagonisms, mutualisms and commensalisms affect outbreak dynamics of the southern pine beetle

Treesearch

Richard W. Hofstetter; James T. Cronin; Kier D. Klepzig; John C. Moser; Matthew P. Ayres

2005-01-01

Feedback from community interactions involving mutualisms are a rarely explored mechanism for generating complex population dynamics. We examined the effects of two linked mutualisms on the population dynamics of a beetle that exhibits outbreak dynamics. One mutualism involves an obligate association between the bark beetle, Dendroctonus frontalis...

[Pharmaco-economics: a point of view of the mutualities].

PubMed

Legrand, D; Simon, I

1998-05-01

In Belgium, the mutualities are responsible for their budgets. They are playing an important role in drug pricing and reimbursement procedures. This document aims at explaining our line of arguments for a critical evaluation and the place for a pharmacoeconomic evaluation in the Belgian social security system. The available economic data for each molecule or pathology are essential but insufficient. Economic evaluations could help to reveal the costs and benefits of different uses of medical therapies and could thereby enhance the resources allocation in a health care system. But this science is still in its infancy, and in practice, the methodological quality of this kind of study is often weak. Furthermore it is not easy to transfer those evaluations to the Belgian reimburse systems. The clinical efficacy and the transparency is price setting should remain the two most important criterions to build reimbursement rules in order to ensure right price, rational use of medicine and accessibility for all.

Parental substance abuse and function of the motivation and behavioral inhibition systems in drug-naïve youth.

PubMed

Ivanov, Iliyan; Liu, Xun; Shulz, Kurt; Fan, Jin; London, Edythe; Friston, Karl; Halperin, Jeffrey M; Newcorn, Jeffrey H

2012-02-28

It is hypothesized that the development of substance abuse (SA) may be due to imbalance in functions of the motivation-reward and behavioral inhibition systems in the brain. This speaks to the search for biological risk factors for SA in drug-naïve children who also exhibit motivational and inhibitory control deficits; however, this type of research is currently lacking. The objective of this study was to establish a neurobiological basis for addiction vulnerability using functional magnetic resonance imaging (fMRI) in drug-naïve youth with attention deficit/hyperactivity disorder (ADHD). We hypothesized that children with ADHD alone would show higher activity in regions of the motivation-reward and behavioral inhibition systems than children with ADHD and a parental history of SA. Toward this goal we scanned 20 drug-naïve children with ADHD ages 8-13 while performing an event-related reward task. High (N=10) and low (N=10) risk subjects were identified, based on parental history of SA. The effects of anticipation, conflict, and reward were assessed with appropriate linear contrasts, and between-group differences were assessed using statistical parametric mapping. The two groups did not differ on behavioral measures of the task. The fMRI results show heightened activation in the brain motivational-reward system and reduced activation of the inhibitory control system in high-risk compared to low-risk children. These results suggest that a functional mismatch between these two systems may represent one possible biological underpinning of SA risk, which is conferred by a parental history of addiction. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Population dynamics and mutualism: Functional responses of benefits and costs

USGS Publications Warehouse

Holland, J. Nathaniel; DeAngelis, Donald L.; Bronstein, Judith L.

2002-01-01

We develop an approach for studying population dynamics resulting from mutualism by employing functional responses based on density‐dependent benefits and costs. These functional responses express how the population growth rate of a mutualist is modified by the density of its partner. We present several possible dependencies of gross benefits and costs, and hence net effects, to a mutualist as functions of the density of its partner. Net effects to mutualists are likely a monotonically saturating or unimodal function of the density of their partner. We show that fundamental differences in the growth, limitation, and dynamics of a population can occur when net effects to that population change linearly, unimodally, or in a saturating fashion. We use the mutualism between senita cactus and its pollinating seed‐eating moth as an example to show the influence of different benefit and cost functional responses on population dynamics and stability of mutualisms. We investigated two mechanisms that may alter this mutualism's functional responses: distribution of eggs among flowers and fruit abortion. Differences in how benefits and costs vary with density can alter the stability of this mutualism. In particular, fruit abortion may allow for a stable equilibrium where none could otherwise exist.

Rényi generalizations of the conditional quantum mutual information

NASA Astrophysics Data System (ADS)

Berta, Mario; Seshadreesan, Kaushik P.; Wilde, Mark M.

2015-02-01

The conditional quantum mutual information I(A; B|C) of a tripartite state ρABC is an information quantity which lies at the center of many problems in quantum information theory. Three of its main properties are that it is non-negative for any tripartite state, that it decreases under local operations applied to systems A and B, and that it obeys the duality relation I(A; B|C) = I(A; B|D) for a four-party pure state on systems ABCD. The conditional mutual information also underlies the squashed entanglement, an entanglement measure that satisfies all of the axioms desired for an entanglement measure. As such, it has been an open question to find Rényi generalizations of the conditional mutual information, that would allow for a deeper understanding of the original quantity and find applications beyond the traditional memoryless setting of quantum information theory. The present paper addresses this question, by defining different α-Rényi generalizations Iα(A; B|C) of the conditional mutual information, some of which we can prove converge to the conditional mutual information in the limit α → 1. Furthermore, we prove that many of these generalizations satisfy non-negativity, duality, and monotonicity with respect to local operations on one of the systems A or B (with it being left as an open question to prove that monotonicity holds with respect to local operations on both systems). The quantities defined here should find applications in quantum information theory and perhaps even in other areas of physics, but we leave this for future work. We also state a conjecture regarding the monotonicity of the Rényi conditional mutual informations defined here with respect to the Rényi parameter α. We prove that this conjecture is true in some special cases and when α is in a neighborhood of one.

A multivariate extension of mutual information for growing neural networks.

PubMed

Ball, Kenneth R; Grant, Christopher; Mundy, William R; Shafer, Timothy J

2017-11-01

Recordings of neural network activity in vitro are increasingly being used to assess the development of neural network activity and the effects of drugs, chemicals and disease states on neural network function. The high-content nature of the data derived from such recordings can be used to infer effects of compounds or disease states on a variety of important neural functions, including network synchrony. Historically, synchrony of networks in vitro has been assessed either by determination of correlation coefficients (e.g. Pearson's correlation), by statistics estimated from cross-correlation histograms between pairs of active electrodes, and/or by pairwise mutual information and related measures. The present study examines the application of Normalized Multiinformation (NMI) as a scalar measure of shared information content in a multivariate network that is robust with respect to changes in network size. Theoretical simulations are designed to investigate NMI as a measure of complexity and synchrony in a developing network relative to several alternative approaches. The NMI approach is applied to these simulations and also to data collected during exposure of in vitro neural networks to neuroactive compounds during the first 12 days in vitro, and compared to other common measures, including correlation coefficients and mean firing rates of neurons. NMI is shown to be more sensitive to developmental effects than first order synchronous and nonsynchronous measures of network complexity. Finally, NMI is a scalar measure of global (rather than pairwise) mutual information in a multivariate network, and hence relies on less assumptions for cross-network comparisons than historical approaches. Copyright © 2017 Elsevier Ltd. All rights reserved.

Inhibition of bacterial growth by iron oxide nanoparticles with and without attached drug: Have we conquered the antibiotic resistance problem?

NASA Astrophysics Data System (ADS)

Armijo, Leisha M.; Jain, Priyanka; Malagodi, Angelina; Fornelli, F. Zuly; Hayat, Allison; Rivera, Antonio C.; French, Michael; Smyth, Hugh D. C.; Osiński, Marek

2015-03-01

Pseudomonas aeruginosa is among the top three leading causative opportunistic human pathogens, possessing one of the largest bacterial genomes and an exceptionally large proportion of regulatory genes therein. It has been known for more than a decade that the size and complexity of the P. aeruginosa genome is responsible for the adaptability and resilience of the bacteria to include its ability to resist many disinfectants and antibiotics. We have investigated the susceptibility of P. aeruginosa bacterial biofilms to iron oxide (magnetite) nanoparticles (NPs) with and without attached drug (tobramycin). We also characterized the susceptibility of zero-valent iron NPs, which are known to inactivate microbes. The particles, having an average diameter of 16 nm were capped with natural alginate, thus doubling the hydrodynamic size. Nanoparticle-drug conjugates were produced via cross-linking drug and alginate functional groups. Drug conjugates were investigated in the interest of determining dosage, during these dosage-curve experiments, NPs unbound to drug were tested in cultures as a negative control. Surprisingly, we found that the iron oxide NPs inhibited bacterial growth, and thus, biofilm formation without the addition of antibiotic drug. The inhibitory dosages of iron oxide NPs were investigated and the minimum inhibitory concentrations are presented. These findings suggest that NP-drug conjugates may overcome the antibiotic drug resistance common in P. aeruginosa infections.

Nonlinear pattern analysis of ventricular premature beats by mutual information

NASA Technical Reports Server (NTRS)

Osaka, M.; Saitoh, H.; Yokoshima, T.; Kishida, H.; Hayakawa, H.; Cohen, R. J.

1997-01-01

The frequency of ventricular premature beats (VPBs) has been related to the risk of mortality. However, little is known about the temporal pattern of occurrence of VPBs and its relationship to autonomic activity. Hence, we applied a general correlation measure, mutual information, to quantify how VPBs are generated over time. We also used mutual information to determine the correlation between VPB production and heart rate in order to evaluate effects of autonomic activity on VPB production. We examined twenty subjects with more than 3000 VPBs/day and simulated random time series of VPB occurrence. We found that mutual information values could be used to characterize quantitatively the temporal patterns of VPB generation. Our data suggest that VPB production is not random and VPBs generated with a higher value of mutual information may be more greatly affected by autonomic activity.

12 CFR 239.12 - Communication between members of a mutual holding company.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 12 Banks and Banking 4 2012-01-01 2012-01-01 false Communication between members of a mutual holding company. 239.12 Section 239.12 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) MUTUAL HOLDING COMPANIES (REGULATION MM) Mutual Holding...

12 CFR 239.12 - Communication between members of a mutual holding company.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 12 Banks and Banking 4 2014-01-01 2014-01-01 false Communication between members of a mutual holding company. 239.12 Section 239.12 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) MUTUAL HOLDING COMPANIES (REGULATION MM) Mutual Holding...

12 CFR 239.12 - Communication between members of a mutual holding company.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 12 Banks and Banking 4 2013-01-01 2013-01-01 false Communication between members of a mutual holding company. 239.12 Section 239.12 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) MUTUAL HOLDING COMPANIES (REGULATION MM) Mutual Holding...

Reducing Interpolation Artifacts for Mutual Information Based Image Registration

PubMed Central

Soleimani, H.; Khosravifard, M.A.

2011-01-01

Medical image registration methods which use mutual information as similarity measure have been improved in recent decades. Mutual Information is a basic concept of Information theory which indicates the dependency of two random variables (or two images). In order to evaluate the mutual information of two images their joint probability distribution is required. Several interpolation methods, such as Partial Volume (PV) and bilinear, are used to estimate joint probability distribution. Both of these two methods yield some artifacts on mutual information function. Partial Volume-Hanning window (PVH) and Generalized Partial Volume (GPV) methods are introduced to remove such artifacts. In this paper we show that the acceptable performance of these methods is not due to their kernel function. It's because of the number of pixels which incorporate in interpolation. Since using more pixels requires more complex and time consuming interpolation process, we propose a new interpolation method which uses only four pixels (the same as PV and bilinear interpolations) and removes most of the artifacts. Experimental results of the registration of Computed Tomography (CT) images show superiority of the proposed scheme. PMID:22606673

Inhibition of lactation.

PubMed

Llewellyn-Jones, D

1975-01-01

The mechanism and hormonal regulation of lactation is explained and illustrated with a schematic representation. Circulating estrogen above a critical amount seems to be the inhibitory factor controlling lactation during pregnancy. Once delivery occurs, the level of estrogen falls, that of prolactin rises, and lactation begins. Nonsuckling can be used to inhibit lactation. Estrogens can also be used to inhibit lactation more quickly and with less pain. The reported association between estrogens and puerperal thromboembolism cannot be considered conclusive due to defects in the reporting studies. There is no reason not to use estrogens in lactation inhibition except for women over 35 who experienced a surgical delivery. Alternative therapy is available for these women. The recently-developed drug, brom-ergocryptine, may replace other methods of lactation inhibition.

Inhibition of herpes simplex virus DNA polymerase by purine ribonucleoside monophosphates.

PubMed

Frank, K B; Cheng, Y C

1986-02-05

Purine ribonucleoside monophosphates were found to inhibit chain elongation catalyzed by herpes simplex virus (HSV) DNA polymerase when DNA template-primer concentrations were rate-limiting. Inhibition was fully competitive with DNA template-primer during chain elongation; however, DNA polymerase-associated exonuclease activity was inhibited noncompetitively with respect to DNA. Combinations of 5'-GMP and phosphonoformate were kinetically mutually exclusive in dual inhibitor studies. Pyrimidine nucleoside monophosphates and deoxynucleoside monophosphates were less inhibitory than purine riboside monophosphates. The monophosphates of 9-beta-D-arabinofuranosyladenine, Virazole (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), 9-(2-hydroxyethoxymethyl)guanine, and 9-(1,3-dihydroxy-2-propoxymethyl)guanine exerted little or no inhibition. In contrast to HSV DNA polymerase, human DNA polymerase alpha was not inhibited by purine ribonucleoside monophosphates. These studies suggest the possibility of a physiological role of purine ribonucleoside monophosphates as regulators of herpesvirus DNA synthesis and a new approach to developing selective anti-herpesvirus compounds.

Synthesis, kinetic studies and pharmacological evaluation of mutual azo prodrug of 5-aminosalicylic acid with D-phenylalanine for colon specific drug delivery in inflammatory bowel disease.

PubMed

Dhaneshwar, Suneela S; Gairola, Neha; Kandpal, Mini; Bhatt, Lokesh; Vadnerkar, Gaurav; Kadam, S S

2007-04-01

Mutual azo prodrug of 5-aminosalicylic acid with d-phenylalanine was synthesized by coupling D-phenylalanine with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure of synthesized prodrug was confirmed by elemental analysis, IR and NMR spectroscopy. In vitro kinetic studies in HCl buffer (pH 1.2) showed negligible release of 5-aminosalicylic acid, whereas in phosphate buffer (pH 7.4) only 15% release was observed over a period of 7h. In rat fecal matter the release of 5-aminosalicylic acid was almost complete (85%), with a half-life of 160.1 min, following first order kinetics. The azo conjugate was evaluated for its ulcerogenic potential by Rainsford's cold stress method. Therapeutic efficacy of the carrier system and the mitigating effect of the azo conjugate were evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model. The synthesized prodrug was found to be equally effective in mitigating the colitis in rats as that of sulfasalazine without the ulcerogenicity of 5-aminosalicylic acid.

Synergistic Inhibition of Her2/neu and p53-MDM2 Pathways. Addendum

DTIC Science & Technology

2007-09-01

Therefore, combination of drugs targeting HER2/neu and MDM2 pathways will allow for a two-pronged attack on breast cancer. The overall objective of our...proposal is to determine if small molecule drugs designed to inhibit HER2/neu can be applied in combination with drugs designed to inhibit p53-MDM2...able to inhibit either the HER2/neu pathway or the p53-MDM2 pathway. Subsequently, designed small molecule drugs able to strongly induce apoptosis

The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy.

PubMed

Kast, Richard E; Skuli, Nicolas; Cos, Samuel; Karpel-Massler, Georg; Shiozawa, Yusuke; Goshen, Ran; Halatsch, Marc-Eric

2017-01-01

Breast cancer metastatic to bone has a poor prognosis despite recent advances in our understanding of the biology of both bone and breast cancer. This article presents a new approach, the ABC7 regimen (Adjuvant for Breast Cancer treatment using seven repurposed drugs), to metastatic breast cancer. ABC7 aims to defeat aspects of epithelial-to-mesenchymal transition (EMT) that lead to dissemination of breast cancer to bone. As add-on to current standard treatment with capecitabine, ABC7 uses ancillary attributes of seven already-marketed noncancer treatment drugs to stop both the natural EMT process inherent to breast cancer and the added EMT occurring as a response to current treatment modalities. Chemotherapy, radiation, and surgery provoke EMT in cancer generally and in breast cancer specifically. ABC7 uses standard doses of capecitabine as used in treating breast cancer today. In addition, ABC7 uses 1) an older psychiatric drug, quetiapine, to block RANK signaling; 2) pirfenidone, an anti-fibrosis drug to block TGF-beta signaling; 3) rifabutin, an antibiotic to block beta-catenin signaling; 4) metformin, a first-line antidiabetic drug to stimulate AMPK and inhibit mammalian target of rapamycin, (mTOR); 5) propranolol, a beta-blocker to block beta-adrenergic signaling; 6) agomelatine, a melatonergic antidepressant to stimulate M1 and M2 melatonergic receptors; and 7) ribavirin, an antiviral drug to prevent eIF4E phosphorylation. All these block the signaling pathways - RANK, TGF-beta, mTOR, beta-adrenergic receptors, and phosphorylated eIF4E - that have been shown to trigger EMT and enhance breast cancer growth and so are worthwhile targets to inhibit. Agonism at MT1 and MT2 melatonergic receptors has been shown to inhibit both breast cancer EMT and growth. This ensemble was designed to be safe and augment capecitabine efficacy. Given the expected outcome of metastatic breast cancer as it stands today, ABC7 warrants a cautious trial.

The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy

PubMed Central

Kast, Richard E; Skuli, Nicolas; Cos, Samuel; Karpel-Massler, Georg; Shiozawa, Yusuke; Goshen, Ran; Halatsch, Marc-Eric

2017-01-01

Breast cancer metastatic to bone has a poor prognosis despite recent advances in our understanding of the biology of both bone and breast cancer. This article presents a new approach, the ABC7 regimen (Adjuvant for Breast Cancer treatment using seven repurposed drugs), to metastatic breast cancer. ABC7 aims to defeat aspects of epithelial-to-mesenchymal transition (EMT) that lead to dissemination of breast cancer to bone. As add-on to current standard treatment with capecitabine, ABC7 uses ancillary attributes of seven already-marketed noncancer treatment drugs to stop both the natural EMT process inherent to breast cancer and the added EMT occurring as a response to current treatment modalities. Chemotherapy, radiation, and surgery provoke EMT in cancer generally and in breast cancer specifically. ABC7 uses standard doses of capecitabine as used in treating breast cancer today. In addition, ABC7 uses 1) an older psychiatric drug, quetiapine, to block RANK signaling; 2) pirfenidone, an anti-fibrosis drug to block TGF-beta signaling; 3) rifabutin, an antibiotic to block beta-catenin signaling; 4) metformin, a first-line antidiabetic drug to stimulate AMPK and inhibit mammalian target of rapamycin, (mTOR); 5) propranolol, a beta-blocker to block beta-adrenergic signaling; 6) agomelatine, a melatonergic antidepressant to stimulate M1 and M2 melatonergic receptors; and 7) ribavirin, an antiviral drug to prevent eIF4E phosphorylation. All these block the signaling pathways – RANK, TGF-beta, mTOR, beta-adrenergic receptors, and phosphorylated eIF4E – that have been shown to trigger EMT and enhance breast cancer growth and so are worthwhile targets to inhibit. Agonism at MT1 and MT2 melatonergic receptors has been shown to inhibit both breast cancer EMT and growth. This ensemble was designed to be safe and augment capecitabine efficacy. Given the expected outcome of metastatic breast cancer as it stands today, ABC7 warrants a cautious trial. PMID:28744157

FAST TRACK COMMUNICATION: Affine constellations without mutually unbiased counterparts

NASA Astrophysics Data System (ADS)

Weigert, Stefan; Durt, Thomas

2010-10-01

It has been conjectured that a complete set of mutually unbiased bases in a space of dimension d exists if and only if there is an affine plane of order d. We introduce affine constellations and compare their existence properties with those of mutually unbiased constellations. The observed discrepancies make a deeper relation between the two existence problems unlikely.

Repurposing the anti-malarial drug dihydroartemisinin suppresses metastasis of non-small-cell lung cancer via inhibiting NF-κB/GLUT1 axis

PubMed Central

Jiang, Jie; Geng, Guojun; Yu, Xiuyi; Liu, Hongming; Gao, Jing; An, Hanxiang; Cai, Chengfu; Li, Ning; Shen, Dongyan; Wu, Xiaoqiang; Zheng, Lisheng; Mi, Yanjun; Yang, Shuyu

2016-01-01

Non-small-cell lung cancer (NSCLC) is an aggressive malignancy and long-term survival remains unsatisfactory for patients with metastatic and recurrent disease. Repurposing the anti-malarial drug dihydroartemisinin (DHA) has been proved to possess potent antitumor effect on various cancers. However, the effects of DHA in preventing the invasion of NSCLC cells have not been studied. In the present study, we determined the inhibitory effects of DHA on invasion and migration and the possible mechanisms involved using A549 and H1975 cells. DHA inhibited in vitro migration and invasion of NSCLC cells even in low concentration with little cytotoxicity. Additionally, low concentration DHA also inhibited Warburg effect in NSCLC cells. Mechanically, DHA negatively regulates NF-κB signaling to inhibit the GLUT1 translocation. Blocking the NF-κB signaling largely abolishes the inhibitory effects of DHA on the translocation of GLUT1 to the plasma membrane and the Warburg effect. Furthermore, GLUT1 knockdown significantly decreased the inhibition of invasion, and migration by DHA. Our results suggested that DHA can inhibit metastasis of NSCLC by targeting glucose metabolism via inhibiting NF-κB signaling pathway and DHA may deserve further investigation in NSCLC treatment. PMID:27895313

Experimental anti-inflammatory drug Semapimod inhibits Toll-like receptor signaling by targeting the TLR chaperone gp961

PubMed Central

Wang, Jin; Grishin, Anatoly V.; Ford, Henri R.

2016-01-01

Semapimod, a tetravalent guanylhydrazone, suppresses inflammatory cytokine production and has potential in a variety of inflammatory and autoimmune disorders. The mechanism of action of Semapimod is not well understood. Here we demonstrate that in rat IEC-6 intestinal epithelioid cells, Semapimod inhibits activation of p38 MAPK, NF-kB and induction of COX-2 by TLR ligands, but not by IL-1β or stresses. Semapimod inhibits TLR4 signaling (IC50≈0.3 μM) and acts by desensitizing cells to LPS; it fails to block responses to LPS concentrations of 5 μg/ml or higher. Inhibition of TLR signaling by Semapimod is almost instantaneous: the drug is effective when applied simultaneously with LPS. Semapimod blocks cell surface recruitment of the MyD88 adapter, one of the earliest events in TLR signaling. gp96, the ER-localized chaperone of the HSP90 family critically involved in the biogenesis of TLRs, was identified as a target of Semapimod using ATP-desthiobiotin pull-down and mass spectroscopy. Semapimod inhibits ATP-binding and ATPase activities of gp96 in vitro (IC50≈0.2-0.4 μM). On prolonged exposure, Semapimod causes accumulation of TLR4 and TLR9 in perinuclear space, consistent with ER retention, an anticipated consequence of impaired gp96 chaperone function. Our data indicate that Semapimod desensitizes TLR signaling via its effect on the TLR chaperone gp96. Fast inhibition by Semapimod is consistent with gp96 participating in high affinity sensing of TLR ligands in addition to its role as a TLR chaperone. PMID:27194788

Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer via p53/PRC1 pathway.

PubMed

Ye, Bai-Liang; Zheng, Ru; Ruan, Xiao-Jiao; Zheng, Zhi-Hai; Cai, Hua-Jie

2018-01-01

Nano-particles have been widely used in target-specific drug delivery system and showed advantages in cancers treatment. This study aims to evaluate the effect of chitosan coated doxorubicin nano-particles drug delivery system in liver cancer. The chitosan nano-particles were prepared by using the ionic gelation method. The characterizations of the nano-particles were determined by transmission electron microscopy. The cytotoxicity was detected by MTT assay, and the endocytosis, cell apoptosis and cell cycle were examined by flow cytometry. The protein level was analyzed with western blot. The dual luciferase reporter assay was performed to assess the interaction between p53 and the promoter of PRC1, and chromatin immune-precipitation was used to verify the binding between them. The FA-CS-DOX nano-particles were irregular and spherical particles around 30-40 nm, with uniform size and no adhesion. No significant difference was noted in doxorubicin release rate between CS-DOX and FA-CS-DOX. FA-CS-DOX nano-particles showed stronger cytotoxicity than CS-DOX. FA-CS-DOX nano-particles promoted the apoptosis and arrested cell cycle at G2/M phase, and they up-regulated p53. FA-CS-DOX nano-particles inhibited cell survival through p53/PRC1 pathway. Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer by promoting apoptosis and arresting cell cycle at G2/M phase through p53/PRC1 pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Drug Discovery Using Chemical Systems Biology: Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis

PubMed Central

Tonge, Peter J.; Xie, Lei; Bourne, Philip E.

2009-01-01

The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-tubercular agents. Previously we developed a chemical systems biology approach to identify off-targets of major pharmaceuticals on a proteome-wide scale. In this paper we further demonstrate the value of this approach through the discovery that existing commercially available drugs, prescribed for the treatment of Parkinson's disease, have the potential to treat MDR and XDR tuberculosis. These drugs, entacapone and tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The prediction is validated by in vitro and InhA kinetic assays using tablets of Comtan, whose active component is entacapone. The minimal inhibition concentration (MIC99) of entacapone for Mycobacterium tuberculosis (M.tuberculosis) is approximately 260.0 µM, well below the toxicity concentration determined by an in vitro cytotoxicity model using a human neuroblastoma cell line. Moreover, kinetic assays indicate that Comtan inhibits InhA activity by 47.0% at an entacapone concentration of approximately 80 µM. Thus the active component in Comtan represents a promising lead compound for developing a new class of anti-tubercular therapeutics with excellent safety profiles. More generally, the protocol described in this paper can be included in a drug discovery pipeline in an effort to discover novel drug leads with desired safety profiles, and therefore accelerate the development of new drugs. PMID:19578428

Possible drug-drug interaction in dogs and cats resulted from alteration in drug metabolism: A mini review.

PubMed

Sasaki, Kazuaki; Shimoda, Minoru

2015-05-01

Pharmacokinetic drug-drug interactions (in particular at metabolism) may result in fatal adverse effects in some cases. This basic information, therefore, is needed for drug therapy even in veterinary medicine, as multidrug therapy is not rare in canines and felines. The aim of this review was focused on possible drug-drug interactions in dogs and cats. The interaction includes enzyme induction by phenobarbital, enzyme inhibition by ketoconazole and fluoroquinolones, and down-regulation of enzymes by dexamethasone. A final conclusion based upon the available literatures and author's experience is given at the end of the review.

Application of data envelopment analysis in measuring the efficiency of mutual fund

NASA Astrophysics Data System (ADS)

Nik, Marzieh Geramian; Mihanzadeh, Hooman; Izadifar, Mozhgan; Nik, Babak Geramian

2015-05-01

The growth of mutual fund industry during the past decades emphasizes the importance of this investment vehicle particularly in prosperity of financial markets and in turn, financial growth of each country. Therefore, evaluating the relative efficiency of mutual funds as investment tool is of importance. In this study, a combined model of DEA (data envelopment analysis), and goal programming (GoDEA) approaches contributes widely to analyze the return efficiency of Mutual Funds in an attempt to separate efficient and inefficient Funds as well as identifying the inefficiency resources. Mixed asset local funds, which are managed jointly by CIMB and Public Mutual Berhad, have been selected for the purpose of this paper. As a result, Public Small Cap Fund (P Small Cap) is regarded as the most efficient mutual fund during the period of study. The integrated model aims to first guide investors to choose the best performing fund among other mutual funds, secondly provides the realistic and appropriate benchmark in compare to other classic method, and finally confirms the utility of data envelopment analysis (DEA) as decision-making tool.

PREPARATION, DRUG RELEASE, AND CELL GROWTH INHIBITION OF A GELATIN – DOXORUBICIN CONJUGATE

PubMed Central

Wu, Darren C.; Cammarata, Christopher R.; Park, Hyun Joo; Rhodes, Brian T.; Ofner, Clyde M.

2013-01-01

Purpose To demonstrate the feasibility of a novel macromolecular delivery system for doxorubicin (DOX) which combines pH dependent DOX release with a high molecular weight and biodegradable gelatin carrier. Methods DOX was conjugated to gelatin using an acid labile hydrazone bond and a glycylglycine linker. The gelatin-doxorubicin conjugate (G-DOX) was evaluated for hydrazide and DOX content by spectrophotometry, molecular weight by HPLC-SEC, in vitro DOX release at various pH, and cell growth inhibition using EL4 mouse lymphoma and PC3 human prostate cells. Results G-DOX hydrazide and DOX content was 47% and 5-7%, respectively of theoretical gelatin carboxylic acid sites. During preparation of G-DOX, the molecular weight decreased to 22 kDa. DOX release was 48% in pH 4.8 phosphate buffer, 22% at pH 6.5, but 10% at pH 7.4. The G-DOX IC50 values in EL4 and PC3 cells were 0.26 μM and 0.77 μM, respectively; the latter value 3 times greater than that of free DOX. Conclusions A 22 kDa macromolecular DOX conjugate containing 3.4-5.0% w/w DOX has been prepared. The pH dependent drug release in combination with a biodegradable gelatin carrier offer potential therapeutic advantages of enhanced tumor cell localization and reduced systemic toxicities of the drug. PMID:23686374

A thiopurine drug inhibits West Nile virus production in cell culture, but not in mice.

PubMed

Lim, Pei-Yin; Keating, Julie A; Hoover, Spencer; Striker, Rob; Bernard, Kristen A

2011-01-01

Many viruses within the Flavivirus genus cause significant disease in humans; however, effective antivirals against these viruses are not currently available. We have previously shown that a thiopurine drug, 6-methylmercaptopurine riboside (6MMPr), inhibits replication of distantly related viruses within the Flaviviridae family in cell culture, including bovine viral diarrhea virus and hepatitis C virus replicon. Here we further examined the potential antiviral effect of 6MMPr on several diverse flaviviruses. In cell culture, 6MMPr inhibited virus production of yellow fever virus, dengue virus-2 (DENV-2) and West Nile virus (WNV) in a dose-dependent manner, and DENV-2 was significantly more sensitive to 6MMPr treatment than WNV. We then explored the use of 6MMPr as an antiviral against WNV in an immunocompetent mouse model. Once a day treatment of mice with 0.5 mg 6MMPr was just below the toxic dose in our mouse model, and this dose was used in subsequent studies. Mice were treated with 6MMPr immediately after subcutaneous inoculation with WNV for eight consecutive days. Treatment with 6MMPr exacerbated weight loss in WNV-inoculated mice and did not significantly affect mortality. We hypothesized that 6MMPr has low bioavailability in the central nervous system (CNS) and examined the effect of pre-treatment with 6MMPr on viral loads in the periphery and CNS. Pre-treatment with 6MMPr had no significant effect on viremia or viral titers in the periphery, but resulted in significantly higher viral loads in the brain, suggesting that the effect of 6MMPr is tissue-dependent. In conclusion, despite being a potent inhibitor of flaviviruses in cell culture, 6MMPr was not effective against West Nile disease in mice; however, further studies are warranted to reduce the toxicity and/or improve the bioavailability of this potential antiviral drug.

Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model

PubMed Central

Yao, X; Anderson, D L; Ross, S A; Lang, D G; Desai, B Z; Cooper, D C; Wheelan, P; McIntyre, M S; Bergquist, M L; MacKenzie, K I; Becherer, J D; Hashim, M A

2008-01-01

Background and purpose: Drug-induced prolongation of the QT interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclinical development, the propensity of drugs to prolong the QT interval in humans. Experimental approach: Sixteen marketed drugs from various pharmacological classes with a known incidence—or lack thereof—of QT prolongation in humans were examined in hERG (human ether a-go-go-related gene) patch-clamp assay and an anaesthetized guinea-pig assay for QT prolongation using specific protocols. Drug concentrations in perfusates from hERG assays and plasma samples from guinea-pigs were determined using liquid chromatography-mass spectrometry. Key results: Various pharmacological agents that inhibit hERG currents prolong the QT interval in anaesthetized guinea-pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compounds not associated with QT prolongation in humans failed to prolong the QT interval in this model. Conclusions and implications: Analysis of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anaesthetized guinea-pigs can reliably predict, during preclinical drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chemical entities during early lead optimization. PMID:18587422

Melanin Protects Paracoccidioides brasiliensis from the Effects of Antimicrobial Photodynamic Inhibition and Antifungal Drugs

PubMed Central

Baltazar, Ludmila Matos; Werneck, Silvia Maria Cordeiro; Soares, Betânia Maria; Ferreira, Marcus Vinicius L.; Souza, Danielle G.; Pinotti, Marcos; Santos, Daniel Assis

2015-01-01

Paracoccidioidomycosis (PCM) is a public health concern in Latin America and South America that when not correctly treated can lead to patient death. In this study, the influence of melanin produced by Paracoccidioides spp. on the effects of treatment with antimicrobial photodynamic inhibition (aPI) and antifungal drugs was evaluated. aPI was performed using toluidine blue (TBO) as a photosensitizer and a 630-nm light-emitting diode (LED) light. The antifungals tested were itraconazole and amphotericin B. We evaluated the effects of each approach, aPI or antifungals, against nonmelanized and melanized yeast cells by performing susceptibility tests and by quantifying oxidative and nitrosative bursts during the experiments. aPI reduced nonmelanized cells by 3.0 log units and melanized cells by 1.3 log units. The results showed that melanization protects the fungal cell, probably by acting as a scavenger of nitric oxide and reactive oxygen species, but not of peroxynitrite. Melanin also increased the MICs of itraconazole and amphotericin B, and the drugs were fungicidal for nonmelanized and fungistatic for melanized yeast cells. Our study shows that melanin production by Paracoccidioides yeast cells serves a protective function during aPI and treatment with itraconazole and amphotericin B. The results suggest that melanin binds to the drugs, changing their antifungal activities, and also acts as a scavenger of reactive oxygen species and nitric oxide, but not of peroxynitrite, indicating that peroxynitrite is the main radical that is responsible for fungal death after aPI. PMID:25896704

47 CFR 101.51 - Comparative evaluation of mutually exclusive applications.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 5 2010-10-01 2010-10-01 false Comparative evaluation of mutually exclusive....51 Comparative evaluation of mutually exclusive applications. (a) In order to expedite action on... this section if: (1) The applications are entitled to comparative consideration pursuant to § 101.45...

47 CFR 101.51 - Comparative evaluation of mutually exclusive applications.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 5 2013-10-01 2013-10-01 false Comparative evaluation of mutually exclusive....51 Comparative evaluation of mutually exclusive applications. (a) In order to expedite action on... this section if: (1) The applications are entitled to comparative consideration pursuant to § 101.45...

47 CFR 101.51 - Comparative evaluation of mutually exclusive applications.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 5 2014-10-01 2014-10-01 false Comparative evaluation of mutually exclusive....51 Comparative evaluation of mutually exclusive applications. (a) In order to expedite action on... this section if: (1) The applications are entitled to comparative consideration pursuant to § 101.45...

47 CFR 101.51 - Comparative evaluation of mutually exclusive applications.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 47 Telecommunication 5 2012-10-01 2012-10-01 false Comparative evaluation of mutually exclusive....51 Comparative evaluation of mutually exclusive applications. (a) In order to expedite action on... this section if: (1) The applications are entitled to comparative consideration pursuant to § 101.45...

47 CFR 101.51 - Comparative evaluation of mutually exclusive applications.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 5 2011-10-01 2011-10-01 false Comparative evaluation of mutually exclusive....51 Comparative evaluation of mutually exclusive applications. (a) In order to expedite action on... this section if: (1) The applications are entitled to comparative consideration pursuant to § 101.45...

31 CFR 103.131 - Customer identification programs for mutual funds.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Finance FINANCIAL RECORDKEEPING AND REPORTING OF CURRENCY AND FOREIGN TRANSACTIONS Anti-Money Laundering Programs Anti-Money Laundering Programs § 103.131 Customer identification programs for mutual funds. (a... mutual fund's anti-money laundering program required under the regulations implementing 31 U.S.C. 5318(h...

Occurrence and characteristics of mutual interference between LIDAR scanners

NASA Astrophysics Data System (ADS)

Kim, Gunzung; Eom, Jeongsook; Park, Seonghyeon; Park, Yongwan

2015-05-01

The LIDAR scanner is at the heart of object detection of the self-driving car. Mutual interference between LIDAR scanners has not been regarded as a problem because the percentage of vehicles equipped with LIDAR scanners was very rare. With the growing number of autonomous vehicle equipped with LIDAR scanner operated close to each other at the same time, the LIDAR scanner may receive laser pulses from other LIDAR scanners. In this paper, three types of experiments and their results are shown, according to the arrangement of two LIDAR scanners. We will show the probability that any LIDAR scanner will interfere mutually by considering spatial and temporal overlaps. It will present some typical mutual interference scenario and report an analysis of the interference mechanism.

31 CFR 1024.210 - Anti-money laundering programs for mutual funds.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Finance (Continued) FINANCIAL CRIMES ENFORCEMENT NETWORK, DEPARTMENT OF THE TREASURY RULES FOR MUTUAL... board of directors or trustees. A mutual fund shall make its anti-money laundering program available for...

31 CFR 1024.210 - Anti-money laundering programs for mutual funds.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Finance (Continued) FINANCIAL CRIMES ENFORCEMENT NETWORK, DEPARTMENT OF THE TREASURY RULES FOR MUTUAL... board of directors or trustees. A mutual fund shall make its anti-money laundering program available for...

31 CFR 1024.210 - Anti-money laundering programs for mutual funds.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Finance (Continued) FINANCIAL CRIMES ENFORCEMENT NETWORK, DEPARTMENT OF THE TREASURY RULES FOR MUTUAL... board of directors or trustees. A mutual fund shall make its anti-money laundering program available for...

Nectar bacteria, but not yeast, weaken a plant-pollinator mutualism.

PubMed

Vannette, Rachel L; Gauthier, Marie-Pierre L; Fukami, Tadashi

2013-02-07

Mutualistic interactions are often subject to exploitation by species that are not directly involved in the mutualism. Understanding which organisms act as such 'third-party' species and how they do so is a major challenge in the current study of mutualistic interactions. Here, we show that even species that appear ecologically similar can have contrasting effects as third-party species. We experimentally compared the effects of nectar-inhabiting bacteria and yeasts on the strength of a mutualism between a hummingbird-pollinated shrub, Mimulus aurantiacus, and its pollinators. We found that the common bacterium Gluconobacter sp., but not the common yeast Metschnikowia reukaufii, reduced pollination success, seed set and nectar consumption by pollinators, thereby weakening the plant-pollinator mutualism. We also found that the bacteria reduced nectar pH and total sugar concentration more greatly than the yeasts did and that the bacteria decreased glucose concentration and increased fructose concentration whereas the yeasts affected neither. These distinct changes to nectar chemistry may underlie the microbes' contrasting effects on the mutualism. Our results suggest that it is necessary to understand the determinants of microbial species composition in nectar and their differential modification of floral rewards to explain the mutual benefits that plants and pollinators gain from each other.

Nectar bacteria, but not yeast, weaken a plant–pollinator mutualism

PubMed Central

Vannette, Rachel L.; Gauthier, Marie-Pierre L.; Fukami, Tadashi

2013-01-01

Mutualistic interactions are often subject to exploitation by species that are not directly involved in the mutualism. Understanding which organisms act as such ‘third-party’ species and how they do so is a major challenge in the current study of mutualistic interactions. Here, we show that even species that appear ecologically similar can have contrasting effects as third-party species. We experimentally compared the effects of nectar-inhabiting bacteria and yeasts on the strength of a mutualism between a hummingbird-pollinated shrub, Mimulus aurantiacus, and its pollinators. We found that the common bacterium Gluconobacter sp., but not the common yeast Metschnikowia reukaufii, reduced pollination success, seed set and nectar consumption by pollinators, thereby weakening the plant–pollinator mutualism. We also found that the bacteria reduced nectar pH and total sugar concentration more greatly than the yeasts did and that the bacteria decreased glucose concentration and increased fructose concentration whereas the yeasts affected neither. These distinct changes to nectar chemistry may underlie the microbes' contrasting effects on the mutualism. Our results suggest that it is necessary to understand the determinants of microbial species composition in nectar and their differential modification of floral rewards to explain the mutual benefits that plants and pollinators gain from each other. PMID:23222453

Oral Multiple Sclerosis Drugs Inhibit the In vitro Growth of Epsilon Toxin Producing Gut Bacterium, Clostridium perfringens.

PubMed

Rumah, Kareem R; Vartanian, Timothy K; Fischetti, Vincent A

2017-01-01

There are currently three oral medications approved for the treatment of multiple sclerosis (MS). Two of these medications, Fingolimod, and Teriflunomide, are considered to be anti-inflammatory agents, while dimethyl fumarate (DMF) is thought to trigger a robust antioxidant response, protecting vulnerable cells during an MS attack. We previously proposed that epsilon toxin from the gut bacterium, Clostridium perfringens , may initiate newly forming MS lesions due to its tropism for blood-brain barrier (BBB) vasculature and central nervous system myelin. Because gut microbiota will be exposed to these oral therapies prior to systemic absorption, we sought to determine if these compounds affect C. perfringens growth in vitro . Here we show that Fingolimod, Teriflunomide, and DMF indeed inhibit C. perfringens growth. Furthermore, several compounds similar to DMF in chemical structure, namely α, β unsaturated carbonyls, also known as Michael acceptors, inhibit C. perfringens . Sphingosine, a Fingolimod homolog with known antibacterial properties, proved to be a potent C. perfringens inhibitor with a Minimal Inhibitory Concentration similar to that of Fingolimod. These findings suggest that currently approved oral MS therapies and structurally related compounds possess antibacterial properties that may alter the gut microbiota. Moreover, inhibition of C. perfringens growth and resulting blockade of epsilon toxin production may contribute to the clinical efficacy of these disease-modifying drugs.

Mutually orthogonal Latin squares from the inner products of vectors in mutually unbiased bases

NASA Astrophysics Data System (ADS)

Hall, Joanne L.; Rao, Asha

2010-04-01

Mutually unbiased bases (MUBs) are important in quantum information theory. While constructions of complete sets of d + 1 MUBs in {\\bb C}^d are known when d is a prime power, it is unknown if such complete sets exist in non-prime power dimensions. It has been conjectured that complete sets of MUBs only exist in {\\bb C}^d if a maximal set of mutually orthogonal Latin squares (MOLS) of side length d also exists. There are several constructions (Roy and Scott 2007 J. Math. Phys. 48 072110; Paterek, Dakić and Brukner 2009 Phys. Rev. A 79 012109) of complete sets of MUBs from specific types of MOLS, which use Galois fields to construct the vectors of the MUBs. In this paper, two known constructions of MUBs (Alltop 1980 IEEE Trans. Inf. Theory 26 350-354 Wootters and Fields 1989 Ann. Phys. 191 363-381), both of which use polynomials over a Galois field, are used to construct complete sets of MOLS in the odd prime case. The MOLS come from the inner products of pairs of vectors in the MUBs.

Quantum correlation in degenerate optical parametric oscillators with mutual injections

NASA Astrophysics Data System (ADS)

Takata, Kenta; Marandi, Alireza; Yamamoto, Yoshihisa

2015-10-01

We theoretically and numerically study the quantum dynamics of two degenerate optical parametric oscillators with mutual injections. The cavity mode in the optical coupling path between the two oscillator facets is explicitly considered. Stochastic equations for the oscillators and mutual injection path based on the positive P representation are derived. The system of two gradually pumped oscillators with out-of-phase mutual injections is simulated, and its quantum state is investigated. When the incoherent loss of the oscillators other than the mutual injections is small, the squeezed quadratic amplitudes p ̂ in the oscillators are positively correlated near the oscillation threshold. It indicates finite quantum correlation, estimated via Gaussian quantum discord, and the entanglement between the intracavity subharmonic fields. When the loss in the injection path is low, each oscillator around the phase transition point forms macroscopic superposition even under a small pump noise. It suggests that the squeezed field stored in the low-loss injection path weakens the decoherence in the oscillators.

Stabilization of a bat-pitcher plant mutualism.

PubMed

Schöner, Michael G; Schöner, Caroline R; Ermisch, Rebecca; Puechmaille, Sébastien J; Grafe, T Ulmar; Tan, Moi Chan; Kerth, Gerald

2017-10-13

Despite the long persistence of many mutualisms, it is largely unknown which mechanisms stabilize these interactions. This is especially true if only one mutualism partner can choose alternative partners while the other cannot, resulting in a power asymmetry. According to biological market theory the choosing partner should prefer the more dependent partner if the latter offers commodities of higher quality than its competitors. We tested this prediction using Bornean carnivorous pitcher plants (Nepenthes hemsleyana) that strongly rely on faecal nitrogen of bats (Kerivoula hardwickii) which roost inside the pitchers. The bats also roost in furled leaves of various plants. Surprisingly, during field observations the bats did not always choose N. hemsleyana pitchers despite their superior quality but were generally faithful either to pitchers or to furled leaves. In behavioural experiments 21% of the leaf-roosting bats switched to pitchers, while the majority of these bats and all pitcher-roosting individuals were faithful to the roost type in which we had found them. Genetic differentiation cannot explain this faithfulness, which likely results from different roosting traditions. Such traditions could have stabilizing or destabilizing effects on various mutualisms and should be investigated in more detail.

Thiopurine Drugs Repositioned as Tyrosinase Inhibitors

PubMed Central

Choi, Joonhyeok; Lee, You-Mie; Jee, Jun-Goo

2017-01-01

Drug repositioning is the application of the existing drugs to new uses and has the potential to reduce the time and cost required for the typical drug discovery process. In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two successive oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule inhibitors of tyrosinase for therapeutic and cosmetic purposes. Structure-based virtual screening predicted inhibitor candidates from the US Food and Drug Administration (FDA)-approved drugs. Enzyme assays confirmed the thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor with the inhibitory constant of 52 μM. Two other thiopurine drugs, mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibition; mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a poor inhibitor. The inhibitory constant of mercaptopurine (16 μM) was comparable to that of the well-known inhibitor kojic acid (13 μM). The cell-based assay using B16F10 melanoma cells confirmed that the compounds inhibit mammalian tyrosinase. Particularly, 50 μM thioguanine reduced the melanin content by 57%, without apparent cytotoxicity. Cheminformatics showed that the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors. PMID:29283382

Studies on Pharmacokinetic Drug Interaction Potential of Vinpocetine

PubMed Central

Manda, Vamshi K.; Avula, Bharathi; Dale, Olivia R.; Chittiboyina, Amar G.; Khan, Ikhlas A.; Walker, Larry A.; Khan, Shabana I.

2015-01-01

Abstract Background Vinpocetine, a semi-synthetic derivative of vincamine, is a popular dietary supplement used for the treatment of several central nervous system related disorders. Despite its wide use, no pharmacokinetic drug interaction studies are reported in the literature. Due to increasing use of dietary supplements in combination with conventional drugs, the risk of adverse effects is on the rise. As a preliminary step to predict a possibility of drug interaction during concomitant use of vinpocetine and conventional drugs, this study was carried out to evaluate the effects of vinpocetine on three main regulators of pharmacokinetic drug interactions namely, cytochromes P450 (CYPs), P-glycoprotein (P-gp), and Pregnane X receptor (PXR). Methods Inhibition of CYPs was evaluated by employing recombinant enzymes. The inhibition of P-gp was determined by calcein-AM uptake method in transfected and wild type MDCKII cells. Modulation of PXR activity was monitored through a reporter gene assay in HepG2 cells. Results Vinpocetine showed a strong inhibition of P-gp (EC50 8 μM) and a moderate inhibition of recombinant CYP3A4 and CYP2D6 (IC50 2.8 and 6.5 μM) with no activity towards CYP2C9, CYP2C19 and CYP1A2 enzymes. In HLM, competitive inhibition of CYP3A4 (IC50 54 and Ki 19 μM) and non-competitive inhibition of CYP2D6 (IC50 19 and Ki 26 μM) was observed. Activation of PXR was observed only at the highest tested concentration of vinpocetine (30 μM) while lower doses were ineffective. Conclusion Strong inhibition of P-gp by vinpocetine is indicative of a possibility of drug interactions by altering the pharmacokinetics of drugs, which are the substrates of P-gp. However, the effects on CYPs and PXR indicate that vinpocetine may not affect CYP-mediated metabolism of drugs, as the inhibitory concentrations are much greater than the expected plasma concentrations in humans. PMID:28930203

Studies on Pharmacokinetic Drug Interaction Potential of Vinpocetine.

PubMed

Manda, Vamshi K; Avula, Bharathi; Dale, Olivia R; Chittiboyina, Amar G; Khan, Ikhlas A; Walker, Larry A; Khan, Shabana I

2015-06-05

Background: Vinpocetine, a semi-synthetic derivative of vincamine, is a popular dietary supplement used for the treatment of several central nervous system related disorders. Despite its wide use, no pharmacokinetic drug interaction studies are reported in the literature. Due to increasing use of dietary supplements in combination with conventional drugs, the risk of adverse effects is on the rise. As a preliminary step to predict a possibility of drug interaction during concomitant use of vinpocetine and conventional drugs, this study was carried out to evaluate the effects of vinpocetine on three main regulators of pharmacokinetic drug interactions namely, cytochromes P450 (CYPs), P-glycoprotein (P-gp), and Pregnane X receptor (PXR). Methods: Inhibition of CYPs was evaluated by employing recombinant enzymes. The inhibition of P-gp was determined by calcein-AM uptake method in transfected and wild type MDCKII cells. Modulation of PXR activity was monitored through a reporter gene assay in HepG2 cells. Results: Vinpocetine showed a strong inhibition of P-gp (EC 50 8 µM) and a moderate inhibition of recombinant CYP3A4 and CYP2D6 (IC 50 2.8 and 6.5 µM) with no activity towards CYP2C9, CYP2C19 and CYP1A2 enzymes. In HLM, competitive inhibition of CYP3A4 (IC 50 54 and K i 19 µM) and non-competitive inhibition of CYP2D6 (IC 50 19 and K i 26 µM) was observed. Activation of PXR was observed only at the highest tested concentration of vinpocetine (30 µM) while lower doses were ineffective. Conclusion: Strong inhibition of P-gp by vinpocetine is indicative of a possibility of drug interactions by altering the pharmacokinetics of drugs, which are the substrates of P-gp. However, the effects on CYPs and PXR indicate that vinpocetine may not affect CYP-mediated metabolism of drugs, as the inhibitory concentrations are much greater than the expected plasma concentrations in humans.

Inhibition of Retinoblastoma Protein Inactivation

DTIC Science & Technology

2016-09-01

Retinoblastoma protein, E2F transcription factor, high throughput screen, drug discovery, x-ray crystallography 16. SECURITY CLASSIFICATION OF: 17...developed a method to perform fragment based screening by x-ray crystallography . 2.0 KEYWORDS Retinoblastoma (Rb) pathway, E2F transcription factor...cancer, cell-cycle inhibition, activation, modulation, inhibition, high throughput screening, fragment-based screening, x-ray crystallography

Inhibition of Retinoblastoma Protein Inactivation

DTIC Science & Technology

2017-11-01

SUBJECT TERMS cell cycle, Retinoblastoma protein, E2F transcription factor, high throughput screen, drug discovery, x-ray crystallography 16. SECURITY...screening by x-ray crystallography . 2.0 KEYWORDS Retinoblastoma (Rb) pathway, E2F transcription factor, cancer, cell-cycle inhibition, activation...modulation, inhibition, high throughput screening, fragment-based screening, x-ray crystallography . 3.0 ACCOMPLISHMENTS Summary: We

Studies on cadmium-induced inhibition of hepatic microsomal drug biotransformation in the rat.

PubMed Central

Schnell, R C; Means, J R; Roberts, S A; Pence, D H

1979-01-01

Cadmium is a potent inhibitor of hepatic microsomal drug biotransformation in the rat. Male rats receiving a single intraperitoneal dose of cadmium exhibit significant decreases in hepatic microsomal metabolism of a variety of substrates. The threshold cadmium dose is 0.84 mg Cd/kg, and the effect lasts at least 28 days. Mechanistically, the inhibitory effect results from decreased cytochrome P-450 content since cadmium does not alter NADPH cytochrome c reductase activity. This effect is also observed following acute oral administration of cadmium in doses greater than 80 mg Cd/kg but is not observed following chronic administration of the metal via drinking water in concentrations of 5-200 ppm for periods ranging from 2 to 50 weeks. A tolerance to the inhibitory cadmium effect is observed if male rats are pretreated with subthreshold doses of the metal prior to the challenge cadmium dose. The degree of tolerance can be overcome by increasing the challenge dose of cadmium. Characterization of the tolerance phenomenon in terms of onset, duration, and intensity reveals a good correlation with the kinetics of metallothionein production, suggesting that the underlying basis for the tolerance phenomenon is likely the induction of metallothionein. A sex-related difference in the inhibitory effect of cadmium was observed. Cadmium did not inhibit the metabolism of hexobarbital or ethylmorphine in female rats but did inhibit that of aniline or zoxazolamine. Cadmium did not lower cytochrome P-450 content in female rats. PMID:488042

26 CFR 1.822-5 - Mutual insurance company taxable income.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Mutual insurance company taxable income. 1.822-5... TAX (CONTINUED) INCOME TAXES (CONTINUED) Mutual Insurance Companies (other Than Life and Certain Marine Insurance Companies and Other Than Fire Or Flood Insurance Companies Which Operate on Basis of...

26 CFR 1.822-5 - Mutual insurance company taxable income.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Mutual insurance company taxable income. 1.822-5... TAX (CONTINUED) INCOME TAXES (CONTINUED) Mutual Insurance Companies (other Than Life and Certain Marine Insurance Companies and Other Than Fire Or Flood Insurance Companies Which Operate on Basis of...

26 CFR 1.822-5 - Mutual insurance company taxable income.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Mutual insurance company taxable income. 1.822-5... TAX (CONTINUED) INCOME TAXES (CONTINUED) Mutual Insurance Companies (other Than Life and Certain Marine Insurance Companies and Other Than Fire Or Flood Insurance Companies Which Operate on Basis of...

26 CFR 1.822-5 - Mutual insurance company taxable income.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Mutual insurance company taxable income. 1.822-5... TAX (CONTINUED) INCOME TAXES (CONTINUED) Mutual Insurance Companies (other Than Life and Certain Marine Insurance Companies and Other Than Fire Or Flood Insurance Companies Which Operate on Basis of...

Rényi generalizations of the conditional quantum mutual information

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berta, Mario; Seshadreesan, Kaushik P.; Wilde, Mark M.

2015-02-15

The conditional quantum mutual information I(A; B|C) of a tripartite state ρ{sub ABC} is an information quantity which lies at the center of many problems in quantum information theory. Three of its main properties are that it is non-negative for any tripartite state, that it decreases under local operations applied to systems A and B, and that it obeys the duality relation I(A; B|C) = I(A; B|D) for a four-party pure state on systems ABCD. The conditional mutual information also underlies the squashed entanglement, an entanglement measure that satisfies all of the axioms desired for an entanglement measure. As such,more » it has been an open question to find Rényi generalizations of the conditional mutual information, that would allow for a deeper understanding of the original quantity and find applications beyond the traditional memoryless setting of quantum information theory. The present paper addresses this question, by defining different α-Rényi generalizations I{sub α}(A; B|C) of the conditional mutual information, some of which we can prove converge to the conditional mutual information in the limit α → 1. Furthermore, we prove that many of these generalizations satisfy non-negativity, duality, and monotonicity with respect to local operations on one of the systems A or B (with it being left as an open question to prove that monotonicity holds with respect to local operations on both systems). The quantities defined here should find applications in quantum information theory and perhaps even in other areas of physics, but we leave this for future work. We also state a conjecture regarding the monotonicity of the Rényi conditional mutual informations defined here with respect to the Rényi parameter α. We prove that this conjecture is true in some special cases and when α is in a neighborhood of one.« less

Clinically Evaluated Cancer Drugs Inhibiting Redox Signaling.

PubMed

Kirkpatrick, D Lynn; Powis, Garth

2017-02-20

There are a number of redox-active anticancer agents currently in development based on the premise that altered redox homeostasis is necessary for cancer cell's survival. Recent Advances: This review focuses on the relatively few agents that target cellular redox homeostasis to have entered clinical trial as anticancer drugs. The success rate of redox anticancer drugs has been disappointing compared to other classes of anticancer agents. This is due, in part, to our incomplete understanding of the functions of the redox targets in normal and cancer tissues, leading to off-target toxicities and low therapeutic indexes of the drugs. The field also lags behind in the use biomarkers and other means to select patients who are most likely to respond to redox-targeted therapy. If we wish to derive clinical benefit from agents that attack redox targets, then the future will require a more sophisticated understanding of the role of redox targets in cancer and the increased application of personalized medicine principles for their use. Antioxid. Redox Signal. 26, 262-273.

Exploring Proxy Measures of Mutuality for Strategic Partnership Development: A Case Study.

PubMed

Mayo-Gamble, Tilicia L; Barnes, Priscilla A; Sherwood-Laughlin, Catherine M; Reece, Michael; DeWeese, Sandy; Kennedy, Carol Weiss; Valenta, Mary Ann

2017-07-01

Partnerships between academic and clinical-based health organizations are becoming increasingly important in improving health outcomes. Mutuality is recognized as a vital component of these partnerships. If partnerships are to achieve mutuality, there is a need to define what it means to partnering organizations. Few studies have described the elements contributing to mutuality, particularly in new relationships between academic and clinical partners. This study seeks to identify how mutuality is expressed and to explore potential proxy measures of mutuality for an alliance consisting of a hospital system and a School of Public Health. Key informant interviews were conducted with faculty and hospital representatives serving on the partnership steering committee. Key informants were asked about perceived events that led to the development of the Alliance; perceived goals, expectations, and outcomes; and current/future roles with the Alliance. Four proxy measures of mutuality for an academic-clinical partnership were identified: policy directives, community beneficence, procurement of human capital, and partnership longevity. Findings can inform the development of tools for assisting in strengthening relationships and ensuring stakeholders' interests align with the mission and goal of the partnership by operationalizing elements necessary to evaluate the progress of the partnership.

78 FR 4145 - Proposed Recommendations Regarding Money Market Mutual Fund Reform

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-18

... FINANCIAL STABILITY OVERSIGHT COUNCIL Proposed Recommendations Regarding Money Market Mutual Fund Reform AGENCY: Financial Stability Oversight Council. ACTION: Proposed recommendation; extension of...'') published in the Federal Register proposed recommendations regarding money market mutual funds (``MMFs...

26 CFR 1.822-5 - Mutual insurance company taxable income.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Mutual insurance company taxable income. 1.822-5... TAX (CONTINUED) INCOME TAXES Mutual Insurance Companies (other Than Life and Certain Marine Insurance Companies and Other Than Fire Or Flood Insurance Companies Which Operate on Basis of Perpetual Policies Or...

Mutual Injection Locking of Monolithically Integrated Coupled-Cavity DBR Lasers

DOE PAGES

Tauke-Pedretti, Anna; Vawter, G. Allen; Skogen, Erik J.; ...

2011-07-01

We present a photonic integrated circuit (PIC) composed of two strongly coupled distributed Bragg reflector (DBR) lasers. This PIC utilizes the dynamics of mutual injection locking to increase the relaxation resonance frequency from 3 GHz to beyond 30 GHz. Mutual injection-locking and external injection-locking operation are then compared.

The Mutual Storytelling Writing Game.

ERIC Educational Resources Information Center

Scorzelli, James F.; Gold, Julie

1999-01-01

Because of differences in cultural backgrounds and learning styles, some children have a difficult time verbalizing their emotions or appear resistant to talking about themselves. Describes a technique, referred to as the mutual storytelling writing game, that has been found to be useful for children who have difficulty in engaging in traditional…

Mutual Respect and Civic Education

ERIC Educational Resources Information Center

Bird, Colin

2010-01-01

Contemporary theories of civic education frequently appeal to an ideal of mutual respect in the context of ethical, ethical and religious disagreement. This paper critically examines two recently popular criticisms of this ideal. The first, coming from a postmodern direction, charges that the ideal is hypocritical in its effort to be maximally…

[Quantitative Prediction of Drug-Drug Interaction Caused by CYP Inhibition and Induction from In Vivo Data and Its Application in Daily Clinical Practices-Proposal for the Pharmacokinetic Interaction Significance Classification System (PISCS)].

PubMed

Ohno, Yoshiyuki

2018-01-01

　Drug-drug interactions (DDIs) can affect the clearance of various drugs from the body; however, these effects are difficult to sufficiently evaluate in clinical studies. This article outlines our approach to improving methods for evaluating and providing drug information relative to the effects of DDIs. In a previous study, total exposure changes to many substrate drugs of CYP caused by the co-administration of inhibitor or inducer drugs were successfully predicted using in vivo data. There are two parameters for the prediction: the contribution ratio of the enzyme to oral clearance for substrates (CR), and either the inhibition ratio for inhibitors (IR) or the increase in clearance of substrates produced by induction (IC). To apply these predictions in daily pharmacotherapy, the clinical significance of any pharmacokinetic changes must be carefully evaluated. We constructed a pharmacokinetic interaction significance classification system (PISCS) in which the clinical significance of DDIs was considered in a systematic manner, according to pharmacokinetic changes. The PISCS suggests that many current 'alert' classifications are potentially inappropriate, especially for drug combinations in which pharmacokinetics have not yet been evaluated. It is expected that PISCS would contribute to constructing a reliable system to alert pharmacists, physicians and consumers of a broad range of pharmacokinetic DDIs in order to more safely manage daily clinical practices.

ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling.

PubMed

Harris, Abigail; Siggers, Pam; Corrochano, Silvia; Warr, Nick; Sagar, Danielle; Grimes, Daniel T; Suzuki, Makoto; Burdine, Rebecca D; Cong, Feng; Koo, Bon-Kyoung; Clevers, Hans; Stévant, Isabelle; Nef, Serge; Wells, Sara; Brauner, Raja; Ben Rhouma, Bochra; Belguith, Neïla; Eozenou, Caroline; Bignon-Topalovic, Joelle; Bashamboo, Anu; McElreavey, Ken; Greenfield, Andy

2018-05-22

Mammalian sex determination is controlled by the antagonistic interactions of two genetic pathways: The SRY-SOX9-FGF9 network promotes testis determination partly by opposing proovarian pathways, while RSPO1/WNT-β-catenin/FOXL2 signals control ovary development by inhibiting SRY-SOX9-FGF9. The molecular basis of this mutual antagonism is unclear. Here we show that ZNRF3, a WNT signaling antagonist and direct target of RSPO1-mediated inhibition, is required for sex determination in mice. XY mice lacking ZNRF3 exhibit complete or partial gonadal sex reversal, or related defects. These abnormalities are associated with ectopic WNT/β-catenin activity and reduced Sox9 expression during fetal sex determination. Using exome sequencing of individuals with 46,XY disorders of sex development, we identified three human ZNRF3 variants in very rare cases of XY female presentation. We tested two missense variants and show that these disrupt ZNRF3 activity in both human cell lines and zebrafish embryo assays. Our data identify a testis-determining function for ZNRF3 and indicate a mechanism of direct molecular interaction between two mutually antagonistic organogenetic pathways. Copyright © 2018 the Author(s). Published by PNAS.

ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling

PubMed Central

Harris, Abigail; Siggers, Pam; Warr, Nick; Sagar, Danielle; Grimes, Daniel T.; Cong, Feng; Koo, Bon-Kyoung; Clevers, Hans; Stévant, Isabelle; Nef, Serge; Wells, Sara; Brauner, Raja; Ben Rhouma, Bochra; Belguith, Neïla; Eozenou, Caroline; Bignon-Topalovic, Joelle; Bashamboo, Anu; McElreavey, Ken

2018-01-01

Mammalian sex determination is controlled by the antagonistic interactions of two genetic pathways: The SRY-SOX9-FGF9 network promotes testis determination partly by opposing proovarian pathways, while RSPO1/WNT-β-catenin/FOXL2 signals control ovary development by inhibiting SRY-SOX9-FGF9. The molecular basis of this mutual antagonism is unclear. Here we show that ZNRF3, a WNT signaling antagonist and direct target of RSPO1-mediated inhibition, is required for sex determination in mice. XY mice lacking ZNRF3 exhibit complete or partial gonadal sex reversal, or related defects. These abnormalities are associated with ectopic WNT/β-catenin activity and reduced Sox9 expression during fetal sex determination. Using exome sequencing of individuals with 46,XY disorders of sex development, we identified three human ZNRF3 variants in very rare cases of XY female presentation. We tested two missense variants and show that these disrupt ZNRF3 activity in both human cell lines and zebrafish embryo assays. Our data identify a testis-determining function for ZNRF3 and indicate a mechanism of direct molecular interaction between two mutually antagonistic organogenetic pathways. PMID:29735715

Inhibition of cation channel function at the nicotinic acethylcholine receptor from Torpedo: Agonist self-inhibition and anesthetic drugs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Forman, S.A.

1989-01-01

Modulation of the nicotinic acethylcholine receptor from Torpedo by cholinergic agonists, local anesthetics, and n-alkanols was studied using {sup 86}Rb{sup +} flux studies in sealed native Torpedo electroplaque membrane vesicles. Reliable concentration-response and kinetic data were obtained using manual ten sec filtration assays in vesicles partially blocked with alpha-bungarotoxin to remove spare receptors and quenched-flow assays to assess initial {sup 86}Rb{sup +} flux rates or the rate of drug-induced receptor inactivation. Concentration response relationships for the agonists acetylcholine, carbamylcholine, suberyldicholine, phenyltrimethylammonium, and (-)-nicotine are all bell-shape due to stimulation of cation channel opening at low concentrations and inhibition of channelsmore » at higher concentrations. The rate of agonist-induced fast desensitization (k{sub d}) increases with (acetylcholine) in parallel with channel activation, suggesting that desensitization proceeds from the open state and/or states in rapid equilibrium with it. At self-inhibitory acetylcholine concentrations, a new rapid inactivation (rate = k{sub f}) is observed before fast desensitization. The rate and extent of rapid inactivation is compatible with bimolecular association between acethylcholine and inhibitory site with K{sub B} = 40 mM.« less

Enhanced mutual capture of colored solitons by matched modulator

NASA Astrophysics Data System (ADS)

Feigenbaum, Eyal; Orenstein, Meir

2004-08-01

The mutual capture of two colored solitons is enhanced by a modulator, to a level which enables its practical exploitation, e.g., for a read- write mechanism in a soliton buffer. The enhanced capture was analyzed using closed form particle-like soliton perturbation, and verified by numerical simulations. Optimal modulator frequency and modulation depth are obtained. This mutual capture can be utilized for all-optical soliton logic and memory.

24 CFR 203.421 - Allocation of Mutual Mortgage Insurance Fund income or loss.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Mortgage Insurance Fund and Distributive Shares § 203.421 Allocation of Mutual Mortgage Insurance Fund... of the entire Mutual Mortgage Insurance Fund, such net income or such loss to the General Surplus... 24 Housing and Urban Development 2 2011-04-01 2011-04-01 false Allocation of Mutual Mortgage...

A consumer-resource approach to the density-dependent population dynamics of mutualism.

PubMed

Holland, J Nathaniel; DeAngelis, Donald L

2010-05-01

Like predation and competition, mutualism is now recognized as a consumer-resource (C-R) interaction, including, in particular, bi-directional (e.g., coral, plant-mycorrhizae) and uni-directional (e.g., ant-plant defense, plant-pollinator) C-R mutualisms. Here, we develop general theory for the density-dependent population dynamics of mutualism based on the C-R mechanism of interspecific interaction. To test the influence of C-R interactions on the dynamics and stability of bi- and uni-directional C-R mutualisms, we developed simple models that link consumer functional response of one mutualistic species with the resources supplied by another. Phase-plane analyses show that the ecological dynamics of C-R mutualisms are stable in general. Most transient behavior leads to an equilibrium of mutualistic coexistence, at which both species densities are greater than in the absence of interactions. However, due to the basic nature of C-R interactions, certain density-dependent conditions can lead to C-R dynamics characteristic of predator-prey interactions, in which one species overexploits and causes the other to go extinct. Consistent with empirical phenomena, these results suggest that the C-R interaction can provide a broad mechanism for understanding density-dependent population dynamics of mutualism. By unifying predation, competition, and mutualism under the common ecological framework of consumer-resource theory, we may also gain a better understanding of the universal features of interspecific interactions in general.

A consumer-resource approach to the density-dependent population dynamics of mutualism

USGS Publications Warehouse

Holland, J. Nathaniel; DeAngelis, Donald L.

2010-01-01

Like predation and competition, mutualism is now recognized as a consumer resource (C-R) interaction, including, in particular, bi-directional (e.g., coral, plant- mycorrhizae) and uni-directional (e.g., ant-plant defense, plant-pollinator) C-R mutualisms. Here, we develop general theory for the density-dependent population dynamics of mutualism based on the C-R mechanism of interspecific interaction. To test the influence of C-R interactions on the dynamics and stability of bi- and uni-directional C-R mutualisms, we developed simple models that link consumer functional response of one mutualistic species with the resources supplied by another. Phase-plane analyses show that the ecological dynamics of C-R mutualisms are stable in general. Most transient behavior leads to an equilibrium of mutualistic coexistence, at which both species densities are greater than in the absence of interactions. However, due to the basic nature of C-R interactions, certain density-dependent conditions can lead to C-R dynamics characteristic of predator-prey interactions, in which one species overexploits and causes the other to go extinct. Consistent with empirical phenomena, these results suggest that the C-R interaction can provide a broad mechanism for understanding density-dependent population dynamics of mutualism. By unifying predation, competition, and mutualism under the common ecological framework of consumer-resource theory, we may also gain a better understanding of the universal features of interspecific interactions in general.

Mutually unbiased projectors and duality between lines and bases in finite quantum systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shalaby, M.; Vourdas, A., E-mail: a.vourdas@bradford.ac.uk

2013-10-15

Quantum systems with variables in the ring Z(d) are considered, and the concepts of weak mutually unbiased bases and mutually unbiased projectors are discussed. The lines through the origin in the Z(d)×Z(d) phase space, are classified into maximal lines (sets of d points), and sublines (sets of d{sub i} points where d{sub i}|d). The sublines are intersections of maximal lines. It is shown that there exists a duality between the properties of lines (resp., sublines), and the properties of weak mutually unbiased bases (resp., mutually unbiased projectors). -- Highlights: •Lines in discrete phase space. •Bases in finite quantum systems. •Dualitymore » between bases and lines. •Weak mutually unbiased bases.« less

Cooperation in Academic Negotiations: A Guide to Mutual Gains Bargaining.

ERIC Educational Resources Information Center

Birnbaum, Robert; And Others

A guide to mutual gains bargaining (MGB) is presented for faculty union leaders and college administrators, as well as school systems. MGB is based on applied behavioral sciences concepts and the use of bargaining teams and emphasizes problem-solving and improving communications and campus relationships. Two different uses of the mutual gains…

Anthelmintic drug niclosamide enhances the sensitivity of chronic myeloid leukemia cells to dasatinib through inhibiting Erk/Mnk1/eIF4E pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Zhong; Li, Yong; Lv, Cao

Chronic myeloid leukemia (CML) responds well to BCR-ABL tyrosine kinase inhibitors (TKI), but becomes resistant to TKIs after it progresses to blast phase (BP). Here we show that niclosamide, a FDA-approved anthelmintic drug, enhances the sensitivity of BP-CML cells to dasatinib (2nd generation of BCR-ABL TKI) through inhibiting Erk/Mnk1/eIF4E signaling pathway. Niclosamide dose-dependently inhibits proliferation and induces apoptosis in a panel of CML cell lines. It also selectively targets BP-CML CD34 stem/progenitor cells through inducing apoptosis, inhibiting colony formation and self-renewal capacity while sparing normal bone marrow (NBM) counterparts. In addition, combination of niclosamide and dasatinib is synergistic in CMLmore » cell lines and BP-CML CD34 cells. Importantly, niclosamide inhibits phosphorylation of Erk, Mnk1 and eIF4E in CML cells. Overexpression of phosphomimetic but not nonphosphorylatable form of eIF4E reverses the inhibitory effects of niclosamide, suggesting that eIF4E inhibition is required for the action of niclosamide in CML. Compared to NBM, the increased levels of eIF4E and its activity in CML CD34 cells might explain the selective toxicity of niclosamide in CML versus NBM. We further show that dasatinib time-dependently induces eIF4E phosphorylation. The combination of eIF4E depletion and dasatinib results in similar effects as the combination of niclosamide and dasatinib, suggesting that niclosamide enhances dasatinib through targeting eIF4E. Our work is the first to demonstrate that niclosamide is a potential drug to overcome resistance to BCR-ABL TKI treatment in BP-CML. Our findings also suggest the therapeutic value of Erk/Mnk/eIF4E in CML treatment.« less

Mutual information and the fidelity of response of gene regulatory models

NASA Astrophysics Data System (ADS)

Tabbaa, Omar P.; Jayaprakash, C.

2014-08-01

We investigate cellular response to extracellular signals by using information theory techniques motivated by recent experiments. We present results for the steady state of the following gene regulatory models found in both prokaryotic and eukaryotic cells: a linear transcription-translation model and a positive or negative auto-regulatory model. We calculate both the information capacity and the mutual information exactly for simple models and approximately for the full model. We find that (1) small changes in mutual information can lead to potentially important changes in cellular response and (2) there are diminishing returns in the fidelity of response as the mutual information increases. We calculate the information capacity using Gillespie simulations of a model for the TNF-α-NF-κ B network and find good agreement with the measured value for an experimental realization of this network. Our results provide a quantitative understanding of the differences in cellular response when comparing experimentally measured mutual information values of different gene regulatory models. Our calculations demonstrate that Gillespie simulations can be used to compute the mutual information of more complex gene regulatory models, providing a potentially useful tool in synthetic biology.

Targeting efflux pumps to overcome antifungal drug resistance

PubMed Central

Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob; Ivnitski-Steele, Irena; Keniya, Mikhail V; Lackovic, Kurt; Monk, Brian C; Sklar, Larry A; Cannon, Richard D

2016-01-01

Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps. PMID:27463566

12 CFR 12.101 - National bank disclosure of remuneration for mutual fund transactions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... mutual fund transactions. 12.101 Section 12.101 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT... Interpretations § 12.101 National bank disclosure of remuneration for mutual fund transactions. A national bank... by § 12.4, for mutual fund transactions by providing this information to the customer in a current...

12 CFR 12.101 - National bank disclosure of remuneration for mutual fund transactions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... mutual fund transactions. 12.101 Section 12.101 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT... Interpretations § 12.101 National bank disclosure of remuneration for mutual fund transactions. A national bank... by § 12.4, for mutual fund transactions by providing this information to the customer in a current...

26 CFR 1.501(c)(14)-1 - Credit unions and mutual insurance funds.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Credit unions and mutual insurance funds. 1.501(c... unions and mutual insurance funds. Credit unions (other than Federal credit unions described in section 501(c)(1)) without capital stock, organized and operated for mutual purposes and without profit, are...

26 CFR 1.501(c)(14)-1 - Credit unions and mutual insurance funds.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Credit unions and mutual insurance funds. 1.501(c... unions and mutual insurance funds. Credit unions (other than Federal credit unions described in section 501(c)(1)) without capital stock, organized and operated for mutual purposes and without profit, are...

Supermode noise suppression with mutual injection locking for coupled optoelectronic oscillator.

PubMed

Dai, Jian; Liu, Anni; Liu, Jingliang; Zhang, Tian; Zhou, Yue; Yin, Feifei; Dai, Yitang; Liu, Yuanan; Xu, Kun

2017-10-30

The coupled optoelectronic oscillator (COEO) is typically used to generate high frequency spectrally pure microwave signal with serious sidemodes noise. We propose and experimentally demonstrate a simple scheme for supermode suppression with mutual injection locking between the COEO (master oscillator with multi-modes oscillation) and the embedded free-running oscillator (slave oscillator with single-mode oscillation). The master and slave oscillators share the same electrical feedback path, which means that the mutually injection-locked COEO brings no additional hardware complexity. Owing to the mode matching and mutually injection locking effect, 9.999 GHz signal has been successfully obtained by the mutually injection-locked COEO with the phase noise about -117 dBc/Hz at 10 kHz offset frequency. Besides, the supermode noise can be significantly suppressed more than 50 dB to below -120 dBc.

Long-range mutual synchronization of spin Hall nano-oscillators

NASA Astrophysics Data System (ADS)

Awad, A. A.; Dürrenfeld, P.; Houshang, A.; Dvornik, M.; Iacocca, E.; Dumas, R. K.; Åkerman, J.

2017-03-01

The spin Hall effect in a non-magnetic metal with spin-orbit coupling injects transverse spin currents into adjacent magnetic layers, where the resulting spin transfer torque can drive spin wave auto-oscillations. Such spin Hall nano-oscillators (SHNOs) hold great promise as extremely compact and broadband microwave signal generators and magnonic spin wave injectors. Here we show that SHNOs can also be mutually synchronized with unprecedented efficiency. We demonstrate mutual synchronization of up to nine individual SHNOs, each separated by 300 nm. Through further tailoring of the connection regions we can extend the synchronization range to 4 μm. The mutual synchronization is observed electrically as an increase in the power and coherence of the microwave signal, and confirmed optically using micro-Brillouin light scattering microscopy as two spin wave regions sharing the same spectral content, in agreement with our micromagnetic simulations.

Ethanol oxidation and the inhibition by drugs in human liver, stomach and small intestine: Quantitative assessment with numerical organ modeling of alcohol dehydrogenase isozymes.

PubMed

Chi, Yu-Chou; Lee, Shou-Lun; Lai, Ching-Long; Lee, Yung-Pin; Lee, Shiao-Pieng; Chiang, Chien-Ping; Yin, Shih-Jiun

2016-10-25

Alcohol dehydrogenase (ADH) is the principal enzyme responsible for metabolism of ethanol. Human ADH constitutes a complex isozyme family with striking variations in kinetic function and tissue distribution. Liver and gastrointestinal tract are the major sites for first-pass metabolism (FPM). Their relative contributions to alcohol FPM and degrees of the inhibitions by aspirin and its metabolite salicylate, acetaminophen and cimetidine remain controversial. To address this issue, mathematical organ modeling of ethanol-oxidizing activities in target tissues and that of the ethanol-drug interactions were constructed by linear combination of the corresponding numerical rate equations of tissue constituent ADH isozymes with the documented isozyme protein contents, kinetic parameters for ethanol oxidation and the drug inhibitions of ADH isozymes/allozymes that were determined in 0.1 M sodium phosphate at pH 7.5 and 25 °C containing 0.5 mM NAD(+). The organ simulations reveal that the ADH activities in mucosae of the stomach, duodenum and jejunum with ADH1C*1/*1 genotype are less than 1%, respectively, that of the ADH1B*1/*1-ADH1C*1/*1 liver at 1-200 mM ethanol, indicating that liver is major site of the FPM. The apparent hepatic KM and Vmax for ethanol oxidation are simulated to be 0.093 ± 0.019 mM and 4.0 ± 0.1 mmol/min, respectively. At 95% clearance in liver, the logarithmic average sinusoidal ethanol concentration is determined to be 0.80 mM in accordance with the flow-limited gradient perfusion model. The organ simulations indicate that higher therapeutic acetaminophen (0.5 mM) inhibits 16% of ADH1B*1/*1 hepatic ADH activity at 2-20 mM ethanol and that therapeutic salicylate (1.5 mM) inhibits 30-31% of the ADH1B*2/*2 activity, suggesting potential significant inhibitions of ethanol FPM in these allelotypes. The result provides systematic evaluations and predictions by computer simulation on potential ethanol FPM in target tissues and hepatic

Oral Multiple Sclerosis Drugs Inhibit the In vitro Growth of Epsilon Toxin Producing Gut Bacterium, Clostridium perfringens

PubMed Central

Rumah, Kareem R.; Vartanian, Timothy K.; Fischetti, Vincent A.

2017-01-01

There are currently three oral medications approved for the treatment of multiple sclerosis (MS). Two of these medications, Fingolimod, and Teriflunomide, are considered to be anti-inflammatory agents, while dimethyl fumarate (DMF) is thought to trigger a robust antioxidant response, protecting vulnerable cells during an MS attack. We previously proposed that epsilon toxin from the gut bacterium, Clostridium perfringens, may initiate newly forming MS lesions due to its tropism for blood-brain barrier (BBB) vasculature and central nervous system myelin. Because gut microbiota will be exposed to these oral therapies prior to systemic absorption, we sought to determine if these compounds affect C. perfringens growth in vitro. Here we show that Fingolimod, Teriflunomide, and DMF indeed inhibit C. perfringens growth. Furthermore, several compounds similar to DMF in chemical structure, namely α, β unsaturated carbonyls, also known as Michael acceptors, inhibit C. perfringens. Sphingosine, a Fingolimod homolog with known antibacterial properties, proved to be a potent C. perfringens inhibitor with a Minimal Inhibitory Concentration similar to that of Fingolimod. These findings suggest that currently approved oral MS therapies and structurally related compounds possess antibacterial properties that may alter the gut microbiota. Moreover, inhibition of C. perfringens growth and resulting blockade of epsilon toxin production may contribute to the clinical efficacy of these disease-modifying drugs. PMID:28180112

Neprilysin inhibition in chronic kidney disease

PubMed Central

Judge, Parminder; Haynes, Richard; Landray, Martin J.; Baigent, Colin

2015-01-01

Despite current practice, patients with chronic kidney disease (CKD) are at increased risk of progression to end-stage renal disease and cardiovascular events. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. NEPi enhances the activity of natriuretic peptide systems leading to natriuresis, diuresis and inhibition of the renin–angiotensin system (RAS), which could act as a potentially beneficial counter-regulatory system in states of RAS activation such as chronic heart failure (HF) and CKD. Early NEPi drugs were combined with angiotensin-converting enzyme inhibitors but were associated with unacceptable rates of angioedema and, therefore, withdrawn. However, one such agent (omapatrilat) showed promise of NEP/RAS inhibition in treating CKD in animal models, producing greater reductions in proteinuria, glomerulosclerosis and tubulointerstitial fibrosis compared with isolated RAS inhibition. A new class of drug called angiotensin receptor neprilysin inhibitor (ARNi) has been developed. One such drug, LCZ696, has shown substantial benefits in trials in hypertension and HF. In CKD, HF is common due to a range of mechanisms including hypertension and structural heart disease (including left ventricular hypertrophy), suggesting that ARNi could benefit patients with CKD by both retarding the progression of CKD (hence delaying the need for renal replacement therapy) and reducing the risk of cardiovascular disease. LCZ696 is now being studied in a CKD population. PMID:25140014

Quantitative estimation of cholinesterase-specific drug metabolism of carbamate inhibitors provided by the analysis of the area under the inhibition-time curve.

PubMed

Zhou, Huimin; Xiao, Qiaoling; Tan, Wen; Zhan, Yiyi; Pistolozzi, Marco

2017-09-10

Several molecules containing carbamate groups are metabolized by cholinesterases. This metabolism includes a time-dependent catalytic step which temporary inhibits the enzymes. In this paper we demonstrate that the analysis of the area under the inhibition versus time curve (AUIC) can be used to obtain a quantitative estimation of the amount of carbamate metabolized by the enzyme. (R)-bambuterol monocarbamate and plasma butyrylcholinesterase were used as model carbamate-cholinesterase system. The inhibition of different concentrations of the enzyme was monitored for 5h upon incubation with different concentrations of carbamate and the resulting AUICs were analyzed. The amount of carbamate metabolized could be estimated with <15% accuracy (RE%) and ≤23% precision (RSD%). Since the knowledge of the inhibition kinetics is not required for the analysis, this approach could be used to determine the amount of drug metabolized by cholinesterases in a selected compartment in which the cholinesterase is confined (e.g. in vitro solutions, tissues or body fluids), either in vitro or in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

Problem decomposition by mutual information and force-based clustering

NASA Astrophysics Data System (ADS)

Otero, Richard Edward

The scale of engineering problems has sharply increased over the last twenty years. Larger coupled systems, increasing complexity, and limited resources create a need for methods that automatically decompose problems into manageable sub-problems by discovering and leveraging problem structure. The ability to learn the coupling (inter-dependence) structure and reorganize the original problem could lead to large reductions in the time to analyze complex problems. Such decomposition methods could also provide engineering insight on the fundamental physics driving problem solution. This work forwards the current state of the art in engineering decomposition through the application of techniques originally developed within computer science and information theory. The work describes the current state of automatic problem decomposition in engineering and utilizes several promising ideas to advance the state of the practice. Mutual information is a novel metric for data dependence and works on both continuous and discrete data. Mutual information can measure both the linear and non-linear dependence between variables without the limitations of linear dependence measured through covariance. Mutual information is also able to handle data that does not have derivative information, unlike other metrics that require it. The value of mutual information to engineering design work is demonstrated on a planetary entry problem. This study utilizes a novel tool developed in this work for planetary entry system synthesis. A graphical method, force-based clustering, is used to discover related sub-graph structure as a function of problem structure and links ranked by their mutual information. This method does not require the stochastic use of neural networks and could be used with any link ranking method currently utilized in the field. Application of this method is demonstrated on a large, coupled low-thrust trajectory problem. Mutual information also serves as the basis for an

76 FR 36625 - Mutual Holding Company

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-22

... DEPARTMENT OF THE TREASURY Office of Thrift Supervision Mutual Holding Company AGENCY: Office of Thrift Supervision (OTS), Treasury. ACTION: Notice and request for comment. SUMMARY: The proposed... Collection Comments, Chief Counsel's Office, Office of Thrift Supervision, 1700 G Street, NW., Washington, DC...

In-vitro and in-vivo inhibition of melanoma growth and metastasis by the drug combination of celecoxib and dacarbazine.

PubMed

Sadhu, Satya S; Wang, Shenggang; Averineni, Ranjith K; Seefeldt, Teresa; Yang, Yang; Guan, Xiangming

2016-12-01

Celecoxib has been found to be effective in cancer prevention and treatment. Its combination with other chemotherapeutic agents was reported to produce synergistic/additive effects on various cancers. Dacarbazine (DTIC) is one of the most commonly used drugs in the treatment of metastatic melanoma. This investigation aimed to determine the in-vitro and in-vivo effects of the drug combination of celecoxib and DTIC on melanoma growth and metastasis. Melanoma cells B16-F10 and SK-MEL-28, and female C57BL/6 mice were used for the study. Our in-vitro data showed that significant synergistic effects were obtained when celecoxib was used together with various concentrations of DTIC. A study with B16-F10 cells using flow cytometry analysis showed that the drug combination induced significantly more apoptosis than each drug used individually. Our in-vivo results showed that the drug combination was much more effective than each drug used alone for the inhibition of both melanoma growth and metastasis in the B16-F10+C57BL/6 mouse models. For melanoma growth, the median survival rates for phosphate-buffered saline (PBS) (control), celecoxib (30 mg/kg), DTIC-1 (10 mg/kg), DTIC-2 (positive control, 50 mg/kg), and the drug combination (DTIC 10 mg/kg+celecoxib 30 mg/kg) were 6, 6.5, 7.5, 7.5, and 9 days, respectively. For melanoma metastasis, the average number of metastatic tumors in murine lungs was 53.7±10.7, 31.8±18.6, 21.2±21.7, 7.0±9.0, and 0.8±2.0 for PBS, DTIC-1, celecoxib, the drug combination, and DTIC-2. Our results warrant further investigation of the combination as an effective treatment for melanoma patients.

Empirical study of the tails of mutual fund size

NASA Astrophysics Data System (ADS)

Schwarzkopf, Yonathan; Farmer, J. Doyne

2010-06-01

The mutual fund industry manages about a quarter of the assets in the U.S. stock market and thus plays an important role in the U.S. economy. The question of how much control is concentrated in the hands of the largest players is best quantitatively discussed in terms of the tail behavior of the mutual fund size distribution. We study the distribution empirically and show that the tail is much better described by a log-normal than a power law, indicating less concentration than, for example, personal income. The results are highly statistically significant and are consistent across fifteen years. This contradicts a recent theory concerning the origin of the power law tails of the trading volume distribution. Based on the analysis in a companion paper, the log-normality is to be expected, and indicates that the distribution of mutual funds remains perpetually out of equilibrium.

77 FR 42553 - Surety Companies Acceptable on Federal Bonds-Termination and Merger: Harleysville Mutual...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-19

...--Termination and Merger: Harleysville Mutual Insurance Company (NAIC 14168) AGENCY: Financial Management... company merged with and into Nationwide Mutual Insurance Company (NAIC 23787) effective May 1, 2012. The surviving corporation of the merger activity is Nationwide Mutual Insurance Company (NAIC 23787), an Ohio...

77 FR 25212 - Praxis Mutual Funds and Everence Community Investments, Inc.; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-27

... Mutual Funds and Everence Community Investments, Inc.; Notice of Application April 23, 2012. AGENCY... Act to permit certain transactions. Applicants: Praxis Mutual Funds (``Trust'') and Everence Community... development investment program. \\1\\ MMA Praxis Mutual Funds, et al., Investment Company Act Release Nos. 25263...

A 3-year study of addiction mutual-help group participation following intensive outpatient treatment.

PubMed

Kelly, John F; Stout, Robert; Zywiak, William; Schneider, Robert

2006-08-01

Addiction-focused mutual-help group participation is associated with better substance use disorder (SUD) treatment outcomes. However, little has been documented regarding which types of mutual-help organizations patients attend, what levels of participation may be beneficial, and which patients, in particular, are more or less likely to participate. Furthermore, much of the evidence supporting the use of these organizations comes from studies examining participation and outcomes concurrently, raising doubts about cause-effect connections, and little is known about influences that may moderate the degree of any general benefit. Alcohol-dependent outpatients (N=227; 27% female; M age=42) enrolled in a randomized-controlled telephone case monitoring trial were assessed at treatment intake and at 1, 2, and 3 years postdischarge. Lagged-panel, hierarchical linear models tested whether mutual-help group participation in the first and second year following treatment predicted subsequent outcomes and whether these effects were moderated by gender, concurrent axis I diagnosis, religious preference, and prior mutual-help experience. Robust regression curve analysis was used to examine dose-response relationships between mutual-help and outcomes. Mutual-help participation was associated with both greater abstinence and fewer drinks per drinking day and this relationship was not found to be influenced by gender, Axis I diagnosis, religious preference, or prior mutual-help participation. Mutual-help participants attended predominantly Alcoholics Anonymous and tended to be Caucasian, be more educated, have prior mutual-help experience, and have more severe alcohol involvement. Dose-response curve analyses suggested that even small amounts of participation may be helpful in increasing abstinence, whereas higher doses may be needed to reduce relapse intensity. Use of mutual-help groups following intensive outpatient SUD treatment appears to be beneficial for many different types

Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Yingying; Fang, Shanshan; Sun, Qiushi

Glioblastoma is one of the most vascular brain tumour and highly resistant to current therapy. Targeting both glioblastoma cells and angiogenesis may present an effective therapeutic strategy for glioblastoma. In our work, we show that an anthelmintic drug, ivermectin, is active against glioblastoma cells in vitro and in vivo, and also targets angiogenesis. Ivermectin significantly inhibits growth and anchorage-independent colony formation in U87 and T98G glioblastoma cells. It induces apoptosis in these cells through a caspase-dependent manner. Ivermectin significantly suppresses the growth of two independent glioblastoma xenograft mouse models. In addition, ivermectin effectively targets angiogenesis through inhibiting capillary network formation, proliferation andmore » survival in human brain microvascular endothelial cell (HBMEC). Mechanistically, ivermectin decreases mitochondrial respiration, membrane potential, ATP levels and increases mitochondrial superoxide in U87, T98G and HBMEC cells exposed to ivermectin. The inhibitory effects of ivermectin are significantly reversed in mitochondria-deficient cells or cells treated with antioxidants, further confirming that ivermectin acts through mitochondrial respiration inhibition and induction of oxidative stress. Importantly, we show that ivermectin suppresses phosphorylation of Akt, mTOR and ribosomal S6 in glioblastoma and HBMEC cells, suggesting its inhibitory role in deactivating Akt/mTOR pathway. Altogether, our work demonstrates that ivermectin is a useful addition to the treatment armamentarium for glioblastoma. Our work also highlights the therapeutic value of targeting mitochondrial metabolism in glioblastoma. - Highlights: • Ivermectin is effective in glioblastoma cells in vitro and in vivo. • Ivermectin inhibits angiogenesis. • Ivermectin induces mitochondrial dysfunction and oxidative stress. • Ivermectin deactivates Akt/mTOR signaling pathway.« less

Methylenedioxy designer drugs: mass spectrometric characterization of their glutathione conjugates by means of liquid chromatography-high-resolution mass spectrometry/mass spectrometry and studies on their glutathionyl transferase inhibition potency.

PubMed

Meyer, Markus R; Richter, Lilian H J; Maurer, Hans H

2014-04-25

Methylenedioxy designer drugs of abuse such as 3,4-methylenedioxymethamphetamine (MDMA) can be selectively toxic to serotonergic neurons and glutathione (GSH) adducts have been implicated in its neurotoxicity. The catecholic demethylenyl metabolites of MDMA, 3,4-dihydroxymethamphetamine and 3,4-dihydroxyamphetamine, are metabolically oxidized to the corresponding ortho-quinones, which are highly reactive intermediates. These intermediates can then be conjugated with GSH preventing cellular damage. Furthermore, glutathionyl transferase (GST) activity was described to be irreversibly inhibited by the catechols dopamine, α-methyldopa and their GSH conjugates. Therefore, the aims of the present work were the detection and characterization of GSH conjugates of ten methylenedioxy drugs of abuse and their phase I metabolites as well as to assess their inhibition potency on GST activity. The substrates were incubated using human placental GST with or without preincubation by cytochrome P450 enzymes preparations. GST inhibition was tested using chlorodinitrobenzene GSH conjugation as marker reaction. GSH conjugates were analyzed and characterized using LC-high-resolution-MS/MS. For confirmation of postulated fragmentation patterns, formation of GSH conjugates of selected deuterated analogs (deuterated analogue approach, DAA) of the investigated drugs was explored. For the methylenedioxy amphetamines the following steps could be identified: conjugation of the parent compounds at position 2, 5, 6, of the demethylenyl metabolites at position 2 and 5, and of the further deaminated demethylenyl metabolites at position 2. For the β-keto-phenylalkylamine and pyrrolidinophenone, conjugation of the demethylenyl metabolites and of the deaminated demethylenyl metabolites at position 2 could be identified. The DAA allowed the differentiation of the 2 and 5/6 isomers by confirmation of the postulated mass spectral fragments. Finally, the tested drugs and phase I metabolites showed no

Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP).

PubMed

Dong, Zhongqi; Ekins, Sean; Polli, James E

2013-03-04

The hepatic bile acid uptake transporter sodium taurocholate cotransporting polypeptide (NTCP) is less well characterized than its ileal paralog, the apical sodium dependent bile acid transporter (ASBT), in terms of drug inhibition requirements. The objectives of this study were (a) to identify FDA approved drugs that inhibit human NTCP, (b) to develop pharmacophore and Bayesian computational models for NTCP inhibition, and (c) to compare NTCP and ASBT transport inhibition requirements. A series of NTCP inhibition studies were performed using FDA approved drugs, in concert with iterative computational model development. Screening studies identified 27 drugs as novel NTCP inhibitors, including irbesartan (Ki = 11.9 μM) and ezetimibe (Ki = 25.0 μM). The common feature pharmacophore indicated that two hydrophobes and one hydrogen bond acceptor were important for inhibition of NTCP. From 72 drugs screened in vitro, a total of 31 drugs inhibited NTCP, while 51 drugs (i.e., more than half) inhibited ASBT. Hence, while there was inhibitor overlap, ASBT unexpectedly was more permissive to drug inhibition than was NTCP, and this may be related to NTCP possessing fewer pharmacophore features. Findings reflected that a combination of computational and in vitro approaches enriched the understanding of these poorly characterized transporters and yielded additional chemical probes for possible drug-transporter interaction determinations.

Complex degree of mutual anisotropy in diagnostics of biological tissues physiological changes

NASA Astrophysics Data System (ADS)

Ushenko, Yu. A.; Dubolazov, O. V.; Karachevtcev, A. O.; Zabolotna, N. I.

2011-05-01

To characterize the degree of consistency of parameters of the optically uniaxial birefringent protein nets of blood plasma a new parameter - complex degree of mutual anisotropy is suggested. The technique of polarization measuring the coordinate distributions of the complex degree of mutual anisotropy of blood plasma is developed. It is shown that statistic approach to the analysis of complex degree of mutual anisotropy distributions of blood plasma is effective in the diagnosis and differentiation of acute inflammation - acute and gangrenous appendicitis.

Complex degree of mutual anisotropy in diagnostics of biological tissues physiological changes

NASA Astrophysics Data System (ADS)

Ushenko, Yu. A.; Dubolazov, A. V.; Karachevtcev, A. O.; Zabolotna, N. I.

2011-09-01

To characterize the degree of consistency of parameters of the optically uniaxial birefringent protein nets of blood plasma a new parameter - complex degree of mutual anisotropy is suggested. The technique of polarization measuring the coordinate distributions of the complex degree of mutual anisotropy of blood plasma is developed. It is shown that statistic approach to the analysis of complex degree of mutual anisotropy distributions of blood plasma is effective in the diagnosis and differentiation of acute inflammation - acute and gangrenous appendicitis.

[New oral anticoagulant drugs].

PubMed

Berkovits, Alejandro; Aizman, Andrés; Zúñiga, Pamela; Pereira, Jaime; Mezzano, Diego

2011-10-01

Thromboembolic disease (TED) is the leading cause of morbidity and mortality worldwide. The hallmark of oral long-term anticoagulant therapy has been the use of vitamin K antagonists, whose anticoagulant effect is exerted inhibiting vitamin K epoxide reductase. Warfarin and acenocoumarol are the most commonly used. In the last five years several new drugs for long term anticoagulation have been developed, which can inhibit single clotting factors with the purpose of improving drug therapeutic range and, ideally, minimizing bleeding risks. This review addresses the state of the art on the clinical use of inhibitors of activated factor X and thrombin.

Hierarchical mutual information for the comparison of hierarchical community structures in complex networks

NASA Astrophysics Data System (ADS)

Perotti, Juan Ignacio; Tessone, Claudio Juan; Caldarelli, Guido

2015-12-01

The quest for a quantitative characterization of community and modular structure of complex networks produced a variety of methods and algorithms to classify different networks. However, it is not clear if such methods provide consistent, robust, and meaningful results when considering hierarchies as a whole. Part of the problem is the lack of a similarity measure for the comparison of hierarchical community structures. In this work we give a contribution by introducing the hierarchical mutual information, which is a generalization of the traditional mutual information and makes it possible to compare hierarchical partitions and hierarchical community structures. The normalized version of the hierarchical mutual information should behave analogously to the traditional normalized mutual information. Here the correct behavior of the hierarchical mutual information is corroborated on an extensive battery of numerical experiments. The experiments are performed on artificial hierarchies and on the hierarchical community structure of artificial and empirical networks. Furthermore, the experiments illustrate some of the practical applications of the hierarchical mutual information, namely the comparison of different community detection methods and the study of the consistency, robustness, and temporal evolution of the hierarchical modular structure of networks.

21 CFR 201.22 - Prescription drugs containing sulfites; required warning statements.

Code of Federal Regulations, 2012 CFR

2012-04-01

... are added to certain drug products to inhibit the oxidation of the active drug ingredient. Oxidation.... Examples of specific sulfites used to inhibit this oxidation process include sodium bisulfite, sodium...

21 CFR 201.22 - Prescription drugs containing sulfites; required warning statements.

Code of Federal Regulations, 2010 CFR

2010-04-01

... are added to certain drug products to inhibit the oxidation of the active drug ingredient. Oxidation.... Examples of specific sulfites used to inhibit this oxidation process include sodium bisulfite, sodium...

21 CFR 201.22 - Prescription drugs containing sulfites; required warning statements.

Code of Federal Regulations, 2013 CFR

2013-04-01

... are added to certain drug products to inhibit the oxidation of the active drug ingredient. Oxidation.... Examples of specific sulfites used to inhibit this oxidation process include sodium bisulfite, sodium...

21 CFR 201.22 - Prescription drugs containing sulfites; required warning statements.

Code of Federal Regulations, 2011 CFR

2011-04-01

... are added to certain drug products to inhibit the oxidation of the active drug ingredient. Oxidation.... Examples of specific sulfites used to inhibit this oxidation process include sodium bisulfite, sodium...

21 CFR 201.22 - Prescription drugs containing sulfites; required warning statements.

Code of Federal Regulations, 2014 CFR

2014-04-01

... are added to certain drug products to inhibit the oxidation of the active drug ingredient. Oxidation.... Examples of specific sulfites used to inhibit this oxidation process include sodium bisulfite, sodium...

Why power matters: creating a foundation of mutual support in couple relationships.

PubMed

Knudson-Martin, Carmen

2013-03-01

Research shows that equal power helps couples create intimacy and relationship success. However, though couples increasingly desire equal relationships, cultural models of mutual support are not well developed. Clinicians often approach heterosexual couple therapy as though partners are inherently equal, thus reinforcing unacknowledged gender inequities. This article examines research that shows why power imbalances are destructive to intimate relationships and focuses on four gender-related aspects of mutual support: (a) shared relational responsibility, (b) mutual vulnerability, (c) mutual attunement, and (d) shared influence. Case examples illustrate how socio-emotional attunement, interrupting the flow of power, and introducing alternative relational experience help couple therapists identify and address power disparities in these important relational processes. Encouraging the powerful person to take relational initiative and introducing alternative gender discourse are especially important. © FPI, Inc.

Retrovirus XMRV Is Inhibited by Host Proteins and Anti-HIV Drugs AZT, Tenofovir, and Raltegravir | Center for Cancer Research

Cancer.gov

A newly discovered retrovirus, XMRV, isolated from prostate cancer tissues for the first time in 2006, has recently been reported in patients with this cancer, as well as in patients with chronic fatigue syndrome (CFS). However, five subsequent studies could not validate these reports. Since XMRV was isolated from the T and B cells of CFS patients, Vinay Pathak and his colleagues in the HIV Drug Resistance Program sought to determine how XMRV was countering intracellular defense mechanisms that inhibit retroviral replication in human cells.

Promiscuous, Multi-Target Lupane-Type Triterpenoids Inhibits Wild Type and Drug Resistant HIV-1 Replication Through the Interference With Several Targets.

PubMed

Bedoya, Luis M; Beltrán, Manuela; García-Pérez, Javier; Obregón-Calderón, Patricia; Callies, Oliver; Jímenez, Ignacio A; Bazzocchi, Isabel L; Alcamí, José

2018-01-01

Current research on antiretroviral therapy is mainly focused in the development of new formulations or combinations of drugs belonging to already known targets. However, HIV-1 infection is not cured by current therapy and thus, new approaches are needed. Bevirimat was developed by chemical modification of betulinic acid, a lupane-type pentacyclic triterpenoid (LPT), as a first-in-class HIV-1 maturation inhibitor. However, in clinical trials, bevirimat showed less activity than expected because of the presence of a natural mutation in Gag protein that conferred resistance to a high proportion of HIV-1 strains. In this work, three HIV-1 inhibitors selected from a set of previously screened LPTs were investigated for their targets in the HIV-1 replication cycle, including their maturation inhibitor effect. LPTs were found to inhibit HIV-1 infection acting as promiscuous compounds with several targets in the HIV-1 replication cycle. LPT12 inhibited HIV-1 infection mainly through reverse transcription, integration, viral transcription, viral proteins (Gag) production and maturation inhibition. LPT38 did it through integration, viral transcription or Gag production inhibition and finally, LPT42 inhibited reverse transcription, viral transcription or Gag production. The three LPTs inhibited HIV-1 infection of human primary lymphocytes and infections with protease inhibitors and bevirimat resistant HIV-1 variants with similar values of IC 50 . Therefore, we show that the LPTs tested inhibited HIV-1 infection through acting on different targets depending on their chemical structure and the activities of the different LPTs vary with slight structural alterations. For example, of the three LPTs under study, we found that only LPT12 inhibited infectivity of newly-formed viral particles, suggesting a direct action on the maturation process. Thus, the multi-target behavior gives a potential advantage to these compounds since HIV-1 resistance can be overcome by modulating more

Long-range RNA pairings contribute to mutually exclusive splicing

PubMed Central

Yue, Yuan; Yang, Yun; Dai, Lanzhi; Cao, Guozheng; Chen, Ran; Hong, Weiling; Liu, Baoping; Shi, Yang; Meng, Yijun; Shi, Feng; Xiao, Mu; Jin, Yongfeng

2016-01-01

Mutually exclusive splicing is an important means of increasing the protein repertoire, by which the Down's syndrome cell adhesion molecule (Dscam) gene potentially generates 38,016 different isoforms in Drosophila melanogaster. However, the regulatory mechanisms remain obscure due to the complexity of the Dscam exon cluster. Here, we reveal a molecular model for the regulation of the mutually exclusive splicing of the serpent pre-mRNA based on competition between upstream and downstream RNA pairings. Such dual RNA pairings confer fine tuning of the inclusion of alternative exons. Moreover, we demonstrate that the splicing outcome of alternative exons is mediated in relative pairing strength-correlated mode. Combined comparative genomics analysis and experimental evidence revealed similar bidirectional structural architectures in exon clusters 4 and 9 of the Dscam gene. Our findings provide a novel mechanistic framework for the regulation of mutually exclusive splicing and may offer potentially applicable insights into long-range RNA–RNA interactions in gene regulatory networks. PMID:26554032

Sparse Bayesian learning for DOA estimation with mutual coupling.

PubMed

Dai, Jisheng; Hu, Nan; Xu, Weichao; Chang, Chunqi

2015-10-16

Sparse Bayesian learning (SBL) has given renewed interest to the problem of direction-of-arrival (DOA) estimation. It is generally assumed that the measurement matrix in SBL is precisely known. Unfortunately, this assumption may be invalid in practice due to the imperfect manifold caused by unknown or misspecified mutual coupling. This paper describes a modified SBL method for joint estimation of DOAs and mutual coupling coefficients with uniform linear arrays (ULAs). Unlike the existing method that only uses stationary priors, our new approach utilizes a hierarchical form of the Student t prior to enforce the sparsity of the unknown signal more heavily. We also provide a distinct Bayesian inference for the expectation-maximization (EM) algorithm, which can update the mutual coupling coefficients more efficiently. Another difference is that our method uses an additional singular value decomposition (SVD) to reduce the computational complexity of the signal reconstruction process and the sensitivity to the measurement noise.

Poor Response Inhibition as a Predictor of Problem Drinking and Illicit Drug Use in Adolescents at Risk for Alcoholism and Other Substance Use Disorders

ERIC Educational Resources Information Center

Nigg, Joel T.; Wong, Maria M.; Martel, Michelle M.; Jester, Jennifer M.; Puttler, Leon I.; Glass, Jennifer M.; Adams, Kenneth M.; Fitzgerald, Hiram E.; Zucker, Robert A.

2006-01-01

Objective: To evaluate the predictive power of executive functions, in particular, response inhibition, in relation to alcohol-related problems and illicit drug use in adolescence. Method: A total of 498 children from 275 families from a longitudinal high-risk study completed executive function measures in early and late adolescence and lifetime…

Acute effects of cocaine and cannabis on response inhibition in humans: an ERP investigation.

PubMed

Spronk, Desirée B; De Bruijn, Ellen R A; van Wel, Janelle H P; Ramaekers, Johannes G; Verkes, Robbert J

2016-11-01

Substance abuse has often been associated with alterations in response inhibition in humans. Not much research has examined how the acute effects of drugs modify the neurophysiological correlates of response inhibition, or how these effects interact with individual variation in trait levels of impulsivity and novelty seeking. This study investigated the effects of cocaine and cannabis on behavioural and event-related potential (ERP) correlates of response inhibition in 38 healthy drug using volunteers. A double-blind placebo-controlled randomized three-way crossover design was used. All subjects completed a standard Go/NoGo task after administration of the drugs. Compared with a placebo, cocaine yielded improved accuracy, quicker reaction times and an increased prefrontal NoGo-P3 ERP. Cannabis produced opposing results; slower reaction times, impaired accuracy and a reduction in the amplitude of the prefrontal NoGo-P3. Cannabis in addition decreased the amplitude of the parietally recorded P3, while cocaine did not affect this. Neither drugs specifically affected the N2 component, suggesting that pre-motor response inhibitory processes remain unaffected. Neither trait impulsivity nor novelty seeking interacted with drug-induced effects on measures of response inhibition. We conclude that acute drug effects on response inhibition seem to be specific to the later, evaluative stages of response inhibition. The acute effects of cannabis appeared less specific to response inhibition than those of cocaine. Together, the results show that the behavioural effects on response inhibition are reflected in electrophysiological correlates. This study did not support a substantial role of vulnerability personality traits in the acute intoxication stage. © 2015 Society for the Study of Addiction.

Caregiving and mutuality among long-term colorectal cancer survivors with ostomies: qualitative study.

PubMed

Altschuler, Andrea; Liljestrand, Petra; Grant, Marcia; Hornbrook, Mark C; Krouse, Robert S; McMullen, Carmit K

2018-02-01

The cancer caregiving literature focuses on the early phases of survivorship, but caregiving can continue for decades when cancer creates disability. Survivors with an ostomy following colorectal cancer (CRC) have caregiving needs that may last decades. Mutuality has been identified as a relationship component that can affect caregiving. This paper discusses how mutuality may affect long-term ostomy caregiving. We conducted semi-structured, in-depth interviews with 31 long-term CRC survivors with ostomies and their primary informal caregivers. Interviewees were members of an integrated health care delivery system in the USA. We used inductive theme analysis techniques to analyze the interviews. Most survivors were 71 years of age or older (67%), female (55%), and with some college education (54%). Two thirds lived with and received care from spouses. Caregiving ranged from minimal support to intimate assistance with daily ostomy care. While some survivors received caregiving far beyond what was needed, others did not receive adequate caregiving for their health care needs. Low mutuality created challenges for ostomy caregiving. Mutuality impacts the quality of caregiving, and this quality may change over time, depending on various factors. Emotional feedback and amplification is the proposed mechanism by which mutuality may shift over time. Survivorship care should include assessment and support of mutuality as a resource to enhance health outcomes and quality of life for survivors with long-term caregiving needs and their caregivers. Appropriate questionnaires can be identified or developed to assess mutuality over the survivorship trajectory.

Mutual understanding: a communication model for general practice.

PubMed

Hantho, Arne; Jensen, Lena; Malterud, Kirsti

2002-12-01

To present our pursuits towards development of a simple model for clinical communication intended for application by the practitioner as a tool for enhancing mutual understanding. Inspired by theories about patient-centredness and interactive modes of understanding, and supported by the perspectives of the Danish philosopher Niels Thomassen, we reviewed audiotapes from our own consultations. Recognising four dimensions assumed to be essential for mutual understanding in the transcripts, we explored these dimensions further. We present a communication model consisting of the following dimensions: The Framework, within which the communication takes place; The Subject, about which the communication takes place; The Persons, between whom the communication takes place; and The Action, verbally and non-verbally, through which communication takes place. We describe these dimensions in detail. The nature of the dimensions indicates that there is an interrelationship between them, implying that the character of the communication may change if one of the factors is changed. Analysis of an ongoing or recent consultation completed in accordance with these four dimensions allows the doctor to refocus the communication, thus leading to a more extensive mutual understanding and perhaps enhanced freedom of action.

Dispersal Mutualism Incorporated into Large-Scale, Infrequent Disturbances

PubMed Central

Parker, V. Thomas

2015-01-01

Because of their influence on succession and other community interactions, large-scale, infrequent natural disturbances also should play a major role in mutualistic interactions. Using field data and experiments, I test whether mutualisms have been incorporated into large-scale wildfire by whether the outcomes of a mutualism depend on disturbance. In this study a seed dispersal mutualism is shown to depend on infrequent, large-scale disturbances. A dominant shrubland plant (Arctostaphylos species) produces seeds that make up a persistent soil seed bank and requires fire to germinate. In post-fire stands, I show that seedlings emerging from rodent caches dominate sites experiencing higher fire intensity. Field experiments show that rodents (Perimyscus californicus, P. boylii) do cache Arctostaphylos fruit and bury most seed caches to a sufficient depth to survive a killing heat pulse that a fire might drive into the soil. While the rodent dispersal and caching behavior itself has not changed compared to other habitats, the environmental transformation caused by wildfire converts the caching burial of seed from a dispersal process to a plant fire adaptive trait, and provides the context for stimulating subsequent life history evolution in the plant host. PMID:26151560

Inhibiting Mycobacterium tuberculosis within and without.

PubMed

Cole, Stewart T

2016-11-05

Tuberculosis remains a scourge of global health with shrinking treatment options due to the spread of drug-resistant strains of Mycobacterium tuberculosis Intensive efforts have been made in the past 15 years to find leads for drug development so that better, more potent drugs inhibiting new targets could be produced and thus shorten treatment duration. Initial attempts focused on repurposing drugs that had been developed for other therapeutic areas but these agents did not meet their goals in clinical trials. Attempts to find new lead compounds employing target-based screens were unsuccessful as the leads were inactive against M. tuberculosis Greater success was achieved using phenotypic screening against live tubercle bacilli and this gave rise to the drugs bedaquiline, pretomanid and delamanid, currently in phase III trials. Subsequent phenotypic screens also uncovered new leads and targets but several of these targets proved to be promiscuous and inhibited by a variety of seemingly unrelated pharmacophores. This setback sparked an interest in alternative screening approaches that mimic the disease state more accurately. Foremost among these were cell-based screens, often involving macrophages, as these should reflect the bacterium's niche in the host more faithfully. A major advantage of this approach is its ability to uncover functions that are central to infection but not necessarily required for growth in vitro For instance, inhibition of virulence functions mediated by the ESX-1 secretion system severely attenuates intracellular M. tuberculosis, preventing intercellular spread and ultimately limiting tissue damage. Cell-based screens have highlighted the druggability of energy production via the electron transport chain and cholesterol metabolism. Here, I review the scientific progress and the pipeline, but warn against over-optimism due to the lack of industrial commitment for tuberculosis drug development and other socio-economic factors.This article is

31 CFR 103.15 - Reports by mutual funds of suspicious transactions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... suspected terrorist financing or ongoing money laundering schemes, a mutual fund shall immediately notify by... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Reports by mutual funds of suspicious transactions. 103.15 Section 103.15 Money and Finance: Treasury Regulations Relating to Money and Finance...

Mutuality in Cambodian International University Partnerships: Looking beyond the Global Discourse

ERIC Educational Resources Information Center

Leng, Phirom

2016-01-01

This study examines the mutuality issue in international partnership programs between Cambodian universities and universities in France, the USA, Japan and South Korea. It adopts Galtung's and Held's four aspects of mutuality as its conceptual framework and follows a qualitative case study research design. The study finds that most partnership…

Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.

PubMed

Pei, Xin-Yan; Dai, Yun; Felthousen, Jessica; Chen, Shuang; Takabatake, Yukie; Zhou, Liang; Youssefian, Leena E; Sanderson, Michael W; Bodie, Wesley W; Kramer, Lora B; Orlowski, Robert Z; Grant, Steven

2014-01-01

The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.

Circumvention of Mcl-1-Dependent Drug Resistance by Simultaneous Chk1 and MEK1/2 Inhibition in Human Multiple Myeloma Cells

PubMed Central

Pei, Xin-Yan; Dai, Yun; Felthousen, Jessica; Chen, Shuang; Takabatake, Yukie; Zhou, Liang; Youssefian, Leena E.; Sanderson, Michael W.; Bodie, Wesley W.; Kramer, Lora B.; Orlowski, Robert Z.; Grant, Steven

2014-01-01

The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM. PMID:24594907

The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis.

PubMed

Nelson, Michaela; Yang, Ming; Dowle, Adam A; Thomas, Jerry R; Brackenbury, William J

2015-01-27

Voltage-gated Na(+) channels (VGSCs) are heteromeric protein complexes containing pore-forming α subunits and smaller, non-pore-forming β subunits. VGSCs are classically expressed in electrically excitable cells, e.g. neurons. VGSCs are also expressed in tumour cells, including breast cancer (BCa) cells, where they enhance cellular migration and invasion. However, despite extensive work defining in detail the molecular mechanisms underlying the expression of VGSCs and their pro-invasive role in cancer cells, there has been a notable lack of clinically relevant in vivo data exploring their value as potential therapeutic targets. We have previously reported that the VGSC-blocking antiepileptic drug phenytoin inhibits the migration and invasion of metastatic MDA-MB-231 cells in vitro. The purpose of the present study was to establish whether VGSCs might be viable therapeutic targets by testing the effect of phenytoin on tumour growth and metastasis in vivo. We found that expression of Nav1.5, previously detected in MDA-MB-231 cells in vitro, was retained on cells in orthotopic xenografts. Treatment with phenytoin, at a dose equivalent to that used to treat epilepsy (60 mg/kg; daily), significantly reduced tumour growth, without affecting animal weight. Phenytoin also reduced cancer cell proliferation in vivo and invasion into surrounding mammary tissue. Finally, phenytoin significantly reduced metastasis to the liver, lungs and spleen. This is the first study showing that phenytoin reduces breast tumour growth and metastasis in vivo. We propose that pharmacologically targeting VGSCs, by repurposing antiepileptic or antiarrhythmic drugs, should be further studied as a potentially novel anti-cancer therapy.

Non-nucleosidic inhibition of Herpes simplex virus DNA polymerase: mechanistic insights into the anti-herpetic mode of action of herbal drug withaferin A.

PubMed

Grover, Abhinav; Agrawal, Vibhuti; Shandilya, Ashutosh; Bisaria, Virendra S; Sundar, Durai

2011-01-01

Herpes Simplex Virus 1 and 2 causes several infections in humans including cold sores and encephalitis. Previous antiviral studies on herpes viruses have focussed on developing nucleoside analogues that can inhibit viral polymerase and terminate the replicating viral DNA. However, these drugs bear an intrinsic non-specificity as they can also inhibit cellular polymerase apart from the viral one. The present study is an attempt to elucidate the action mechanism of naturally occurring withaferin A in inhibiting viral DNA polymerase, thus providing an evidence for its development as a novel anti-herpetic drug. Withaferin A was found to bind very similarly to that of the previously reported 4-oxo-DHQ inhibitor. Withaferin A was observed binding to the residues Gln 617, Gln 618, Asn 815 and Tyr 818, all of which are crucial to the proper functioning of the polymerase. A comparison of the conformation obtained from docking and the molecular dynamics simulations shows that substantial changes in the binding conformations have occurred. These results indicate that the initial receptor-ligand interaction observed after docking can be limited due to the receptor rigid docking algorithm and that the conformations and interactions observed after simulation runs are more energetically favoured. We have performed docking and molecular dynamics simulation studies to elucidate the binding mechanism of prospective herbal drug withaferin A onto the structure of DNA polymerase of Herpes simplex virus. Our docking simulations results give high binding affinity of the ligand to the receptor. Long de novo MD simulations for 10 ns performed allowed us to evaluate the dynamic behaviour of the system studied and corroborate the docking results, as well as identify key residues in the enzyme-inhibitor interactions. The present MD simulations support the hypothesis that withaferin A is a potential ligand to target/inhibit DNA polymerase of the Herpes simplex virus. Results of these studies

Non-nucleosidic inhibition of Herpes simplex virus DNA polymerase: mechanistic insights into the anti-herpetic mode of action of herbal drug withaferin A

PubMed Central

2011-01-01

Background Herpes Simplex Virus 1 and 2 causes several infections in humans including cold sores and encephalitis. Previous antiviral studies on herpes viruses have focussed on developing nucleoside analogues that can inhibit viral polymerase and terminate the replicating viral DNA. However, these drugs bear an intrinsic non-specificity as they can also inhibit cellular polymerase apart from the viral one. The present study is an attempt to elucidate the action mechanism of naturally occurring withaferin A in inhibiting viral DNA polymerase, thus providing an evidence for its development as a novel anti-herpetic drug. Results Withaferin A was found to bind very similarly to that of the previously reported 4-oxo-DHQ inhibitor. Withaferin A was observed binding to the residues Gln 617, Gln 618, Asn 815 and Tyr 818, all of which are crucial to the proper functioning of the polymerase. A comparison of the conformation obtained from docking and the molecular dynamics simulations shows that substantial changes in the binding conformations have occurred. These results indicate that the initial receptor-ligand interaction observed after docking can be limited due to the receptor rigid docking algorithm and that the conformations and interactions observed after simulation runs are more energetically favoured. Conclusions We have performed docking and molecular dynamics simulation studies to elucidate the binding mechanism of prospective herbal drug withaferin A onto the structure of DNA polymerase of Herpes simplex virus. Our docking simulations results give high binding affinity of the ligand to the receptor. Long de novo MD simulations for 10 ns performed allowed us to evaluate the dynamic behaviour of the system studied and corroborate the docking results, as well as identify key residues in the enzyme-inhibitor interactions. The present MD simulations support the hypothesis that withaferin A is a potential ligand to target/inhibit DNA polymerase of the Herpes simplex

Evolutionary stability of mutualism: interspecific population regulation as an evolutionarily stable strategy

USGS Publications Warehouse

Holland, J. Nathaniel; DeAngelis, Donald L.; Schultz, Stewart T.

2004-01-01

Interspecific mutualisms are often vulnerable to instability because low benefit : cost ratios can rapidly lead to extinction or to the conversion of mutualism to parasite–host or predator–prey interactions. We hypothesize that the evolutionary stability of mutualism can depend on how benefits and costs to one mutualist vary with the population density of its partner, and that stability can be maintained if a mutualist can influence demographic rates and regulate the population density of its partner. We test this hypothesis in a model of mutualism with key features of senita cactus (Pachycereus schottii) – senita moth (Upiga virescens) interactions, in which benefits of pollination and costs of larval seed consumption to plant fitness depend on pollinator density. We show that plants can maximize their fitness by allocating resources to the production of excess flowers at the expense of fruit. Fruit abortion resulting from excess flower production reduces pre–adult survival of the pollinating seed–consumer, and maintains its density beneath a threshold that would destabilize the mutualism. Such a strategy of excess flower production and fruit abortion is convergent and evolutionarily stable against invasion by cheater plants that produce few flowers and abort few to no fruit. This novel mechanism of achieving evolutionarily stable mutualism, namely interspecific population regulation, is qualitatively different from other mechanisms invoking partner choice or selective rewards, and may be a general process that helps to preserve mutualistic interactions in nature.

Evolutionary stability of mutualism: interspecific population regulation as an evolutionarily stable strategy.

PubMed

Holland, J Nathaniel; DeAngelis, Donald L; Schultz, Stewart T

2004-09-07

Interspecific mutualisms are often vulnerable to instability because low benefit : cost ratios can rapidly lead to extinction or to the conversion of mutualism to parasite-host or predator-prey interactions. We hypothesize that the evolutionary stability of mutualism can depend on how benefits and costs to one mutualist vary with the population density of its partner, and that stability can be maintained if a mutualist can influence demographic rates and regulate the population density of its partner. We test this hypothesis in a model of mutualism with key features of senita cactus (Pachycereus schottii)-senita moth (Upiga virescens) interactions, in which benefits of pollination and costs of larval seed consumption to plant fitness depend on pollinator density. We show that plants can maximize their fitness by allocating resources to the production of excess flowers at the expense of fruit. Fruit abortion resulting from excess flower production reduces pre-adult survival of the pollinating seed-consumer, and maintains its density beneath a threshold that would destabilize the mutualism. Such a strategy of excess flower production and fruit abortion is convergent and evolutionarily stable against invasion by cheater plants that produce few flowers and abort few to no fruit. This novel mechanism of achieving evolutionarily stable mutualism, namely interspecific population regulation, is qualitatively different from other mechanisms invoking partner choice or selective rewards, and may be a general process that helps to preserve mutualistic interactions in nature.

12 CFR 250.406 - Serving member bank and investment advisor with mutual fund affiliation.

Code of Federal Regulations, 2011 CFR

2011-01-01

... mutual fund affiliation. 250.406 Section 250.406 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED... Section 32 of the Glass-Steagall Act § 250.406 Serving member bank and investment advisor with mutual fund... management services to mutual funds and others (“Manager”) and as director of a member bank. (b) Section 32...

Aspects of mutually unbiased bases in odd-prime-power dimensions

NASA Astrophysics Data System (ADS)

Chaturvedi, S.

2002-04-01

We rephrase the Wootters-Fields construction [W. K. Wootters and B. C. Fields, Ann. Phys. 191, 363 (1989)] of a full set of mutually unbiased bases in a complex vector space of dimensions N=pr, where p is an odd prime, in terms of the character vectors of the cyclic group G of order p. This form may be useful in explicitly writing down mutually unbiased bases for N=pr.

Structure Activity Relationship for FDA Approved Drugs as Inhibitors of the Human Sodium Taurocholate Co-transporting Polypeptide (NTCP)

PubMed Central

Dong, Zhongqi; Ekins, Sean; Polli, James E.

2013-01-01

The hepatic bile acid uptake transporter Sodium Taurocholate Cotransporting Polypeptide (NTCP) is less well characterized than its ileal paralog, the Apical Sodium Dependent Bile Acid Transporter (ASBT), in terms of drug inhibition requirements. The objectives of this study were a) to identify FDA approved drugs that inhibit human NTCP, b) to develop pharmacophore and Bayesian computational models for NTCP inhibition, and c) to compare NTCP and ASBT transport inhibition requirements. A series of NTCP inhibition studies were performed using FDA approved drugs, in concert with iterative computational model development. Screening studies identified 27 drugs as novel NTCP inhibitors, including irbesartan (Ki =11.9 μM) and ezetimibe (Ki = 25.0 μM). The common feature pharmacophore indicated that two hydrophobes and one hydrogen bond acceptor were important for inhibition of NTCP. From 72 drugs screened in vitro, a total of 31 drugs inhibited NTCP, while 51 drugs (i.e. more than half) inhibited ASBT. Hence, while there was inhibitor overlap, ASBT unexpectedly was more permissive to drug inhibition than was NTCP, and this may be related to NTCP’s possessing fewer pharmacophore features. Findings reflected that a combination of computational and in vitro approaches enriched the understanding of these poorly characterized transporters and yielded additional chemical probes for possible drug-transporter interaction determinations. PMID:23339484

Inhibition of Growth and Metastasis of Ovarian Carcinoma by Administering a Drug Capable of Interfering with Vascular Endothelial Growth Factor Activity

PubMed Central

Mu, Jie; Abe, Yoshiko; Tsutsui, Tateki; Yamamoto, Norihiko; Tai, Xu‐Guang; Niwa, Ohtsura; Tsujimura, Takahiro; Sato, Bunzo; Terano, Hiroshi; Hamaoka, Toshiyuki

1996-01-01

The present study investigates the relationship between in vivo growth/metastasis of tumor cells and their capacity to produce the vascular endothelial growth factor (VEGF), as well as the regulation of tumor growth/metastasis using an angiogenesis‐inhibitory drug. Two cloned tumor cell lines designated OV‐LM and OV‐HM were isolated from a murine ovarian carcinoma OV2944. OV‐LM and OV‐HM cells grew in cultures at comparable rates. However, when transplanted s.c. into syngeneic mice, OV‐HM exhibited a faster growth rate and a much higher incidence of metastasis to lymph nodes and lung. Histologically, intense neovascularization was detected in sections of OV‐HM but not of OV‐LM tumor. OV‐HM and OV‐LM tumor cells obtained from in vitro cultures expressed high and low levels of VEGF mRNA, respectively. A difference in VEGF mRNA expression was much more clearly observed between RNAs prepared from fresh OV‐HM and OV‐LM tumor masses: RNA from OV‐HM contained larger amounts of VEGF mRNA, whereas RNA from OV‐LM exhibited only marginal levels of VEGF mRNA. An angiogenesis‐inhibitory drug, FR118487 inhibited the VEGF‐mediated in vitro growth of endothelial cells but did not affect the expression in vitro of VEGF mRNA by OV‐HM tumor cells. Intraperitoneal injections of FR118487 into mice bearing OV‐HM tumors resulted in: (i) a subsequent growth inhibition of primary tumors; (ii) a marked decrease in neovascularization inside tumor masses expressing comparable levels of VEGF mRNA to those detected in control OV‐HM masses; and (iii) almost complete inhibition of metastasis to lymph nodes and lung. These results indicate that growth/metastasis of tumor cells correlates with their VEGF‐producing capacity and that an angiogenesis inhibitor, FR118487, inhibits tumor growth and metastasis through mechanism(s) including the suppression of VEGF function in vivo. PMID:8878460

A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition.

PubMed

Ilari, Andrea; Baiocco, Paola; Messori, Luigi; Fiorillo, Annarita; Boffi, Alberto; Gramiccia, Marina; Di Muccio, Trentina; Colotti, Gianni

2012-02-01

Auranofin is a gold(I)-containing drug in clinical use as an antiarthritic agent. Recent studies showed that auranofin manifests interesting antiparasitic actions very likely arising from inhibition of parasitic enzymes involved in the control of the redox metabolism. Trypanothione reductase is a key enzyme of Leishmania infantum polyamine-dependent redox metabolism, and a validated target for antileishmanial drugs. As trypanothione reductase contains a dithiol motif at its active site and gold(I) compounds are known to be highly thiophilic, we explored whether auranofin might behave as an effective enzyme inhibitor and as a potential antileishmanial agent. Notably, enzymatic assays revealed that auranofin causes indeed a pronounced enzyme inhibition. To gain a deeper insight into the molecular basis of enzyme inhibition, crystals of the auranofin-bound enzyme, in the presence of NADPH, were prepared, and the X-ray crystal structure of the auranofin-trypanothione reductase-NADPH complex was solved at 3.5 Å resolution. In spite of the rather low resolution, these data were of sufficient quality as to identify the presence of the gold center and of the thiosugar of auranofin, and to locate them within the overall protein structure. Gold binds to the two active site cysteine residues of TR, i.e. Cys52 and Cys57, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin appears to inhibit TR through a dual mechanism. Auranofin kills the promastigote stage of L. infantum at micromolar concentration; these findings will contribute to the design of new drugs against leishmaniasis.

The upcoming mutual event season for the Patroclus-Menoetius Trojan binary

NASA Astrophysics Data System (ADS)

Grundy, W. M.; Noll, K. S.; Buie, M. W.; Levison, H. F.

2018-05-01

We present new Hubble Space Telescope and ground-based Keck observations and new Keplerian orbit solutions for the mutual orbit of binary Jupiter Trojan asteroid (617) Patroclus and Menoetius, targets of NASA's Lucy mission. We predict event times for the upcoming mutual event season, which is anticipated to run from late 2017 through mid 2019.

A unified multicomponent stress-diffusion model of drug release from non-biodegradable polymeric matrix tablets.

PubMed

Salehi, Ali; Zhao, Jin; Cabelka, Tim D; Larson, Ronald G

2016-02-28

We propose a new transport model of drug release from hydrophilic polymeric matrices, based on Stefan-Maxwell flux laws for multicomponent transport. Polymer stress is incorporated in the total mixing free energy, which contributes directly to the diffusion driving force while leading to time-dependent boundary conditions at the tablet interface. Given that hydrated matrix tablets are dense multicomponent systems, extended Stefan-Maxwell (ESM) flux laws are adopted to ensure consistency with the Onsager reciprocity principle and the Gibbs-Duhem thermodynamic constraint. The ESM flux law for any given component takes into account the friction exerted by all other species and is invariant with respect to reference velocity, thus satisfying Galilean translational invariance. Our model demonstrates that penetrant-induced plasticization of polymer chains partially or even entirely offsets the steady decline of chemical potential gradients at the tablet-medium interface that drive drug release. Utilizing a Flory-Huggins thermodynamic model, a modified form of the upper convected Maxwell constitutive equation for polymer stress and a Fujita-type dependence of mutual diffusivities on composition, depending on parameters, Fickian, anomalous or case II drug transport arises naturally from the model, which are characterized by quasi-power-law release profiles with exponents ranging from 0.5 to 1, respectively. A necessary requirement for non-Fickian release in our model is that the matrix stress relaxation time is comparable to the time scale for water diffusion. Mutual diffusivities and their composition dependence are the most decisive factors in controlling drug release characteristics in our model. Regression of the experimental polymer dissolution and drug release profiles in a system of Theophylline/cellulose (K15M) demonstrate that API-water mutual diffusivity in the presence of excipient cannot generally be taken as a constant. Copyright © 2016 Elsevier B.V. All

Cross Correlation versus Normalized Mutual Information on Image Registration

NASA Technical Reports Server (NTRS)

Tan, Bin; Tilton, James C.; Lin, Guoqing

2016-01-01

This is the first study to quantitatively assess and compare cross correlation and normalized mutual information methods used to register images in subpixel scale. The study shows that the normalized mutual information method is less sensitive to unaligned edges due to the spectral response differences than is cross correlation. This characteristic makes the normalized image resolution a better candidate for band to band registration. Improved band-to-band registration in the data from satellite-borne instruments will result in improved retrievals of key science measurements such as cloud properties, vegetation, snow and fire.

Inhibition of plasma lipid oxidation induced by peroxyl radicals, peroxynitrite, hypochlorite, 15-lipoxygenase, and singlet oxygen by clinical drugs.

PubMed

Morita, Mayuko; Naito, Yuji; Yoshikawa, Toshikazu; Niki, Etsuo

2016-11-15

With increasing evidence showing the involvement of oxidative stress in the pathogenesis of various diseases, the effects of clinical drugs possessing antioxidant functions have received much attention. The unregulated oxidative modification of biological molecules leading to diseases is mediated by multiple oxidants including free radicals, peroxynitrite, hypochlorite, lipoxygenase, and singlet oxygen. The capacity of antioxidants to scavenge or quench oxidants depends on the nature of oxidants. In the present study, the antioxidant effects of several clinical drugs against plasma lipid oxidation induced by the aforementioned five kinds of oxidants were investigated from the production of lipid hydroperoxides, which have been implicated in the pathogenesis of various diseases. Troglitazone acted as a potent peroxyl radical scavenger, whereas probucol and edaravone showed only moderate reactivity and carvedilol, pentoxifylline, and ebselen did not act as radical scavenger. Probucol and edaravone suppressed plasma oxidation mediated by peroxynitrite and hypochlorite. Troglitazone and edaravone inhibited 15-lipoxygenase mediated plasma lipid oxidation, the IC 50 being 20 and 34μM respectively. None of the drugs used in this study suppressed plasma lipid oxidation by singlet oxygen. This study shows that the antioxidant effects of drugs depend on the nature of oxidants and that antioxidants against multiple oxidants are required to cope with oxidative stress in vivo. Copyright © 2016 Elsevier Ltd. All rights reserved.

Risperidone increases the cortical silent period in drug-naive patients with first-episode schizophrenia: A transcranial magnetic stimulation study.

PubMed

Ustohal, Libor; Mayerova, Michaela; Hublova, Veronika; Prikrylova Kucerova, Hana; Ceskova, Eva; Kasparek, Tomas

2017-04-01

Schizophrenia is accompanied by impaired cortical inhibition, as measured by several markers including the cortical silent period (CSP). It is thought that CSP measures gamma-aminobutyric acid receptors B (GABA B ) mediated inhibitory activity. But the mutual roles of schizophrenia as a disease and the drugs used for the treatment of psychosis on GABA mediated neurotransmission are not clear. We recruited 13 drug-naive patients with first-episode schizophrenia. We used transcranial magnetic stimulation to assess CSP prior to initiating risperidone monotherapy and again four weeks later. At the same time, we rated the severity of psychopathology using the Positive and Negative Syndrome Scale (PANSS). We obtained data from 12 patients who showed a significant increase in CSP, from 134.20±41.81 ms to 162.95±61.98 ms ( p=0.041; Cohen's d=0.544). After the treatment, the PANSS total score was significantly lower, as were the individual subscores ( p<0.05). However, no correlation was found between ΔCSP and ΔPANSS. Our study in patients with first-episode schizophrenia demonstrated an association between risperidone monotherapy and an increase in GABA B mediated inhibitory neurotransmission.

T-18, a stemonamide synthetic intermediate inhibits Pim kinase activity and induces cell apoptosis, acting as a potent anticancer drug.

PubMed

Wang, Zhen; Li, Xing-Min; Shang, Kun; Zhang, Peng; Wang, Chao-Fu; Xin, Yu-Hu; Zhou, Lu; Li, Ying-Yi

2013-03-01

Pim-3 kinase has been shown to be aberrantly expressed in premalignant and malignant lesions of endoderm-derived organs such as the liver, pancreas, colon and stomach. Pim-3 kinase inactivates the Bad protein, a proapoptotic molecule, and improves the expression of Bcl-xL, an antiapoptotic molecule, to promote cell proliferation. Thus, blocking Pim-3 kinase activity may be a new strategy for the treatment of pancreatic cancer. In this study, we screened low molecular compounds and observed that the stemonamide synthetic intermediate, T-18, potently inhibited Pim kinase activity. Moreover, T-18 inhibited the proliferation of human pancreatic, as well as that of hepatocellular and colon cancer cells in vitro. It also induced the apoptosis of human pancreatic carcinoma cells in vitro by decreasing the levels of phospho-Ser112-Bad; the levels of Pim-3 kinase and total Bad protein were not altered. Furthermore, T-18 inhibited the growth of human pancreatic cancer cells in nude mice without apparent adverse effects when the tumor was palpable. These observations indicate that stemonamide synthetic intermediates may be novel drugs for the treatment of gastrointestinal cancers, particularly pancreatic cancer.

Pharmacodynamics and common drug-drug interactions of the third-generation antiepileptic drugs.

PubMed

Stefanović, Srđan; Janković, Slobodan M; Novaković, Milan; Milosavljević, Marko; Folić, Marko

2018-02-01

Anticonvulsants that belong to the third generation are considered as 'newer' antiepileptic drugs, including: eslicarbazepine acetate, lacosamide, perampanel, brivaracetam, rufinamide and stiripentol. Areas covered: This article reviews pharmacodynamics (i.e. mechanisms of action) and clinically relevant drug-drug interactions of the third-generation antiepileptic drugs. Expert opinion: Newer antiepileptic drugs have mechanisms of action which are not shared with the first and the second generation anticonvulsants, like inhibition of neurotransmitters release, blocking receptors for excitatory amino acids and new ways of sodium channel inactivation. New mechanisms of action increase chances of controlling forms of epilepsy resistant to older anticonvulsants. Important advantage of the third-generation anticonvulsants could be their little propensity for interactions with both antiepileptic and other drugs observed until now, making prescribing much easier and safer. However, this may change with new studies specifically designed to discover drug-drug interactions. Although the third-generation antiepileptic drugs enlarged therapeutic palette against epilepsy, 20-30% of patients with epilepsy is still treatment-resistant and need new pharmacological approach. There is great need to explore all molecular targets that may directly or indirectly be involved in generation of seizures, so a number of candidate compounds for even newer anticonvulsants could be generated.

78 FR 24445 - Symetra Mutual Funds Trust, et al.; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-25

... Mutual Funds Trust, et al.; Notice of Application April 19, 2013 AGENCY: Securities and Exchange... shareholder approval and would grant relief from certain disclosure requirements. Applicants: Symetra Mutual Funds Trust (the ``Trust'') and Symetra Investment Management, Inc. (the ``Adviser''). Filing Dates: The...

Defining the Timing of Action of Antimalarial Drugs against Plasmodium falciparum

PubMed Central

Langer, Christine; Goodman, Christopher D.; McFadden, Geoffrey I.

2013-01-01

Most current antimalarials for treatment of clinical Plasmodium falciparum malaria fall into two broad drug families and target the food vacuole of the trophozoite stage. No antimalarials have been shown to target the brief extracellular merozoite form of blood-stage malaria. We studied a panel of 12 drugs, 10 of which have been used extensively clinically, for their invasion, schizont rupture, and growth-inhibitory activity using high-throughput flow cytometry and new approaches for the study of merozoite invasion and early intraerythrocytic development. Not surprisingly, given reported mechanisms of action, none of the drugs inhibited merozoite invasion in vitro. Pretreatment of erythrocytes with drugs suggested that halofantrine, lumefantrine, piperaquine, amodiaquine, and mefloquine diffuse into and remain within the erythrocyte and inhibit downstream growth of parasites. Studying the inhibitory activity of the drugs on intraerythrocytic development, schizont rupture, and reinvasion enabled several different inhibitory phenotypes to be defined. All drugs inhibited parasite replication when added at ring stages, but only artesunate, artemisinin, cycloheximide, and trichostatin A appeared to have substantial activity against ring stages, whereas the other drugs acted later during intraerythrocytic development. When drugs were added to late schizonts, only artemisinin, cycloheximide, and trichostatin A were able to inhibit rupture and subsequent replication. Flow cytometry proved valuable for in vitro assays of antimalarial activity, with the free merozoite population acting as a clear marker for parasite growth inhibition. These studies have important implications for further understanding the mechanisms of action of antimalarials, studying and evaluating drug resistance, and developing new antimalarials. PMID:23318799

Prostaglandin E(2) synthase inhibition as a therapeutic target.

PubMed

Iyer, Jitesh P; Srivastava, Punit K; Dev, Rishabh; Dastidar, Sunanda G; Ray, Abhijit

2009-07-01

Most NSAIDs function by inhibiting biosynthesis of PGE(2) by inhibition of COX-1 and/or COX-2. Since COX-1 has a protective function in the gastro-intestinal tract (GIT), non-selective inhibition of both cycloxy genases leads to moderate to severe gastro-intestinal intolerance. Attempts to identify selective inhibitors of COX-2, led to the identification of celecoxib and rofecoxib. However, long-term use of these drugs has serious adverse effects of sudden myocardial infarction and thrombosis. Drug-mediated imbalance in the levels of prostaglandin I(2) (PGI(2)) and thromboxane A(2) (TXA(2)) with a bias towards TXA(2) may be the primary reason for these events. This resulted in the drugs being withdrawn from the market, leaving a need for an effective and safe anti-inflammatory drug. Recently, the focus of research has shifted to enzymes downstream of COX in the prosta glandin biosynthetic pathway such as prostaglandin E(2) synthases. Microsomal prostaglandin E(2) synthase-1 (mPGES-1) specifically isomerizes PGH(2) to PGE(2), under inflammatory conditions. In this review, we examine the biology of mPGES-1 and its role in disease. Progress in designing molecules that can selectively inhibit mPGES-1 is reviewed. mPGES-1 has the potential to be a target for anti-inflammatory therapy, devoid of adverse GIT and cardiac effects and warrants further investigation.

Miniature short hairpin RNA screens to characterize antiproliferative drugs.

PubMed

Kittanakom, Saranya; Arnoldo, Anthony; Brown, Kevin R; Wallace, Iain; Kunavisarut, Tada; Torti, Dax; Heisler, Lawrence E; Surendra, Anuradha; Moffat, Jason; Giaever, Guri; Nislow, Corey

2013-08-07

The application of new proteomics and genomics technologies support a view in which few drugs act solely by inhibiting a single cellular target. Indeed, drug activity is modulated by complex, often incompletely understood cellular mechanisms. Therefore, efforts to decipher mode of action through genetic perturbation such as RNAi typically yields "hits" that fall into several categories. Of particular interest to the present study, we aimed to characterize secondary activities of drugs on cells. Inhibiting a known target can result in clinically relevant synthetic phenotypes. In one scenario, drug perturbation could, for example, improperly activate a protein that normally inhibits a particular kinase. In other cases, additional, lower affinity targets can be inhibited as in the example of inhibition of c-Kit observed in Bcr-Abl-positive cells treated with Gleevec. Drug transport and metabolism also play an important role in the way any chemicals act within the cells. Finally, RNAi per se can also affect cell fitness by more general off-target effects, e.g., via the modulation of apoptosis or DNA damage repair. Regardless of the root cause of these unwanted effects, understanding the scope of a drug's activity and polypharmacology is essential for better understanding its mechanism(s) of action, and such information can guide development of improved therapies. We describe a rapid, cost-effective approach to characterize primary and secondary effects of small-molecules by using small-scale libraries of virally integrated short hairpin RNAs. We demonstrate this principle using a "minipool" composed of shRNAs that target the genes encoding the reported protein targets of approved drugs. Among the 28 known reported drug-target pairs, we successfully identify 40% of the targets described in the literature and uncover several unanticipated drug-target interactions based on drug-induced synthetic lethality. We provide a detailed protocol for performing such screens and for

Inhibitory Effect of Anti-rheumatic Drug Iguratimod for Hepatocellular Carcinogenesis by Inhibition of Serum Interleukin-8 Production.

PubMed

Sakamoto, Taro; Ishii, Yuji; Shiba, Hiroaki; Furukawa, Kenei; Fujiwara, Yuki; Haruki, Koichiro; Iwase, Ryota; Shirai, Yoshihiro; Yanaga, Katsuhiko

2016-07-01

Angiogenesis is a known factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to assess the property of iguratimod, that is an anti-inflammatory drug for rheumatoid arthritis, on anti-angiogenesis and anti-carcinogensis for HCC. In vitro, human umbilical vein endothelial cells were cultured under interleukin-8 (IL-8) with or without iguratimod. In vivo, a rat model with HCC received iguratimod or distilled water for 6 weeks. Diameter of the largest tumor, number of tumors and serum interleukin-8 concentration were compared between iguratimod and control groups. By an in vitro angiogenesis assay, it was found angiogenesis in iguratimod group was significantly lower than that in control group (p=0.013). In vivo, largest tumor diameter (p=0.036), number of the tumor (p=0.011) and serum interleukin-8 concentration (p=0.036) in the iguratimod group were significantly smaller and lower than those in the control group. Iguratimod may inhibit hepatocellular carcinogensis by inhibition of interleukin-8 production in a rat model. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

The roles of tolerance in the evolution, maintenance and breakdown of mutualism

NASA Astrophysics Data System (ADS)

Edwards, David P.

2009-10-01

Tolerance strategies are cost-reduction mechanisms that enable organisms to recover some of the fitness lost to damage, but impose limited or no cost on antagonists. They are frequently invoked in studies of plant-herbivore and of host-parasite interactions, but the possible roles of tolerance in mutualism (interspecific cooperation) have yet to be thoroughly examined. This review identifies candidate roles for tolerance in the evolution, maintenance and breakdown of mutualism. Firstly, by reducing the cost of damage, tolerance provides a key pathway by which pre-mutualistic hosts can reduce the cost of association with their parasites, promoting cooperation. This holds for the evolution of ‘evolved dependency’ type mutualism, where a host requires an antagonist that does not direct any reward to their partner for some resource, and of ‘outright mutualism’, where participants directly trade benefits. Secondly, in outright mutualism, tolerance might maintain cooperation by reducing the cost of a persisting negative trait in a symbiotic partner. Finally, the evolution of tolerance might also provide a pathway out of mutualism because the host could evolve a cheaper alternative to continued cooperation with its mutualistic partner, permitting autonomy. A key consequence of tolerance is that it contrasts with partner choice mechanisms that impose large costs on cheats, and I highlight understanding any trade-off between tolerance and partner choice as an important research topic in the evolution of cooperation. I conclude by identifying tolerance as part of a more general phenomenon of co-adaptation in mutualism and parasitism that drives the evolution of the cost/benefit ratio from the interaction.

Inhibition of UDP-Glucuronosyltransferase (UGT) Isoforms by Arctiin and Arctigenin.

PubMed

Zhang, Hui; Zhao, Zhenying; Wang, Tao; Wang, Yijia; Cui, Xiao; Zhang, Huijuan; Fang, Zhong-Ze

2016-07-01

Arctiin is the major pharmacological ingredient of Fructus Arctii, and arctigenin is the metabolite of arctiin formed via the catalysis of human intestinal bacteria. The present study aims to investigate the inhibition profile of arctiin and arctigenin on important phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs), indicating the possible herb-drug interaction. In vitro screening experiment showed that 100 μM of arctiin and arctigenin inhibited the activity of UGT1A3, 1A9, 2B7, and 2B15. Homology modeling-based in silico docking of arctiin and arctigenin into the activity cavity of UGT2B15 showed that hydrogen bonds and hydrophobic interactions contributed to the strong binding free energy of arctiin (-8.14 kcal/mol) and arctigenin (-8.43 kcal/mol) with UGT2B15. Inhibition kinetics study showed that arctiin and arctigenin exerted competitive and noncompetitive inhibition toward UGT2B15, respectively. The inhibition kinetic parameters (Ki ) were calculated to be 16.0 and 76.7 μM for the inhibition of UGT2B15 by arctiin and arctigenin, respectively. Based on the plasma concentration of arctiin and arctigenin after administration of 100 mg/kg of arctiin, the [I]/Ki values were calculated to be 0.3 and 0.007 for arctiin and arctigenin, respectively. Based on the inhibition evaluation standard ([I]/Ki  < 0.1, low possibility; 0.1 < [I]/Ki  < 1, medium possibility; [I]/Ki  > 1, high possibility), arctiin might induce drug-drug interaction with medium possibility. Based on these results, clinical monitoring the utilization of Fructus Arctii is very important and necessary. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Long-range RNA pairings contribute to mutually exclusive splicing.

PubMed

Yue, Yuan; Yang, Yun; Dai, Lanzhi; Cao, Guozheng; Chen, Ran; Hong, Weiling; Liu, Baoping; Shi, Yang; Meng, Yijun; Shi, Feng; Xiao, Mu; Jin, Yongfeng

2016-01-01

Mutually exclusive splicing is an important means of increasing the protein repertoire, by which the Down's syndrome cell adhesion molecule (Dscam) gene potentially generates 38,016 different isoforms in Drosophila melanogaster. However, the regulatory mechanisms remain obscure due to the complexity of the Dscam exon cluster. Here, we reveal a molecular model for the regulation of the mutually exclusive splicing of the serpent pre-mRNA based on competition between upstream and downstream RNA pairings. Such dual RNA pairings confer fine tuning of the inclusion of alternative exons. Moreover, we demonstrate that the splicing outcome of alternative exons is mediated in relative pairing strength-correlated mode. Combined comparative genomics analysis and experimental evidence revealed similar bidirectional structural architectures in exon clusters 4 and 9 of the Dscam gene. Our findings provide a novel mechanistic framework for the regulation of mutually exclusive splicing and may offer potentially applicable insights into long-range RNA-RNA interactions in gene regulatory networks. © 2015 Yue et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Mutual coupling, channel model, and BER for curvilinear antenna arrays

NASA Astrophysics Data System (ADS)

Huang, Zhiyong

This dissertation introduces a wireless communications system with an adaptive beam-former and investigates its performance with different antenna arrays. Mutual coupling, real antenna elements and channel models are included to examine the system performance. In a beamforming system, mutual coupling (MC) among the elements can significantly degrade the system performance. However, MC effects can be compensated if an accurate model of mutual coupling is available. A mutual coupling matrix model is utilized to compensate mutual coupling in the beamforming of a uniform circular array (UCA). Its performance is compared with other models in uplink and downlink beamforming scenarios. In addition, the predictions are compared with measurements and verified with results from full-wave simulations. In order to accurately investigate the minimum mean-square-error (MSE) of an adaptive array in MC, two different noise models, the environmental and the receiver noise, are modeled. The minimum MSEs with and without data domain MC compensation are analytically compared. The influence of mutual coupling on the convergence is also examined. In addition, the weight compensation method is proposed to attain the desired array pattern. Adaptive arrays with different geometries are implemented with the minimum MSE algorithm in the wireless communications system to combat interference at the same frequency. The bit-error-rate (BER) of systems with UCA, uniform rectangular array (URA) and UCA with center element are investigated in additive white Gaussian noise plus well-separated signals or random direction signals scenarios. The output SINR of an adaptive array with multiple interferers is analytically examined. The influence of the adaptive algorithm convergence on the BER is investigated. The UCA is then investigated in a narrowband Rician fading channel. The channel model is built and the space correlations are examined. The influence of the number of signal paths, number of the

Mutual information-based analysis of JPEG2000 contexts.

PubMed

Liu, Zhen; Karam, Lina J

2005-04-01

Context-based arithmetic coding has been widely adopted in image and video compression and is a key component of the new JPEG2000 image compression standard. In this paper, the contexts used in JPEG2000 are analyzed using the mutual information, which is closely related to the compression performance. We first show that, when combining the contexts, the mutual information between the contexts and the encoded data will decrease unless the conditional probability distributions of the combined contexts are the same. Given I, the initial number of contexts, and F, the final desired number of contexts, there are S(I, F) possible context classification schemes where S(I, F) is called the Stirling number of the second kind. The optimal classification scheme is the one that gives the maximum mutual information. Instead of using an exhaustive search, the optimal classification scheme can be obtained through a modified generalized Lloyd algorithm with the relative entropy as the distortion metric. For binary arithmetic coding, the search complexity can be reduced by using dynamic programming. Our experimental results show that the JPEG2000 contexts capture the correlations among the wavelet coefficients very well. At the same time, the number of contexts used as part of the standard can be reduced without loss in the coding performance.

Competition as a mechanism structuring mutualisms

Treesearch

Robert J. Warren; Itamar Giladi; Mark A. Bradford

2014-01-01

Summary 1. Hutchinsonian niche theory posits that organisms have fundamental abiotic resource requirements from which they are limited by competition. Organisms also have fundamental biotic requirements, such as mutualists, for which they also might compete. 2. We test this idea with a widespread ant–plant mutualism. Ant-mediated seed dispersal (myrmecochory) in...

On-command drug release from nanochains inhibits growth of breast tumors.

PubMed

Peiris, Pubudu M; Tam, Morgan; Vicente, Peter; Abramowski, Aaron; Toy, Randall; Bauer, Lisa; Mayer, Aaron; Pansky, Jenna; Doolittle, Elizabeth; Tucci, Samantha; Schmidt, Erik; Shoup, Christopher; Rao, Swetha; Murray, Kaitlyn; Gopalakrishnan, Ramamurthy; Keri, Ruth A; Basilion, James P; Griswold, Mark A; Karathanasis, Efstathios

2014-06-01

To evaluate the ability of radiofrequency (RF)-triggered drug release from a multicomponent chain-shaped nanoparticle to inhibit the growth of an aggressive breast tumor. A two-step solid phase chemistry was employed to synthesize doxorubicin-loaded nanochains, which were composed of three iron oxide nanospheres and one doxorubicin-loaded liposome assembled in a 100-nm-long linear nanochain. The nanochains were tested in the 4T1-LUC-GFP orthotopic mouse model, which is a highly aggressive breast cancer model. The 4T1-LUC-GFP cell line stably expresses firefly luciferase, which allowed the non-invasive in vivo imaging of tumor response to the treatment using bioluminescence imaging (BLI). Longitudinal BLI imaging showed that a single nanochain treatment followed by application of RF resulted in an at least 100-fold lower BLI signal compared to the groups treated with nanochains (without RF) or free doxorubicin followed by RF. A statistically significant increase in survival time of the nanochain-treated animals followed by RF (64.3 days) was observed when compared to the nanochain-treated group without RF (35.7 days), free doxorubicin-treated group followed by RF (38.5 days), and the untreated group (30.5 days; n=5 animals per group). These studies showed that the combination of RF and nanochains has the potential to effectively treat highly aggressive cancers and prolong survival.

A Study of Shared-Memory Mutual Exclusion Protocols Using CADP

NASA Astrophysics Data System (ADS)

Mateescu, Radu; Serwe, Wendelin

Mutual exclusion protocols are an essential building block of concurrent systems: indeed, such a protocol is required whenever a shared resource has to be protected against concurrent non-atomic accesses. Hence, many variants of mutual exclusion protocols exist in the shared-memory setting, such as Peterson's or Dekker's well-known protocols. Although the functional correctness of these protocols has been studied extensively, relatively little attention has been paid to their non-functional aspects, such as their performance in the long run. In this paper, we report on experiments with the performance evaluation of mutual exclusion protocols using Interactive Markov Chains. Steady-state analysis provides an additional criterion for comparing protocols, which complements the verification of their functional properties. We also carefully re-examined the functional properties, whose accurate formulation as temporal logic formulas in the action-based setting turns out to be quite involved.

MLL-ENL inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells

PubMed Central

Maethner, Emanuel; Garcia-Cuellar, Maria-Paz; Breitinger, Constanze; Takacova, Sylvia; Divoky, Vladimir; Hess, Jay L.; Slany, Robert K.

2014-01-01

Summary Stimulation of transcriptional elongation is a key activity of leukemogenic MLL fusion proteins. Here we provide evidence that MLL-ENL also inhibits polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as scaffold that contacted the elongation machinery as well as the PRC1 (polycomb repressive complex 1) component CBX8. These interactions were mutually exclusive in vitro corresponding to an antagonistic behavior of MLL-ENL and CBX8 in vivo. CBX8 inhibited elongation in a specific reporter assay and this effect was neutralized by direct association with ENL. Correspondingly MLL-ENL defective in CBX8 binding could not fully activate gene loci necessary for transformation. Finally, we demonstrate dimerization of MLL-ENL as neomorphic activity that may augment polycomb inhibition and transformation. PMID:23623499

Wideband Direction of Arrival Estimation in the Presence of Unknown Mutual Coupling

PubMed Central

Li, Weixing; Zhang, Yue; Lin, Jianzhi; Guo, Rui; Chen, Zengping

2017-01-01

This paper investigates a subarray based algorithm for direction of arrival (DOA) estimation of wideband uniform linear array (ULA), under the presence of frequency-dependent mutual coupling effects. Based on the Toeplitz structure of mutual coupling matrices, the whole array is divided into the middle subarray and the auxiliary subarray. Then two-sided correlation transformation is applied to the correlation matrix of the middle subarray instead of the whole array. In this way, the mutual coupling effects can be eliminated. Finally, the multiple signal classification (MUSIC) method is utilized to derive the DOAs. For the condition when the blind angles exist, we refine DOA estimation by using a simple approach based on the frequency-dependent mutual coupling matrixes (MCMs). The proposed method can achieve high estimation accuracy without any calibration sources. It has a low computational complexity because iterative processing is not required. Simulation results validate the effectiveness and feasibility of the proposed algorithm. PMID:28178177

12 CFR 575.7 - Issuances of stock by savings association subsidiaries of mutual holding companies.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 12 Banks and Banking 6 2014-01-01 2012-01-01 true Issuances of stock by savings association..., DEPARTMENT OF THE TREASURY MUTUAL HOLDING COMPANIES § 575.7 Issuances of stock by savings association subsidiaries of mutual holding companies. (a) Requirements. No savings association subsidiary of a mutual...

12 CFR 575.7 - Issuances of stock by savings association subsidiaries of mutual holding companies.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 12 Banks and Banking 6 2013-01-01 2012-01-01 true Issuances of stock by savings association..., DEPARTMENT OF THE TREASURY MUTUAL HOLDING COMPANIES § 575.7 Issuances of stock by savings association subsidiaries of mutual holding companies. (a) Requirements. No savings association subsidiary of a mutual...

12 CFR 575.7 - Issuances of stock by savings association subsidiaries of mutual holding companies.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 12 Banks and Banking 6 2012-01-01 2012-01-01 false Issuances of stock by savings association..., DEPARTMENT OF THE TREASURY MUTUAL HOLDING COMPANIES § 575.7 Issuances of stock by savings association subsidiaries of mutual holding companies. (a) Requirements. No savings association subsidiary of a mutual...

Risk Assessment Using Cytochrome P450 Time-Dependent Inhibition Assays at Single Time and Concentration in the Early Stage of Drug Discovery.

PubMed

Kosaka, Mai; Kosugi, Yohei; Hirabayashi, Hideki

2017-09-01

In this article, we proposed a risk assessment strategy for CYP3A time-dependent inhibition (TDI) during drug discovery based on a thorough retrospective study of 13 reference drugs, some of which are known to have in vitro TDI potential but have unknown clinical relevance. First, the traditional parameter k inact /K I , recommended by regulatory authorities for necessity decision making in clinical drug-drug interaction (DDI) studies, was investigated as a predictive index for clinical TDI liability. The cutoff value of 1.1 for k inact /K I , established by the Food and Drug Administration, tended to produce false-positive prediction results for clinical DDI occurrence. The value of 1.25 recommended in the European Medicines Evaluation Agency draft guideline yielded better predictions with only 1 false negative for diltiazem. Second, to enable earlier risk assessment, remaining activity, defined as the residual CYP3A activity in vitro obtained in the screening conditions, was investigated as an alternative index. As a result, the ratios of unbound C max or area under the curve to remaining activity precisely predicted clinical DDI occurrence. In conclusion, we demonstrated the predictive power of k inact /K I and remaining activity values for clinical DDIs. These findings provide insights that enable TDI risk assessment, even during drug discovery. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Mutual support groups for long-term recipients of TANF.

PubMed

Anderson-Butcher, Dawn; Khairallah, Angela Oliver; Race-Bigelow, Janis

2004-01-01

This study examined the effect of involvement in mutual support groups on long-term recipients of Temporary Assistance for Needy Families (TANF) and other vulnerable individuals. From qualitative interviews with nine group members, the study identified key themes, benefits, and barriers related to involvement in the groups. Content analysis of the data revealed insights about characteristics of effective self-help and mutual support groups, which social workers and other professionals can use to develop effective support groups in the future. Participants discussed benefits for themselves and their families, such as enhanced parenting and social skills, increased knowledge, and enhanced self-esteem.

Elements of well-being affected by criminalizing the drug user.

PubMed Central

Iguchi, Martin Y.; London, Jennifer A.; Forge, Nell Griffith; Hickman, Laura; Fain, Terry; Riehman, Kara

2002-01-01

OBJECTIVE: The authors examine the possible adverse consequences of incarceration on drug offenders, their families, and their communities. OBSERVATIONS: State and federal policies on drug felons may affect eight elements of personal and community well-being: children and families, access to health benefits, access to housing benefits, access to assistance for higher education, immigration status, employment, eligibility to vote, and drug use or recidivism. CONCLUSIONS: Minorities have a high chance of felony conviction and an increasing lack of access to resources, suggesting that patterns of drug conviction and health disparities may be mutually reinforcing. Large numbers of people sent to prison for drug offenses are now completing their terms and reentering communities. Their reentry will disproportionately affect minority communities. Without resources (education, job opportunities, insurance, health care, housing, and the right to vote) drug abusers face a higher risk of recidivism and increase the burden on their communities. PMID:12435838

A role for parasites in stabilising the fig-pollinator mutualism.

PubMed

Dunn, Derek W; Segar, Simon T; Ridley, Jo; Chan, Ruth; Crozier, Ross H; Yu, Douglas W; Cook, James M

2008-03-11

Mutualisms are interspecific interactions in which both players benefit. Explaining their maintenance is problematic, because cheaters should outcompete cooperative conspecifics, leading to mutualism instability. Monoecious figs (Ficus) are pollinated by host-specific wasps (Agaonidae), whose larvae gall ovules in their "fruits" (syconia). Female pollinating wasps oviposit directly into Ficus ovules from inside the receptive syconium. Across Ficus species, there is a widely documented segregation of pollinator galls in inner ovules and seeds in outer ovules. This pattern suggests that wasps avoid, or are prevented from ovipositing into, outer ovules, and this results in mutualism stability. However, the mechanisms preventing wasps from exploiting outer ovules remain unknown. We report that in Ficus rubiginosa, offspring in outer ovules are vulnerable to attack by parasitic wasps that oviposit from outside the syconium. Parasitism risk decreases towards the centre of the syconium, where inner ovules provide enemy-free space for pollinator offspring. We suggest that the resulting gradient in offspring viability is likely to contribute to selection on pollinators to avoid outer ovules, and by forcing wasps to focus on a subset of ovules, reduces their galling rates. This previously unidentified mechanism may therefore contribute to mutualism persistence independent of additional factors that invoke plant defences against pollinator oviposition, or physiological constraints on pollinators that prevent oviposition in all available ovules.

A Role for Parasites in Stabilising the Fig-Pollinator Mutualism

PubMed Central

Dunn, Derek W; Segar, Simon T; Ridley, Jo; Chan, Ruth; Crozier, Ross H; Yu, Douglas W; Cook, James M

2008-01-01

Mutualisms are interspecific interactions in which both players benefit. Explaining their maintenance is problematic, because cheaters should outcompete cooperative conspecifics, leading to mutualism instability. Monoecious figs (Ficus) are pollinated by host-specific wasps (Agaonidae), whose larvae gall ovules in their “fruits” (syconia). Female pollinating wasps oviposit directly into Ficus ovules from inside the receptive syconium. Across Ficus species, there is a widely documented segregation of pollinator galls in inner ovules and seeds in outer ovules. This pattern suggests that wasps avoid, or are prevented from ovipositing into, outer ovules, and this results in mutualism stability. However, the mechanisms preventing wasps from exploiting outer ovules remain unknown. We report that in Ficus rubiginosa, offspring in outer ovules are vulnerable to attack by parasitic wasps that oviposit from outside the syconium. Parasitism risk decreases towards the centre of the syconium, where inner ovules provide enemy-free space for pollinator offspring. We suggest that the resulting gradient in offspring viability is likely to contribute to selection on pollinators to avoid outer ovules, and by forcing wasps to focus on a subset of ovules, reduces their galling rates. This previously unidentified mechanism may therefore contribute to mutualism persistence independent of additional factors that invoke plant defences against pollinator oviposition, or physiological constraints on pollinators that prevent oviposition in all available ovules. PMID:18336072

26 CFR 1.594-1 - Mutual savings banks conducting life insurance business.