Enhancement of the p27Kip1-mediated antiproliferative effect of trastuzumab (Herceptin) on HER2-overexpressing tumor cells.

PubMed

Marches, Radu; Uhr, Jonathan W

2004-11-10

The oncogenic activity of the overexpressed HER2 tyrosine kinase receptor requires its localization in the plasma membrane. The antitumor effect of anti-HER2 antibodies (Abs) is mainly dependent on receptor downregulation and comprises p27Kip1-mediated G1 cell cycle arrest. However, one major limitation of anti-HER2 therapy is the reversibility of tumor growth inhibition after discontinuation of treatment caused by the mitogenic signaling associated with cell surface receptor re-expression. We found that the level of p27Kip1 upregulation, inhibition of Cdk2 activity and magnitude of G1 arrest induced by the humanized Ab trastuzumab (Herceptin, HCT) on BT474 and SKBr3 HER2-overexpressing breast cancer cells correlates with the level of cell surface receptor. Thus, continuous exposure of cells to HCT for 72 hr results in downregulation of the cell surface receptor and a concurrent increase in the level of p27Kip1 protein. Discontinuation of Ab exposure after the first 8 hr results in failure to upregulate p27Kip1 and arrest of cell cycle progression. We show that the lysosomotropic amine chloroquine (CQ) augments receptor internalization in HER2-overexpressing cells either pretreated or continuously treated with HCT and leads to an increased and sustained inhibitory effect. The enhanced CQ-dependent loss of functional HER2 from the cell surface resulted in sustained inactivation of the serine/threonine kinase Akt, upregulation of p27Kip1 protein and inhibition of cyclin E/Cdk2 activity. Potentiation of the inhibitory effect of HCT by CQ was directly related to loss of HER2 from the plasma membrane since prevention of Ab-mediated receptor endocytosis by engagement of the receptor with immobilized HCT abrogated the effect of CQ.

Preparation and characterization of gellan gum/glucosamine/clioquinol film as oral cancer treatment patch.

PubMed

Tsai, Wanchi; Tsai, Huifang; Wong, Yinuan; Hong, Juiyen; Chang, Shwujen; Lee, Mingwei

2018-01-01

To administer cancer drugs with improved convenience to patients and to enhance the bioavailability of cancer drugs for oral cancer therapy, this study prepared gellan gum/glucosamine/clioquinol (GG/GS/CQ) film as the oral cancer treatment patch. GG/GS/CQ film fabricated through the EDC-mediated coupling reactions (GG/GS/CQ/EDC film). The film of the physicochemical properties and drug release kinetics were studied. The effectiveness of GG/GS/CQ/EDC film as oral cancer treatment patch were evaluated with the animal model. The results confirmed that CQ can be incorporated via EDC-mediated covalent conjugation to gellan gum/glucosamine. Mechanical testing revealed that the maximum tensile strength and elongation percentage at break were 1.91kgf/mm 2 and 5.01% for GG/GS/CQ/EDC film. After a drug release experiment lasting 45days, 86.8% of CQ was released from GG/GS/CQ/EDC film. The Huguchi model fit the GG/GS/CQ/EDC drug release data with high correlation coefficients (R 2 =0.9994, respectively). The effect of the CQ dose on oral cancer cells (OC-2) was tested, and the IC 50 of CQ alone and CQ with 10μM CuCl 2 were 9.59 and 2.22μM, respectively. The animal testing indicated that GG/GS/CQ/EDC film was decreased epidermal growth factor receptor (EGFR) expression and suppress tumor progression. These findings provide insights into a possible use for GG/GS/CQ/EDC film for oral ca in clinical practice. The GG/GS/CQ/EDC film is suitable as the dressing for use in the treatment of early-stage cancer or as wound care after surgery in late-stage of oral cancer treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Chlorpheniramine Analogues Reverse Chloroquine Resistance in Plasmodium falciparum by Inhibiting PfCRT.

PubMed

Deane, Karen J; Summers, Robert L; Lehane, Adele M; Martin, Rowena E; Barrow, Russell A

2014-05-08

The emergence and spread of malaria parasites that are resistant to chloroquine (CQ) has been a disaster for world health. The antihistamine chlorpheniramine (CP) partially resensitizes CQ-resistant (CQR) parasites to CQ but possesses little intrinsic antiplasmodial activity. Mutations in the parasite's CQ resistance transporter (PfCRT) confer resistance to CQ by enabling the protein to transport the drug away from its site of action, and it is thought that resistance-reversers such as CP exert their effect by blocking this CQ transport activity. Here, a series of new structural analogues and homologues of CP have been synthesized. We show that these compounds (along with other in vitro CQ resistance-reversers) inhibit the transport of CQ via a resistance-conferring form of PfCRT expressed in Xenopus laevis oocytes. Furthermore, the level of PfCRT-inhibition was found to correlate well with both the restoration of CQ accumulation and the level of CQ resensitization in CQR parasites.

Plasmodium falciparum and Plasmodium vivax Demonstrate Contrasting Chloroquine Resistance Reversal Phenotypes.

PubMed

Wirjanata, Grennady; Handayuni, Irene; Prayoga, Pak; Leonardo, Leo; Apriyanti, Dwi; Trianty, Leily; Wandosa, Ruland; Gobay, Basbak; Kenangalem, Enny; Poespoprodjo, Jeanne Rini; Noviyanti, Rintis; Kyle, Dennis E; Cheng, Qin; Price, Ric N; Marfurt, Jutta

2017-08-01

High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum , CQ 50% inhibitory concentrations (IC 50 s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs ( R 2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC 50 s was observed with any of the CQRRAs in P. vivax , even in those isolates with high chloroquine IC 50 s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species. © Crown copyright 2017.

Apolipoprotein gene polymorphisms as cause of cholesterol QTLs in mice.

PubMed

Suto, Jun-ichi

2005-06-01

Quantitative trait locus (QTL) analyses of plasma cholesterol levels were carried out in three sets of F(2) mice that were formed in a 'round-robin' manner from C57BL/6J, KK (-A(y)), and RR strains. Six QTLs were identified on chromosomes 1 (Cq1, Cq2, and Cq6), 3 (Cq3), and 9 (Cq4 and Cq5); of these, Cq2 colocalized with Cq6, and Cq4 colocalized with Cq5. The major candidate gene for Cq2 and Cq6 is Apoa2, and that for Cq4 and Cq5 is Apoa4. The adequacy of polymorphisms in candidate genes as cause of QTLs was investigated in this study. For Apoa2, three different alleles (Apoa2(a), Apoa2(b), and Apoa2(c)) are known. Since there was no significant physiologic difference between Apoa2(a) and Apoa2(c) alleles, previous hypothesis that Apoa2(b) was different from Apoa2(a) and Apoa2(c) in the ability to increase cholesterol levels was further supported. Presumably, G-to-A substitution at nucleotide 84 and/or C-to-T substitution at nucleotide 182 are crucial to make the Apoa2(b) unique. On the other hand, for Apoa4, the most striking polymorphism was the number of Glu-Gln-Ala/Val-Gln repeats in carboxyl end; however, this might not be responsible for QTLs. Instead, a silent mutation, C-to-T substitution at nucleotide 771, was shown to be completely correlated with the occurrence of QTLs in a total of six F(2) intercrosses. Provisionally, but reasonably, these base substitutions are qualified as primary causes that constitute QTL effect. The potential strategy for identifying genes and base substitutions underlying QTLs is discussed.

Direct elicitation of template concentration from quantification cycle (Cq) distributions in digital PCR.

PubMed

Mojtahedi, Mitra; Fouquier d'Hérouël, Aymeric; Huang, Sui

2014-01-01

Digital PCR (dPCR) exploits limiting dilution of a template into an array of PCR reactions. From this array the number of reactions that contain at least one (as opposed to zero) initial template is determined, allowing inferring the original template concentration. Here we present a novel protocol to efficiently infer the concentration of a sample and its optimal dilution for dPCR from few targeted qPCR assays. By taking advantage of the real-time amplification feature of qPCR as opposed to relying on endpoint PCR assessment as in standard dPCR prior knowledge of template concentration is not necessary. This eliminates the need for serial dilutions in a separate titration and reduces the number of necessary reactions. We describe the theory underlying our approach and discuss experimental moments that contribute to uncertainty. We present data from a controlled experiment where the initial template concentration is known as proof of principle and apply our method on directly monitoring transcript level change during cell differentiation as well as gauging amplicon numbers in cDNA samples after pre-amplification. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Combined chloroquine, sulfadoxine/pyrimethamine and primaquine against Plasmodium falciparum in Central Java, Indonesia

PubMed Central

Lederman, Edith R; Maguire, Jason D; Sumawinata, Iwa W; Chand, Krisin; Elyazar, Iqbal; Estiana, Lusi; Sismadi, Priyanto; Bangs, Michael J; Baird, J Kevin

2006-01-01

Background Chloroquine (CQ) or sulfadoxine-pyrimethamine (SP) monotherapy for Plasmodium falciparum often leads to therapeutic failure in Indonesia. Combining CQ with other drugs, like SP, may provide an affordable, available and effective option where artemisinin-combined therapies (ACT) are not licensed or are unavailable. Methods This study compared CQ (n = 29 subjects) versus CQ + SP (with or without primaquine; n = 88) for clinical and parasitological cure of uncomplicated falciparum malaria in the Menoreh Hills region of southern Central Java, Indonesia. Gametocyte clearance rates were measured with (n = 56 subjects) and without (n = 61) a single 45 mg dose of primaquine (PQ). Results After 28 days, 58% of subjects receiving CQ had cleared parasitaemia and remained aparasitaemic, compared to 94% receiving CQ combined with SP (p < 0.001). Msp-2 genotyping permitted reinfection-adjusted cure rates for CQ and CQ combined with SP, 70% and 99%, respectively (p = 0.0006). Conclusion Primaquine exerted no apparent affect on cure of asexual stage parasitaemia, but clearly accelerated clearance of gametocytes. CQ combined with SP was safe and well-tolerated with superior efficacy over CQ for P. falciparum parasitaemia in this study. PMID:17105658

Clinical trial of extended-dose chloroquine for treatment of resistant falciparum malaria among Afghan refugees in Pakistan.

PubMed

Howard, Natasha; Durrani, Naeem; Sanda, Sanda; Beshir, Khalid; Hallett, Rachel; Rowland, Mark

2011-06-23

Falciparum malaria is a significant problem for Afghan refugees in Pakistan. Refugee treatment guidelines recommended standard three-day chloroquine treatment (25 mg/kg) for first episodes and extended five-day treatment (40 mg/kg) for recrudescent infections, based on the assumption that a five-day course would more likely achieve a cure. An in-vivo randomized controlled trial was conducted among refugees with uncomplicated falciparum malaria to determine whether five-day treatment (CQ40) was more effective than standard treatment (CQ25). 142 falciparum patients were recruited into CQ25 or CQ40 treatment arms and followed up to 60 days with regular blood smears. The primary outcome was parasitological cure without recrudescence. Treatment failures were retreated with CQ40. PCR genotyping of 270 samples, from the same and nearby sites, was used to support interpretation of outcomes. 84% of CQ25 versus 51% of CQ40 patients experienced parasite recrudescence during follow-up (adjusted odds ratio 0.17, 95%CI 0.08-0.38). Cure rates were significantly improved with CQ40, particularly among adults. Fever clearance time, parasite clearance time, and proportions gametocytaemic post-treatment were similar between treatment groups. Second-line CQ40 treatment resulted in higher failure rates than first-line CQ40 treatment. CQ-resistance marker pfcrt 76T was found in all isolates analysed, while pfmdr1 86Y and 184Y were found in 18% and 37% of isolates respectively. CQ is not suitable for first-line falciparum treatment in Afghan refugee communities. The extended-dose CQ regimen can overcome 39% of resistant infections that would recrudesce under the standard regimen, but the high failure rate after directly observed treatment demonstrates its use is inappropriate.

Structure-function correlation of chloroquine and analogues as transgene expression enhancers in nonviral gene delivery.

PubMed

Cheng, Jianjun; Zeidan, Ryan; Mishra, Swaroop; Liu, Aijie; Pun, Suzie H; Kulkarni, Rajan P; Jensen, Gregory S; Bellocq, Nathalie C; Davis, Mark E

2006-11-02

To understand how chloroquine (CQ) enhances transgene expression in polycation-based, nonviral gene delivery systems, a number of CQ analogues with variations in the aliphatic amino side chain or in the aromatic ring are synthesized and investigated. Our studies indicate that the aliphatic amino moiety of CQ is essential to provide increased gene expression. Further, the enhancements are more dramatically affected by changes to the aromatic ring and are positively correlated to the strength of intercalation between DNA and the CQ analogues. Quinacrine (QC), a CQ analogue with a fused acridinyl structure that can strongly intercalate DNA, enhances transfection similarly to CQ at a concentration 10 times lower, while N(4)-(4-pyridinyl)-N(1),N(1)-diethyl-1,4-pentanediamine (CP), a CQ analogue that has a weakly intercalating pyridinyl ring, shows no effect on gene expression. Subtle change on the 7-substituent of the chloroquine aromatic structure can also greatly affect the ability of the CQ analogues to enhance transgene expression. Transfection in the presence of N(4)-(7-trifluoromethyl-4-quinolinyl)-N(1),N(1)-diethyl-1,4-pentanediamin e (CQ7a) shows expression efficiency 10 times higher than in the presence of CQ at same concentration, while transfection in the presence of N(4)-(4-quinolinyl)-N(1),N(1)-diethyl-1,4-pentanediamine (CQ7b) does not reveal any enhancing effects on expression. Through a number of comparative studies with CQ and its analogues, we conclude that there are at least three mechanistic features of CQ that lead to the enhancement in gene expression: (i) pH buffering in endocytic vesicles, (ii) displacement of polycations from the nucleic acids in polyplexes, and (iii) alteration of the biophysical properties of the released nucleic acid.

Pharmacokinetics, Pharmacodynamics, and Allometric Scaling of Chloroquine in a Murine Malaria Model▿

PubMed Central

Moore, Brioni R.; Page-Sharp, Madhu; Stoney, Jillian R.; Ilett, Kenneth F.; Jago, Jeffrey D.; Batty, Kevin T.

2011-01-01

Chloroquine (CQ) is an important antimalarial drug for the treatment of special patient groups and as a comparator for preclinical testing of new drugs. Pharmacokinetic data for CQ in animal models are limited; thus, we conducted a three-part investigation, comprising (i) pharmacodynamic studies of CQ and CQ plus dihydroartemisinin (DHA) in Plasmodium berghei-infected mice, (ii) pharmacokinetic studies of CQ in healthy and malaria-infected mice, and (iii) interspecies allometric scaling for CQ from 6 animal and 12 human studies. The single-dose pharmacodynamic study (10 to 50 mg CQ/kg of body weight) showed dose-related reduction in parasitemia (5- to >500-fold) and a nadir 2 days after the dose. Multiple-dose regimens (total dose, 50 mg/kg CQ) demonstrated a lower nadir and longer survival time than did the same single dose. The CQ-DHA combination provided an additive effect compared to each drug alone. The elimination half-life (t1/2), clearance (CL), and volume of distribution (V) of CQ were 46.6 h, 9.9 liters/h/kg, and 667 liters/kg, respectively, in healthy mice and 99.3 h, 7.9 liters/h/kg, and 1,122 liters/kg, respectively, in malaria-infected mice. The allometric equations for CQ in healthy mammals (CL = 3.86 × W0.56, V = 230 × W0.94, and t1/2 = 123 × W0.2) were similar to those for malaria-infected groups. CQ showed a delayed dose-response relationship in the murine malaria model and additive efficacy when combined with DHA. The biphasic pharmacokinetic profiles of CQ are similar across mammalian species, and scaling of specific parameters is plausible for preclinical investigations. PMID:21646487

Degree of conversion and monomer elution of CQ/amine and TPO adhesives.

PubMed

Pongprueksa, Pong; Miletic, Vesna; Janssens, Henriette; Van Landuyt, Kirsten L; De Munck, Jan; Godderis, Lode; Van Meerbeek, Bart

2014-06-01

To evaluate the effect of photo-initiator on the degree of conversion (DC) and elution of Bis-GMA and HEMA for 8 one-step adhesive formulations. We used Scotchbond Universal ('SBU-CQ/amine_4.0', 3M ESPE), containing about 2wt% camphorquinone (CQ) and 2wt% ethyl-4-dimethylamino benzoate (EDMAB), an experimental 'SBU-TPO_2.1' version, containing 2.1wt% diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO), and 6 experimental LUB adhesives (Kuraray Noritake), namely 'LUB-CQ/amine_0.7', 'LUB-CQ/amine_1.4', 'LUB-CQ/amine_4.0', 'LUB-TPO_0.35', 'LUB-TPO_0.7' and 'LUB-TPO_2.0', respectively containing 0.35wt% CQ and 0.35wt% EDMAB, 0.7wt% CQ and 0.7wt% EDMAB, 2.0wt% CQ and 2.0wt% EDMAB, 0.35wt% TPO, 0.7wt% TPO, and 2.0wt% TPO. DC was measured using micro-Raman spectroscopy. Additional specimens were immersed in ethanol for 24h to determine the elution of Bis-GMA and HEMA using HPLC. DC of the respective SBU and LUB adhesives was alike at high photo-initiator concentration. At low concentration, TPO was significantly more efficient than CQ/amine (LUB adhesives only). A statistically significant positive photo-initiator concentration effect on DC was noted for both CQ/amine and TPO (LUB adhesives only). A statistically significant inverse photo-initiator concentration effect on HEMA elution was noted for both the CQ/amine- and TPO-containing LUB adhesives. A significantly strong correlation was found between DC and Bis-GMA elution (R(2)=0.744, p=0.026), and between DC and HEMA elution (R(2)=0.913, p=0.002) for the LUB adhesives. The photo-initiator kind and concentration affect DC and the Bis-GMA/HEMA elution. TPO can be used as an alternative photo-initiator for CQ/amine. Copyright © 2014 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Plasma metabolomics reveals membrane lipids, aspartate/asparagine and nucleotide metabolism pathway differences associated with chloroquine resistance in Plasmodium vivax malaria

PubMed Central

Salinas, Jorge L.; Monteiro, Wuelton M.; Val, Fernando; Cordy, Regina J.; Liu, Ken; Melo, Gisely C.; Siqueira, Andre M.; Magalhaes, Belisa; Galinski, Mary R.; Lacerda, Marcus V. G.; Jones, Dean P.

2017-01-01

Background Chloroquine (CQ) is the main anti-schizontocidal drug used in the treatment of uncomplicated malaria caused by Plasmodium vivax. Chloroquine resistant P. vivax (PvCR) malaria in the Western Pacific region, Asia and in the Americas indicates a need for biomarkers of resistance to improve therapy and enhance understanding of the mechanisms associated with PvCR. In this study, we compared plasma metabolic profiles of P. vivax malaria patients with PvCR and chloroquine sensitive parasites before treatment to identify potential molecular markers of chloroquine resistance. Methods An untargeted high-resolution metabolomics analysis was performed on plasma samples collected in a malaria clinic in Manaus, Brazil. Male and female patients with Plasmodium vivax were included (n = 46); samples were collected before CQ treatment and followed for 28 days to determine PvCR, defined as the recurrence of parasitemia with detectable plasma concentrations of CQ ≥100 ng/dL. Differentially expressed metabolic features between CQ-Resistant (CQ-R) and CQ-Sensitive (CQ-S) patients were identified using partial least squares discriminant analysis and linear regression after adjusting for covariates and multiple testing correction. Pathway enrichment analysis was performed using Mummichog. Results Linear regression and PLS-DA methods yielded 69 discriminatory features between CQ-R and CQ-S groups, with 10-fold cross-validation classification accuracy of 89.6% using a SVM classifier. Pathway enrichment analysis showed significant enrichment (p<0.05) of glycerophospholipid metabolism, glycosphingolipid metabolism, aspartate and asparagine metabolism, purine and pyrimidine metabolism, and xenobiotics metabolism. Glycerophosphocholines levels were significantly lower in the CQ-R group as compared to CQ-S patients and also to independent control samples. Conclusions The results show differences in lipid, amino acids, and nucleotide metabolism pathways in the plasma of CQ-R versus CQ-S patients prior to antimalarial treatment. Metabolomics phenotyping of P. vivax samples from patients with well-defined clinical CQ-resistance is promising for the development of new tools to understand the biological process and to identify potential biomarkers of PvCR. PMID:28813452

Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies.

PubMed

Pellegrini, Paola; Strambi, Angela; Zipoli, Chiara; Hägg-Olofsson, Maria; Buoncervello, Maria; Linder, Stig; De Milito, Angelo

2014-04-01

Acidic pH is an important feature of tumor microenvironment and a major determinant of tumor progression. We reported that cancer cells upregulate autophagy as a survival mechanism to acidic stress. Inhibition of autophagy by administration of chloroquine (CQ) in combination anticancer therapies is currently evaluated in clinical trials. We observed in 3 different human cancer cell lines cultured at acidic pH that autophagic flux is not blocked by CQ. This was consistent with a complete resistance to CQ toxicity in cells cultured in acidic conditions. Conversely, the autophagy-inhibiting activity of Lys-01, a novel CQ derivative, was still detectable at low pH. The lack of CQ activity was likely dependent on a dramatically reduced cellular uptake at acidic pH. Using cell lines stably adapted to chronic acidosis we could confirm that CQ lack of activity was merely caused by acidic pH. Moreover, unlike CQ, Lys-01 was able to kill low pH-adapted cell lines, although higher concentrations were required as compared with cells cultured at normal pH conditions. Notably, buffering medium pH in low pH-adapted cell lines reverted CQ resistance. In vivo analysis of tumors treated with CQ showed that accumulation of strong LC3 signals was observed only in normoxic areas but not in hypoxic/acidic regions. Our observations suggest that targeting autophagy in the tumor environment by CQ may be limited to well-perfused regions but not achieved in acidic regions, predicting possible limitations in efficacy of CQ in antitumor therapies.

Functional analysis of a novel glioma antigen, EFTUD1

PubMed Central

Saito, Katsuya; Iizuka, Yukihiko; Ohta, Shigeki; Takahashi, Satoshi; Nakamura, Kenta; Saya, Hideyuki; Yoshida, Kazunari; Kawakami, Yutaka; Toda, Masahiro

2014-01-01

Background A cDNA library made from 2 glioma cell lines, U87MG and T98G, was screened by serological identification of antigens by recombinant cDNA expression (SEREX) using serum from a glioblastoma patient. Elongation factor Tu GTP binding domain containing protein 1 (EFTUD1), which is required for ribosome biogenesis, was identified. A cancer microarray database showed overexpression of EFTUD1 in gliomas, suggesting that EFTUD1 is a candidate molecular target for gliomas. Methods EFTUD1 expression in glioma cell lines and glioma tissue was assessed by Western blot, quantitative PCR, and immunohistochemistry. The effect on ribosome biogenesis, cell growth, cell cycle, and induction of apoptosis and autophagy in glioma cells during the downregulation of EFTUD1 was investigated. To reveal the role of autophagy, the autophagy-blocker, chloroquine (CQ), was used in glioma cells downregulating EFTUD1. The effect of combining CQ with EFTUD1 inhibition in glioma cells was analyzed. Results EFTUD1 expression in glioma cell lines and tissue was higher than in normal brain tissue. Downregulating EFTUD1 induced G1 cell-cycle arrest and apoptosis, leading to reduced glioma cell proliferation. The mechanism underlying this antitumor effect was impaired ribosome biogenesis via EFTUD1 inhibition. Additionally, protective autophagy was induced by glioma cells as an adaptive response to EFTUD1 inhibition. The antitumor effect induced by the combined treatment was significantly higher than that of either EFTUD1 inhibition or CQ alone. Conclusion These results suggest that EFTUD1 represents a novel therapeutic target and that the combination of EFTUD1 inhibition with autophagy blockade may be effective in the treatment of gliomas. PMID:25015090

Peripheral NMDA Receptor/NO System Blockage Inhibits Itch Responses Induced by Chloroquine in Mice

PubMed Central

Haddadi, Nazgol-Sadat; Foroutan, Arash; Ostadhadi, Sattar; Azimi, Ehsan; Rahimi, Nastaran; Nateghpour, Mehdi; Lerner, Ethan A.; Dehpour, Ahmad Reza

2017-01-01

Intradermal administration of chloroquine (CQ) provokes scratching behavior in mice. Chloroquine-induced itch is histamine-independent and we have reported that the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway is involved in CQ-induced scratching behavior in mice. Previous studies have demonstrated that activation of N-methyl-d-aspartate receptors (NMDARs) induces NO production. Here we show that NMDAR antagonists significantly decrease CQ-induced scratching in mice while a non-effective dose of an NMDAR agonist potentiates the scratching behavior provoked by sub-effective doses of CQ. In contrast, combined pre-treatment with sub-effective doses of an NMDAR antagonist, MK-801, and the NO synthase inhibitor, L-N-nitro arginine methyl ester (L-NAME), decreases CQ-induced scratching behavior. While intradermal administration of CQ significantly increases the concentration of intradermal nitrite, the end product of NO metabolism, effective doses of intraperitoneal and intradermal MK-801 significantly decrease intradermal nitrite levels. Likewise, administration of an effective dose of L-NAME significantly decreases CQ-induced nitrite production. We conclude that the NMDA/NO pathway in the skin modulates CQ-induced scratching behavior. PMID:28119997

The effect of the lectin from Cherax quadricarinatus on its granular hemocytes.

PubMed

Sánchez-Salgado, José Luis; Pereyra, Mohamed Alí; Agundis, Concepción; Vivanco-Rojas, Oscar; Rosales, Carlos; Pascual, Cristina; Alpuche-Osorno, Juan José; Zenteno, Edgar

2018-06-01

In crustaceans, lectins and hemocytes of the innate immune system provide the first line of defense. Although evidence points to the potential role of lectins in regulating hemocyte activity, the processes underlying the lectin activation have not been evaluated. In the present study, the receptor for CqL, a humoral lectin from Cherax quadricarinatus specific for galactose/sialic acid, was identified in a granular subset of hemocytes. The CqL receptor (CqLR) is a 490-kDa glycoprotein, composed of four identical 120-kDa subunits. As shown by immunohistochemistry, CqL at 7.5 μg/mL as optimal dose, after 2 min, induced, specifically on granular hemocytes, increased phosphorylation of serine (152%), threonine (192%), and tyrosine (242%) as compared with non-treated hemocytes; moreover, CqL induced increased generation of reactive oxygen species (ROS). Specific kinase inhibitors showed inhibition (P < 0.001) of ROS production induced by CqL. These results strongly suggest that CqL actively participated in the generation of ROS through kinases induced by a CqLR in a subset of granular hemocytes of the crayfish C. quadricarinatus. The results provide strong evidence that CqL activates, through specific granular hemocytes, receptors that modulate cellular functions in C. quadricarinatus. Copyright © 2018 Elsevier Ltd. All rights reserved.

Cellular Uptake of Chloroquine Is Dependent on Binding to Ferriprotoporphyrin IX and Is Independent of NHE Activity in Plasmodium falciparum

PubMed Central

Bray, Patrick G.; Janneh, Omar; Raynes, Kaylene J.; Mungthin, Mathirut; Ginsburg, Hagai; Ward, Stephen A.

1999-01-01

Here we provide definitive evidence that chloroquine (CQ) uptake in Plasmodium falciparum is determined by binding to ferriprotoporphyrin IX (FPIX). Specific proteinase inhibitors that block the degradation of hemoglobin and stop the generation of FPIX also inhibit CQ uptake. Food vacuole enzymes can generate cell-free binding, using human hemoglobin as a substrate. This binding accounts for CQ uptake into intact cells and is subject to identical inhibitor specificity. Inhibition of CQ uptake by amiloride derivatives occurs because of inhibition of CQ–FPIX binding rather than inhibition of the Na+/H+ exchanger (NHE). Inhibition of parasite NHE using a sodium-free medium does not inhibit CQ uptake nor does it alter the ability of amilorides to inhibit uptake. CQ resistance is characterized by a reduced affinity of CQ–FPIX binding that is reversible by verapamil. Diverse compounds that are known to disrupt lysosomal pH can mimic the verapamil effect. These effects are seen in sodium-free medium and are not due to stimulation of the NHE. We propose that these compounds increase CQ accumulation and overcome CQ resistance by increasing the pH of lysosomes and endosomes, thereby causing an increased affinity of binding of CQ to FPIX. PMID:10209030

Diverse mutational pathways converge on saturable chloroquine transport via the malaria parasite’s chloroquine resistance transporter

PubMed Central

Summers, Robert L.; Dave, Anurag; Dolstra, Tegan J.; Bellanca, Sebastiano; Marchetti, Rosa V.; Nash, Megan N.; Richards, Sashika N.; Goh, Valerie; Schenk, Robyn L.; Stein, Wilfred D.; Kirk, Kiaran; Sanchez, Cecilia P.; Lanzer, Michael; Martin, Rowena E.

2014-01-01

Mutations in the chloroquine resistance transporter (PfCRT) are the primary determinant of chloroquine (CQ) resistance in the malaria parasite Plasmodium falciparum. A number of distinct PfCRT haplotypes, containing between 4 and 10 mutations, have given rise to CQ resistance in different parts of the world. Here we present a detailed molecular analysis of the number of mutations (and the order of addition) required to confer CQ transport activity upon the PfCRT as well as a kinetic characterization of diverse forms of PfCRT. We measured the ability of more than 100 variants of PfCRT to transport CQ when expressed at the surface of Xenopus laevis oocytes. Multiple mutational pathways led to saturable CQ transport via PfCRT, but these could be separated into two main lineages. Moreover, the attainment of full activity followed a rigid process in which mutations had to be added in a specific order to avoid reductions in CQ transport activity. A minimum of two mutations sufficed for (low) CQ transport activity, and as few as four conferred full activity. The finding that diverse PfCRT variants are all limited in their capacity to transport CQ suggests that resistance could be overcome by reoptimizing the CQ dosage. PMID:24728833

Effect of Phospholipidosis on the Cellular Pharmacokinetics of ChloroquineS⃞

PubMed Central

Zheng, Nan; Zhang, Xinyuan

2011-01-01

In vivo, the weakly basic, lipophilic drug chloroquine (CQ) accumulates in the kidney to concentrations more than a thousand-fold greater than those in plasma. To study the cellular pharmacokinetics of chloroquine in cells derived from the distal tubule, Madin-Darby canine kidney cells were incubated with CQ under various conditions. CQ progressively accumulated without exhibiting steady-state behavior. Experiments failed to yield evidence that known active transport mechanisms mediated CQ uptake at the plasma membrane. CQ induced a phospholipidosis-like phenotype, characterized by the appearance of numerous multivesicular and multilamellar bodies (MLBs/MVBs) within the lumen of expanded cytoplasmic vesicles. Other induced phenotypic changes including changes in the volume and pH of acidic organelles were measured, and the integrated effects of all these changes were computationally modeled to establish their impact on intracellular CQ mass accumulation. Based on the passive transport behavior of CQ, the measured phenotypic changes fully accounted for the continuous, nonsteady-state CQ accumulation kinetics. Consistent with the simulation results, Raman confocal microscopy of live cells confirmed that CQ became highly concentrated within induced, expanded cytoplasmic vesicles that contained multiple MLBs/MVBs. Progressive CQ accumulation was increased by sucrose, a compound that stimulated the phospholipidosis-like phenotype, and was decreased by bafilomycin A1, a compound that inhibited this phenotype. Thus, phospholipidosis-associated changes in organelle structure and intracellular membrane content can exert a major influence on the local bioaccumulation and biodistribution of drugs. PMID:21156819

Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects.

PubMed

Miller, Ann K; Harrell, Emma; Ye, Li; Baptiste-Brown, Sharon; Kleim, Jőrg-Peter; Ohrt, Colin; Duparc, Stephan; Möhrle, Jörg J; Webster, Alison; Stinnett, Sandra; Hughes, Arlene; Griffith, Sandy; Beelen, Andrew P

2013-12-01

The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. Healthy subjects, 18-55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1-2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. The coadministration of CQ + TQ had no effect on TQ AUC0-t , AUC0-∞ , Tmax or t1/2 . The 90% confidence intervals of CQ + TQ vs. TQ for AUC0-t , AUC0-∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0-24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects. © 2013 The British Pharmacological Society.

Efficacy and safety of chloroquine for treatment in patients with uncomplicated Plasmodium vivax infections in endemic countries.

PubMed

Naing, Cho; Aung, Kyan; Win, Daw-Khin; Wah, Mak Joon

2010-11-01

Chloroquine (CQ) is a relatively inexpensive drug for treatment of malaria. If efficacy of CQ is still assumed, then it should be indicated in malaria treatment policies as the drug of choice for uncomplicated Plasmodium vivax malaria in endemic countries with resource constraints. The objective of this review is to summarize the existing evidence on the relative efficacy and safety of CQ in treating patients with uncomplicated P. vivax malaria in endemic countries. We searched online data bases (PUBMED, MEDLINE, EMBASE, The Cochrane Library) and the reference lists of the retrieved articles. Fifteen randomized controlled trials (n=6215) assessing the relative efficacy and safety of CQ for treatment of uncomplicated P. vivax malaria were included. CQ monotherapy was compared to CQ plus primaquine (PQ), artemisinin/artemether, artemisinin based combination therapy, quinine, CQ plus tafenoquine, chlorguanil plus dapsone, azithromycin, or placebo. Treatment efficacy was not significantly different between the CQ monotherapy group and that of the CQ with PQ 14 day group at 28 day follow-up (55/711, 7.7% vs 35/712, 4.9%; P=0.16). Evidence from the trials identified for this review draw a fairly clear conclusion about the relative efficacy and safety of CQ for treating uncomplicated P. vivax malaria infection. However, further research in this field with well powered, randomized, non-inferiority design, using the standardized protocol is needed. Copyright © 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

Chloroquine transport in Plasmodium falciparum. 1. Influx and efflux kinetics for live trophozoite parasites using a novel fluorescent chloroquine probe.

PubMed

Cabrera, Mynthia; Natarajan, Jayakumar; Paguio, Michelle F; Wolf, Christian; Urbach, Jeffrey S; Roepe, Paul D

2009-10-13

Several models for how amino acid substitutions in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) confer resistance to chloroquine (CQ) and other antimalarial drugs have been proposed. Distinguishing between these models requires detailed analysis of high-resolution CQ transport data that is unfortunately impossible to obtain with traditional radio-tracer methods. Thus, we have designed and synthesized fluorescent CQ analogues for drug transport studies. One probe places a NBD (6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid) group at the tertiary aliphatic N of CQ, via a flexible 6 C amide linker. This probe localizes to the malarial parasite digestive vacuole (DV) during initial perfusion under physiologic conditions and exhibits similar pharmacology relative to CQ, vs both CQ-sensitive (CQS) and CQ-resistant (CQR) parasites. Using live, synchronized intraerythrocytic parasites under continuous perfusion, we define NBD-CQ influx and efflux kinetics for CQS vs CQR parasites. Since this fluorescence approach provides data at much higher kinetic resolution relative to fast-filtration methods using (3)H-CQ, rate constants vs linear initial rates for CQ probe flux can be analyzed in detail. Importantly, we find that CQR parasites have a decreased rate constant for CQ influx into the DV and that this is due to mutation of PfCRT. Analysis of zero trans efflux for CQS and CQR parasites suggests that distinguishing between bound vs free pools of intra-DV drug probe is essential for proper kinetic analysis of efflux. The accompanying paper (DOI 10.1021/bi901035j ) further probes efflux kinetics for proteoliposomes containing purified, reconstituted PfCRT.

Identification of an anti-lipopolysacchride factor possessing both antiviral and antibacterial activity from the red claw crayfish Cherax quadricarinatus.

PubMed

Lin, Feng-Yu; Gao, Yan; Wang, Hao; Zhang, Qiu-Xia; Zeng, Chang-Lin; Liu, Hai-Peng

2016-10-01

It is well-known that anti-lipopolysacchride factors (ALFs) are involved in the recognition and elimination of invading pathogens. In this study, the full-length ALF cDNA sequence of the red claw crayfish Cherax quadricarinatus (termed CqALF) was cloned from a suppression subtractive hybridization library constructed using red claw crayfish hematopoietic tissue cell (Hpt cell) cultures following challenge with white spot syndrome virus (WSSV). The full-length cDNA sequence of CqALF was 863 bp, and the open reading frame encoded 123 amino acids with a signal peptide in the N-terminus and a conserved LPS-binding domain. Unlike most ALFs, which are highly expressed in haemocytes, high expression levels of CqALF were detected in epithelium, the stomach and eyestalks, while lower expression was detected in Hpt, nerves, the heart, muscle tissue, gonads, haemocytes, intestines, gills and the hepatopancreas. To further explore the biological activities of CqALF, mature recombinant CqALF protein (rCqALF) was expressed and purified using a eukaryotic expression system, and an antimicrobial activity test was carried out. rCqALF clearly exerted antiviral activity, as evidenced by the severe disruption of the envelope of intact WSSV virions following co-incubation of virions with rCqALF. Additionally, pre-incubation of WSSV with rCqALF resulted in both a significant reduction in WSSV replication in red claw crayfish Hpt cell cultures and an increased survival rate among animals. Furthermore, rCqALF was effective against both Gram-negative bacteria and Gram-positive bacteria, particularly Shigella flexneri and Staphylococcus aureus. A membrane integrity assay suggested that rCqALF was unlikely to disrupt bacterial membrane integrity compared to cecropin P1. Taken together, these data suggest that CqALF may play an important role in immune defence in the crustacean C. quadricarinatus. Copyright © 2016 Elsevier Ltd. All rights reserved.

Return of chloroquine sensitivity to Africa? Surveillance of African Plasmodium falciparum chloroquine resistance through malaria imported to China.

PubMed

Lu, Feng; Zhang, Meihua; Culleton, Richard L; Xu, Sui; Tang, Jianxia; Zhou, Huayun; Zhu, Guoding; Gu, Yaping; Zhang, Chao; Liu, Yaobao; Wang, Weiming; Cao, Yuanyuan; Li, Julin; He, Xinlong; Cao, Jun; Gao, Qi

2017-07-26

Chloroquine (CQ) was the cornerstone of anti-malarial treatment in Africa for almost 50 years, but has been widely withdrawn due to the emergence and spread of resistance. Recent reports have suggested that CQ-susceptibility may return following the cessation of CQ usage. Here, we monitor CQ sensitivity and determine the prevalence of genetic polymorphisms in the CQ resistance transporter gene (pfcrt) of Plasmodium falciparum isolates recently imported from Africa to China. Blood samples were collected from falciparum malaria patients returning to China from various countries in Africa. Isolates were tested for their sensitivity to CQ using the SYBR Green I test ex vivo, and for a subset of samples, in vitro following culture adaptation. Mutations at positions 72-76 and codon 220 of the pfcrt gene were analyzed by sequencing and confirmed by PCR-RFLP. Correlations between drug sensitivity and pfcrt polymorphisms were investigated. Of 32 culture adapted isolates assayed, 17 (53.1%), 6 (18.8%) and 9 (28.1%) were classified as sensitive, moderately resistant, and highly resistant, respectively. In vitro CQ susceptibility was related to point mutations in the pfcrt gene, the results indicating a strong association between pfcrt genotype and drug sensitivity. A total of 292 isolates were typed at the pfcrt locus, and the prevalence of the wild type (CQ sensitive) haplotype CVMNK in isolates from East, South, North, West and Central Africa were 91.4%, 80.0%, 73.3%, 53.3% and 51.7%, respectively. The only mutant haplotype observed was CVIET, and this was almost always linked to an additional mutation at A220S. Our results suggest that a reduction in drug pressure following withdrawal of CQ as a first-line drug may lead to a resurgence in CQ sensitive parasites. The prevalence of wild-type pfcrt CQ sensitive parasites from East, South and North Africa was higher than from the West and Central areas, but this varied greatly between countries. Further surveillance is required to assess whether the prevalence of CQ resistant parasites will continue to decrease in the absence of widespread CQ usage.

Structural specificity of chloroquine-hematin binding related to inhibition of hematin polymerization and parasite growth.

PubMed

Vippagunta, S R; Dorn, A; Matile, H; Bhattacharjee, A K; Karle, J M; Ellis, W Y; Ridley, R G; Vennerstrom, J L

1999-11-04

Considerable data now support the hypothesis that chloroquine (CQ)-hematin binding in the parasite food vacuole leads to inhibition of hematin polymerization and parasite death by hematin poisoning. To better understand the structural specificity of CQ-hematin binding, 13 CQ analogues were chosen and their hematin binding affinity, inhibition of hematin polymerization, and inhibition of parasite growth were measured. As determined by isothermal titration calorimetry (ITC), the stoichiometry data and exothermic binding enthalpies indicated that, like CQ, these analogues bind to two or more hematin mu-oxo dimers in a cofacial pi-pi sandwich-type complex. Association constants (K(a)'s) ranged from 0.46 to 2.9 x 10(5) M(-1) compared to 4.0 x 10(5) M(-1) for CQ. Remarkably, we were not able to measure any significant interaction between hematin mu-oxo dimer and 11, the 6-chloro analogue of CQ. This result indicates that the 7-chloro substituent in CQ is a critical structural determinant in its binding affinity to hematin mu-oxo dimer. Molecular modeling experiments reinforce the view that the enthalpically favorable pi-pi interaction observed in the CQ-hematin mu-oxo dimer complex derives from a favorable alignment of the out-of-plane pi-electron density in CQ and hematin mu-oxo dimer at the points of intermolecular contact. For 4-aminoquinolines related to CQ, our data suggest that electron-withdrawing functional groups at the 7-position of the quinoline ring are required for activity against both hematin polymerization and parasite growth and that chlorine substitution at position 7 is optimal. Our results also confirm that the CQ diaminoalkyl side chain, especially the aliphatic tertiary nitrogen atom, is an important structural determinant in CQ drug resistance. For CQ analogues 1-13, the lack of correlation between K(a) and hematin polymerization IC(50) values suggests that other properties of the CQ-hematin mu-oxo dimer complex, rather than its association constant alone, play a role in the inhibition of hematin polymerization. However, there was a modest correlation between inhibition of hematin polymerization and inhibition of parasite growth when hematin polymerization IC(50) values were normalized for hematin mu-oxo dimer binding affinities, adding further evidence that antimalarial 4-aminoquinolines act by this mechanism.

Exploring the Relationship between Cultural Intelligence, Transformational Leadership, and Burnout in Doctorate of Education Students

ERIC Educational Resources Information Center

Stokes, D. Michelle.

2013-01-01

This correlational study used standard multiple regression to determine if there was a relationship between the factors of cultural intelligence (metacognitive CQ, cognitive CQ, motivational CQ, and behavioral CQ) and transformational leadership in doctoral students. This study also sought to determine the best predictor of burnout by using a…

Concentration-Discharge Relationships, Nested Reaction Fronts, and the Balance of Oxidative and Acid-Base Weathering Fluxes in an Alpine Catchment, East River, Colorado

NASA Astrophysics Data System (ADS)

Winnick, M.; Carroll, R. W. H.; Williams, K. H.; Maxwell, R. M.; Maher, K.

2016-12-01

Although important for solute production and transport, the varied interactions between biogeochemical processes and subsurface hydrology remain poorly characterized. We investigate these couplings in the headwaters of the East River, CO, a high-elevation shale-dominated catchment system in the Rocky Mountains, using concentration-discharge (C-Q) relationships for major cations, anions, and organic carbon. Dissolved organic carbon (DOC) displays a positive C-Q relationship with well-defined clockwise hysteresis, indicating the mobilization and depletion of DOC in the upper soil horizons and highlighting the importance of shallow flowpaths through the snowmelt period. Cation and anion concentrations demonstrate that carbonate weathering, which dominates solute fluxes, is promoted by both carbonic acid and sulfuric acid derived from oxidation of pyrite in the shale bedrock. Sulfuric acid weathering in the deep subsurface dominates during base flow conditions when waters have infiltrated below the hypothesized pyrite oxidation front, whereas carbonic acid weathering plays a dominant role during the snowmelt period as a result of shallow flowpaths. Differential C-Q relationships between solutes suggest that infiltrating waters approach calcite saturation before reaching the pyrite oxidation front, after which sulfuric acid reduces carbonate alkalinity. This increase in CO2(aq) at the expense of HCO3- results in outgassing of CO2 when waters equilibrate to surface conditions, and reduces the export of carbon and alkalinity from the East River by roughly 33% annually. Future changes in snowmelt dynamics that control the balance of carbonic and sulfuric acid weathering therefore have the capacity to substantially alter the cycling of carbon in the East River catchment. Ultimately, we demonstrate that differential C-Q relationships between major solutes can provide unique insights into the complex subsurface flow and biogeochemical dynamics that operate at catchment scales.

Snowmelt controls on concentration-discharge relationships and the balance of oxidative and acid-base weathering fluxes in an alpine catchment, East River, Colorado: ACID-BASE VERSUS OXIDATIVE WEATHERING FLUXES

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

Winnick, Matthew J.; Carroll, Rosemary W. H.; Williams, Kenneth H.

Although important for riverine solute and nutrient fluxes, the connections between biogeochemical processes and subsurface hydrology remain poorly characterized. We investigate these couplings in the East River, CO, a high-elevation shale-dominated catchment in the Rocky Mountains, using concentration-discharge (C-Q) relationships for major cations, anions, and organic carbon. Dissolved organic carbon (DOC) displays a positive C-Q relationship with clockwise hysteresis, indicating mobilization and depletion of DOC in the upper soil horizons and emphasizing the importance of shallow flowpaths during snowmelt. Cation and anion concentrations demonstrate that carbonate weathering, which dominates solute fluxes, is promoted by both sulfuric acid derived from pyritemore » oxidation in the shale bedrock and carbonic acid derived from subsurface respiration. Sulfuric acid weathering dominates during baseflow conditions when waters infiltrate below the inferred pyrite oxidation front, whereas carbonic acid weathering plays a dominant role during snowmelt as a result of shallow flowpaths. Differential C-Q relationships between solutes suggest that infiltrating waters approach calcite saturation before reaching the pyrite oxidation front, after which sulfuric acid reduces carbonate alkalinity. This reduction in alkalinity results in CO 2 outgassing when waters equilibrate to surface conditions, and reduces the riverine export of carbon and alkalinity by roughly 33% annually. In conclusion, future changes in snowmelt dynamics that control the balance of carbonic and sulfuric acid weathering may substantially alter carbon cycling in the East River. Ultimately, we demonstrate that differential C-Q relationships between major solutes can provide unique insights into the complex subsurface flow and biogeochemical dynamics that operate at catchment scales.« less

Snowmelt controls on concentration-discharge relationships and the balance of oxidative and acid-base weathering fluxes in an alpine catchment, East River, Colorado: ACID-BASE VERSUS OXIDATIVE WEATHERING FLUXES

DOE PAGES

Winnick, Matthew J.; Carroll, Rosemary W. H.; Williams, Kenneth H.; ...

2017-03-01

Although important for riverine solute and nutrient fluxes, the connections between biogeochemical processes and subsurface hydrology remain poorly characterized. We investigate these couplings in the East River, CO, a high-elevation shale-dominated catchment in the Rocky Mountains, using concentration-discharge (C-Q) relationships for major cations, anions, and organic carbon. Dissolved organic carbon (DOC) displays a positive C-Q relationship with clockwise hysteresis, indicating mobilization and depletion of DOC in the upper soil horizons and emphasizing the importance of shallow flowpaths during snowmelt. Cation and anion concentrations demonstrate that carbonate weathering, which dominates solute fluxes, is promoted by both sulfuric acid derived from pyritemore » oxidation in the shale bedrock and carbonic acid derived from subsurface respiration. Sulfuric acid weathering dominates during baseflow conditions when waters infiltrate below the inferred pyrite oxidation front, whereas carbonic acid weathering plays a dominant role during snowmelt as a result of shallow flowpaths. Differential C-Q relationships between solutes suggest that infiltrating waters approach calcite saturation before reaching the pyrite oxidation front, after which sulfuric acid reduces carbonate alkalinity. This reduction in alkalinity results in CO 2 outgassing when waters equilibrate to surface conditions, and reduces the riverine export of carbon and alkalinity by roughly 33% annually. In conclusion, future changes in snowmelt dynamics that control the balance of carbonic and sulfuric acid weathering may substantially alter carbon cycling in the East River. Ultimately, we demonstrate that differential C-Q relationships between major solutes can provide unique insights into the complex subsurface flow and biogeochemical dynamics that operate at catchment scales.« less

A Crayfish Insulin-like-binding Protein

PubMed Central

Rosen, Ohad; Weil, Simy; Manor, Rivka; Roth, Ziv; Khalaila, Isam; Sagi, Amir

2013-01-01

Across the animal kingdom, the involvement of insulin-like peptide (ILP) signaling in sex-related differentiation processes is attracting increasing attention. Recently, a gender-specific ILP was identified as the androgenic sex hormone in Crustacea. However, moieties modulating the actions of this androgenic insulin-like growth factor were yet to be revealed. Through molecular screening of an androgenic gland (AG) cDNA library prepared from the crayfish Cherax quadricarinatus, we have identified a novel insulin-like growth factor-binding protein (IGFBP) termed Cq-IGFBP. Based on bioinformatics analyses, the deduced Cq-IGFBP was shown to share high sequence homology with IGFBP family members from both invertebrates and vertebrates. The protein also includes a sequence determinant proven crucial for ligand binding, which according to three-dimensional modeling is assigned to the exposed outer surface of the protein. Recombinant Cq-IGFBP (rCq-IGFBP) protein was produced and, using a “pulldown” methodology, was shown to specifically interact with the insulin-like AG hormone of the crayfish (Cq-IAG). Particularly, using both mass spectral analysis and an immunological tool, rCq-IGFBP was shown to bind the Cq-IAG prohormone. Furthermore, a peptide corresponding to residues 23–38 of the Cq-IAG A-chain was found sufficient for in vitro recognition by rCq-IGFBP. Cq-IGFBP is the first IGFBP family member shown to specifically interact with a gender-specific ILP. Unlike their ILP ligands, IGFBPs are highly conserved across evolution, from ancient arthropods, like crustaceans, to humans. Such conservation places ILP signaling at the center of sex-related phenomena in early animal development. PMID:23775079

Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects

PubMed Central

Miller, Ann K; Harrell, Emma; Ye, Li; Baptiste-Brown, Sharon; Kleim, Jőrg-Peter; Ohrt, Colin; Duparc, Stephan; Möhrle, Jörg J; Webster, Alison; Stinnett, Sandra; Hughes, Arlene; Griffith, Sandy; Beelen, Andrew P

2013-01-01

Aims The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. Methods Healthy subjects, 18–55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1–2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. Results The coadministration of CQ + TQ had no effect on TQ AUC0–t, AUC0–∞, Tmax or t1/2. The 90% confidence intervals of CQ + TQ vs. TQ for AUC0–t, AUC0–∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0–24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. Conclusions No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects. PMID:23701202

In utero exposure to chloroquine alters sexual development in the male fetal rat

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

Clewell, Rebecca A.; Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709; Pluta, Linda

Chloroquine (CQ), a drug that has been used extensively for the prevention and treatment of malaria, is currently considered safe for use during pregnancy. However, CQ has been shown to disrupt steroid homeostasis in adult rats and similar compounds, such as quinacrine, inhibit steroid production in the Leydig cell in vitro. To explore the effect of in utero CQ exposure on fetal male sexual development, pregnant Sprague-Dawley rats were given a daily dose of either water or chloroquine diphosphate from GD 16-18 by oral gavage. Chloroquine was administered as 200 mg/kg CQ base on GD 16, followed by two maintenancemore » doses of 100 mg/kg CQ base on GD 16 and 18. Three days of CQ treatment resulted in reduced maternal and fetal weight on GD 19 and increased necrosis and steatosis in the maternal liver. Fetal livers also displayed mild lipid accumulation. Maternal serum progesterone was increased after CQ administration. Fetal testes testosterone, however, was significantly decreased. Examination of the fetal testes revealed significant alterations in vascularization and seminiferous tubule development after short-term CQ treatment. Anogenital distance was not altered. Microarray and RT-PCR showed down-regulation of several genes associated with cholesterol transport and steroid synthesis in the fetal testes. This study indicates that CQ inhibits testosterone synthesis and normal testis development in the rat fetus at human relevant doses.« less

International Space Station USOS Crew Quarters Ventilation and Acoustic Design Implementation

NASA Technical Reports Server (NTRS)

Broyan, James Lee, Jr.

2009-01-01

The International Space Station (ISS) United States Operational Segment (USOS) has four permanent rack sized ISS Crew Quarters (CQ) providing a private crewmember space. The CQ uses Node 2 cabin air for ventilation/thermal cooling, as opposed to conditioned ducted air from the ISS Temperature Humidity Control System or the ISS fluid cooling loop connections. Consequently, CQ can only increase the air flow rate to reduce the temperature delta between the cabin and the CQ interior. However, increasing airflow causes increased acoustic noise so efficient airflow distribution is an important design parameter. The CQ utilized a two fan push-pull configuration to ensure fresh air at the crewmember s head position and reduce acoustic exposure. The CQ interior needs to be below Noise Curve 40 (NC-40). The CQ ventilation ducts are open to the significantly louder Node 2 cabin aisle way which required significantly acoustic mitigation controls. The design implementation of the CQ ventilation system and acoustic mitigation are very inter-related and require consideration of crew comfort balanced with use of interior habitable volume, accommodation of fan failures, and possible crew uses that impact ventilation and acoustic performance. This paper illustrates the types of model analysis, assumptions, vehicle interactions, and trade-offs required for CQ ventilation and acoustics. Additionally, on-orbit ventilation system performance and initial crew feedback is presented. This approach is applicable to any private enclosed space that the crew will occupy.

Inhibition of autophagy by chloroquine induces apoptosis in primary effusion lymphoma in vitro and in vivo through induction of endoplasmic reticulum stress.

PubMed

Masud Alam, Md; Kariya, Ryusho; Kawaguchi, Azusa; Matsuda, Kouki; Kudo, Eriko; Okada, Seiji

2016-10-01

Autophagy plays a crucial role in cancer cell survival and the inhibition of autophagy is attracting attention as an emerging strategy for the treatment of cancer. Chloroquine (CQ) is an anti-malarial drug, and is also known as an inhibitor of autophagy. Recently, it has been found that CQ induces cancer cell death through the inhibition of autophagy; however, the underlying mechanism is not entirely understood. In this study, we identified the role of CQ-induced cancer cell death using Primary Effusion Lymphoma (PEL) cells. We found that a CQ treatment induced caspase-dependent apoptosis in vitro. CQ also suppressed PEL cell growth in a PEL xenograft mouse model. We showed that CQ activated endoplasmic reticulum (ER) stress signal pathways and induced CHOP, which is an inducer of apoptosis. CQ-induced cell death was significantly decreased by salbrinal, an ER stress inhibitor, indicating that CQ-induced apoptosis in PEL cells depended on ER stress. We show here for the first time that the inhibition of autophagy induces ER stress-mediated apoptosis in PEL cells. Thus, the inhibition of autophagy is a novel strategy for cancer chemotherapy.

Novel short chain chloroquine analogues retain activity against chloroquine resistant K1 Plasmodium falciparum.

PubMed

Stocks, Paul A; Raynes, Kaylene J; Bray, Patrick G; Park, B Kevin; O'Neill, Paul M; Ward, Stephen A

2002-11-07

A series of short chain chloroquine (CQ) derivatives have been synthesized in one step from readily available starting materials. The diethylamine function of CQ is replaced by shorter alkylamine groups (4-9) containing secondary or tertiary terminal nitrogens. Some of these derivatives are significantly more potent than CQ against a CQ resistant strain of Plasmodium falciparum in vitro. We conclude that the ability to accumulate at higher concentrations within the food vacuole of the parasite is an important parameter that dictates their potency against CQ sensitive and the chloroquine resistant K1 P. falciparum.

Simultaneous Administration of 2-Aminoethyl Diphenylborinate and Chloroquine Reverses Chloroquine Resistance in Malaria Parasites

PubMed Central

Mossaad, Ehab; Furuyama, Wakako; Enomoto, Masahiro; Kawai, Satoru; Mikoshiba, Katsuhiko

2015-01-01

A nearly complete reversal of chloroquine (CQ) resistance in the CQ-resistant Plasmodium falciparum K-1 strain, with a significant decrease in the mean ± standard deviation (SD) 50% inhibitory concentration (IC50) from 1,050 ± 95 nM to 14 ± 2 nM, was achieved in vitro by the simultaneous administration of 2-aminoethyl diphenylborinate (2-APB). The CQ resistance-reversing activity of 2-APB, which showed the same efficacy as verapamil, was also observed in an in vivo mouse infection model with the CQ-resistant Plasmodium chabaudi AS(30CQ) strain. PMID:25691631

Real-time PCR using SYBR Green for the detection of Shigella spp. in food and stool samples.

PubMed

Mokhtari, W; Nsaibia, S; Gharbi, A; Aouni, M

2013-02-01

Shigella spp are exquisitely fastidious Gram negative organisms that frequently get missed in the detection by traditional culture methods. For this reason, this work has adapted a classical PCR for detection of Shigella in food and stool specimens to real-time PCR using the SYBR Green format. This method follows a melting curve analysis to be more rapid and provide both qualitative and quantitative data about the targeted pathogen. A total of 117 stool samples with diarrhea and 102 food samples were analyzed in Public Health Regional Laboratory of Nabeul by traditional culture methods and real-time PCR. To validate the real-time PCR assay, an experiment was conducted with both spiked and naturally contaminated stool samples. All Shigella strains tested were ipaH positive and all non-Shigella strains yielded no amplification products. The melting temperature (T(m) = 81.5 ± 0.5 °C) was consistently specific for the amplicon. Correlation coefficients of standard curves constructed using the quantification cycle (C(q)) versus copy numbers of Shigella showed good linearity (R² = 0.995; slope = 2.952) and the minimum level of detection was 1.5 × 10³ CFU/g feces. All food samples analyzed were negative for Shigella by standard culture methods, whereas ipaH was detected in 8.8% culture negative food products. Moreover, the ipaH specific PCR system increased the detection rate over that by culture alone from 1.7% to 11.1% among patients with diarrhea. The data presented here shows that the SYBR Green I was suitable for use in the real-time PCR assay, which provided a specific, sensitive and efficient method for the detection and quantification of Shigella spp in food and stool samples. Copyright © 2012 Elsevier Ltd. All rights reserved.

A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults.

PubMed

Tricou, Vianney; Minh, Nguyet Nguyen; Van, Toi Pham; Lee, Sue J; Farrar, Jeremy; Wills, Bridget; Tran, Hien Tinh; Simmons, Cameron P

2010-08-10

There is currently no licensed antiviral drug for treatment of dengue. Chloroquine (CQ) inhibits the replication of dengue virus (DENV) in vitro. A double-blind, randomized, placebo-controlled trial of CQ in 307 adults hospitalized for suspected DENV infection was conducted at the Hospital for Tropical Diseases (Ho Chi Minh City, Vietnam) between May 2007 and July 2008. Patients with illness histories of 72 hours or less were randomized to a 3-day course of CQ (n = 153) or placebo (n = 154). Laboratory-confirmation of DENV infection was made in 257 (84%) patients. The primary endpoints were time to resolution of DENV viraemia and time to resolution of DENV NS1 antigenaemia. In patients treated with CQ there was a trend toward a longer duration of DENV viraemia (hazard ratio (HR) = 0.80, 95% CI 0.62-1.05), but we did not find any difference for the time to resolution of NS1 antigenaemia (HR = 1.07, 95% CI 0.76-1.51). Interestingly, CQ was associated with a significant reduction in fever clearance time in the intention-to-treat population (HR = 1.37, 95% CI 1.08-1.74) but not in the per-protocol population. There was also a trend towards a lower incidence of dengue hemorrhagic fever (odds ratio = 0.60, PP 95% CI 0.34-1.04) in patients treated with CQ. Differences in levels of T cell activation or pro- or anti-inflammatory plasma cytokine concentrations between CQ- and placebo-treated patients did not explain the trend towards less dengue hemorrhagic fever in the CQ arm. CQ was associated with significantly more adverse events, primarily vomiting. CQ does not reduce the durations of viraemia and NS1 antigenaemia in dengue patients. Further trials, with appropriate endpoints, would be required to determine if CQ treatment has any clinical benefit in dengue. Current Controlled Trials number ISRCTN38002730.

Optimal antimalarial dose regimens for chloroquine in pregnancy based on population pharmacokinetic modelling.

PubMed

Salman, Sam; Baiwog, Francesca; Page-Sharp, Madhu; Kose, Kay; Karunajeewa, Harin A; Mueller, Ivo; Rogerson, Stephen J; Siba, Peter M; Ilett, Kenneth F; Davis, Timothy M E

2017-10-01

Despite extensive use and accumulated evidence of safety, there have been few pharmacokinetic studies from which appropriate chloroquine (CQ) dosing regimens could be developed specifically for pregnant women. Such optimised CQ-based regimens, used as treatment for acute malaria or as intermittent preventive treatment in pregnancy (IPTp), may have a valuable role if parasite CQ sensitivity returns following reduced drug pressure. In this study, population pharmacokinetic/pharmacodynamic modelling was used to simultaneously analyse plasma concentration-time data for CQ and its active metabolite desethylchloroquine (DCQ) in 44 non-pregnant and 45 pregnant Papua New Guinean women treated with CQ and sulfadoxine/pyrimethamine or azithromycin (AZM). Pregnancy was associated with 16% and 49% increases in CQ and DCQ clearance, respectively, as well as a 24% reduction in CQ relative bioavailability. Clearance of DCQ was 22% lower in those who received AZM in both groups. Simulations based on the final multicompartmental model demonstrated that a 33% CQ dose increase may be suitable for acute treatment for malaria in pregnancy as it resulted in equivalent exposure to that in non-pregnant women receiving recommended doses, whilst a double dose would likely be required for an effective duration of post-treatment prophylaxis when used as IPTp especially in areas of CQ resistance. The impact of co-administered AZM was clinically insignificant in simulations. The results of past/ongoing trials employing recommended adult doses of CQ-based regimens in pregnant women should be interpreted in light of these findings, and consideration should be given to using increased doses in future trials. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Effect of proanthocyanidins and photo-initiators on photo-polymerization of a dental adhesive

PubMed Central

Liu, Yi; Wang, Yong

2012-01-01

Objectives To evaluate the effects of proanthocyanidins (PA) and photoinitiator type on the degree of conversion (DC) and polymerization rate (PR) of a model dental adhesive. Methods Three types of photo-initiation systems were introduced into the Bis-GMA/HEMA co-monomer mixture, resulting in four resin formulations including CQ/A (0.5 wt% CQ and EDMAB), CQ/A/I-1 (0.5 wt% CQ, EDMAB and DPIHP), CQ/A/I-2 (1.0 wt% CQ, EDMAB and DPIHP), and TPO (2.1 wt% TPO). For each resin formulation, adhesives containing 0, 2.5%, 5% and 10% of PA with respect to the weight of resin were produced after mixing the resin with various amount of PA/ethanol solution. When light-cured, the RP and DC of each adhesive was determined using ATR- FTIR spectroscopy. Results Across and within the initiator groups, the DC followed the general trend of CQ/A < CQ/A/I-1 < CQ/A/I-2 < TPO and 0-PA > 2.5-PA > 5-PA > 10-PA, respectively. The change of PR with respect to photo-initiation systems and PA content was in a similar but less pronounced pattern. Conclusion PA hampered the polymerization of all adhesives regardless of photoinitiators used. The initiator formulations CQ/A/I-2 and TPO are better fit for PA-containing adhesives, both leading to > 65% DC in the presence of 5% PA. Clinical significance The inclusion of PA in dental adhesives has been limited by its interference with the light-curing of adhesive resins. This study found photo-initiation formulations that could maintain a satisfactory degree of monomer conversion while a significant amount of PA is incorporated. PMID:23079281

Genotoxic effects of camphorquinone and DMT on human oral and intestinal cells.

PubMed

Wessels, Miriam; Rimkus, Julia; Leyhausen, Gabriele; Volk, Joachim; Geurtsen, Werner

2015-10-01

Released components of oral biomaterials can leach into the oral cavity and may subsequently reach the gastrointestinal tract. Camphorquinone (CQ) is the most common used photoinitiator in resinous restorative materials and is often combined with the co-initiator N,N-dimethyl-p-toluidine (DMT). It has been shown that CQ exerts cytotoxic effects, at least partially due to the generation of reactive oxygen species (ROS). Objective of this study was to examine the cytotoxic and genotoxic potential of CQ in human oral keratinocytes (OKF6/TERT2) and immortalized epithelial colorectal adenocarcinoma cells (Caco-2). Furthermore, the effects of visible-light irradiation and the co-initiator DMT were investigated as well as the generation of ROS, the potential protective effect of glutathione (GSH) and a recovery period of CQ-treated Caco-2 cells. The alkaline comet assay was used to determine DNA damage. Additionally, an enzyme modified comet assay was applied, which detects 7,8-dihydro-8-oxoguanine (8-oxoguanine), a reliable marker for oxidative stress. Our data revealed that high concentrations of CQ induced DNA lesions in OKF6/TERT2 cells. This DNA damage is at least partly caused by the generation of 8-oxoguanine. In addition, CQ and DMT increased ROS formation and induced DNA damage in Caco-2 cells. CQ-treatment resulted in generation of 8-oxoguanine. The antioxidant GSH efficiently prevented CQ-associated DNA damage. Furthermore, a recovery following CQ-treatment significantly reduced DNA damage. We conclude that CQ-induced DNA damage is caused by oxidative stress in oral and intestinal cells. These lesions can be prevented and possibly repaired by GSH-treatment and recovery of cells after the photoinitiator is removed from cultures. Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Biogeochemical and hydrological constraints on concentration-discharge curves

NASA Astrophysics Data System (ADS)

Moatar, Florentina; Abbott, Ben; Minaudo, Camille; Curie, Florence; Pinay, Gilles

2017-04-01

The relationship between concentration and discharge (C-Q) can give insight into the location, abundance, rate of production or consumption, and transport dynamics of elements in coupled terrestrial-aquatic ecosystems. Consequently, the investigation of C-Q relationships for multiple elements at multiple spatial and temporal scales can be a powerful tool to address three of ecohydrology's fundamental questions: where does water comes from, how long does it stay, and what happens to the solutes and particulates it carries along the way. We analyzed long-term water quality data from 300 monitoring stations covering nearly half of France to investigate how elemental properties, catchment characteristics, and hydrological parameters influence C-Q. Based on previous work, we segmented the hydrograph, calculating independent C-Q slopes for flows above and below the median discharge. We found that most elements only expressed two of the nine possible C-Q modalities, indicating strong elemental control of C-Q shape. Catchment characteristics including land use and human population had a strong impact on concentration but typically did not influence the C-Q slopes, also suggesting inherent constraints on elemental production and transport. Biological processes appeared to regulate C-Q slope at low flows for biologically-reactive elements, but at high flows, these processes became unimportant, and most parameters expressed chemostatic behavior. This study provides a robust description of possible C-Q shapes for a wide variety of catchments and elements and demonstrates the value of low-frequency, long-term data collected by water quality agencies.

Antimalarial Activity and Mechanisms of Action of Two Novel 4-Aminoquinolines against Chloroquine-Resistant Parasites

PubMed Central

Aguiar, Anna Caroline Campos; Santos, Raquel de Meneses; Figueiredo, Flávio Júnior Barbosa; Cortopassi, Wilian Augusto; Pimentel, André Silva; França, Tanos Celmar Costa; Meneghetti, Mario Roberto; Krettli, Antoniana Ursine

2012-01-01

Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation. PMID:22649514

Antimalarial activity and mechanisms of action of two novel 4-aminoquinolines against chloroquine-resistant parasites.

PubMed

Aguiar, Anna Caroline Campos; Santos, Raquel de Meneses; Figueiredo, Flávio Júnior Barbosa; Cortopassi, Wilian Augusto; Pimentel, André Silva; França, Tanos Celmar Costa; Meneghetti, Mario Roberto; Krettli, Antoniana Ursine

2012-01-01

Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation.

Mosquitocidal and antiplasmodial activity of Senna occidentalis (Cassiae) and Ocimum basilicum (Lamiaceae) from Maruthamalai hills against Anopheles stephensi and Plasmodium falciparum.

PubMed

Murugan, Kadarkarai; Aarthi, Narayanan; Kovendan, Kalimuthu; Panneerselvam, Chellasamy; Chandramohan, Balamurugan; Kumar, Palanisamy Mahesh; Amerasan, Duraisamy; Paulpandi, Manickam; Chandirasekar, Ramachandran; Dinesh, Devakumar; Suresh, Udaiyan; Subramaniam, Jayapal; Higuchi, Akon; Alarfaj, Abdullah A; Nicoletti, Marcello; Mehlhorn, Heinz; Benelli, Giovanni

2015-10-01

Each year, mosquito-borne diseases infect nearly 700 million people, resulting to more than 1 million deaths. In this study, we evaluated the larvicidal, pupicidal, and smoke toxicity of Senna occidentalis and Ocimum basilicum leaf extracts against the malaria vector Anopheles stephensi. Furthermore, the antiplasmodial activity of plant extracts was evaluated against chloroquine (CQ)-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. In larvicidal and pupicidal experiments, S. occidentalis LC50 ranged from 31.05 (I instar larvae) to 75.15 ppm (pupae), and O. basilicum LC50 ranged from 29.69 (I instar larvae) to 69 ppm (pupae). Smoke toxicity experiments conducted against adults showed that S. occidentalis and O. basilicum coils evoked mortality rates comparable to the pyrethrin-based positive control (38, 52, and 42%, respectively). In antiplasmodial assays, Senna occidentalis 50% inhibitory concentration (IC50) were 48.80 μg/ml (CQ-s) and 54.28 μg/ml (CQ-r), while O. basilicum IC50 were 68.14 μg/ml (CQ-s) and 67.27 μg/ml (CQ-r). Overall, these botanicals could be considered as potential sources of metabolites to build newer and safer malaria control tools.

The chemotherapy of rodent malaria. LXI. Drug combinations to impede the selection of drug resistance, part 4: the potential role of 8-aminoquinolines.

PubMed

Peters, W; Stewart, L B; Robinson, B L

2003-04-01

The influence of combinations containing the blood schizontocides chloroquine (CQ) or mefloquine (MEF), together with the 8-aminoquinolines (8AQ) primaquine (PQ) or the new, long-acting compound, tafenoquine (TAF), on the rate of selection of resistance to the individual compounds was examined using the asexual, intra-erythrocytic stages in rodent malaria models. The two main procedures used were a 'serial technique' (ST) and the '2%- relapse technique' (2%RT). The ST provided evidence for the contention that a combination with PQ slowed the selection of resistance to CQ or MEF; it has been shown previously that synergism exists between CQ and either PQ or TAF in rodent malaria. Data obtained with the 2%RT, and three parasite lines derived from Plasmodium berghei N (the 238B line), P. chabaudi ASS (the 238C line) or P. yoelii ssp. NS (the 238Y line), indicated that resistance to TAF used alone is acquired rapidly under drug pressure and that this resistance is stable when selection pressure is removed. In the 2%RT, resistance to CQ developed when another line of P. chabaudi (AS15) was exposed to that compound alone, although more slowly than the development of resistance to TAF in the 238C line. However, treatment of a TC line of P. chabaudi, developed in a 2%RT using a combination of CQ with TAF, led to little resistance to either compound. A totally unforeseen phenomenon was the appearance of a high level of resistance to CQ in the 238C line of P. chabaudi that had been exposed only to TAF; this was not observed with the 238B or 238Y lines. Attention has been refocused recently on the use of 8AQ for prophylaxis in man. It remains to be determined if resistance in the asexual intra-erythrocytic forms is carried over to the other stages of the malarial life-cycle, especially the hepatic, pre-erythrocytic schizonts. The implications of the present results for the possible clinical deployment of 8AQ in the future are discussed. It is concluded that, whereas use of an 8AQ alone carries a high risk of selecting resistance, combinations containing 8AQ may have a place in the protection of blood schizontocides that are to be deployed in endemic areas. Furthermore, the inherent gametocytocidal action of the 8AQ should promote the reduction of transmission.

Emerging Plasmodium vivax resistance to chloroquine in South America: an overview

PubMed Central

Gonçalves, Lígia Antunes; Cravo, Pedro; Ferreira, Marcelo Urbano

2014-01-01

The global emergence of Plasmodium vivax strains resistant to chloroquine (CQ) since the late 1980s is complicating the current international efforts for malaria control and elimination. Furthermore, CQ-resistant vivax malaria has already reached an alarming prevalence in Indonesia, East Timor and Papua New Guinea. More recently, in vivo studies have documented CQ-resistant P. vivax infections in Guyana, Peru and Brazil. Here, we summarise the available data on CQ resistance across P. vivax-endemic areas of Latin America by combining published in vivo and in vitro studies. We also review the current knowledge regarding the molecular mechanisms of CQ resistance in P. vivax and the prospects for developing and standardising reliable molecular markers of drug resistance. Finally, we discuss how the Worldwide Antimalarial Resistance Network, an international collaborative effort involving malaria experts from all continents, might contribute to the current regional efforts to map CQ-resistant vivax malaria in South America. PMID:25184999

Efficacy of chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in Honduras.

PubMed

Mejia Torres, Rosa Elena; Banegas, Engels Ilich; Mendoza, Meisy; Diaz, Cesar; Bucheli, Sandra Tamara Mancero; Fontecha, Gustavo A; Alam, Md Tauqeer; Goldman, Ira; Udhayakumar, Venkatachalam; Zambrano, Jose Orlinder Nicolas

2013-05-01

Chloroquine (CQ) is officially used for the primary treatment of Plasmodium falciparum malaria in Honduras. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated P. falciparum malaria in the municipality of Puerto Lempira, Gracias a Dios, Honduras was evaluated using the Pan American Health Organization-World Health Organization protocol with a follow-up of 28 days. Sixty-eight patients from 6 months to 60 years of age microscopically diagnosed with uncomplicated P. falciparum malaria were included in the final analysis. All patients who were treated with CQ (25 mg/kg over 3 days) cleared parasitemia by day 3 and acquired no new P. falciparum infection within 28 days of follow-up. All the parasite samples sequenced for CQ resistance mutations (pfcrt) showed only the CQ-sensitive genotype (CVMNK). This finding shows that CQ remains highly efficacious for the treatment of uncomplicated P. falciparum malaria in Gracias a Dios, Honduras.

Chloroquine-induced cardiomyopathy: a reversible cause of heart failure.

PubMed

Yogasundaram, Haran; Hung, Whitney; Paterson, Ian D; Sergi, Consolato; Oudit, Gavin Y

2018-06-01

Chloroquine (CQ) and hydroxychloroquine (HCQ) are anti-rheumatic medications frequently used in the treatment of connective tissue disorders. We present the case of a 45-year-old woman with CQ-induced cardiomyopathy leading to severe heart failure. Electrocardiographic abnormalities included bifascicular block, while structural disease consisted of severe biventricular and biatrial hypertrophy. Appropriate diagnosis via endomyocardial biopsy led to cessation of CQ and subsequent dramatic improvement in symptoms and structural heart disease. Cardiac toxicity is an under-recognized adverse effect of CQ/HCQ leading to cardiomyopathy with concentric hypertrophy and conduction abnormalities, with the potential for significant morbidity and mortality. Predisposing factors for CQ/HCQ-induced cardiomyopathy have been proposed. CQ/HCQ cardiomyopathy is a phenocopy of Fabry disease, and α-galactosidase A polymorphism may account for some heterogeneity of disease presentation. © 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Solution structures of chloroquine-ferriheme complexes modeled using MD simulation and investigated by EXAFS spectroscopy.

PubMed

Kuter, David; Streltsov, Victor; Davydova, Natalia; Venter, Gerhard A; Naidoo, Kevin J; Egan, Timothy J

2016-01-01

The interaction of chloroquine (CQ) and the μ-oxo dimer of iron(III) protoporphyrin IX (ferriheme) in aqueous solution was modeled using molecular dynamics (MD) simulations. Two models of the CQ-(μ-oxo ferriheme) complex were investigated, one involving CQ π-stacked with an unligated porphyrin face of μ-oxo ferriheme and the other in which CQ was docked between the two porphyrin rings. The feasibility of both models was tested by fitting computed structures to the experimental extended X-ray absorption fine structure (EXAFS) spectrum of the CQ-(μ-oxo ferriheme) complex in frozen aqueous solution. The docked model produced better agreement with experimental data, suggesting that this is the more likely structure in aqueous solution. The EXAFS fit indicated a longer than expected Fe-O bond of 1.87Å, accounting for the higher than expected magnetic moment of the complex. As a consequence, the asymmetric Fe-O-Fe stretch shifts much lower in frequency and was identified in the precipitated solid at 744cm(-1) with the aid of the O(18) isomer shift. Three important CQ-ferriheme interactions were identified in the docked structure. These were a hydrogen bond between the oxide bridge of μ-oxo ferriheme and the protonated quinolinium nitrogen atom of CQ; π-stacking between the quinoline ring of CQ and the porphyrin rings; and a close contact between the 7-chloro substituent of CQ and the porphyrin methyl hydrogen atoms. These interactions can be used to rationalize previously observed structure-activity relationships for quinoline-ferriheme association. Copyright © 2015 Elsevier Inc. All rights reserved.

Chloroquine and hydroxychloroquine inhibit bladder cancer cell growth by targeting basal autophagy and enhancing apoptosis.

PubMed

Lin, Yi-Chia; Lin, Ji-Fan; Wen, Sheng-I; Yang, Shan-Che; Tsai, Te-Fu; Chen, Hung-En; Chou, Kuang-Yu; Hwang, Thomas I-Sheng

2017-05-01

Chloroquine (CQ) and hydroxychloroquine (HCQ), two antimalarial drugs, are suggested to have potential anticancer properties. in the present study, we investigated the effects of CQ and HCQ on cell growth of bladder cancer with emphasis on autophagy inhibition and apoptosis induction in vitro. The results showed that CQ and HCQ inhibited the proliferation of multiple human bladder cell lines (including RT4, 5637, and T24) in a time- and dose-dependent fashion, especially in advanced bladder cancer cell lines (5637 and T24) compared to immortalized uroepithelial cells (SV-Huc-1) or other reference cancer cell lines (PC3 and MCF-7). We found that 24-hour treatment of CQ or HCQ significantly decreased the clonogenic formation in 5637 and T24 cells compared to SV-Huc-1. As human bladder cancer tumor exhibits high basal level of autophagic activities, we detected the autophagic flux in cells treated with CQ and HCQ, showing an alternation in LC3 flux in CQ- or HCQ-treated cells. Moreover, bladder cancer cells treated with CQ and HCQ underwent apoptosis, resulting in increased caspase 3/7 activities, increased level of cleaved poly(ADP-ribose) polymerase (PARP), caspase 3, and DNA fragmentation. Given these results, targeting autophagy with CQ and HCQ represents an effective cancer therapeutic strategy against human bladder cancer. Copyright © 2017. Published by Elsevier Taiwan.

Development of PMA real-time PCR method to quantify viable cells of Pantoea agglomerans CPA-2, an antagonist to control the major postharvest diseases on oranges.

PubMed

Soto-Muñoz, Lourdes; Teixidó, Neus; Usall, Josep; Viñas, Inmaculada; Crespo-Sempere, Ana; Torres, Rosario

2014-06-16

Dilution plating is the quantification method commonly used to estimate the population level of postharvest biocontrol agents, but this method does not permit a distinction among introduced and indigenous strains. Recently, molecular techniques based on DNA amplification such as quantitative real-time PCR (qPCR) have been successfully applied for their high strain-specific detection level. However, the ability of qPCR to distinguish viable and nonviable cells is limited. A promising strategy to avoid this issue relies on the use of nucleic acid intercalating dyes, such as propidium monoazide (PMA), as a sample pretreatment prior to the qPCR. The objective of this study was to optimize a protocol based on PMA pre-treatment samples combined with qPCR to distinguish and quantify viable cells of the biocontrol agent P. agglomerans CPA-2 applied as a postharvest treatment on orange. The efficiency of PMA-qPCR method under the established conditions (30μM PMA for 20min of incubation followed by 30min of LED light exposure) was evaluated on an orange matrix. Results showed no difference in CFU or cells counts of viable cells between PMA-qPCR and dilution plating. Samples of orange matrix inoculated with a mixture of viable/dead cells showed 5.59log10 CFU/ml by dilution plating, 8.25log10 cells/ml by qPCR, and 5.93log10 cells/ml by PMA-qPCR. Furthermore, samples inoculated with heat-killed cells were not detected by dilution plating and PMA-qPCR, while by qPCR was of 8.16log10 cells/ml. The difference in quantification cycles (Cq) among qPCR and PMA-qPCR was approximately 16cycles, which means a reduction of 65,536 fold of the dead cells detected. In conclusion, PMA-qPCR method is a suitable tool for quantify viable CPA-2 cells, which could be useful to estimate the ability of this antagonist to colonize the orange surface. Copyright © 2014 Elsevier B.V. All rights reserved.

Evaluation of cell responses toward adhesives with different photoinitiating systems.

PubMed

Van Landuyt, Kirsten L; Krifka, Stephanie; Hiller, Karl-Anton; Bolay, Carola; Waha, Claudia; Van Meerbeek, Bart; Schmalz, Gottfried; Schweikl, Helmut

2015-08-01

The photoinitiator diphenyl-(2,4,6-trimethylbenzoyl)phosphine oxide (TPO) is more reactive than a camphorquinone/amine (CQ) system, and TPO-based adhesives obtained a higher degree of conversion (DC) with fewer leached monomers. The hypothesis tested here is that a TPO-based adhesive is less toxic than a CQ-based adhesive. A CQ-based adhesive (SBU-CQ) (Scotchbond Universal, 3M ESPE) and its experimental counterpart with TPO (SBU-TPO) were tested for cytotoxicity in human pulp-derived cells (tHPC). Oxidative stress was analyzed by the generation of reactive oxygen species (ROS) and by the expression of antioxidant enzymes. A dentin barrier test (DBT) was used to evaluate cell viability in simulated clinical circumstances. Unpolymerized SBU-TPO was significantly more toxic than SBU-CQ after a 24h exposure, and TPO alone (EC50=0.06mM) was more cytotoxic than CQ (EC50=0.88mM), EDMAB (EC50=0.68mM) or CQ/EDMAB (EC50=0.50mM). Cultures preincubated with BSO (l-buthionine sulfoximine), an inhibitor of glutathione synthesis, indicated a minor role of glutathione in cytotoxic responses toward the adhesives. Although the generation of ROS was not detected, a differential expression of enzymatic antioxidants revealed that cells exposed to unpolymerized SBU-TPO or SBU-CQ are subject to oxidative stress. Polymerized SBU-TPO was more cytotoxic than SBU-CQ under specific experimental conditions only, but no cytotoxicity was detected in a DBT with a 200μm dentin barrier. Not only DC and monomer-release determine the biocompatibility of adhesives, but also the cytotoxicity of the (photo-)initiator should be taken into account. Addition of TPO rendered a universal adhesive more toxic compared to CQ; however, this effect could be annulled by a thin dentin barrier. Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Cloning and characterization of WRKY gene homologs in Chieh-qua (Benincasa hispida Cogn. var. Chieh-qua How) and their expression in response to fusaric acid treatment.

PubMed

Mao, Yizhou; Jiang, Biao; Peng, Qingwu; Liu, Wenrui; Lin, Yue; Xie, Dasen; He, Xiaoming; Li, Shaoshan

2017-05-01

The WRKY transcription factors play an important role in plant resistance for biotic and abiotic stresses. In the present study, we cloned 10 WRKY gene homologs (CqWRKY) in Chieh-qua (Benincasa hispida Cogn. var. Chieh-qua) using the rapid-amplification of cDNA ends (RACE) or homology-based cloning methods. We characterized the structure of these CqWRKY genes. Phylogenetic analysis of these sequences with cucumber homologs suggested possible structural conservation of these genes among cucurbit crops. We examined the expression levels of these genes in response to fusaric acid (FA) treatment between resistant and susceptible Chieh-qua lines with quantitative real-time PCR. All genes could be upregulated upon FA treatment, but four CqWRKY genes exhibited differential expression between resistant and susceptible lines before and after FA application. CqWRKY31 seemed to be a positive regulator while CqWRKY1, CqWRKY23 and CqWRKY53 were negative regulators of fusaric resistance. This is the first report of characterization of WRKY family genes in Chieh-qua. The results may also be useful in breeding Chieh-qua for Fusarium wilt resistance.

Chloroquine inhibits lytic replication of Kaposi's sarcoma-associated herpesvirus by disrupting mTOR and p38-MAPK activation.

PubMed

Yang, Mengtian; Huang, Lu; Li, Xiaojuan; Kuang, Ersheng

2016-09-01

Lytic infection is essential for the persistent infection and pathogenesis of Kaposi's sarcoma-associated herpesvirus (KSHV), and inhibiting KSHV lytic replication may effectively prevent the occurrence of KSHV-related diseases. Chloroquine (CQ), a well-known antimalarial drug and autophagy inhibitor, exerts broad-spectrum antiviral effects and shows anti-cancer therapeutic potential. However, the ability of CQ and its derivatives to control infection of oncogenic γ-herpesvirus remains undefined. Here we reveal that CQ suppresses KSHV lytic gene expression and virion production, and shows cytotoxicity toward KSHV lytically infected B cells at clinically acceptable doses. CQ suppresses mTOR and p38-MAPK pathway activation during KSHV lytic replication but not latent infection. Furthermore, CQ blocks Epstein-Barr virus (EBV) lytic replication via a distinct mechanism that is invoked to block virion production but does not affect viral gene expression. These results suggest that CQ is an effective antiviral drug against KSHV lytic infection. Our findings indicate that CQ treatment should be considered for controlling KSHV-related diseases, particularly for primary use in co-infection of KSHV with malaria. Copyright © 2016 Elsevier B.V. All rights reserved.

Efficacy of Chloroquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Honduras

PubMed Central

Torres, Rosa Elena Mejia; Banegas, Engels Ilich; Mendoza, Meisy; Diaz, Cesar; Bucheli, Sandra Tamara Mancero; Fontecha, Gustavo A.; Alam, Md Tauqeer; Goldman, Ira; Udhayakumar, Venkatachalam; Zambrano, Jose Orlinder Nicolas

2013-01-01

Chloroquine (CQ) is officially used for the primary treatment of Plasmodium falciparum malaria in Honduras. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated P. falciparum malaria in the municipality of Puerto Lempira, Gracias a Dios, Honduras was evaluated using the Pan American Health Organization—World Health Organization protocol with a follow-up of 28 days. Sixty-eight patients from 6 months to 60 years of age microscopically diagnosed with uncomplicated P. falciparum malaria were included in the final analysis. All patients who were treated with CQ (25 mg/kg over 3 days) cleared parasitemia by day 3 and acquired no new P. falciparum infection within 28 days of follow-up. All the parasite samples sequenced for CQ resistance mutations (pfcrt) showed only the CQ-sensitive genotype (CVMNK). This finding shows that CQ remains highly efficacious for the treatment of uncomplicated P. falciparum malaria in Gracias a Dios, Honduras. PMID:23458957

Hyporheic zone influences on concentration-discharge relationships in a headwater sandstone stream

NASA Astrophysics Data System (ADS)

Hoagland, Beth; Russo, Tess A.; Gu, Xin; Hill, Lillian; Kaye, Jason; Forsythe, Brandon; Brantley, Susan L.

2017-06-01

Complex subsurface flow dynamics impact the storage, routing, and transport of water and solutes to streams in headwater catchments. Many of these hydrogeologic processes are indirectly reflected in observations of stream chemistry responses to rain events, also known as concentration-discharge (CQ) relations. Identifying the relative importance of subsurface flows to stream CQ relationships is often challenging in headwater environments due to spatial and temporal variability. Therefore, this study combines a diverse set of methods, including tracer injection tests, cation exchange experiments, geochemical analyses, and numerical modeling, to map groundwater-surface water interactions along a first-order, sandstone stream (Garner Run) in the Appalachian Mountains of central Pennsylvania. The primary flow paths to the stream include preferential flow through the unsaturated zone ("interflow"), flow discharging from a spring, and groundwater discharge. Garner Run stream inherits geochemical signatures from geochemical reactions occurring along each of these flow paths. In addition to end-member mixing effects on CQ, we find that the exchange of solutes, nutrients, and water between the hyporheic zone and the main stream channel is a relevant control on the chemistry of Garner Run. CQ relationships for Garner Run were compared to prior results from a nearby headwater catchment overlying shale bedrock (Shale Hills). At the sandstone site, solutes associated with organo-mineral associations in the hyporheic zone influence CQ, while CQ trends in the shale catchment are affected by preferential flow through hillslope swales. The difference in CQ trends document how the lithology and catchment hydrology control CQ relationships.

Contact Quotient of Female Singers Singing Four Pitches for Five Vowels in Normal and Pressed Phonations.

PubMed

Ong Tan, Kendrich Graemer

2017-09-01

The present study aimed to investigate the contact quotient (CQ) values of breathy, normal, and pressed phonation types in four different sections of the female singing range. Electroglottography (EGG) and acoustic signals were recorded from 10 female singing teachers. Five vowels were sung for 1-3 seconds each, in three phonation types-normal, breathy, and pressed, in four pitches representing registration change points in the singing range. CQ values were automatically generated from the EGG signal using VoceVista at 35% threshold level. Sound pressure levels were checked in Praat. Unianova and correlations were performed using an SPSS program. CQ values of female participants in the study yielded ranges of 0.25-0.62 in normal and 0.34-0.73 in pressed. Normal and pressed CQ differed significantly from each other at P < 0.00. Breathy samples were not viable for analysis. A concentration of CQ values from 0.5 to 0.6 of both pressed low and pressed break samples was noted, but CQ values across the pitch range showed no significant trend. Normal and pressed phonation CQ values beyond the speaking pitch varied among the subjects. Pressed phonation CQ values were mostly higher, but the values were only relative to the corresponding normal phonation on the same pitch. Other measurements may be more suitable for measuring vocal fold impact stress in higher frequencies, thus, distinguishing normal from pressed singing. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Longitudinal study assessing the return of chloroquine susceptibility of Plasmodium falciparum in isolates from travellers returning from West and Central Africa, 2000–2011

PubMed Central

2013-01-01

Background Chloroquine (CQ) was the main malaria therapy worldwide from the 1940s until the 1990s. Following the emergence of CQ-resistant Plasmodium falciparum, most African countries discontinued the use of CQ, and now promote artemisinin-based combination therapy as the first-line treatment. This change was generally initiated during the last decade in West and Central Africa. The aim of this study is to describe the changes in CQ susceptibility in this African region, using travellers returning from this region as a sentinel system. Methods The study was conducted by the Malaria National Reference Centre, France. The database collated the pfcrtK76T molecular marker for CQ susceptibility and the in vitro response to CQ of parasites from travellers’ isolates returning from Senegal, Mali, Ivory Coast or Cameroon. As a proxy of drug pressure, data regarding CQ intake in febrile children were collated for the study period. Logistic regression models were used to detect trends in the proportions of CQ resistant isolates. Results A total of 2874 parasite isolates were genotyped between 2000–2011. The prevalence of the pfcrt76T mutant genotype significantly decreased for Senegal (from 78% to 47%), Ivory Coast (from 63% to 37%), Cameroon (from 90% to 59%) and remained stable for Mali. The geometric mean of the 50% inhibitory concentration (IC50) of CQ in vitro susceptibility and the proportion of resistant isolates (defining resistance as an IC50 value > 100 nM) significantly decreased for Senegal (from 86 nM (59%) to 39 nM (25%)), Mali (from 84 nM (50%) to 51 nM (31%)), Ivory Coast (from 75 nM (59%) to 29 nM (16%)) and Cameroon (from 181 nM (75%) to 51 nM (37%)). Both analyses (molecular and in vitro susceptibility) were performed for the 2004–2011 period, after the four countries had officially discontinued CQ and showed an accelerated decline of the resistant isolates for the four countries. Meanwhile, CQ use among children significantly deceased in this region (fixed effects slope = −0.3, p < 10-3). Conclusions An increase in CQ susceptibility following official withdrawal of the drug was observed in travellers returning from West and Central African countries. The same trends were observed for molecular and in vitro analysis between 2004-2011and they correlated to the decrease of the drug pressure. PMID:23351608

Longitudinal study assessing the return of chloroquine susceptibility of Plasmodium falciparum in isolates from travellers returning from West and Central Africa, 2000-2011.

PubMed

Gharbi, Myriam; Flegg, Jennifer A; Hubert, Véronique; Kendjo, Eric; Metcalf, Jessica E; Bertaux, Lionel; Guérin, Philippe J; Le Bras, Jacques; Aboubaca, Ahmed; Agnamey, Patrice; Angoulvant, Adela; Barbut, Patricia; Basset, Didier; Belkadi, Ghania; Bellanger, Anne Pauline; Bemba, Dieudonné; Benoit-Vica, Françoise; Berry, Antoine; Bigel, Marie-Laure; Bonhomme, Julie; Botterel, Françoise; Bouchaud, Olivier; Bougnoux, Marie-Elisabeth; Bourée, Patrice; Bourgeois, Nathalie; Branger, Catherine; Bret, Laurent; Buret, Bernadette; Casalino, Enrique; Chevrier, Sylviane; Conquere de Monbrison, Frédérique; Cuisenier, Bernadette; Danis, Martin; Darde, Marie-Laure; De Gentile, Ludovic; Delarbre, Jean-Marie; Delaunay, Pascal; Delaval, Anne; Desoubeaux, Guillaume; Develoux, Michel; Dunand, Jean; Durand, Rémy; Eloy, Odile; Fauchet, Nathalie; Faugere, Bernard; Faye, Alber; Fenneteau, Odile; Flori, Pierre; Fontrouge, Madeleine; Garabedian, Chantal; Gayandrieu, Françoise; Godineau, Nadine; Houzé, Pascal; Houzé, Sandrine; Hurst, Jean-Pierre; Ichou, Houria; Lachaud, Laurence; Lebuisson, Agathe; Lefevre, Magalie; LeGuern, Anne-Sophie; Le Moal, Gwenaë; Lusina, Daniel; Machouart, Marie-Claude; Malvy, Denis; Matheron, Sophie; Maubon, Danièle; Mechali, Denis; Megarbane, Bruno; Menard, Guillaume; Millon, Laurence; Aiach, Muriel Mimoun; Minodier, Philippe; Morelle, Christelle; Nevez, Gilles; Parola, Philippe; Parzy, Daniel; Patey, Olivier; Patoz, Pierre; Penn, Pascale; Perignon, Alice; Picot, Stéphane; Pilo, Jean-Etienne; Poilane, Isabelle; Pons, Denis; Poupart, Marie; Pradines, Bruno; Raffenot, Didier; Rapp, Christophe; Receveur, Marie-Catherine; Sarfati, Claudine; Senghor, Yaye; Simon, Fabrice; Siriez, Jean-Yves; Taudon, Nicolas; Thellier, Marc; Thouvenin, Maxime; Toubas, Dominique

2013-01-25

Chloroquine (CQ) was the main malaria therapy worldwide from the 1940s until the 1990s. Following the emergence of CQ-resistant Plasmodium falciparum, most African countries discontinued the use of CQ, and now promote artemisinin-based combination therapy as the first-line treatment. This change was generally initiated during the last decade in West and Central Africa. The aim of this study is to describe the changes in CQ susceptibility in this African region, using travellers returning from this region as a sentinel system. The study was conducted by the Malaria National Reference Centre, France. The database collated the pfcrtK76T molecular marker for CQ susceptibility and the in vitro response to CQ of parasites from travellers' isolates returning from Senegal, Mali, Ivory Coast or Cameroon. As a proxy of drug pressure, data regarding CQ intake in febrile children were collated for the study period. Logistic regression models were used to detect trends in the proportions of CQ resistant isolates. A total of 2874 parasite isolates were genotyped between 2000-2011. The prevalence of the pfcrt76T mutant genotype significantly decreased for Senegal (from 78% to 47%), Ivory Coast (from 63% to 37%), Cameroon (from 90% to 59%) and remained stable for Mali. The geometric mean of the 50% inhibitory concentration (IC50) of CQ in vitro susceptibility and the proportion of resistant isolates (defining resistance as an IC50 value > 100 nM) significantly decreased for Senegal (from 86 nM (59%) to 39 nM (25%)), Mali (from 84 nM (50%) to 51 nM (31%)), Ivory Coast (from 75 nM (59%) to 29 nM (16%)) and Cameroon (from 181 nM (75%) to 51 nM (37%)). Both analyses (molecular and in vitro susceptibility) were performed for the 2004-2011 period, after the four countries had officially discontinued CQ and showed an accelerated decline of the resistant isolates for the four countries. Meanwhile, CQ use among children significantly deceased in this region (fixed effects slope = -0.3, p < 10-3). An increase in CQ susceptibility following official withdrawal of the drug was observed in travellers returning from West and Central African countries. The same trends were observed for molecular and in vitro analysis between 2004-2011 and they correlated to the decrease of the drug pressure.

An Experiential Approach to Cultural Intelligence Education

ERIC Educational Resources Information Center

MacNab, Brent R.

2012-01-01

Cultural intelligence (CQ) represents a promising advancement in the area of cross-cultural training and management. Experiential approaches for CQ development have been proposed as highly effective; however, there is a lack of CQ-specific approaches in the management literature. This work overviews the concept of cultural intelligence and its…

Understanding the Role of Cultural Intelligence in Individual Creativity

ERIC Educational Resources Information Center

Yunlu, Dilek G.; Clapp-Smith, Rachel; Shaffer, Margaret

2017-01-01

Employing creative cognition theory, this study investigates the relationship between cultural intelligence (CQ) and creativity. Using data from 394 full-time employees, metacognitive, cognitive, and motivational forms of CQ were found to have positive relationships with individual creativity. In addition, the positive effect of cognitive CQ on…

Poly(L-lactic acid) nanofibers containing Cissus quadrangularis induced osteogenic differentiation in vitro.

PubMed

Parvathi, K; Krishnan, Amit G; Anitha, A; Jayakumar, R; Nair, Manitha B

2018-04-15

Cissus quadrangularis (CQ) is known as "bone setter" in Ayurvedic Medicine because of its ability to promote fracture healing. Polymers incorporated with CQ at lower concentration have shown to enhance osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro. However, for the healing of clinically relevant critical sized bone defects, large amount of CQ would be required. Based on this perception, a herbal fibrous sheet containing high weight percentage of CQ [20,40 and 60wt/wt% in poly (L-lactic acid) (PLLA)] was fabricated through electrospinning. The solution concentration, flow rate, voltage and tip-target distance was optimized to obtain nanofibers. The hydrophobicity of PLLA fibers was reduced through CQ incorporation. There was considerable increase in the adhesion, proliferation and osteogenic differentiation of MSCs on herbal fibers than normal fibers, mainly on P-Q20 and P-CQ40. MSCs were differentiated into osteoblasts without providing any osteogenic supplements in the medium, indicating its osteoinductive capability. The herbal sheet also could promote mineralization when immersed in simulated body fluid for 14days. These studies specify that PLLA nanofibers loaded with 20 and 40wt% of CQ could serve as a potential candidate for bone tissue engineering applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Monomer-to-polymer conversion and micro-tensile bond strength to dentine of experimental and commercial adhesives containing diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide or a camphorquinone/amine photo-initiator system.

PubMed

Miletic, Vesna; Pongprueksa, Pong; De Munck, Jan; Brooks, Neil R; Van Meerbeek, Bart

2013-10-01

To compare the degree of conversion (DC) of adhesives initiated by diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO) or a camphorquinone/tertiary amine system (CQ/Amine) as well as their 'immediate' micro-tensile bond strength (μTBS) to bur-cut dentine. DC of Scotchbond Universal ('SBU'; 3M ESPE), its experimental counterpart containing TPO as photo-initiator system, an experimental G-aenial Bond ('Ga-B'; GC) adhesive formulation, and an experimental LUB-102 adhesive formulation ('LUB', Kuraray Noritake), containing as photo-initiatior system either 2wt% CQ along with 2wt% tertiary amine ('SBU_CQ/Amine'; 'Ga-B_CQ/Amine'; 'LUB_CQ/Amine'), or 2wt% TPO ('SBU_TPO'; 'Ga-B_TPO'; 'LUB_TPO'), was determined using Fourier-transform infrared spectroscopy (FTIR), after being cured with a dual-wavelength light-curing unit (bluephase 20i, Ivoclar Vivadent). The same adhesive formulations were applied to bur-cut mid-coronal dentine of intact human molars, and subjected to a μTBS test after 1-week water storage. Besides being applied following a self-etch (SE) application mode, the adhesive formulations SBU_CQ/Amine and SBU_TPO were also applied following an etch-and-rinse (E&R) mode, this both for DS and μTBS measurement. No significant difference in DC was found for any of the adhesive formulations, except for SBU_CQ/Amine_SE and SBU_TPO_SE. For both SBU formulations, a significantly higher DC was reached for the E&R than the SE approach. Regarding μTBS, no significant differences were recorded, except for the significantly higher μTBS measured for SBU_CQ/Amine_E&R and SBU_TPO_E&R. In self-etch adhesives, the photo-initiator TPO may be used instead of CQ/Amine. The curing and 'immediate' bonding efficiency depended on the application protocol (E&R versus SE), but not on the photo-initiator system. The photo-initiator TPO may be used in self-etch adhesives instead of CQ/Amine with similar curing and 'immediate' bonding efficiency. Copyright © 2013 Elsevier Ltd. All rights reserved.

Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion.

PubMed

Mauthe, Mario; Orhon, Idil; Rocchi, Cecilia; Zhou, Xingdong; Luhr, Morten; Hijlkema, Kerst-Jan; Coppes, Robert P; Engedal, Nikolai; Mari, Muriel; Reggiori, Fulvio

2018-06-25

Macroautophagy/autophagy is a conserved transport pathway where targeted structures are sequestered by phagophores, which mature into autophagosomes, and then delivered into lysosomes for degradation. Autophagy is involved in the pathophysiology of numerous diseases and its modulation is beneficial for the outcome of numerous specific diseases. Several lysosomal inhibitors such as bafilomycin A 1 (BafA 1 ), protease inhibitors and chloroquine (CQ), have been used interchangeably to block autophagy in in vitro experiments assuming that they all primarily block lysosomal degradation. Among them, only CQ and its derivate hydroxychloroquine (HCQ) are FDA-approved drugs and are thus currently the principal compounds used in clinical trials aimed to treat tumors through autophagy inhibition. However, the precise mechanism of how CQ blocks autophagy remains to be firmly demonstrated. In this study, we focus on how CQ inhibits autophagy and directly compare its effects to those of BafA 1 . We show that CQ mainly inhibits autophagy by impairing autophagosome fusion with lysosomes rather than by affecting the acidity and/or degradative activity of this organelle. Furthermore, CQ induces an autophagy-independent severe disorganization of the Golgi and endo-lysosomal systems, which might contribute to the fusion impairment. Strikingly, HCQ-treated mice also show a Golgi disorganization in kidney and intestinal tissues. Altogether, our data reveal that CQ and HCQ are not bona fide surrogates for other types of late stage lysosomal inhibitors for in vivo experiments. Moreover, the multiple cellular alterations caused by CQ and HCQ call for caution when interpreting results obtained by blocking autophagy with this drug.

International Space Station Crew Quarters Ventilation and Acoustic Design Implementation

NASA Technical Reports Server (NTRS)

Broyan, James L., Jr.; Cady, Scott M; Welsh, David A.

2010-01-01

The International Space Station (ISS) United States Operational Segment has four permanent rack sized ISS Crew Quarters (CQs) providing a private crew member space. The CQs use Node 2 cabin air for ventilation/thermal cooling, as opposed to conditioned ducted air-from the ISS Common Cabin Air Assembly (CCAA) or the ISS fluid cooling loop. Consequently, CQ can only increase the air flow rate to reduce the temperature delta between the cabin and the CQ interior. However, increasing airflow causes increased acoustic noise so efficient airflow distribution is an important design parameter. The CQ utilized a two fan push-pull configuration to ensure fresh air at the crew member's head position and reduce acoustic exposure. The CQ ventilation ducts are conduits to the louder Node 2 cabin aisle way which required significant acoustic mitigation controls. The CQ interior needs to be below noise criteria curve 40 (NC-40). The design implementation of the CQ ventilation system and acoustic mitigation are very inter-related and require consideration of crew comfort balanced with use of interior habitable volume, accommodation of fan failures, and possible crew uses that impact ventilation and acoustic performance. Each CQ required 13% of its total volume and approximately 6% of its total mass to reduce acoustic noise. This paper illustrates the types of model analysis, assumptions, vehicle interactions, and trade-offs required for CQ ventilation and acoustics. Additionally, on-orbit ventilation system performance and initial crew feedback is presented. This approach is applicable to any private enclosed space that the crew will occupy.

The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin

PubMed Central

Kumar, Rajinder; Musiyenko, Alla; Barik, Sailen

2003-01-01

Background The naturally occurring benzoquinone ansamycin compound, geldanamycin (GA), is a specific inhibitor of heat shock protein 90 (Hsp90) and is a potential anticancer agent. Since Plasmodium falciparum has been reported to have an Hsp90 ortholog, we tested the possibility that GA might inhibit it and thereby display antiparasitic activity. Results We provide direct recombinant DNA evidence for the Hsp90 protein of Plasmodium falciparum, the causative agent of fatal malaria. While the mRNA of Hsp90 was mainly expressed in ring and trophozoite stages, the protein was found in all stages, although schizonts contained relatively lower amounts. In vitro the parasitic Hsp90 exhibited an ATP-binding activity that could be specifically inhibited by GA. Plasmodium growth in human erythrocyte culture was strongly inhibited by GA with an IC50 of 20 nM, compared to the IC50 of 15 nM for chloroquine (CQ) under identical conditions. When used in combination, the two drugs acted synergistically. GA was equally effective against CQ-sensitive and CQ-resistant strains (3D7 and W2, respectively) and on all erythrocytic stages of the parasite. Conclusions Together, these results suggest that an active and essential Hsp90 chaperone cycle exists in Plasmodium and that the ansamycin antibiotics will be an important tool to dissect its role in the parasite. Additionally, the favorable pharmacology of GA, reported in human trials, makes it a promising antimalarial drug. PMID:14514358

The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin.

PubMed

Kumar, Rajinder; Musiyenko, Alla; Barik, Sailen

2003-09-15

The naturally occurring benzoquinone ansamycin compound, geldanamycin (GA), is a specific inhibitor of heat shock protein 90 (Hsp90) and is a potential anticancer agent. Since Plasmodium falciparum has been reported to have an Hsp90 ortholog, we tested the possibility that GA might inhibit it and thereby display antiparasitic activity. We provide direct recombinant DNA evidence for the Hsp90 protein of Plasmodium falciparum, the causative agent of fatal malaria. While the mRNA of Hsp90 was mainly expressed in ring and trophozoite stages, the protein was found in all stages, although schizonts contained relatively lower amounts. In vitro the parasitic Hsp90 exhibited an ATP-binding activity that could be specifically inhibited by GA. Plasmodium growth in human erythrocyte culture was strongly inhibited by GA with an IC50 of 20 nM, compared to the IC50 of 15 nM for chloroquine (CQ) under identical conditions. When used in combination, the two drugs acted synergistically. GA was equally effective against CQ-sensitive and CQ-resistant strains (3D7 and W2, respectively) and on all erythrocytic stages of the parasite. Together, these results suggest that an active and essential Hsp90 chaperone cycle exists in Plasmodium and that the ansamycin antibiotics will be an important tool to dissect its role in the parasite. Additionally, the favorable pharmacology of GA, reported in human trials, makes it a promising antimalarial drug.

Efficacy of Artesunate-mefloquine for Chloroquine-resistant Plasmodium vivax Malaria in Malaysia: An Open-label, Randomized, Controlled Trial

PubMed Central

Grigg, Matthew J.; William, Timothy; Menon, Jayaram; Barber, Bridget E.; Wilkes, Christopher S.; Rajahram, Giri S.; Edstein, Michael D.; Auburn, Sarah; Price, Ric N.; Yeo, Tsin W.; Anstey, Nicholas M.

2016-01-01

Background. Chloroquine (CQ)-resistant Plasmodium vivax is increasingly reported throughout southeast Asia. The efficacy of CQ and alternative artemisinin combination therapies (ACTs) for vivax malaria in Malaysia is unknown. Methods. A randomized, controlled trial of CQ vs artesunate-mefloquine (AS-MQ) for uncomplicated vivax malaria was conducted in 3 district hospitals in Sabah, Malaysia. Primaquine was administered on day 28. The primary outcome was the cumulative risk of treatment failure by day 28 by Kaplan–Meier analysis. Results. From 2012 to 2014, 103 adults and children were enrolled. Treatment failure by day 28 was 61.1% (95% confidence interval [CI], 46.8–75.6) after CQ and 0% (95% CI, 0–.08) following AS-MQ (P < .001), of which 8.2% (95% CI, 2.5–9.6) were early treatment failures. All patients with treatment failure had therapeutic plasma CQ concentrations at day 7. Compared with CQ, AS-MQ was associated with faster parasite clearance (normalized clearance slope, 0.311 vs 0.127; P < .001) and fever clearance (mean, 19.0 vs 37.7 hours; P = .001) and with lower risk of anemia at day 28 (odds ratio = 3.7; 95% CI, 1.5–9.3; P = .005). Gametocytes were present at day 28 in 23.8% (10/42) of patients following CQ vs none with AS-MQ (P < .001). AS-MQ resulted in lower bed occupancy: 4037 vs 6510 days/1000 patients (incidence rate ratio 0.62; 95% CI, .60–.65; P < .001). One patient developed severe anemia not regarded as related to their AS-MQ treatment. Conclusions. High-grade CQ-resistant P. vivax is prevalent in eastern Malaysia. AS-MQ is an efficacious ACT for all malaria species. Wider CQ-efficacy surveillance is needed in vivax-endemic regions with earlier replacement with ACT when treatment failure is detected. Clinical Trials Registration. NCT01708876. PMID:27107287

Efficacy of Artesunate-mefloquine for Chloroquine-resistant Plasmodium vivax Malaria in Malaysia: An Open-label, Randomized, Controlled Trial.

PubMed

Grigg, Matthew J; William, Timothy; Menon, Jayaram; Barber, Bridget E; Wilkes, Christopher S; Rajahram, Giri S; Edstein, Michael D; Auburn, Sarah; Price, Ric N; Yeo, Tsin W; Anstey, Nicholas M

2016-06-01

Chloroquine (CQ)-resistant Plasmodium vivax is increasingly reported throughout southeast Asia. The efficacy of CQ and alternative artemisinin combination therapies (ACTs) for vivax malaria in Malaysia is unknown. A randomized, controlled trial of CQ vs artesunate-mefloquine (AS-MQ) for uncomplicated vivax malaria was conducted in 3 district hospitals in Sabah, Malaysia. Primaquine was administered on day 28. The primary outcome was the cumulative risk of treatment failure by day 28 by Kaplan-Meier analysis. From 2012 to 2014, 103 adults and children were enrolled. Treatment failure by day 28 was 61.1% (95% confidence interval [CI], 46.8-75.6) after CQ and 0% (95% CI, 0-.08) following AS-MQ (P < .001), of which 8.2% (95% CI, 2.5-9.6) were early treatment failures. All patients with treatment failure had therapeutic plasma CQ concentrations at day 7. Compared with CQ, AS-MQ was associated with faster parasite clearance (normalized clearance slope, 0.311 vs 0.127; P < .001) and fever clearance (mean, 19.0 vs 37.7 hours; P =001) and with lower risk of anemia at day 28 (odds ratio = 3.7; 95% CI, 1.5-9.3; P =005). Gametocytes were present at day 28 in 23.8% (10/42) of patients following CQ vs none with AS-MQ (P < .001). AS-MQ resulted in lower bed occupancy: 4037 vs 6510 days/1000 patients (incidence rate ratio 0.62; 95% CI, .60-.65; P < .001). One patient developed severe anemia not regarded as related to their AS-MQ treatment. High-grade CQ-resistant P. vivax is prevalent in eastern Malaysia. AS-MQ is an efficacious ACT for all malaria species. Wider CQ-efficacy surveillance is needed in vivax-endemic regions with earlier replacement with ACT when treatment failure is detected.Clinical Trials Registration NCT01708876. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Ketosteroid Standardized Cissus quadrangularis L. Extract and its Anabolic Activity: Time to Look Beyond Ketosteroid?

PubMed

Jadhav, Atul N; Rafiq, Mohammed; Devanathan, Rajendran; Azeemuddin, Mohammed; Anturlikar, Suryakanth D; Ahmed, Akhil; Sundaram, Ramchandran; Babu, U V; Paramesh, Rangesh

2016-05-01

Cissus quadrangularis (CQ) L. reported to contain 3-ketosteroids and have bone health benefits. This study aimed at establishing the relationship between the ketosteroid content and anabolic as well as bone health-promoting activities of various Cissus extracts in well-established orchidectomized (ORX) rat model. Supercritical carbon dioxide, ethyl acetate, and aqueous extracts (AE) of CQ L. were prepared and standardized for ketosteroid content by two methods used in commerce. Moreover, ketosteroid standardized extracts of this plant were evaluated for anabolic activity in rats in well-established ORX rat model. The increase in the absolute weight was appreciable in the CQ-AE treated group. Similarly, with respect to bone parameters, a similar trend was seen. The mean bone density, strength, and calcium content were found to be highest in the group treated with CQ-AE compared to groups treated with other extracts. This study reveals for the first time that 3-ketosteroids are not linked to the beneficial activities on bone and highlights the need for extensive characterization of biological active principles from CQ L. In light of the above estimation studies, we believe that current standardization of Cissus extraction "3-ketosteroids" is incorrect. We also did not find any report suggesting the presence of androgenic steroids in this plant and hence the characterization based on "3-ketosteroids" is scientifically incorrect. This study highlights the insufficient understanding of biological active principles from CQ L. and underlines the need for extensive bioactivity guided studies. Cissus quadrangularis (CQ) L. reported to contain 3.ketosteroids and have bone health benefitsWe did not find correlation between ketosteroid content obtained by conventional methods and its biological effectStudies indicate that claims of ketosteroid content need not necessarily correlate to biological effects and hence warrants extensive phytochemical characterization of biological active principles from CQ L. Abbreviations used: CQ: Cissus quadrangularis, ORX: Orchidectomized, AE: Aqueous extract, EE: Ethyl acetate extract, SFE: Supercritical fluid extract.

The mechanism of antimalarial action of the ruthenium(II)-chloroquine complex [RuCl(2)(CQ)] (2).

PubMed

Martínez, Alberto; Rajapakse, Chandima S K; Naoulou, Becky; Kopkalli, Yasemin; Davenport, Lesley; Sánchez-Delgado, Roberto A

2008-06-01

The mechanism of antimalarial action of the ruthenium-chloroquine complex [RuCl(2)(CQ)](2) (1), previously shown by us to be active in vitro against CQ-resistant strains of Plasmodium falciparum and in vivo against P. berghei, has been investigated. The complex is rapidly hydrolyzed in aqueous solution to [RuCl(OH(2))(3)(CQ)](2)[Cl](2), which is probably the active species. This compound binds to hematin in solution and inhibits aggregation to beta-hematin at pH approximately 5 to a slightly lower extent than chloroquine diphosphate; more importantly, the heme aggregation inhibition activity of complex 1 is significantly higher than that of CQ when measured at the interface of n-octanol-aqueous acetate buffer mixtures under acidic conditions modeling the food vacuole of the parasite. Partition coefficient measurements confirmed that complex 1 is considerably more lipophilic than CQ in n-octanol-water mixtures at pH approximately 5. This suggests that the principal target of complex 1 is the heme aggregation process, which has recently been reported to be fast and spontaneous at or near water-lipid interfaces. The enhanced antimalarial activity of complex 1 is thus probably due to a higher effective concentration of the drug at or near the interface compared with that of CQ, which accumulates strongly in the aqueous regions of the vacuole under those conditions. Furthermore, the activity of complex 1 against CQ-resistant strains of P. falciparum is probably related to its greater lipophilicity, in line with previous reports indicating a lowered ability of the mutated transmembrane transporter PfCRT to promote the efflux of highly lipophilic drugs. The metal complex also interacts with DNA by intercalation, to a comparable extent and in a similar manner to uncomplexed CQ and therefore DNA binding does not appear to be an important part of the mechanism of antimalarial action in this case.

The mechanism of antimalarial action of the ruthenium (II)-chloroquine complex [RuCl2(CQ)]2

PubMed Central

Martínez, Alberto; Rajapakse, Chandima S. K.; Naoulou, Becky; Kopkalli, Yasemin; Davenport, Lesley; Sánchez-Delgado, Roberto A.

2008-01-01

The mechanism of antimalarial action of the ruthenium-chloroquine complex [RuCl2(CQ)]2 (1), previously shown by us to be active in vitro against CQ-resistant strains of Plasmodium falciparum and in vivo against P. berghei, has been investigated. The complex is rapidly hydrolyzed in aqueous solution to [RuCl(OH2)3(CQ)]2 [Cl]2, which is probably the active species. This compound binds to hematin in solution and inhibits aggregation to β-hematin at pH ∼ 5 to a slightly lower extent than chloroquine diphosphate; more importantly, the heme aggregation inhibition activity of complex 1 is significantly higher than that of CQ when measured at the interface of n-octanol-aqueous acetate buffer mixtures under acidic conditions modeling the food vacuole of the parasite. Partition coefficient measurements confirmed that complex 1 is considerably more lipophilic than CQ in n-octanol-water mixtures at pH ∼ 5. This suggests that the principal target of complex 1 is the heme aggregation process, which has recently been reported to be fast and spontaneous at or near water-lipid interfaces. The enhanced antimalarial activity of complex 1 is thus probably due to a higher effective concentration of the drug at or near the interface compared with that of CQ, which accumulates strongly in the aqueous regions of the vacuole under those conditions. Furthermore, the activity of complex 1 against CQ-resistant strains of P. falciparum is probably related to its greater lipophilicity, in line with previous reports indicating a lowered ability of the mutated transmembrane transporter PfCRT to promote the efflux of highly lipophilic drugs. The metal complex also interacts with DNA by intercalation, to a comparable extent and in a similar manner to uncomplexed CQ and therefore DNA binding does not appear to be an important part of the mechanism of antimalarial action in this case. PMID:18305967

A simple method for detection of changes in relations between solute concentration and stream discharge

NASA Astrophysics Data System (ADS)

Huntington, T. G.; Shanley, J. B.

2015-12-01

The relation between constituent concentrations and stream discharge (C/Q relations) are fundamental to the estimation of fluxes or loads in biogeochemical studies. C/Q relations are useful for understanding nutrient, trace element, and contaminant behavior in response to storm and snowmelt related changes in discharge. The shape and seasonal variation of C/Q relations provides information about availability, mobilization, and release of solutes to streams. The properties of C/Q relations can allude to flowpaths, antecedent moisture conditions, and solute availability. Changes in C/Q relations over time for certain constituents like dissolved organic carbon (DOC) may be indicative of changes in supply that may have resulted from changes in climate, vegetation, or land use and land cover. The focus of this presentation is on a simple method for detection of change in C/Q relations using the LOADEST regression model. The LOADEST model fits a seasonally variable C/Q relation to discrete water quality data. For a continuously gauged stream or river, a relatively long record of C/Q data can be partitioned into distinct periods and regression models can be determined for each period. By running each model with the same discharge record and subsequently plotting each flux time series, differences between models can be visualized graphically. Plotting differences between periods (models) illustrates at what times of year the differences are largest. Running each model with a range of discharges for each day of the year provides additional insight into whether the changes in C/Q relations are evident at all levels of discharge or only at specific levels of discharge. The DOC record (1991 to 2014) from a research watershed at Sleepers River in Vermont was used in this analysis. The analysis showed that there have been increases in DOC concentration for certain seasons and rates of discharge.

The zinc ionophore clioquinol reverses autophagy arrest in chloroquine-treated ARPE-19 cells and in APP/mutant presenilin-1-transfected Chinese hamster ovary cells.

PubMed

Seo, Bo-Ra; Lee, Sook-Jeong; Cho, Kyung Sook; Yoon, Young Hee; Koh, Jae-Young

2015-12-01

Arrested autophagy may contribute to the pathogenesis of Alzheimer's disease. Because we found that chloroquine (CQ) causes arrested autophagy but clioquinol (ClioQ), a zinc ionophore, activates autophagic flux, in the present study, we examined whether ClioQ can overcome arrested autophagy induced by CQ or mutant presenilin-1 (mPS1). CQ induced vacuole formation and cell death in adult retinal pigment epithelial (ARPE-19) cells, but co-treatment with ClioQ attenuated CQ-associated toxicity in a zinc-dependent manner. Increases in lysosome dilation and blockage of autophagic flux by CQ were also markedly attenuated by ClioQ treatment. Interestingly, CQ increased lysosomal pH in amyloid precursor protein (APP)/mPS1-expressing Chinese hamster ovary 7WΔE9 (CHO-7WΔE9) cell line, and ClioQ partially re-acidified lysosomes. Furthermore, accumulation of amyloid-β (Aβ) oligomers in CHO-7WΔE9 cells was markedly attenuated by ClioQ. Moreover, intracellular accumulation of exogenously applied fluorescein isothiocyanate-conjugated Aβ(1-42) was also increased by CQ but was returned to control levels by ClioQ. These results suggest that modulation of lysosomal functions by manipulating lysosomal zinc levels may be a useful strategy for clearing intracellular Aβ oligomers. Copyright © 2015 Elsevier Inc. All rights reserved.

Therapeutic Efficacy of Chloroquine for the Treatment of Uncomplicated Plasmodium falciparum in Haiti after Many Decades of its Use

PubMed Central

Okech, Bernard A.; Existe, Alexandre; Romain, Jean R.; Memnon, Gladys; Victor, Yves Saint; de Rochars, Madsen Beau; Fukuda, Mark

2015-01-01

Chloroquine (CQ) has been used for malaria treatment in Haiti for several decades, but reports of CQ resistance are scarce. The efficacy of CQ in patients with uncomplicated Plasmodium falciparum undergoing treatment in Haiti was evaluated. Malaria patients were enrolled, treated with CQ, and monitored over a 42-day period. The treatment outcomes were evaluated on day 28 by microscopy. The P. falciparum slide-confirmed rate was 9.5% (121 of 1,277). Malaria infection was seasonal, with peak observations between October and January; 88% (107 of 121) of patients consented to participate. Sixty patients successfully completed the 42-day follow-up, whereas 47 patients withdrew consent or were lost to follow-up. The mean parasite density declined rapidly within the first few days after treatment. Seven patients did not clear their malaria infections and were clinically asymptomatic; therefore, they were considered late parasitological failures. About 90% (95% confidence interval = 84.20–97.90) of patients had no detectable parasitemia by day 28 and remained malaria-free to day 42. Testing for recrudescence, reinfection, and CQ serum levels was not done in the seven patients, and therefore, their CQ resistance status is unresolved. CQ resistance surveillance by patient follow-up, in vitro drug sensitivity studies, and molecular markers is urgently needed in Haiti. PMID:25601993

ReadqPCR and NormqPCR: R packages for the reading, quality checking and normalisation of RT-qPCR quantification cycle (Cq) data.

PubMed

Perkins, James R; Dawes, John M; McMahon, Steve B; Bennett, David L H; Orengo, Christine; Kohl, Matthias

2012-07-02

Measuring gene transcription using real-time reverse transcription polymerase chain reaction (RT-qPCR) technology is a mainstay of molecular biology. Technologies now exist to measure the abundance of many transcripts in parallel. The selection of the optimal reference gene for the normalisation of this data is a recurring problem, and several algorithms have been developed in order to solve it. So far nothing in R exists to unite these methods, together with other functions to read in and normalise the data using the chosen reference gene(s). We have developed two R/Bioconductor packages, ReadqPCR and NormqPCR, intended for a user with some experience with high-throughput data analysis using R, who wishes to use R to analyse RT-qPCR data. We illustrate their potential use in a workflow analysing a generic RT-qPCR experiment, and apply this to a real dataset. Packages are available from http://www.bioconductor.org/packages/release/bioc/html/ReadqPCR.htmland http://www.bioconductor.org/packages/release/bioc/html/NormqPCR.html These packages increase the repetoire of RT-qPCR analysis tools available to the R user and allow them to (amongst other things) read their data into R, hold it in an ExpressionSet compatible R object, choose appropriate reference genes, normalise the data and look for differential expression between samples.

4-Aminoquinolines Active against Chloroquine-Resistant Plasmodium falciparum: Basis of Antiparasite Activity and Quantitative Structure-Activity Relationship Analyses▿

PubMed Central

Hocart, Simon J.; Liu, Huayin; Deng, Haiyan; De, Dibyendu; Krogstad, Frances M.; Krogstad, Donald J.

2011-01-01

Chloroquine (CQ) is a safe and economical 4-aminoquinoline (AQ) antimalarial. However, its value has been severely compromised by the increasing prevalence of CQ resistance. This study examined 108 AQs, including 68 newly synthesized compounds. Of these 108 AQs, 32 (30%) were active only against CQ-susceptible Plasmodium falciparum strains and 59 (55%) were active against both CQ-susceptible and CQ-resistant P. falciparum strains (50% inhibitory concentrations [IC50s], ≤25 nM). All AQs active against both CQ-susceptible and CQ-resistant P. falciparum strains shared four structural features: (i) an AQ ring without alkyl substitution, (ii) a halogen at position 7 (Cl, Br, or I but not F), (iii) a protonatable nitrogen at position 1, and (iv) a second protonatable nitrogen at the end of the side chain distal from the point of attachment to the AQ ring via the nitrogen at position 4. For activity against CQ-resistant parasites, side chain lengths of ≤3 or ≥10 carbons were necessary but not sufficient; they were identified as essential factors by visual comparison of 2-dimensional (2-D) structures in relation to the antiparasite activities of the AQs and were confirmed by computer-based 3-D comparisons and differential contour plots of activity against P. falciparum. The advantage of the method reported here (refinement of quantitative structure-activity relationship [QSAR] descriptors by random assignment of compounds to multiple training and test sets) is that it retains QSAR descriptors according to their abilities to predict the activities of unknown test compounds rather than according to how well they fit the activities of the compounds in the training sets. PMID:21383099

Resistance of infection by Plasmodium vivax to chloroquine in Bolivia.

PubMed

Añez, Arletta; Moscoso, Manuel; Laguna, Ángel; Garnica, Cecilia; Melgar, Viviana; Cuba, Mauren; Gutierrez, Sonia; Ascaso, Carlos

2015-07-01

Chloroquine (CQ) over three days plus primaquine (PQ) for seven days is the treatment of choice of infections by Plasmodium vivax in Bolivia, where 95% of the cases of malaria are attributed to this species. The aim of this study was to evaluate the therapeutic efficacy of CQ in this setting. Patients in the Amazon region of northern Bolivia, were included in the study from May to November 2011 and the therapeutic efficacy of CQ was evaluated over a 28-day follow-up period. Patients with P. vivax mono-infection received 25 mg/Kg body weight of CQ over three days. The concentrations of CQ + desethylchloroquine (DCQ) in blood were determined at days 7 and 28 of follow up; at follow-up and on the day of treatment failure was administered PQ. One hundred patients fulfilled the inclusion criteria, two were lost to follow up and another two were later excluded for protocol violation. Of the 96 patients who completed the follow up 10 showed TF; one presented continued parasitaemia until day 7 of follow up, three on day 21 and six on day 28 of follow up. The geometric mean of CQ + DCQ on day 7 was 321.7 ng/ml (range 197-535 ng/ml). In six patients with TF the CQ + DCQ concentrations in blood on the day of TF were >100 ng/ml. The rate of resistance was 6.5%. The present study demonstrates the presence of resistance to CQ in the treatment of malaria by P. vivax in the Amazon region of Bolivia. New clinical trials are needed to establish alternative treatments against these parasites in this region of South America.

Effect of Khat (Catha edulis) Use on the Bioavailability, Plasma Levels and Antimalarial Activity of Chloroquine.

PubMed

Issa, Faiza H; Al-Habori, Molhem; Chance, Michael L

2016-05-01

This study aimed to evaluate the effect of khat (Catha edulis) on chloroquine (CQ) bioavailability in healthy Yemeni adults and its effect on CQ plasma levels and parasite clearance among malaria patients. This study took place between January and April 2007 in Bajil and Sana'a, Yemen. Two CQ doses (600 mg each) were given to 15 healthy males on separate occasions; the first dose was followed by a khat-chewing session (phase one) while controls abstained from khat-chewing for the second (phase two). Additionally, 103 patients with Plasmodium falciparum-induced malaria, including both regular khat chewers (n = 57) and non-khat chewers (n = 46), were treated with CQ (25 mg/kg) over three days. Pharmacokinetic parameters were analysed among both controls and malaria patients. Parasite clearance was also investigated for the latter group. The mean area under the concentration-time curve (AUC) was 2,108.9 versus 2,797.4 ng/hour/mL, mean peak plasma concentration (Cmax) was 415.6 versus 508.7 ng/mL and mean time to reach Cmax was 3.8 versus 3.6 hours for controls in phase one versus phase two, respectively; both AUC and Cmax levels were significantly reduced by khat-chewing (P <0.050). For khat- versus non-khat-chewing malaria patients, mean plasma CQ concentrations were 266.4 ng/mL versus 427.5 ng/mL (P <0.001). Furthermore, CQ was effective in 71.7% and 75.4% of non-khat and khat-chewing malaria patients, respectively (P = 0.823). Khat-chewing was found to significantly reduce plasma CQ levels among healthy volunteers and malaria patients. While receiving CQ treatment, patients should be advised not to chew khat.

Benefits and risks of emerging technologies: integrating life cycle assessment and decision analysis to assess lumber treatment alternatives.

PubMed

Tsang, Michael P; Bates, Matthew E; Madison, Marcus; Linkov, Igor

2014-10-07

Assessing the best options among emerging technologies (e.g., new chemicals, nanotechnologies) is complicated because of trade-offs across benefits and risks that are difficult to quantify given limited and fragmented availability of information. This study demonstrates the integration of multicriteria decision analysis (MCDA) and life cycle assessment (LCA) to address technology alternative selection decisions. As a case study, prioritization of six lumber treatment alternatives [micronized copper quaternary (MCQ); alkaline copper quaternary (ACQ); water-borne copper naphthenate (CN); oil-borne copper naphthenate (CNo); water-borne copper quinolate (CQ); and water-borne zinc naphthenate (ZN)] for military use are considered. Multiattribute value theory (MAVT) is used to derive risk and benefit scores. Risk scores are calculated using a cradle-to-gate LCA. Benefit scores are calculated by scoring of cost, durability, and corrosiveness criteria. Three weighting schemes are used, representing Environmental, Military and Balanced stakeholder perspectives. Aggregated scores from all three perspectives show CQ to be the least favorable alterative. MCQ is identified as the most favorable alternative from the Environmental stakeholder perspective. From the Military stakeholder perspective, ZN is determined to be the most favorable alternative, followed closely by MCQ. This type of scoring and ranking of multiple heterogeneous criteria in a systematic and transparent way facilitates better justification of technology selection and regulation.

Development and preliminary reliability of a multitasking assessment for executive functioning after concussion.

PubMed

Smith, Laurel B; Radomski, Mary Vining; Davidson, Leslie Freeman; Finkelstein, Marsha; Weightman, Margaret M; McCulloch, Karen L; Scherer, Matthew R

2014-01-01

OBJECTIVES. Executive functioning deficits may result from concussion. The Charge of Quarters (CQ) Duty Task is a multitask assessment designed to assess executive functioning in servicemembers after concussion. In this article, we discuss the rationale and process used in the development of the CQ Duty Task and present pilot data from the preliminary evaluation of interrater reliability (IRR). METHOD. Three evaluators observed as 12 healthy participants performed the CQ Duty Task and measured performance using various metrics. Intraclass correlation coefficient (ICC) quantified IRR. RESULTS. The ICC for task completion was .94. ICCs for other assessment metrics were variable. CONCLUSION. Preliminary IRR data for the CQ Duty Task are encouraging, but further investigation is needed to improve IRR in some domains. Lessons learned in the development of the CQ Duty Task could benefit future test development efforts with populations other than the military. Copyright © 2014 by the American Occupational Therapy Association, Inc.

Development and Preliminary Reliability of a Multitasking Assessment for Executive Functioning After Concussion

PubMed Central

Radomski, Mary Vining; Davidson, Leslie Freeman; Finkelstein, Marsha; Weightman, Margaret M.; McCulloch, Karen L.; Scherer, Matthew R.

2014-01-01

OBJECTIVES. Executive functioning deficits may result from concussion. The Charge of Quarters (CQ) Duty Task is a multitask assessment designed to assess executive functioning in servicemembers after concussion. In this article, we discuss the rationale and process used in the development of the CQ Duty Task and present pilot data from the preliminary evaluation of interrater reliability (IRR). METHOD. Three evaluators observed as 12 healthy participants performed the CQ Duty Task and measured performance using various metrics. Intraclass correlation coefficient (ICC) quantified IRR. RESULTS. The ICC for task completion was .94. ICCs for other assessment metrics were variable. CONCLUSION. Preliminary IRR data for the CQ Duty Task are encouraging, but further investigation is needed to improve IRR in some domains. Lessons learned in the development of the CQ Duty Task could benefit future test development efforts with populations other than the military. PMID:25005507

Cultural Intelligence and Writing Ability: Delving into Fluency, Accuracy and Complexity

ERIC Educational Resources Information Center

Ghonsooly, Behzad; Shalchy, Somayye

2013-01-01

Over the recent decades, cultural intelligence, now referred to as CQ has become a burgeoning area of research in the domain of business and management. Given the paucity of research on the effects of CQ on second or foreign language learning especially writing, this study intends to examine the effects of CQ on L2 learners' written performance…

Limitations of a Modified Stages of Concern Questionnaire for Use with Preservice Teachers.

ERIC Educational Resources Information Center

O'Sullivan, Kathleen A.; Zielinski, Edward J.

One of the most widely used instruments for assessing concerns has been the Stages of Concern Questionnaire (SoCQ) developed by the Concerns Based Adoption Model Project. In this research, different aspects of the validity of a modified version of the SoCQ produced for use with preservice teachers (PSSoCQ) are examined. In all, 10 different…

Chloroquine Binding Reveals Flavin Redox Switch Function of Quinone Reductase 2*

PubMed Central

Leung, Kevin K. K.; Shilton, Brian H.

2013-01-01

Quinone reductase 2 (NQO2) is an FAD-linked enzyme and the only known human target of two antimalarial drugs, primaquine (PQ) and chloroquine (CQ). The structural differences between oxidized and reduced NQO2 and the structural basis for inhibition by PQ and CQ were investigated by x-ray crystallography. Structures of oxidized NQO2 in complex with PQ and CQ were solved at 1.4 Å resolution. CQ binds preferentially to reduced NQO2, and upon reduction of NQO2-CQ crystals, the space group changed from P212121 to P21, with 1-Å decreases in all three unit cell dimensions. The change in crystal packing originated in the negative charge and 4–5º bend in the reduced isoalloxazine ring of FAD, which resulted in a new mode of CQ binding and closure of a flexible loop (Phe126–Leu136) over the active site. This first structure of a reduced quinone reductase shows that reduction of the FAD cofactor and binding of a specific inhibitor lead to global changes in NQO2 structure and is consistent with a functional role for NQO2 as a flavin redox switch. PMID:23471972

Therapeutic efficacy of chloroquine and chloroquine plus primaquine for the treatment of Plasmodium vivax in Ethiopia.

PubMed

Yeshiwondim, Asnakew K; Tekle, Afework H; Dengela, Dereje O; Yohannes, Ambachew M; Teklehaimanot, Awash

2010-02-01

Plasmodium vivax is the second most important cause of morbidity in Ethiopia. There is, however, little information on P. vivax resistance to chloroquine and chloroquine plus primaquine treatment although these drugs have been used as the first line treatment for over 50 years. We assessed the efficacy of standard chloroquine and chloroquine plus primaquine treatment for P. vivax infections in a randomized open-label comparative study in Debre Zeit and Nazareth in East Shoa, Ethiopia. A total of 290 patients with microscopically confirmed P. vivax malaria who presented to the outpatient settings of the two laboratory centers were enrolled: 145 patients were randomized to receive CQ and 145 to receive CQ+PQ treatment. Participants were followed-up for 28-157 days according to the WHO procedures. There were 12 (6.5%) lost to follow-up patients and 9 (3.1%) withdrawals. In all, 96% (277/290) of patients were analysed at day 28. Baseline characteristics were similar in all treatment groups. In all, 98.6% (275/277) of patients had cleared their parasitemia on day 3 with no difference in mean parasite clearance time between regimens (48.34+/-17.68, 50.67+/-15.70 h for the CQ and CQ+PQ group, respectively, P=0.25). The cumulative incidence of therapeutic failure at day 28 by a life-table analysis method was 5.76% (95% CI: 2.2-14.61) and 0.75% (95% CI: 0.11-5.2%) in the CQ and CQ+PQ group, respectively (P=0.19). The relapse rate was 8% (9/108) for the CQ group and 3% (4/132) for the comparison group (P=0.07). The cumulative risk of relapse at day 157 by a life-table method was 61.8% (95% CI: 20.1-98.4%) in the CQ group, compared with 26.3% (95% CI: 7.5-29.4%) in the CQ+PQ group (P=0.0038). The study confirms the emergence of CQ and PQ resistance/treatment failure in P. vivax malaria in Ethiopia. Although treatment failures were detected, they were similar between the treatment groups. We recommend regular monitoring and periodic evaluation of the efficacy of these antimalarial drugs in systematically selected sentinel sites to detect further development of resistance and to make timely national antimalarial drug policy changes. Copyright 2009 Elsevier B.V. All rights reserved.

A Proposed Alternative Measure for Climate Change Potential

NASA Astrophysics Data System (ADS)

DeGroff, F. A.

2015-12-01

Background/Issue There currently exists no comprehensive metric to measure and value anthropogenic changes in carbon flux between geospheric carbon sinks. We propose that changes in carbon residence time within geospheres be used as a metric to assess anthropogenic changes in carbon flux, and the term 'carbon quality' (cq) be used to describe such changes. Carbon residence time represents the inverse of carbon flux; as carbon flux increases, the corresponding cq will decrease, and vice versa. Focusing on atmospheric carbon emissions as a measure of anthropogenic activity on the environment ignores the fungible characteristics of carbon that are crucial in both the biosphere and the worldwide economy. The ubiquitous carbon molecule enables the enormous diversity in the biosphere, as well as the widespread, strategic economic presence of carbon in the world economy. Focusing on a single form of inorganic carbon as a proxy metric for the plethora of anthropogenic activity and carbon compounds will prove inadequate, convoluted, and unmanageable. A broader, more basic metric is needed to capture the breath and scope of carbon activity. Results/Conclusions We propose a logarithmic vector scale for cq to measure anthropogenic carbon flux. The distance between vector points, e.g. the starting and ending residence times, would represent the change in cq. A base-10 logarithmic scale would allow the addition and subtraction of exponents to calculate changes in cq. As carbon moves between carbon reservoirs, the change in cq is measured as: cq = b ( log10 [mean carbon residence time] ) where b represents the carbon price coefficient for a particular country. For any country, cq measures the climate change potential for any organic carbon when converted to inorganic CO2, or to any lower residence time carbon state. The greater the carbon fees for a country, the larger the b coefficient would be, and the greater the import fees would be to achieve carbon parity on imports from countries with lower carbon fees. By assessing embodied carbon within imports for carbon parity with domestic production, cq would eliminate the incentives to use spatial shifts in carbon emissions to avoid carbon fees. Similarity, cq would temper the incentives to use temporal displacement of carbon emissions, such as with biomass or CCS, to reduce carbon fees.

Photoaffinity Labeling of the Plasmodium falciparum Chloroquine Resistance Transporter with a Novel Perfluorophenylazido Chloroquine†

PubMed Central

Lekostaj, Jacqueline K.; Natarajan, Jayakumar K.; Paguio, Michelle F.; Wolf, Christian; Roepe, Paul D.

2009-01-01

Several models describing how amino acid substitutions in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) confer resistance to chloroquine (CQ) and other antimalarial drugs have been proposed. Further progress requires molecular analysis of interactions between purified reconstituted PfCRT protein and these drugs. We have thus designed and synthesized several perfluorophenyl azido (pfpa) CQ analogues for PfCRT photolabeling studies. One particularly useful probe (AzBCQ) places the pfpa group at the terminal aliphatic N of CQ via a flexible four-carbon ester linker and includes a convenient biotin tag. This probe photolabels PfCRT in situ with high specificity. Using reconstituted proteoliposomes harboring partially purified recombinant PfCRT, we analyze AzBCQ photolabeling versus competition with CQ and other drugs to probe the nature of the CQ binding site. We also inspect how pH, the chemoreversal agent verapamil (VPL), and various amino acid mutations in PfCRT that cause CQ resistance (CQR) affect the efficiency of AzBCQ photolabeling. Upon gel isolation of AzBCQ-labeled PfCRT followed by trypsin digestion and mass spectrometry analysis, we are able to define a single AzBCQ covalent attachment site lying within the digestive vacuolar-disposed loop between putative helices 9 and 10 of PfCRT. Taken together, the data provide important new insight into PfCRT function and, along with previous results, allow us to propose a model for a single CQ binding site in the PfCRT protein. PMID:18767816

Photoaffinity labeling of the Plasmodium falciparum chloroquine resistance transporter with a novel perfluorophenylazido chloroquine.

PubMed

Lekostaj, Jacqueline K; Natarajan, Jayakumar K; Paguio, Michelle F; Wolf, Christian; Roepe, Paul D

2008-09-30

Several models describing how amino acid substitutions in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) confer resistance to chloroquine (CQ) and other antimalarial drugs have been proposed. Further progress requires molecular analysis of interactions between purified reconstituted PfCRT protein and these drugs. We have thus designed and synthesized several perfluorophenyl azido (pfpa) CQ analogues for PfCRT photolabeling studies. One particularly useful probe (AzBCQ) places the pfpa group at the terminal aliphatic N of CQ via a flexible four-carbon ester linker and includes a convenient biotin tag. This probe photolabels PfCRT in situ with high specificity. Using reconstituted proteoliposomes harboring partially purified recombinant PfCRT, we analyze AzBCQ photolabeling versus competition with CQ and other drugs to probe the nature of the CQ binding site. We also inspect how pH, the chemoreversal agent verapamil (VPL), and various amino acid mutations in PfCRT that cause CQ resistance (CQR) affect the efficiency of AzBCQ photolabeling. Upon gel isolation of AzBCQ-labeled PfCRT followed by trypsin digestion and mass spectrometry analysis, we are able to define a single AzBCQ covalent attachment site lying within the digestive vacuolar-disposed loop between putative helices 9 and 10 of PfCRT. Taken together, the data provide important new insight into PfCRT function and, along with previous results, allow us to propose a model for a single CQ binding site in the PfCRT protein.

River Mixing in the Amazon as a Driver of Concentration-Discharge Relationships

NASA Astrophysics Data System (ADS)

Bouchez, Julien; Moquet, Jean-Sébastien; Espinoza, Jhan Carlo; Martinez, Jean-Michel; Guyot, Jean-Loup; Lagane, Christelle; Filizola, Naziano; Noriega, Luis; Hidalgo Sanchez, Liz; Pombosa, Rodrigo

2017-11-01

Large hydrological systems aggregate compositionally different waters derived from a variety of pathways. In the case of continental-scale rivers, such aggregation occurs noticeably at confluences between tributaries. Here we explore how such aggregation can affect solute concentration-discharge (C-Q) relationships and thus obscure the message carried by these relationships in terms of weathering properties of the Critical Zone. We build up a simple model for tributary mixing to predict the behavior of C-Q relationships during aggregation. We test a set of predictions made in the context of the largest world's river, the Amazon. In particular, we predict that the C-Q relationships of the rivers draining heterogeneous catchments should be the most "dilutional" and should display the widest hysteresis loops. To check these predictions, we compute 10 day-periodicity time series of Q and major solute (Si, Ca2+, Mg2+, K+, Na+, Cl-, SO42-) C and fluxes (F) for 13 gauging stations located throughout the Amazon basin. In agreement with the model predictions, C-Q relationships of most solutes shift from a fairly "chemostatic" behavior (nearly constant C) at the Andean mountain front and in pure lowland areas, to more "dilutional" patterns (negative C-Q relationship) toward the system mouth. More prominent C-Q hysteresis loops are also observed at the most downstream stations. Altogether, this study suggests that mixing of water and solutes between different flowpaths exerts a strong control on C-Q relationships of large-scale hydrological systems.

Molecular surveillance of Plasmodium falciparum drug resistance markers reveals partial recovery of chloroquine susceptibility but sustained sulfadoxine-pyrimethamine resistance at two sites of different malaria transmission intensities in Rwanda.

PubMed

Kateera, Fredrick; Nsobya, Sam L; Tukwasibwe, Steven; Hakizimana, Emmanuel; Mutesa, Leon; Mens, Petra F; Grobusch, Martin P; van Vugt, Michèle; Kumar, Nirbhay

2016-12-01

Faced with intense levels of chloroquine (CQ) resistance in Plasmodium falciparum malaria, Rwanda replaced CQ with amodiaquine (AQ)+sulfadoxine-pyrimethamine (SP) in 2001, and subsequently with artemether-lumefantrine (AL) in 2006, as first-line treatments for uncomplicated malaria. Following years of discontinuation of CQ use, re-emergence of CQ-susceptible parasites has been reported in countries including Malawi, Kenya and Tanzania. In contrast, high levels of SP resistant mutant parasites continue to be reported even in countries of presumed reduced SP drug selection pressure. The prevalence and distributions of genetic polymorphisms linked with CQ and SP resistance at two sites of different malaria transmission intensities are described here to better understand drug-related genomic adaptations over time and exposure to varying drug pressures in Rwanda. Using filter paper blood isolates collected from P. falciparum infected patients, DNA was extracted and a nested PCR performed to identify resistance-mediating polymorphisms in the pfcrt, pfmdr1, pfdhps and pfdhfr genes. Amplicons from a total of 399 genotyped samples were analysed by ligase detection reaction fluorescent microsphere assay. CQ susceptible pfcrt 76K and pfmdr1 86N wild-type parasites were found in about 50% and 81% of isolates, respectively. Concurrently, SP susceptible pfdhps double (437G-540E), pfdhfr triple (108N-51I-59R), quintuple pfdhps 437G-540E/pfdhfr 51I-59R-108N and sextuple haplotypes were found in about 84%, 85%, 74% and 18% of isolates, respectively. High-level SP resistance associated pfdhfr 164L and pfdhps 581G mutant prevalences were noted to decline. Mutations pfcrt 76T, pfdhfr 59R and pfdhfr 164L were found differentially distributed between the two study sites with the pfdhfr 164L mutants found only at Ruhuha site, eastern Rwanda. Overall, sustained intense levels of SP resistance mutations and a recovery of CQ susceptible parasites were found in this study following 7 years and 14 years of drug withdrawal from use, respectively. Most likely, the sustained high prevalence of resistant parasites is due to the use of DHFR/DHPS inhibitors like trimethoprim-sulfamethoxazole (TS) for the treatment of and prophylaxis against bacterial infections among HIV infected individuals as well as the continued use of IPTp-SP within the East and Central African regions for malaria prevention among pregnant women. With regard to CQ, the slow recovery of CQ susceptible parasites may have been caused partly by the continued use of CQ and/or CQ mimicking antimalarial drugs like AQ in spite of policies to withdraw it from Rwanda and the neighbouring countries of Uganda and Tanzania. Continued surveillance of P. falciparum CQ and SP associated polymorphisms is recommended for guiding future rational drug policy-making and mitigation of future risk of anti-malaria drug resistance development. Copyright © 2016 Elsevier B.V. All rights reserved.

Can Concentration - Discharge Relationships Diagnose Material Source During Extreme Events?

NASA Astrophysics Data System (ADS)

Karwan, D. L.; Godsey, S.; Rose, L.

2017-12-01

Floods can carry >90% of the basin material exported in a given year as well as alter flow pathways and material sources. In turn, sediment and solute fluxes can increase flood damages and negatively impact water quality and integrate physical and chemical weathering of landscapes and channels. Concentration-discharge (C-Q) relationships are used to both describe export patterns as well as compute them. Metrics for describing C-Q patterns and inferring their controls are vulnerable to infrequent sampling that affects how C-Q relationships are interpolated and interpreted. C-Q relationships are typically evaluated from multiple samples, but because hydrological extremes are rare, data are often unavailable for extreme events. Because solute and sediment C-Q relationships likely respond to changes in hydrologic extremes in different ways, there is a pressing need to define their behavior under extreme conditions, including how to properly sample to capture these patterns. In the absence of such knowledge, improving load estimates in extreme floods will likely remain difficult. Here we explore the use of C-Q relationships to determine when an event alters a watershed system such that it enters a new material source/transport regime. We focus on watersheds with sediment and discharge time series include low-frequency and/or extreme events. For example, we compare solute and sediment patterns in White Clay Creek in southeastern Pennsylvania across a range of flows inclusive of multiple hurricanes for which we have ample ancillary hydrochemical data. TSS is consistently mobilized during high flow events, even during extreme floods associated with hurricanes, and sediment fingerprinting indicates different sediment sources, including in-channel remobilization and landscape erosion, are active at different times. In other words, TSS mobilization in C-Q space is not sensitive to the source of material being mobilized. Unlike sediments, weathering solutes in this watershed tend to exhibit a relatively chemostatic C-Q pattern, except during the runoff-dominated Hurricane Irene, when they exhibit a diluting C-Q pattern. Finally, we summarize the vulnerability of these observations to shifts in sampling effort to highlight the utility and limitations of C-Q-derived export patterns.

Contrasting ex vivo efficacies of "reversed chloroquine" compounds in chloroquine-resistant Plasmodium falciparum and P. vivax isolates.

PubMed

Wirjanata, Grennady; Sebayang, Boni F; Chalfein, Ferryanto; Prayoga; Handayuni, Irene; Noviyanti, Rintis; Kenangalem, Enny; Poespoprodjo, Jeanne Rini; Burgess, Steven J; Peyton, David H; Price, Ric N; Marfurt, Jutta

2015-09-01

Chloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistance ex vivo. Between March to October 2011 and January to September 2013, two "reversed chloroquine" (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates of Plasmodium falciparum (n = 41) and Plasmodium vivax (n = 45) in Papua, Indonesia, using a modified ex vivo schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant P. falciparum and P. vivax field isolates. For P. falciparum, the median 50% inhibitory concentrations (IC50s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ (P < 0.001 and P = 0.036, respectively). The corresponding values for P. vivax were 19.0, 60.0, and 60.9 nM (P < 0.001 and P = 0.018, respectively). There was a significant correlation between IC50s of CQ and PL69 (Spearman's rank correlation coefficient [r s] = 0.727, P < 0.001) and PL106 (rs = 0.830, P < 0.001) in P. vivax but not in P. falciparum. Both RCQs were equally active against the ring and trophozoite stages of P. falciparum, but in P. vivax, PL69 and PL106 showed less potent activity against trophozoite stages (median IC50s, 130.2 and 172.5 nM) compared to ring stages (median IC50s, 17.6 and 91.3 nM). RCQ compounds have enhanced ex vivo activity against CQ-resistant clinical isolates of P. falciparum and P. vivax, suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the two Plasmodium species. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Researching Reciprocal Leadership: Using the Consciousness Quotient Inventory (CQ-i) as a Pilot Methodology to Explore Leadership with the Context of a School-University Partnership

ERIC Educational Resources Information Center

Poultney, Val; Fordham, Jon

2018-01-01

This article looks at the potential of using an online self-completing inventory that measures leadership consciousness awareness. The Consciousness Quotient inventory (CQ-i) has been developed to encourage leaders to be more conscious of their ability to be accountable and responsible for their leadership practice. The CQ-i as a method for…

Synthesis and exploration of novel curcumin analogues as anti-malarial agents.

PubMed

Mishra, Satyendra; Karmodiya, Krishanpal; Surolia, Namita; Surolia, Avadhesha

2008-03-15

Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Recent studies have indicated that curcumin inhibits chloroquine-sensitive (CQ-S) and chloroquine-resistant (CQ-R) Plasmodium falciparum growth in culture with an IC(50) of approximately 3.25 microM (MIC=13.2 microM) and IC(50) 4.21 microM (MIC=14.4 microM), respectively. In order to expand their potential as anti-malarials a series of novel curcumin derivatives were synthesized and evaluated for their ability to inhibit P. falciparum growth in culture. Several curcumin analogues examined show more effective inhibition of P. falciparum growth than curcumin. The most potent curcumin compounds 3, 6, and 11 were inhibitory for CQ-S P. falciparum at IC(50) of 0.48, 0.87, 0.92 microM and CQ-R P. falciparum at IC(50) of 0.45 microM, 0.89, 0.75 microM, respectively. Pyrazole analogue of curcumin (3) exhibited sevenfold higher anti-malarial potency against CQ-S and ninefold higher anti-malarial potency against CQ-R. Curcumin analogues described here represent a novel class of highly selective P. falciparum inhibitors and promising candidates for the design of novel anti-malarial agents.

Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

PubMed Central

Sá, Juliana Martha; Twu, Olivia; Hayton, Karen; Reyes, Sahily; Fay, Michael P.; Ringwald, Pascal; Wellems, Thomas E.

2009-01-01

Chloroquine (CQ) resistance (CQR) in Plasmodium falciparum originated from at least six foci in South America, Asia, and Oceania. Malaria parasites from these locations exhibit contrasting resistance phenotypes that are distinguished by point mutations and microsatellite polymorphisms in and near the CQR transporter gene, pfcrt, and the multidrug resistance transporter gene, pfmdr1. Amodiaquine (AQ), a 4-aminoquinoline related to CQ, is recommended and often used successfully against CQ-resistant P. falciparum in Africa, but it is largely ineffective across large regions of South America. The relationship of different pfcrt and pfmdr1 combinations to these drug-resistant phenotypes has been unclear. In two P. falciparum genetic crosses, particular pfcrt and pfmdr1 alleles from South America interact to yield greater levels of resistance to monodesethylamodiaquine (MDAQ; the active metabolite of AQ) than to CQ, whereas a pfcrt allele from Southeast Asia and Africa is linked to greater CQ than MDAQ resistance with all partner pfmdr1 alleles. These results, together with (i) available haplotype data from other parasites; (ii) evidence for an emerging focus of AQ resistance in Tanzania; and (iii) the persistence of 4-aminoquinoline-resistant parasites in South America, where CQ and AQ use is largely discontinued, suggest that different histories of drug use on the two continents have driven the selection of distinct suites of pfcrt and pfmdr1 mutations. Increasing use of AQ in Africa poses the threat of a selective sweep of highly AQ-resistant, CQ-resistant parasites with pfcrt and pfmdr1 mutations that are as advantaged and persistent as in South America. PMID:19884511

Dynamic mechanical thermal analysis of composite resins with CQ and PPD as photo-initiators photoactivated by QTH and LED units.

PubMed

Brandt, William Cunha; Silva, Cristina Gomes; Frollini, Elisabete; Souza-Junior, Eduardo Jose Carvalho; Sinhoreti, Mário Alexandre Coelho

2013-08-01

The aim of this study was to evaluate the thermal and mechanical properties of the composite resins containing the photo-initiators camphorquinone (CQ) and/or phenyl-propanodione (PPD) when photoactivated with halogen lamp (XL2500/3M-ESPE), monowave (UltraBlueIS/DMC) and polywave (UltraLume5/Ultradent) LED units. A blend of BisGMA, UDMA, BisEMA and TEGDMA was prepared with the same wt% of photo-initiators CQ and/or PPD and 65wt% of silaneted filler particles. Compression strength (CS), diametral tensile strength (DTS) and diametral modulus (DM) were tested. Thermogravimetric analysis (TGA) was made and the lost residual monomer were verified. Dynamic mechanical thermal analysis (DMTA) was used for to analyze the glass transition temperature (Tg) and the storage modulus in 37°C. Degree of conversion (DC) was accomplished in the same samples of DMA using middle-infrared spectroscopy (mid-IR). CQ, CQ/PPD and PPD obtained the same results for all mechanical properties (CS, DTS and DM), lost residual monomer and storage modulus in 37°C, regardless LCU used. The results of Tg showed that the combination PPD-UltraLume5 produced the highest values. DC showed that the combination CQ-UltraLume5 resulted in the highest values and PPD-XL2500 in the lowest DC values. The study shows that PPD is not only effective photosensitizers, but also photocrosslinking agents for dental composite resins with a similar efficiency to CQ. Copyright © 2013 Elsevier Ltd. All rights reserved.

Seaweed-synthesized silver nanoparticles: an eco-friendly tool in the fight against Plasmodium falciparum and its vector Anopheles stephensi?

PubMed

Murugan, Kadarkarai; Samidoss, Christina Mary; Panneerselvam, Chellasamy; Higuchi, Akon; Roni, Mathath; Suresh, Udaiyan; Chandramohan, Balamurugan; Subramaniam, Jayapal; Madhiyazhagan, Pari; Dinesh, Devakumar; Rajaganesh, Rajapandian; Alarfaj, Abdullah A; Nicoletti, Marcello; Kumar, Suresh; Wei, Hui; Canale, Angelo; Mehlhorn, Heinz; Benelli, Giovanni

2015-11-01

Malaria, the most widespread mosquito-borne disease, affects 350-500 million people each year. Eco-friendly control tools against malaria vectors are urgently needed. This research proposed a novel method of plant-mediated synthesis of silver nanoparticles (AgNP) using a cheap seaweed extract of Ulva lactuca, acting as a reducing and capping agent. AgNP were characterized by UV-vis spectrophotometry, Fourier transform infrared (FTIR) spectroscopy, energy-dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM), and X-ray diffraction (XRD). The U. lactuca extract and the green-synthesized AgNP were tested against larvae and pupae of the malaria vector Anopheles stephensi. In mosquitocidal assays, LC50 values of U. lactuca extract against A. stephensi larvae and pupae were 18.365 ppm (I instar), 23.948 ppm (II), 29.701 ppm (III), 37.517 ppm (IV), and 43.012 ppm (pupae). LC50 values of AgNP against A. stephensi were 2.111 ppm (I), 3.090 ppm (II), 4.629 ppm (III), 5.261 ppm (IV), and 6.860 ppm (pupae). Smoke toxicity experiments conducted against mosquito adults showed that U. lactuca coils evoked mortality rates comparable to the permethrin-based positive control (66, 51, and 41%, respectively). Furthermore, the antiplasmodial activity of U. lactuca extract and U. lactuca-synthesized AgNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. Fifty percent inhibitory concentration (IC50) values of U. lactuca were 57.26 μg/ml (CQ-s) and 66.36 μg/ml (CQ-r); U. lactuca-synthesized AgNP IC50 values were 76.33 μg/ml (CQ-s) and 79.13 μg/ml (CQ-r). Overall, our results highlighted out that U. lactuca-synthesized AgNP may be employed to develop newer and safer agents for malaria control.

Concentration-discharge relationships under the microscope: high frequency measurement in rivers

NASA Astrophysics Data System (ADS)

Floury, P.; Gaillardet, J.; Bouchez, J.; Tallec, G.; Gayer, E.; Ansart, P.; Blanchouin, A.

2017-12-01

Concentration-discharge relationships (C-Q) of river water is a powerful tool to track the coupling between water flow and chemical reactions in the Critical Zone. C-Q have been extensively studied the last two decades. We present a new C-Q data series recorded at 40-minutes frequency by a prototype called River Lab (RL) (Floury et al., 2017). Confined in a bungalow next to the river, the RL performs an of all major dissolved species (Na+, K+, Mg2+, Ca2+, Cl-, SO42-, NO3-) using ion chromatographs, through continuous sampling and filtration of the river water. The RL was deployed in 2015 in the Orgeval hydrological Observatory (OZCAR French Research Infrastructure), an agricultural watershed underlain by carbonates, France. We present five major flood events recorded over one hydrological year. We present the C-Q for each of the flood events. We observe i) element-specific C-Q ii) C-Q loops, the size and the excentricity of which decrease with the intensity of the flood. The most reproducible C-Q patterns are observed for Na+, Mg2+, Ca2+, Cl-, SO42-, whereas K+ and NO3- present a more erratic behaviour. We discuss the chemostatic behaviour of species concentrations using a fitting by a power law function. It is likely that C-Q will depend on the time during a single flood event and also over the year. The chemostatic behaviour of each species change over the year and also during a single flood event. We focus our interpretations on the recession of each flood event, where precipitation and evapotrapiration can be considered as negligible. We propose a "grey box" aproach such as already developed from stream flow (Kirchner, 2009) but here extended to solute fluxes. Floury et al. Hydrol. Earth Syst. Sci. Discuss., doi:10.5194/hess-2017-12, 2017. Kirchner. Water Ressources Research, VOL. 45, W02429, doi:10.1029/2008WR006912, 2009.

Interpersonal learning is associated with improved self-esteem in group psychotherapy for women with binge eating disorder.

PubMed

Gallagher, Meagan E; Tasca, Giorgio A; Ritchie, Kerri; Balfour, Louise; Maxwell, Hilary; Bissada, Hany

2014-03-01

Yalom and Leszcz (2005) indicated that interpersonal learning is a key therapeutic factor in group psychotherapy. In this study, we conceptualized interpersonal learning as the convergence over time between an individual's and the group's perception of the individual's cohesion to the group. First, we developed parallel measures of: (a) an individual's self-rated cohesion to the group (Cohesion Questionnaire-Individual Version [CQ-I]), and (b) the group's rating of the individual's cohesion to the group (CQ-G) based on the original Cohesion Questionnaire (CQ; Piper, Marache, Lacroix, Richardsen, & Jones, 1983). Second, we used these parallel scales to assess differences between an individual's self-rating and the mean of the group's ratings of the individual's cohesion to the group. Women with binge eating disorder (N = 102) received Group Psychodynamic Interpersonal Psychotherapy. Participants were assigned to homogeneously composed groups of either high or low attachment anxiety. Outcomes were measured pre- and post-treatment, and the CQ-I and CQ-G were administered every fourth group session. We found significant convergence over time between the CQ-I and mean CQ-G scale scores in both attachment anxiety conditions. Participants with higher attachment anxiety had lower individual self-ratings of cohesion and had greater discrepancies between the CQ-I and CG-G compared with those with lower attachment anxiety. There was a significant relationship between greater convergence in cohesion ratings and improved self-esteem at post-treatment. More accurate self-perceptions through feedback from group members may be a key factor in facilitating increased self-esteem in group therapy. Group therapists may facilitate such interpersonal learning, especially for those higher in attachment anxiety, by noting discrepancies and then encouraging convergence between an individual and the group in their perceptions of cohesion to the group. (c) 2014 APA, all rights reserved.

Influence of viscosity and amine content on C==C conversion and color stability of experimental composites.

PubMed

Camargo, Fernanda Missio; Della Bona, Álvaro; Moraes, R R; Coutinho de Souza, C R; Schneider, Luis Felipe

2015-05-01

To investigate the influence of camphorquinone (CQ):amine ratio on the degree of CC conversion (DC) and color stability of experimental dental composites formulated with different co-monomer viscosities, indirectly determined by variations in the co-monomer ratios. Experimental composites were formulated in two different BisGMA:TEGDMA molar ratios (50:50 and 70:30). Viscosities were assessed with a viscometer. For each composite formulation, four different CQ:amine ratios were added: 1:1, 1:2, 1:3 or 1:4 mol%. Materials were loaded with 40 wt% of silanized glass particles. DC was determined by Fourier-transformed infrared spectroscopy with attenuated reflectance mode (ATR-FTIR). A spectrophotometer was used to measure the CIE L*a*b* color coordinates 24h after polymerization and after 2 months stored in water. Color changes (ΔE) were calculated. Data were statistically analyzed using analyses of variance (ANOVA), Tukey's and Student-t tests (α=0.05). The 50:50 BisGMA:TEGDMA co-monomer showed lower viscosity than 70:30. DC was affected by CQ:amine ratio, and not by the co-monomer viscosity, but the interaction between these two factors was significant. a* and b* coordinates were dependent on CQ:amine or BisGMA:TEGDMA ratios, while L* was not. b* values were directly related to the amount of amine in the formulation, regardless of co-monomer viscosity. ΔE was dependent on the amount of amine, but not on the viscosity of the material. DC was influenced by the CQ:amine ratio. The influence of viscosity on DC was dependent on the CQ:amine ratio and exhibited distinguished behavior. a* and b* coordinates were affected by CQ:amine and BisGMA:TEGDMA ratios. The color change (ΔE) was affected by CQ:amine ratio, but not by viscosity. Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Photopolymerization of N,N-dimethylaminobenzyl alcohol as amine co-initiator for light-cured dental resins.

PubMed

Schroeder, Walter F; Cook, Wayne D; Vallo, Claudia I

2008-05-01

The present study was carried out in order to assess the suitability of N,N-dimethylaminobenzyl alcohol (DMOH) as co-initiator of camphorquinone (CQ) and 1-phenyl-1,2-propanedione (PPD) in light-cured dental resins. DMOH was synthesized and used as co-initiator for the photopolymerization of a model resin based on {2,2-bis[4-(2-hydroxy-3-methacryloxyprop-1-oxy)phenyl]propane} (Bis-GMA)/triethylene glycol dimethacrylate (TEGDMA). Experimental formulations containing CQ or PPD in combination with DMOH at different concentrations were studied. The photopolymerization was carried out by means of a commercial light-emitting diode (LED) curing unit. The evolution of double bonds consumption versus irradiation time was followed by near-infrared spectroscopy (NIR). The photon absorption efficiency (PAE) of the photopolymerization process was calculated from the spectral distribution of the LED unit and the molar absorption coefficient distributions of PPD and CQ. DMOH is an efficient photoreducer of CQ and PPD resulting in higher polymerization rate and higher double bond conversion compared with dimethylaminoethylmethacrylate. The PAE for PPD was higher than that for CQ. However, the polymerization initiated by PPD progressed at a lower rate and exhibited lower values of final conversion compared with the resins containing CQ. This observation indicates that the lower polymerization rate of the PPD/amine system should be explained in terms of the mechanism of generating primary radicals by PPD, which is less efficient compared with CQ. The DMOH/benzoyl peroxide redox system, has recently been proposed as a more biocompatible accelerator for the polymerization of bone cements based on poly(methyl methacrylate), because cytotoxity tests have demonstrated that DMOH possesses better biocompatibility properties compared with traditional tertiary amines. The results obtained in the present study reveal the suitability of the CQ/DMOH initiator system for the polymerization of light-cured dental composites.

Comparison of artemether-lumefantrine and chloroquine with and without primaquine for the treatment of Plasmodium vivax infection in Ethiopia: A randomized controlled trial

PubMed Central

Tadesse, Yehualashet; Melaku, Zenebe; Assef, Ashenafi; Kassa, Moges; Chatfield, Mark D.; Landman, Keren Z.; Chenet, Stella M.; Lucchi, Naomi W.; Udhayakumar, Venkatachalam; Zhou, Zhiyong; Shi, Ya Ping; Kachur, S. Patrick; Jima, Daddi; Kebede, Amha; Solomon, Hiwot; Mekasha, Addis; Alemayehu, Bereket Hailegiorgis; Malone, Joseph L.; Dissanayake, Gunewardena; Teka, Hiwot; Price, Ric N.

2017-01-01

Background Recent efforts in malaria control have resulted in great gains in reducing the burden of Plasmodium falciparum, but P. vivax has been more refractory. Its ability to form dormant liver stages confounds control and elimination efforts. To compare the efficacy and safety of primaquine regimens for radical cure, we undertook a randomized controlled trial in Ethiopia. Methods and findings Patients with normal glucose-6-phosphate dehydrogenase status with symptomatic P. vivax mono-infection were enrolled and randomly assigned to receive either chloroquine (CQ) or artemether-lumefantrine (AL), alone or in combination with 14 d of semi-supervised primaquine (PQ) (3.5 mg/kg total). A total of 398 patients (n = 104 in the CQ arm, n = 100 in the AL arm, n = 102 in the CQ+PQ arm, and n = 92 in the AL+PQ arm) were followed for 1 y, and recurrent episodes were treated with the same treatment allocated at enrolment. The primary endpoints were the risk of P. vivax recurrence at day 28 and at day 42. The risk of recurrent P. vivax infection at day 28 was 4.0% (95% CI 1.5%–10.4%) after CQ treatment and 0% (95% CI 0%–4.0%) after CQ+PQ. The corresponding risks were 12.0% (95% CI 6.8%–20.6%) following AL alone and 2.3% (95% CI 0.6%–9.0%) following AL+PQ. On day 42, the risk was 18.7% (95% CI 12.2%–28.0%) after CQ, 1.2% (95% CI 0.2%–8.0%) after CQ+PQ, 29.9% (95% CI 21.6%–40.5%) after AL, and 5.9% (95% CI 2.4%–13.5%) after AL+PQ (overall p < 0.001). In those not prescribed PQ, the risk of recurrence by day 42 appeared greater following AL treatment than CQ treatment (HR = 1.8 [95% CI 1.0–3.2]; p = 0.059). At the end of follow-up, the incidence rate of P. vivax was 2.2 episodes/person-year for patients treated with CQ compared to 0.4 for patients treated with CQ+PQ (rate ratio: 5.1 [95% CI 2.9–9.1]; p < 0.001) and 2.3 episodes/person-year for AL compared to 0.5 for AL+PQ (rate ratio: 6.4 [95% CI 3.6–11.3]; p < 0.001). There was no difference in the occurrence of adverse events between treatment arms. The main limitations of the study were the early termination of the trial and the omission of haemoglobin measurement after day 42, resulting in an inability to estimate the cumulative risk of anaemia. Conclusions Despite evidence of CQ-resistant P. vivax, the risk of recurrence in this study was greater following treatment with AL unless it was combined with a supervised course of PQ. PQ combined with either CQ or AL was well tolerated and reduced recurrence of vivax malaria by 5-fold at 1 y. Trial registration ClinicalTrials.gov NCT01680406 PMID:28510573

Evolution of concentration-discharge relations revealed by high frequency diurnal sampling of stream water during spring snowmelt

NASA Astrophysics Data System (ADS)

Olshansky, Y.; White, A. M.; Thompson, M.; Moravec, B. G.; McIntosh, J. C.; Chorover, J.

2017-12-01

Concentration discharge (C-Q) relations contain potentially important information on critical zone (CZ) processes including: weathering reactions, water flow paths and nutrient export. To examine the C-Q relations in a small (3.3 km2) headwater catchment - La Jara Creek located in the Jemez River Basin Critical Zone Observatory, daily, diurnal stream water samples were collected during spring snow melt 2017, from two flumes located in outlets of the La Jara Creek and a high elevation zero order basin within this catchment. Previous studies from this site (McIntosh et al., 2017) suggested that high frequency sampling was needed to improve our interpretation of C-Q relations. The dense sampling covered two ascending and two descending limbs of the snowmelt hydrograph, from March 1 to May 15, 2017. While Na showed inverse correlation (dilution) with discharge, most other solutes (K, Mg, Fe, Al, dissolved organic carbon) exhibited positive (concentration) or chemostatic trends (Ca, Mn, Si, dissolved inorganic carbon and dissolved nitrogen). Hysteresis in the C-Q relation was most pronounced for bio-cycled cations (K, Mg) and for Fe, which exhibited concentration during the first ascending limb followed by a chemostatic trend. A pulsed increase in Si concentration immediately after the first ascending limb in both flumes suggests mixing of deep groundwater with surface water. A continual increase in Ge/Si concentrations followed by a rapid decrease after the second rising limb may suggest a fast transition between soil water to ground water dominating the stream flow. Fourier transform infrared spectroscopy of selected samples across the hydrograph demonstrated pronounced changes in dissolved organic matter molecular composition with the advancement of the spring snow melt. X-ray micro-spectroscopy of colloidal material isolated from the collected water samples indicated a significant role for organic matter in the transport of inorganic colloids. Analyses of high frequency diurnal sampling greatly improve our ability to probe rapid CZ changes occurring during spring snowmelt, and provide useful information for evaluation and modeling of CZ processes in other snow melt dominated regions.

75 FR 63710 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-18

...: * * * Effective Upon Publication AIRAC date State City Airport FDC No. FDC date Subject 18-Nov-10 CQ SAIPAN ISLAND...... FRANCISCO C. ADA/ 0/1358 9/29/10 ILS OR LOC/DME RWY 7, AMDT 5B. SAIPAN INTL. 18-Nov-10 CQ SAIPAN ISLAND...... FRANCISCO C. ADA/ 0/1359 9/29/10 NDB/DME RWY 25, AMDT 2A SAIPAN INTL. 18-Nov-10 CQ SAIPAN ISLAND...

The effect of the polymerization initiator and light source on the elution of residual Bis-GMA and TEGDMA monomers: A study using liquid chromatography with UV detection.

PubMed

Denis, Aline B; Diagone, Cristina A; Plepis, Ana M G; Viana, Rommel B

2015-12-05

A method for the extraction and quantification of two residual monomers, bisphenol glycidyl dimethacrylate (Bis-GMA) and triethylene glycol dimethacrylate (TEGDMA), that were evaluated using high efficiency liquid chromatography with UV detection was developed and validated in this study. Three types of solvents were applied in the extraction of the monomers (methanol, ethanol and acetonitrile), where the highest extraction efficiency was obtained using acetonitrile. The different resins were prepared by photoactivation of Bis-GMA and TEGDMA monomers. Additionally, the effects of the addition of two photoinitiators (camphorquinone (CQ) and phenyl propanodione (PPD) and that of a co-initiator (N,N-dimethyl-p-toluidine) were also analyzed. When only the CQ photoinitiator was used, a smaller amount of residual monomers was obtained, whereas a larger amount was obtained with PPD. When the two photoinitiators were used in the same matrix, however, no significant changes were observed in relation to the amount of residual TEGDMA monomers. For the addition of the co-initiator, there were no large changes in the extraction of residual monomers. The effect of the two photoactivation sources (halogen lamp and LED) led to small differences in the elution of the two monomers, although all of the resins differed significantly when photoactivated with a LED. Quantum chemical calculations using Density Functional Theory were carried out to characterize several molecular properties of each monomer. Copyright © 2015 Elsevier B.V. All rights reserved.

Critical zone structure controls concentration-discharge relationships and solute generation in forested tropical montane watersheds

NASA Astrophysics Data System (ADS)

Wymore, Adam S.; Brereton, Richard L.; Ibarra, Daniel E.; Maher, Kate; McDowell, William H.

2017-07-01

Concentration-discharge (C-Q) relationships are poorly known for tropical watersheds, even though the tropics contribute a disproportionate amount of solutes to the global ocean. The Luquillo Mountains in Puerto Rico offer an ideal environment to examine C-Q relationships across a heterogeneous tropical landscape. We use 10-30 years of weekly stream chemistry data across 10 watersheds to examine C-Q relationships for weathering products (SiO2(aq), Ca2+, Mg2+, and Na+) and biologically controlled solutes (dissolved organic carbon [DOC], dissolved organic nitrogen [DON], NH4+, NO3-, PO43-, K+, and SO42-). We analyze C-Q relationships using power law equations and a solute production model and use principal component analysis to test hypotheses regarding how the structure of the critical zone controls solute generation. Volcaniclastic watersheds had higher concentrations of weathering solutes and smaller tributaries were approximately threefold more efficient at generating these solutes than larger rivers. Lithology and vegetation explained a significant amount of variation in the theoretical maximum concentrations of weathering solutes (r2 = 0.43-0.48) and in the C-Q relationships of PO43- (r2 = 0.63) and SiO2(aq) (r2 = 0.47). However, the direction and magnitude of these relationships varied. Across watersheds, various forms of N and P displayed variable C-Q relationships, while DOC was consistently enriched with increasing discharge. Results suggest that PO43- may be a useful indicator of watershed function. Relationships between C-Q and landscape characteristics indicate the extent to which the structure and function of the Critical zone controls watershed solute fluxes.

Alkaline phosphatase activity-guided isolation of active compounds and new dammarane-type triterpenes from Cissus quadrangularis hexane extract.

PubMed

Pathomwichaiwat, Thanika; Ochareon, Pannee; Soonthornchareonnon, Noppamas; Ali, Zulfiqar; Khan, Ikhlas A; Prathanturarug, Sompop

2015-02-03

The stem of Cissus quadrangularis L. (CQ) is used in traditional medicine to treat bone fractures and swelling. Anti-osteoporotic activity of CQ hexane extract has been reported, but the active compounds in this extract remain unknown. Thus, we aimed to identify the active compounds in CQ hexane extract using bioassay-guided isolation. The CQ hexane extract was fractionated sequentially with benzene, dichloromethane, ethyl acetate, and methanol. The examination of CQ extract and its fractions was guided by bioassays for alkaline phosphatase (ALP) activity during the differentiation of MC3T3-E1 osteoblastic cells. The cells were treated with or without the CQ extract and its fractions for a period of time, and then the stimulatory effect of the alkaline phosphatase enzyme, a bone differentiation marker, was investigated. The compounds obtained were structurally elucidated using spectroscopic techniques and re-evaluated for activity during bone differentiation. A total of 29 compounds were isolated, viz., triterpenes, fatty acid methyl esters, glycerolipids, steroids, phytols, and cerebrosides. Four new dammarane-type triterpenes were isolated for the first time from nature, and this report is the first to identify this group of compounds from the Vitaceae family. Seven compounds, viz., glycerolipids and squalene, stimulated ALP activity at a dose of 10μg/mL. Moreover, the synergistic effect of these compounds on bone formation was demonstrated. This report describes, for the first time, the isolation of active compounds from CQ hexane extract; these active compounds will be useful for the quality control of extracts from this plant used to treat osteoporosis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Is chloroquine chemoprophylaxis still effective to prevent low birth weight? Results of a study in Benin

PubMed Central

Denoeud, Lise; Fievet, Nadine; Aubouy, Agnès; Ayemonna, Paul; Kiniffo, Richard; Massougbodji, Achille; Cot, Michel

2007-01-01

Background In areas of stable transmission, malaria during pregnancy is associated with severe maternal and foetal outcomes, especially low birth weight (LBW). To prevent these complications, weekly chloroquine (CQ) chemoprophylaxis is now being replaced by intermittent preventive treatment with sulfadoxine-pyrimethamine in West Africa. The prevalence of placental malaria and its burden on LBW were assessed in Benin to evaluate the efficacy of weekly CQ chemoprophylaxis, prior to its replacement by intermittent preventive treatment. Methods In two maternity clinics in Ouidah, an observational study was conducted between April 2004 and April 2005. At each delivery, placental blood smears were examined for malaria infection and women were interviewed on their pregnancy history including CQ intake and dosage. CQ was measured in the urine of a sub-sample (n = 166). Multiple logistic and linear regression were used to assess factors associated with LBW and placental malaria. Results Among 1090 singleton live births, prevalence of placental malaria and LBW were 16% and 17% respectively. After adjustment, there was a non-significant association between placental malaria and LBW (adjusted OR = 1.43; P = 0.10). Multiple linear regression showed a positive association between placental malaria and decreased birth weight in primigravidae. More than 98% of the women reported regular chemoprophylaxis and CQ was detectable in 99% of urine samples. Protection from LBW was high in women reporting regular CQ prophylaxis, with a strong duration-effect relationship (test for linear trend: P < 0,001). Conclusion Despite high parasite resistance and limited effect on placental malaria, a CQ chemoprophylaxis taken at adequate doses showed to be still effective in reducing LBW in Benin. PMID:17341298

Evaluation of phenyl-propanedione on yellowing and chemical-mechanical properties of experimental dental resin-based materials.

PubMed

Oliveira, Dayane Carvalho Ramos Salles de; Souza-Junior, Eduardo José; Dobson, Adam; Correr, Ana Rosa Costa; Brandt, William Cunha; Sinhoreti, Mário Alexandre Coelho

2016-01-01

To evaluate the influence of phenyl-propanedione on yellowing and chemical-mechanical properties of experimental resin-based materials photoactivated using different light curing units (LCUs). Experimental resin-based materials with the same organic matrix (60:40 wt% BisGMA:TEGDMA) were mechanically blended using a centrifugal mixing device. To this blend, different photoinitiator systems were added in equimolar concentrations with aliphatic amine doubled by wt%: 0.4 wt% CQ; 0.38 wt% PPD; or 0.2 wt% CQ and 0.19 wt% PPD. The degree of conversion (DC), flexural strength (FS), Young's modulus (YM), Knoop hardness (KNH), crosslinking density (CLD), and yellowing (Y) were evaluated (n=10). All samples were light cured with the following LCUs: a halogen lamp (XL 2500), a monowave LED (Radii), or a polywave LED (Valo) with 16 J/cm2. The results were analysed by two-way ANOVA and Tukey's test (α=0.05). No statistical differences were found between the different photoinitiator systems to KNH, CLS, FS, and YM properties (p≥0.05). PPD/CQ association showed the higher DC values compared with CQ and PPD isolated systems when photoactivated by a polywave LED (p≤0.05). Y values were highest for the CQ compared with the PPD systems (p≤0.05). PPD isolated system promoted similar chemical and mechanical properties and less yellowing compared with the CQ isolated system, regardless of the LCU used.

Optimizing light-cured composite through variations in camphorquinone and butylhydroxytoluene concentrations.

PubMed

Nassar, Hani; Chu, Tien-Min; Platt, Jeffrey

2016-05-20

The use of a free-radical polymerization inhibitor, butylhydroxytoluene (BHT), and a common photo-initiator, camphorquinone (CQ), to reduce polymerization stress in dental composite was investigated in this study. Samples were prepared by mixing Bis-GMA, UDMA, and TEGDMA at a 1:1:1 ratio (wt%), and silanized borosilicate glass fillers at 70 wt% were added to form the composite. Sixteen groups of resin composite were prepared using combinations of four CQ (0.1%, 0.5%, 1.0%, and 1.5%) and four BHT (0.0%, 0.5%, 1.0%, and 1.5%) concentrations. For each group, six properties were tested, including flexural strength (FS), flexural modulus (FM), degree of conversion (DC), contraction stress (CS), stress rate, and gel point (GP). The effects of CQ and BHT combinations on each of these properties were evaluated using two-way analysis of variance (ANOVA) and Fisher's Protected Least Significant Differences test at the 5% significance level. Groups with low CQ and BHT showed moderate values for FS, FM, and CS with a 70% DC. Increasing the BHT concentration caused a decrease in CS and DC with an increase in GP values. Increasing the CQ content led to a steady increase in values for FS and FM. High CQ and BHT combinations showed the most promising values for mechanical properties with low stress values.

Enhanced Gene and siRNA Delivery by Polycation-Modified Mesoporous Silica Nanoparticles Loaded with Chloroquine

PubMed Central

Bhattarai, Shanta Raj; Muthuswamy, Elayaraja; Wani, Amit; Brichacek, Michal; Castañeda, Antonio L.; Brock, Stephanie L.

2014-01-01

Purpose To prepare mesoporous silica-based delivery systems capable of simultaneous delivery of drugs and nucleic acids. Methods The surface of mesoporous silica nanoparticles (MSN) was modified with poly(ethylene glycol) (PEG) and poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA) or poly (2-(diethylamino)ethylmethacrylate) (PDEAEMA). The particles were then loaded with a lysosomotropic agent chloroquine (CQ) and complexed with plasmid DNA or siRNA. The ability of the synthesized particles to deliver combinations of CQ and nucleic acids was evaluated using luciferase plasmid DNA and siRNA targeting luciferase and GAPDH. Results The results show a slow partial MSN dissolution to form hollow silica nanoparticles in aqueous solution. The biological studies show that polycation-modified MSN are able to simultaneously deliver CQ with DNA and siRNA. The co-delivery of CQ and the nucleic acids leads to a significantly increased transfection and silencing activity of the complexes compared with MSN not loaded with CQ. Conclusion PEGylated MSN modified with polycations are promising delivery vectors for combination drug/nucleic acid therapies. PMID:20730557

Development of a New Generation of 4-Aminoquinoline Antimalarial Compounds Using Predictive Pharmacokinetic and Toxicology Models

PubMed Central

Ray, Sunetra; Madrid, Peter B.; Catz, Paul; LeValley, Susanna E.; Furniss, Michael J.; Rausch, Linda L.; Guy, R. Kiplin; DeRisi, Joseph L.; Iyer, Lalitha V.; Green, Carol E.; Mirsalis, Jon C.

2010-01-01

Among the known antimalarial drugs, chloroquine (CQ) and other 4-aminoquinolines have shown high potency and good bioavailability, yet complications associated with drug resistance necessitate the discovery of effective new antimalarial agents. ADMETa prediction studies were employed to evaluate a library of new molecules based on the 4-aminoquinolone-related structure of CQ. Extensive in vitro screening and in vivo pharmacokinetic studies in mice helped to identify two lead molecules, 18 and 4, with promising in vitro therapeutic efficacy, improved ADMET properties, low risk for drug-drug interactions, and desirable pharmacokinetic profiles. Both 18 and 4 are highly potent antimalarial compounds, with IC50 values = 5.6 nM and 17.3 nM, respectively, against the W2 (CQ-resistant) strain of Plasmodium falciparum (IC50 for CQ = 382 nM). When tested in mice, these compounds were found to have biological half-lives and plasma exposure values similar to or higher than those of CQ; they are therefore desirable candidates to pursue in future clinical trials. PMID:20361799

Variation of electrolaryngographically derived closed quotient for trained and untrained adult female singers.

PubMed

Howard, D M

1995-06-01

The derivation of larynx closed quotient (CQ) measures from the electrolarynogograph output is discussed and data are presented for a group of trained and untrained adult female singers (N = 26) for a sung two-octave G major scale. Statistically significant trends are observed between the trained and untrained groups that suggest for the trained group: (a) CQ tends to be lower for pitches below D4 and higher for pitches above B4, and (b) the gradient [CQ/log(F0)] tends to correlate positively with the number of years singing training/experience. These data are compared with those reported previously for an adult male group, and it is suggested that CQ could be a useful parameter to include in a real-time visual display for singing training.

Optimization of Daily Flight Training Schedules

DTIC Science & Technology

2014-03-01

iep iep ip X s e p Y i e p L i e p W...SOLO L CQ CQ | | 2 , | d d d iep iep ip p P p Pe e E e e E p P P Y L W i d i I               (3) SOLO L CQ | | 2 , | d d iep ... iep p P p Pe e E e e E Y L i d i I           (4) 1 , | , "CQ" o s sep s p p X s e e C e      (5) 0 0 | 2 , s d s sep s e C p

The early identification of anxiety-laden material with the aid of skin conductance measurements.

PubMed

Lukens, H R

1979-01-01

Measured electrodermal responses (EDR), in the form of changes in skin conductivity, during administration of a calibration questionnaire (CQ) and a personal history questionnaire (PHQ) to each of 25 Ss. "Strong" changes were defined statistically for each S from the amplitudes of EDR evoked by the CQ. The free-floating anxiety of each S also was measured. As predicted on the grounds that questions of the PHQ were more likely than the non-personal questions of the CQ to intersect unresolved, anxiety-laden material, it was found that strong EDR evoked by the PHQ were significantly more likely to perseverate than those evoked by the CQ. Hence, the technique has potential clinical use in identifying anxiety-laden material. Free-floating anxiety did not correlate significantly with EDR data.

ReadqPCR and NormqPCR: R packages for the reading, quality checking and normalisation of RT-qPCR quantification cycle (Cq) data

PubMed Central

2012-01-01

Background Measuring gene transcription using real-time reverse transcription polymerase chain reaction (RT-qPCR) technology is a mainstay of molecular biology. Technologies now exist to measure the abundance of many transcripts in parallel. The selection of the optimal reference gene for the normalisation of this data is a recurring problem, and several algorithms have been developed in order to solve it. So far nothing in R exists to unite these methods, together with other functions to read in and normalise the data using the chosen reference gene(s). Results We have developed two R/Bioconductor packages, ReadqPCR and NormqPCR, intended for a user with some experience with high-throughput data analysis using R, who wishes to use R to analyse RT-qPCR data. We illustrate their potential use in a workflow analysing a generic RT-qPCR experiment, and apply this to a real dataset. Packages are available from http://www.bioconductor.org/packages/release/bioc/html/ReadqPCR.htmland http://www.bioconductor.org/packages/release/bioc/html/NormqPCR.html Conclusions These packages increase the repetoire of RT-qPCR analysis tools available to the R user and allow them to (amongst other things) read their data into R, hold it in an ExpressionSet compatible R object, choose appropriate reference genes, normalise the data and look for differential expression between samples. PMID:22748112

Earthworm-mediated synthesis of silver nanoparticles: A potent tool against hepatocellular carcinoma, Plasmodium falciparum parasites and malaria mosquitoes.

PubMed

Jaganathan, Anitha; Murugan, Kadarkarai; Panneerselvam, Chellasamy; Madhiyazhagan, Pari; Dinesh, Devakumar; Vadivalagan, Chithravel; Aziz, Al Thabiani; Chandramohan, Balamurugan; Suresh, Udaiyan; Rajaganesh, Rajapandian; Subramaniam, Jayapal; Nicoletti, Marcello; Higuchi, Akon; Alarfaj, Abdullah A; Munusamy, Murugan A; Kumar, Suresh; Benelli, Giovanni

2016-06-01

The development of parasites and pathogens resistant to synthetic drugs highlighted the needing of novel, eco-friendly and effective control approaches. Recently, metal nanoparticles have been proposed as highly effective tools towards cancer cells and Plasmodium parasites. In this study, we synthesized silver nanoparticles (EW-AgNP) using Eudrilus eugeniae earthworms as reducing and stabilizing agents. EW-AgNP showed plasmon resonance reduction in UV-vis spectrophotometry, the functional groups involved in the reduction were studied by FTIR spectroscopy, while particle size and shape was analyzed by FESEM. The effect of EW-AgNP on in vitro HepG2 cell proliferation was measured using MTT assays. Apoptosis assessed by flow cytometry showed diminished endurance of HepG2 cells and cytotoxicity in a dose-dependent manner. EW-AgNP were toxic to Anopheles stephensi larvae and pupae, LC(50) were 4.8 ppm (I), 5.8 ppm (II), 6.9 ppm (III), 8.5 ppm (IV), and 15.5 ppm (pupae). The antiplasmodial activity of EW-AgNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. EW-AgNP IC(50) were 49.3 μg/ml (CQ-s) and 55.5 μg/ml (CQ-r), while chloroquine IC(50) were 81.5 μg/ml (CQ-s) and 86.5 μg/ml (CQ-r). EW-AgNP showed a valuable antibiotic potential against important pathogenic bacteria and fungi. Concerning non-target effects of EW-AgNP against mosquito natural enemies, the predation efficiency of the mosquitofish Gambusia affinis towards the II and II instar larvae of A. stephensi was 68.50% (II) and 47.00% (III), respectively. In EW-AgNP-contaminated environments, predation was boosted to 89.25% (II) and 70.75% (III), respectively. Overall, this research highlighted the EW-AgNP potential against hepatocellular carcinoma, Plasmodium parasites and mosquito vectors, with little detrimental effects on mosquito natural enemies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Characterization of Cq3, a quantitative trait locus that controls plasma cholesterol and phospholipid levels in mice.

PubMed

Suto, Jun-ichi

2006-04-01

Cq3 was identified in C57BL/6J (B6) x KK-Ay F2 mice as a quantitative trait locus (QTL) that controls plasma cholesterol and phospholipid levels, and normolipidemic B6 allele was associated with increased lipids. Cq3 was statistically significant in F2-a/a, but not in F2-Ay/a; probably because the Cq3 effect was obscured by introduction of the Ay allele, which in itself has a strong hyperlipidemic effect. Because the peak LOD score for Cq3 was identified near D3Mit102 (49.7 cM) on chromosome 3, linkage analyses with microsatellite markers located at 49.7 cM were performed in KK x RR F2, B6 x RR F2, and KK x CF1 F2. However, even a suggestive QTL was not identified in any of the three F2. By testing all pairs of marker loci, I found a significant interaction between Cq3 and the Apoa2 locus, and F2 mice with the Apoa2(KK)/Apoa2(KK); D3Mit102(B6)/D3Mit102(B6) genotype had significantly higher cholesterol levels than did F2 mice with other genotypes. The results showed that the ;round-robin' strategy was not always applicable to the search for QTL genes; probably because specific gene-to-gene interaction limited the validity of the strategy to the utmost extent.

Multipurpose effectiveness of Couroupita guianensis-synthesized gold nanoparticles: high antiplasmodial potential, field efficacy against malaria vectors and synergy with Aplocheilus lineatus predators.

PubMed

Subramaniam, Jayapal; Murugan, Kadarkarai; Panneerselvam, Chellasamy; Kovendan, Kalimuthu; Madhiyazhagan, Pari; Dinesh, Devakumar; Kumar, Palanisamy Mahesh; Chandramohan, Balamurugan; Suresh, Udaiyan; Rajaganesh, Rajapandian; Alsalhi, Mohamad Saleh; Devanesan, Sandhanasamy; Nicoletti, Marcello; Canale, Angelo; Benelli, Giovanni

2016-04-01

Mosquito-borne diseases represent a deadly threat for millions of people worldwide. According to recent estimates, about 3.2 billion people, almost half of the world's population, are at risk of malaria. Malaria control is particularly challenging due to a growing number of chloroquine-resistant Plasmodium and pesticide-resistant Anopheles vectors. Newer and safer control tools are required. In this research, gold nanoparticles (AuNPs) were biosynthesized using a cheap flower extract of Couroupita guianensis as reducing and stabilizing agent. The biofabrication of AuNP was confirmed by UV-vis spectrophotometry, Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), energy-dispersive X-ray (EDX) spectroscopy, X-ray diffraction (XRD), zeta potential, and particle size analysis. AuNP showed different shapes including spheres, ovals, and triangles. AuNPs were crystalline in nature with face-centered cubic geometry; mean size was 29.2-43.8 nm. In laboratory conditions, AuNPs were toxic against Anopheles stephensi larvae, pupae, and adults. LC50 was 17.36 ppm (larva I), 19.79 ppm (larva II), 21.69 ppm (larva III), 24.57 ppm (larva IV), 28.78 ppm (pupa), and 11.23 ppm (adult). In the field, a single treatment with C. guianensis flower extract and AuNP (10 × LC50) led to complete larval mortality after 72 h. In standard laboratory conditions, the predation efficiency of golden wonder killifish, Aplocheilus lineatus, against A. stephensi IV instar larvae was 56.38 %, while in an aquatic environment treated with sub-lethal doses of the flower extract or AuNP, predation efficiency was boosted to 83.98 and 98.04 %, respectively. Lastly, the antiplasmodial activity of C. guianensis flower extract and AuNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. IC50 of C. guianensis flower extract was 43.21 μg/ml (CQ-s) and 51.16 μg/ml (CQ-r). AuNP IC50 was 69.47 μg/ml (CQ-s) and 76.33 μg/ml (CQ-r). Overall, our results showed the multipurpose effectiveness of C. guianensis-synthesized AuNPs, since they may be proposed as newer and safer tools in the fight against CQ-r strains of P. falciparum and for field control of malaria vectors, in synergy with wonder killifish predators.

Are Long-Term Chloroquine or Hydroxychloroquine Users Being Checked Regularly for Toxic Maculopathy?

PubMed Central

Nika, Melisa; Blachley, Taylor S.; Edwards, Paul; Lee, Paul P.; Stein, Joshua D.

2014-01-01

Importance According to evidence-based, expert recommendations, long-term users of chloroquine (CQ) or hydroxychloroquine (HCQ) should undergo regular visits to eye-care providers and diagnostic testing to check for maculopathy. Objective To determine whether patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) taking CQ or HCQ are regularly visiting eye-care providers and being screened for maculopathy. Setting, Design and Participants Patients with RA or SLE who were continuously enrolled in a particular managed-care network for ≥5 years during 2001-2011 were studied. Patients' amount of CQ/HCQ use in the 5 years since initial RA/SLE diagnosis was calculated, along with their number of eye-care visits and diagnostic tests for maculopathy. Those at high risk for maculopathy were identified. Visits to eye providers and diagnostic testing for maculopathy were assessed for each enrollee over the study period. Logistic regression was performed to assess potential factors associated with regular eye-care-provider visits (≥3 in 5 years) among CQ/HCQ users, including those at greatest risk for maculopathy. Main Outcome Measures Among CQ/HCQ users and those at high risk for toxic maculopathy, the proportions with regular eye-care visits and diagnostic testing, and the likelihood of regular eye-care visits (odds ratios [ORs] with 95% confidence intervals [CI]). Results Among 18,051 beneficiaries with RA or SLE, 6,339 (35.1%) had ≥1 record of HCQ/CQ use and 1,409 (7.8%) used HCQ/CQ for ≥4 years. Among those at high risk for maculopathy, 27.9% lacked regular eye-provider visits, 6.1% had no visits to eye providers, and 34.5% had no diagnostic testing for maculopathy during the 5-year period. Among high-risk patients, each additional month of HCQ/CQ use was associated with a 2.0%-increased likelihood of regular eye care (adjusted OR=1.02, CI=1.01-1.03). High-risk patients whose SLE/RA were managed by rheumatologists had a 77%-increased likelihood of regular eye care (adjusted OR=1.77, CI=1.27-2.47), relative to other patients. Conclusions and Relevance In this insured population, many patients at high risk for HCQ/CQ-associated maculopathy are not undergoing routine monitoring for this serious side effect. Future studies should explore factors contributing to suboptimal adherence to expert guidelines and the potential impact on patients' vision-related outcomes. PMID:24970348

Chandra Observations of the Eclipsing Wolf-Rayet Binary CQ CepOver a Full Orbital Cycle

NASA Astrophysics Data System (ADS)

Skinner, Steve L.; Guedel, Manuel; Schmutz, Werner; Zhekov, Svetozar

2018-06-01

We present results of Chandra X-ray observations and simultaneous optical light curves of the short-period (1.64 d) eclipsing WN6+O9 binary system CQ Cep obtained in 2013 and 2017 covering a full binary orbit. Our primary objective was to compare the observed X-ray properties with colliding wind shock theory, which predicts that the hottest shock plasma (T > 20 MK) will form on or near the line-of-centers between the stars. Thus, X-ray variability is expected during eclipses when the hottest plasma is occulted. The X-ray spectrum is strikingly similar to apparently single WN6 stars such as WR 134 and spectral lines reveal plasma over a broad range of temperatures T ~ 4 - 40 MK. Both primary and secondary optical eclipses were clearly detected and provide an accurate orbital period determination (P = 1.6412 d). The X-ray emission remained remarkably steady throughout the orbit and statistical tests give a low probability of variability. The lack of significant X-ray variabililty during eclipses indicates that the X-ray emission is not confined along the line-of-centers but is extended on larger spatial scales, contrary to colliding wind predictions.

International Space Station USOS Crew Quarters On-orbit vs Design Performance Comparison

NASA Technical Reports Server (NTRS)

Broyan, James Lee, Jr.; Borrego, Melissa Ann; Bahr, Juergen F.

2008-01-01

The International Space Station (ISS) United States Operational Segment (USOS) received the first two permanent ISS Crew Quarters (CQ) on Utility Logistics Flight Two (ULF2) in November 2008. Up to four CQs can be installed into the Node 2 element to increase the ISS crewmember size to six. The CQs provide private crewmember space with enhanced acoustic noise mitigation, integrated radiation reduction material, communication equipment, redundant electrical systems, and redundant caution and warning systems. The racksized CQ is a system with multiple crewmember restraints, adjustable lighting, controllable ventilation, and interfaces that allow each crewmember to personalize their CQ workspace. The deployment and initial operational checkout during integration of the ISS CQ to the Node is described. Additionally, the comparison of on-orbit to original design performance is outlined for the following key operational parameters: interior acoustic performance, air flow rate, temperature rise, and crewmember feedback on provisioning and restraint layout.

Antimalarial activity of methanolic extracts from plants used in Kenyan ethnomedicine and their interactions with chloroquine (CQ) against a CQ-tolerant rodent parasite, in mice.

PubMed

Muregi, Francis W; Ishih, Akira; Miyase, Toshio; Suzuki, Tohru; Kino, Hideto; Amano, Teruaki; Mkoji, Gerald M; Terada, Mamoru

2007-04-20

Methanolic extracts from 15 medicinal plants representing 11 families, used traditionally for malaria treatment in Kenya were screened for their in vivo antimalarial activity in mice against a chloroquine (CQ)-tolerant Plasmodium berghei NK65, either alone or in combination with CQ. The plant parts used ranged from leaves (L), stem bark (SB), root bark (RB), seeds (S) and whole plant (W). When used alone, extracts from seven plants, Clerodendrum myricoides (RB), Ficus sur (L/SB/RB), Maytenus acuminata (L/RB), Rhamnus prinoides (L/RB), Rhamnus staddo (RB), Toddalia asiatica (RB) and Vernonia lasiopus (RB) had statistically significant parasitaemia suppressions of 31.7-59.3%. In combination with CQ, methanolic extracts of Albizia gummifera (SB), Ficus sur (RB), Rhamnus prinoides and Rhamnus staddo (L/RB), Caesalpinia volkensii (L), Maytenus senegalensis (L/RB), Withania somnifera (RB), Ekebergia capensis (L/SB), Toddalia asiatica (L/RB) and Vernonia lasiopus (L/SB/RB) gave statistically significant and improved suppressions which ranged from 45.5 to 85.1%. The fact that these activities were up to five-fold higher than that of extract alone may suggest synergistic interactions. Remarkable parasitaemia suppression by the extracts, either alone or in combination with CQ mostly resulted into longer mouse survival relative to the controls, in some cases by a further 2 weeks. Plants, which showed significant antimalarial activity including Vernonia lasiopus, Toddalia asiatica, Ficus sur, Rhamnus prinoides and Rhamnus staddo warrant further evaluation in the search for novel antimalarial agents against drug-resistant malaria.

Clioquinol and vitamin B12 (cobalamin) synergistically rescue the lead-induced impairments of synaptic plasticity in hippocampal dentate gyrus area of the anesthetized rats in vivo.

PubMed

Chen, W-H; Wang, M; Yu, S-S; Su, L; Zhu, D-M; She, J-Q; Cao, X-J; Ruan, D-Y

2007-07-13

Lead (Pb(2+)) exposure in development induces impairments of synaptic plasticity in the hippocampal dentate gyrus (DG) area of the anesthetized rats in vivo. The common chelating agents have many adverse effects and are incapable of alleviating lead-induced neurotoxicity. Recently, CQ, clioquinol (5-chloro-7-iodo-8-hydroxy-quinoline), which is a transition metal ion chelator and/or ionophore with low affinity for metal ions, has yielded some promising results in animal models and clinical trials related to dysfunctions of metal ions. In addition, CQ-associated side effects are believed to be overcome with vitamin B12 (VB12) supplementation. To determine whether CQ treatment could rescue impairments of synaptic plasticity induced by chronic Pb(2+) exposure, we investigated the input/output functions (I/Os), paired-pulse reactions (PPRs) and long-term potentiation (LTP) of different treatment groups in hippocampal DG area of the anesthetized rat in vivo by recording field potentials and measured hippocampal Pb(2+) concentrations of different treatment groups by PlasmaQuad 3 inductive coupled plasma mass spectroscopy. The results show: CQ alone does not rescue the lead-induced impairments of synaptic plasticity in hippocampal DG area of the anesthetized rats in vivo; VB12 alone partly rescues the lead-induced impairments of LTP; however the co-administration of CQ and VB12 totally rescues these impairments of synaptic plasticity and moreover, the effects of CQ and VB12 co-administration are specific to the lead-exposed animals.

Primary weathering rates, water transit times and concentration-discharge relations: A theoretical analysis for the critical zone

NASA Astrophysics Data System (ADS)

Ameli, Ali; Erlandsson, Martin; Beven, Keith; Creed, Irena; McDonnell, Jeffrey; Bishop, Kevin

2017-04-01

The permeability architecture of the critical zone exerts a major influence on the hydrogeochemistry of the critical zone. Water flowpath dynamics drive the spatio-temporal pattern of geochemical evolution and resulting streamflow concentration-discharge (C-Q) relation, but these flowpaths are complex and difficult to map quantitatively. Here, we couple a new integrated flow and particle tracking transport model with a general reversible Transition-State-Theory style dissolution rate-law to explore theoretically how C-Q relations and concentration in the critical zone respond to decline in saturated hydraulic conductivity (Ks) with soil depth. We do this for a range of flow rates and mineral reaction kinetics. Our results show that for minerals with a high ratio of equilibrium concentration to intrinsic weathering rate, vertical heterogeneity in Ks enhances the gradient of weathering-derived solute concentration in the critical zone and strengthens the inverse stream C-Q relation. As the ratio of equilibrium concentration to intrinsic weathering rate decreases, the spatial distribution of concentration in the critical zone becomes more uniform for a wide range of flow rates, and stream C-Q relation approaches chemostatic behaviour, regardless of the degree of vertical heterogeneity in Ks. These findings suggest that the transport-controlled mechanisms in the hillslope can lead to chemostatic C-Q relations in the stream while the hillslope surface reaction-controlled mechanisms are associated with an inverse stream C-Q relation. In addition, as the ratio of equilibrium concentration to intrinsic weathering rate decreases, the concentration in the critical zone and stream become less dependent on groundwater age (or transit time)

Primary weathering rates, water transit times, and concentration-discharge relations: A theoretical analysis for the critical zone

NASA Astrophysics Data System (ADS)

Ameli, Ali A.; Beven, Keith; Erlandsson, Martin; Creed, Irena F.; McDonnell, Jeffrey J.; Bishop, Kevin

2017-01-01

The permeability architecture of the critical zone exerts a major influence on the hydrogeochemistry of the critical zone. Water flow path dynamics drive the spatiotemporal pattern of geochemical evolution and resulting streamflow concentration-discharge (C-Q) relation, but these flow paths are complex and difficult to map quantitatively. Here we couple a new integrated flow and particle tracking transport model with a general reversible Transition State Theory style dissolution rate law to explore theoretically how C-Q relations and concentration in the critical zone respond to decline in saturated hydraulic conductivity (Ks) with soil depth. We do this for a range of flow rates and mineral reaction kinetics. Our results show that for minerals with a high ratio of equilibrium concentration (Ceq) to intrinsic weathering rate (Rmax), vertical heterogeneity in Ks enhances the gradient of weathering-derived solute concentration in the critical zone and strengthens the inverse stream C-Q relation. As CeqRmax decreases, the spatial distribution of concentration in the critical zone becomes more uniform for a wide range of flow rates, and stream C-Q relation approaches chemostatic behavior, regardless of the degree of vertical heterogeneity in Ks. These findings suggest that the transport-controlled mechanisms in the hillslope can lead to chemostatic C-Q relations in the stream while the hillslope surface reaction-controlled mechanisms are associated with an inverse stream C-Q relation. In addition, as CeqRmax decreases, the concentration in the critical zone and stream become less dependent on groundwater age (or transit time).

Prevalence of molecular markers of anti-malarial drug resistance in Plasmodium vivax and Plasmodium falciparum in two districts of Nepal

PubMed Central

2011-01-01

Background Sulphadoxine-pyrimethamine (SP) and chloroquine (CQ) have been used in treatment of falciparum and vivax malaria in Nepal. Recently, resistance to both drugs have necessitated a change towards artemisinin combination therapy (ACT) against Plasmodium falciparum in highly endemic areas. However, SP is still used against P. falciparum infections in low endemic areas while CQ is used in suspected cases in areas with lack of diagnostic facilities. This study examines the prevalence of molecular markers of CQ and SP resistance in P. falciparum and Plasmodium vivax to determine if high levels of in vivo resistance are reflected at molecular level as well. Methods Finger prick blood samples (n = 189) were collected from malaria positive patients from two high endemic districts and analysed for single nucleotide polymorphisms (SNPs) in the resistance related genes of P. falciparum and P. vivax for CQ (Pfcrt, Pfmdr1, Pvmdr1) and SP (Pfdhfr, Pfdhps, Pvdhfr), using various PCR-based methods. Results and discussion Positive P. vivax and P. falciparum infections were identified by PCR in 92 and 41 samples respectively. However, some of these were negative in subsequent PCRs. Based on a few P. falciparum samples, the molecular level of CQ resistance in P. falciparum was high since nearly all parasites had the Pfcrt mutant haplotypes CVIET (55%) or SVMNT (42%), though frequency of the Pfmdr1 wild type haplotype was relatively low (35%). Molecular level of SP resistance in P. falciparum was found to be high. The most prevalent Pfdhfr haplotype was double mutant CNRNI (91%), while frequency of Pfdhps double mutant SGEAA and AGEAA were 38% and 33% respectively. Combined, the frequency of quadruple mutations (CNRNI-SGEAA/AGEAA) was 63%. Based on P. vivax samples, low CQ and SP resistance were most likely due to low prevalence of Pvmdr1 Y976F mutation (5%) and absence of triple/quadruple mutations in Pvdhfr. Conclusions Based on the limited number of samples, prevalence of CQ and SP resistance at molecular levels in the population in the study area were determined as high in P. falciparum and low in P. vivax. Therefore, CQ could still be used in the treatment of P. vivax infections, but this remains to be tested in vivo while the change to ACT for P. falciparum seems justified. PMID:21457533

Analysis of Probabilistic Orbital Evolution of the Asteroids 2011 CQ1 and 2011 MD

NASA Astrophysics Data System (ADS)

Sambarov, G. E.; Syusina, O. M.

2018-06-01

The orbital evolution of asteroids 2011 CQ1 and 2011 MD approaching to the Earth is investigated. The influence of perturbing forces on the accuracy of constructing the regions of their possible motions is investigated.

Determination of absorbed dose to water from a miniature kilovoltage x-ray source using a parallel-plate ionization chamber

NASA Astrophysics Data System (ADS)

Watson, Peter G. F.; Popovic, Marija; Seuntjens, Jan

2018-01-01

Electronic brachytherapy sources are widely accepted as alternatives to radionuclide-based systems. Yet, formal dosimetry standards for these devices to independently complement the dose protocol provided by the manufacturer are lacking. This article presents a formalism for calculating and independently verifying the absorbed dose to water from a kV x-ray source (The INTRABEAM System) measured in a water phantom with an ionization chamber calibrated in terms of air-kerma. This formalism uses a Monte Carlo (MC) calculated chamber conversion factor, CQ , to convert air-kerma in a reference beam to absorbed dose to water in the measurement beam. In this work CQ was determined for a PTW 34013 parallel-plate ionization chamber. Our results show that CQ was sensitive to the chamber plate separation tolerance, with differences of up to 15%. CQ was also found to have a depth dependence which varied with chamber plate separation (0 to 10% variation for the smallest and largest cavity height, over 3 to 30 mm depth). However for all chamber dimensions investigated, CQ was found to be significantly larger than the manufacturer reported value, suggesting that the manufacturer recommended method of dose calculation could be underestimating the dose to water.

Establishment and application of a novel isothermal amplification assay for rapid detection of chloroquine resistance (K76T) in Plasmodium falciparum

PubMed Central

Chahar, Madhvi; Mishra, Neelima; Anvikar, Anup; Dixit, Rajnikant; Valecha, Neena

2017-01-01

Chloroquine (CQ) resistance in Plasmodium falciparum is determined by the mutations in the chloroquine resistance transporter (Pfcrt) gene. The point mutation at codon 76 (K76T), which has been observed in more than 91% of P. falciparum isolates in India, is the major determinant of CQ resistance. To overcome the limitations and challenges of traditional methods, in this investigation we developed an easy to use loop mediated isothermal amplification (LAMP) protocol for rapid detection of the K76T mutation associated with CQ resistance in P. falciparum with naked eye visualization. In- house designed primers were synthesized and optimized to specifically distinguish the CQ resistant mutants of P. falciparum. The LAMP reaction was optimal at 61 °C for 60 min and calcein dye was added prior to amplification to enable visual detection. We demonstrate the detection limit of <2 ng/μl respectively, supporting the high sensitivity of this calcein based LAMP method. To the best of our knowledge this is the first report on the establishment of an easy, reliable and cost effective LAMP assay for rapid and specific detection of highly CQ resistance in P. falciparum malaria. PMID:28134241

76 FR 58086 - Proposed Collections; Comment Requests

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-19

... the Office of Management and Budget. The Office of International Affairs within the Department of the Treasury is soliciting comments concerning Treasury International Capital Forms CQ-1 and CQ-2, Financial... written comments to Dwight Wolkow, International Portfolio Investment Data Systems, Department of the...

Ligational behavior of clioquinol antifungal drug towards Ag(I), Hg(II), Cr(III) and Fe(III) metal ions: Synthesis, spectroscopic, thermal, morphological and antimicrobial studies

NASA Astrophysics Data System (ADS)

El-Megharbel, Samy M.; Refat, Moamen S.

2015-04-01

This article presents a synthesis, characterization, theoretical and biological (anti-bacterial, and anti-fugal) evaluation studies of Ag(I), Hg(II), Cr(III) and Fe(III) complexes of clioquinol (CQ) drug ligand. Structures of the titled complexes cited herein were discussed using elemental analyses and spectral measurements e.g., IR, 1H NMR, and electronic studies. The results confirmed the formation of the clioquinol complexes by three molar ratios (1:1) for Ag(I), (1:2) for Hg(II) and (1:3) for both Cr(III) and Fe(III) metal ions. The clioquinol reacts as a bidentate chelate bound to all respected metal ions through the oxygen and nitrogen of quinoline-8-ol. The metal(II) ions coordinated to clioquinol ligand through deprotonation of sbnd OH terminal group. Infrared and 1H NMR spectral data confirm that coordination is via the oxygen of phenolic group and nitrogen atom of quinoline moiety. The molar conductance measurements of the CQ complexes in DMSO correspond to be non-electrolyte nature. Thus, these complexes may be formulated as [Ag(CQ)(H2O)2] H2O, [Hg(CQ)2]ṡ2H2O, [Cr(CQ)3] and [Fe(CQ)3]H2O. The Coats-Redfern method, the kinetic thermodynamic parameters like activation energies (E∗), entropies (ΔS∗), enthalpies (ΔH∗), and Gibbs free energies (ΔG∗) of the thermal decomposition reactions have been deduced from thermogravimetric curves (TG) with helpful of differential thermo gravimetric (DTG) curves. The narrow size distribution in nano-scale range for the clioquinol complexes have been discussed using X-ray powder diffraction (XRD), scanning electron microscope (SEM), and X-ray energy dispersive spectrometer (EDX) analyzer.

The dual PI3K/mTOR inhibitor NVP-BEZ235 and chloroquine synergize to trigger apoptosis via mitochondrial-lysosomal cross-talk.

PubMed

Seitz, Christian; Hugle, Manuela; Cristofanon, Silvia; Tchoghandjian, Aurélie; Fulda, Simone

2013-06-01

On the basis of our previous identification of aberrant phosphatidylinositol-3-kinase (PI3K)/Akt signaling as a novel poor prognostic factor in neuroblastoma, we evaluated the dual PI3K/mTOR inhibitor BEZ235 in the present study. Here, BEZ235 acts in concert with the lysosomotropic agent chloroquine (CQ) to trigger apoptosis in neuroblastoma cells in a synergistic manner, as calculated by combination index (CI < 0.5). Surprisingly, inhibition of BEZ235-induced autophagy is unlikely the primary mechanism of this synergism as reported in other cancers, since neither inhibition of autophagosome formation by knockdown of Atg7 or Atg5 nor disruption of the autophagic flux by Bafilomycin A1 (BafA1) enhance BEZ235-induced apoptosis. BEZ235 stimulates enlargement of the lysosomal compartment and generation of reactive oxygen species (ROS), while CQ promotes lysosomal membrane permeabilization (LMP). In combination, BEZ235 and CQ cooperate to trigger LMP, Bax activation, loss of mitochondrial membrane potential (MMP) and caspase-dependent apoptosis. Lysosome-mediated apoptosis occurs in a ROS-dependent manner, as ROS scavengers significantly reduce BEZ235/CQ-induced loss of MMP, LMP and apoptosis. There is a mitochondrial-lysosomal cross-talk, since lysosomal enzyme inhibitors significantly decrease BEZ235- and CQ-induced drop of MMP and apoptosis. In conclusion, BEZ235 and CQ act in concert to trigger LMP and lysosome-mediated apoptosis via a mitochondrial-lysosomal cross-talk. These findings have important implications for the rational development of PI3K/mTOR inhibitor-based combination therapies. Copyright © 2012 UICC.

Chiral Platinum(II) Complexes Featuring Phosphine and Chloroquine Ligands as Cytotoxic and Monofunctional DNA-Binding Agents.

PubMed

Villarreal, Wilmer; Colina-Vegas, Legna; Rodrigues de Oliveira, Clayton; Tenorio, Juan C; Ellena, Javier; Gozzo, Fábio C; Cominetti, Marcia Regina; Ferreira, Antonio G; Ferreira, Marco Antonio Barbosa; Navarro, Maribel; Batista, Alzir A

2015-12-21

Chiral molecules in nature are involved in many biological events; their selectivity and specificity make them of great interest for understanding the behavior of bioactive molecules, by providing information about the chiral discrimination. Inspired by these conformational properties, we present the design and synthesis of novel chiral platinum(II) complexes featuring phosphine and chloroquine ligands with the general formula [PtCl(P)2(CQ)]PF6 (where (P)2 = triphenylphosphine (PPh3) (5), 1,3-bis(diphenylphosphine)propane (dppp) (6), 1,4-bis(diphenylphosphine)butane (dppb) (7), 1,1'-bis(diphenylphosphine)ferrocene (dppf) (8), and CQ = chloroquine] and their precursors of the type [PtCl2(P)2] are described. The complexes were characterized by elemental analysis, absorption spectroscopy in the infrared and ultraviolet-visible (UV-vis) regions, multinuclear ((1)H, (13)C, (31)P, (15)N, and (195)Pt) NMR spectroscopy, cyclic voltammetry, and mass spectrometry (in the case of chloroquine complexes). The interactions of the new platinum-chloroquine complexes with both albumin (BSA), using fluorescence spectroscopy, and DNA, by four widely reported methods were also evaluated. These experiments showed that these Pt-CQ complexes interact strongly with DNA and have high affinities for BSA, in contrast to CQ and CQDP (chloroquine diphosphate), which interact weakly with these biomolecules. Additional assays were performed in order to investigate the cytotoxicity of the platinum complexes against two healthy cell lines (mouse fibroblasts (L929) and the Chinese hamster lung (V79-4)) and four tumor cell lines (human breast (MDA-MB-231 and MCF-7), human lung (A549), and human prostate (DU-145)). The results suggest that the Pt-CQ complexes are generally more cytotoxic than the free CQ, showing that they are promising as anticancer drugs.

Effects of coenzyme Q10 supplementation on plasma C-reactive protein concentrations: A systematic review and meta-analysis of randomized controlled trials.

PubMed

Mazidi, Mohsen; Kengne, Andre Pascal; Banach, Maciej

2018-02-01

The aim of this systematic review and meta-analysis of prospective interventional studies was to investigate the effects of coenzyme Q10 (CQ10) on plasma C-reactive protein (CRP) levels. PubMed/Medline, Web of Science (WoS), Cochrane Database and Google Scholar databases were searched (up to December 2016) to identify prospective studies evaluating the impact of CQ10 supplementation on CRP. Random effects models meta-analysis was used for quantitative data synthesis. Sensitivity analysis used the leave-one-out method, and heterogeneity was quantitatively assessed using the I 2 index. Systematic review PROSPERO database registration: CRD42016038155. From a total of 119 entries identified via searches, 7 studies were finally included to the analysis. The results of the meta-analysis indicated a non-significant reduction in CRP concentrations following supplementation with CQ10 with a weighted mean difference [WMD] of -0.25mg/l (95% confidence intervals [CI] -0.56 to 0.06, I 2 =42.0%). The WMD for the effects on interleukin 6 (IL6) was -0.72pg/dl, (95% CI -1.24 to -0.24, I 2 =51.8%). These findings were robust in sensitivity analyses. Random-effects meta-regression revealed that changes in plasma CRP levels were independent of the dosage of CQ10 (slope: -0.0005; 95% CI: -0.005, 0.004; p=0.832) while duration of supplementation was the dependent mediator (slope: slope: -0.111; 95% CI: -0.21, -0.004; p=0.042). In conclusion, CQ10 supplementation has a borderline favourable effect on CRP levels, and a significant effect on IL-6 level. This suggests that CQ10 supplementation likely attenuates subclinical inflammation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Development of new photopolymerizable dental sealants.

PubMed

Davidenko, N; Cohen, M E; Diaz, J M; Sastre, R

1998-01-01

This paper describes the results obtained in the optimization of the composition of dental sealants in relation to the nature and proportions of monomer mixtures and photoinitiating system employed. The quantification and variation of certain parameters which determine the quality of a dental sealant (such as viscosity and penetrating power, residual double bonds, solubility and absorption, volume shrinkage and certain specific mechanical properties) have resulted in the development of new formulations. The composition which has achieved the best results of all the above properties was that corresponding to the monomer mixture bis-GMA/tri(ethylene glycol) dimethacrylate (TEGDMA) 40/60 wt%, and the photoinitiating system camphorquinone (CQ) with co-initiators N,N,3,5-tetramethyaniline (TMA) or N,N-dimethyl-p-toluidine (DMPT) in the ratio 1:1. The final properties and characteristics of the obtained formulations are superior to those of commercial dental sealants currently in use.

Dissolution and fractionation of nut shells in ionic liquids.

PubMed

Carneiro, Aristides P; Rodríguez, Oscar; Macedo, Eugénia A

2017-03-01

The aim of this work was to study the dissolution of raw peanut and chestnut shells in ionic liquids. Dissolution of raw biomass up to 7wt% was achieved under optimized operatory conditions. Quantification of polysaccharides dissolved through quantitative 13 Cq NMR revealed extractions of the cellulosic material to ionic liquids as high as 87%. Regeneration experiments using an antisolvent mixture allowed to recover the cellulosic material and the ionic liquid. The overall mass balance presented very low loss rates (<8%), recoveries of 75% and 95% of cellulosic material from peanut and chestnut shells, respectively, and the recovery of more than 95% of the ionic liquid in both cases. These results show the high potential of using nut shells and ionic liquids for biorefining purposes. Moreover, high recovery of ionic liquids favors the process from an economical point of view. Copyright © 2016 Elsevier Ltd. All rights reserved.

4-N, 4-S & 4-O Chloroquine Analogues: Influence of Side Chain Length and Quinolyl Nitrogen pKa on Activity vs. Chloroquine Resistant Malaria+, #

PubMed Central

Natarajan, Jayakumar K.; Alumasa, John; Yearick, Kimberly; Ekoue-Kovi, Kekeli A.; Casabianca, Leah B.; de Dios, Angel C.; Wolf, Christian; Roepe, Paul D.

2009-01-01

Using predictions from heme – quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure – function principles. We vary side chain length for both monoethyl and diethyl 4N CQ derivatives. We alter the pKa of the quinolyl N by introducing alkylthio or alkoxy substituents into the 4 position, and vary side chain length for these analogues. We introduce an additional titratable amino group to the side chain of 4O analogues with promising CQR strain selectivity and increase activity while retaining selectivity. We solve atomic resolution structures for complexes formed between representative 4N, 4S and 4O derivatives vs. μ-oxo dimeric heme, measure binding constants for monomeric vs. dimeric heme, and quantify hemozoin (Hz) formation inhibition in vitro. The data provide additional insight for the design of CQ analogues with improved activity vs. CQR malaria. PMID:18512900

4-N-, 4-S-, and 4-O-chloroquine analogues: influence of side chain length and quinolyl nitrogen pKa on activity vs chloroquine resistant malaria.

PubMed

Natarajan, Jayakumar K; Alumasa, John N; Yearick, Kimberly; Ekoue-Kovi, Kekeli A; Casabianca, Leah B; de Dios, Angel C; Wolf, Christian; Roepe, Paul D

2008-06-26

Using predictions from heme-quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure-function principles. We vary side chain length for both monoethyl and diethyl 4-N CQ derivatives. We alter the pKa of the quinolyl N by introducing alkylthio or alkoxy substituents into the 4 position and vary side chain length for these analogues. We introduce an additional titratable amino group to the side chain of 4-O analogues with promising CQR strain selectivity and increase activity while retaining selectivity. We solve atomic resolution structures for complexes formed between representative 4-N, 4-S, and 4-O derivatives vs mu-oxo dimeric heme, measure binding constants for monomeric vs dimeric heme, and quantify hemozoin (Hz) formation inhibition in vitro. The data provide additional insight for the design of CQ analogues with improved activity vs CQR malaria.

A Whole Cell Pathway Screen Reveals Seven Novel Chemosensitizers to Combat Chloroquine Resistant Malaria

PubMed Central

Ch'ng, Jun-Hong; Mok, Sachel; Bozdech, Zbynek; Lear, Martin James; Boudhar, Aicha; Russell, Bruce; Nosten, Francois; Tan, Kevin Shyong-Wei

2013-01-01

Due to the widespread prevalence of resistant parasites, chloroquine (CQ) was removed from front-line antimalarial chemotherapy in the 1990s despite its initial promise of disease eradication. Since then, resistance-conferring mutations have been identified in transporters such as the PfCRT, that allow for the efflux of CQ from its primary site of action, the parasite digestive vacuole. Chemosensitizing/chemoreversing compounds interfere with the function of these transporters thereby sensitizing parasites to CQ once again. However, compounds identified thus far have disappointing in vivo efficacy and screening for alternative candidates is required to revive this strategy. In this study, we propose a simple and direct means to rapidly screen for such compounds using a fluorescent-tagged CQ molecule. When this screen was applied to a small library, seven novel chemosensitizers (octoclothepin, methiothepin, metergoline, loperamide, chlorprothixene, L-703,606 and mibefradil) were quickly elucidated, including two which showed greater potency than the classical chemosensitizers verapamil and desipramine. PMID:23615863

Glottal contact quotient in Mediterranean tongue trill.

PubMed

Hamdan, Abdul-latif; Nassar, Jihad; Al Zaghal, Zeid; El-Khoury, Eleine; Bsat, Marwa; Tabri, Dollen

2012-09-01

To determine the effect of a Mediterranean tongue trill (Zalghouta) on estimated glottal closed quotient (CQ). A total of 10 female subjects participated in this study. Vocal fold CQ was measured for both sustained vowel [a] and the tongue trill named Zlaghouta using electroglottography. Frequencies and means (±standard deviation) were used to describe categorical and continuous variables, respectively. The Wilcoxon signed nonparametric test was used to determine any significant changes in CQ means pretrill and during trill. There was a significant decrease in the mean CQ during the Mediterranean tongue trill (Zalghouta) versus the sustained vowel [a] (P value of 0.002) by 15.98. When stratified by training status there was a significant decrease for the trained group (P value of 0.031) and a nonsignificant decrease for the untrained group (P value of 0.125). Zalghouta induces a decrease in the vocal fold contact time. The potential benefits of the Mediterranean tongue trill in vocal therapy need consideration. Copyright © 2012 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

Relating runoff generation mechanisms to concentration-discharge relationships in catchments with well-characterized Critical Zone structures and hydrologic dynamics

NASA Astrophysics Data System (ADS)

Hahm, W. J.; Wang, J.; Druhan, J. L.; Rempe, D.; Dietrich, W. E.

2017-12-01

Stream solute concentration-discharge (C-Q) relationships integrate catchment-scale hydrologic and geochemical processes, potentially yielding valuable information about runoff generation and weathering mechanisms. However, recent compilations have established that chemostasis—the condition where solute concentrations are invariant across large ranges of runoff—is observed in watersheds of diverse lithology, climate, and topography, suggesting an equifinality of the C-Q relationship independent of hydrologic process. Here we explore C-Q signals in contrasting catchments of the Eel River Critical Zone (CZ) Observatory in the Northern California Coast Ranges, where, unlike most watersheds where chemostasis has been observed, hillslope hydrologic processes are well characterized via years of intensive hydrologic monitoring. Our two catchments in the Franciscan Complex have radically different runoff generation mechanisms arising from differences in CZ structure: at Elder Creek (Coastal Belt), rain passes vertically as unsaturated flow through soil, saprolite, and a thick weathered rock zone before perching as groundwater on fresh bedrock and flowing laterally through fractures to generate streamflow, resulting in nearly chemostatic major cation behavior (power law C-Q slopes (B) ≈ 0 to -0.1). At Dry Creek (Central Belt), the thin (2 to 3 m) hydrologically active CZ completely saturates in most storm events, generating saturation overland flow across the landscape. New data from Dry Creek reveal log-log C-Q relationships for major cations that exhibit negative curvature, indicating a trend towards increasing dilution at higher flow rates and a possible C-Q signature of overland flow. High geomorphic channel drainage density (16.9 km/km2) results in short flow paths and, presumably, short water hillslope residence times at high runoff when overland flow dominates (> 50 mm d-1). Surprisingly, even at these high runoff rates, pure dilution does not occur (high runoff B ≈ -0.5), suggesting a role for extremely rapid cation exchange reactions and equilibration as water flows over and through the soil surface, and underscoring limitations on the ability to interpret hydrologic processes from C-Q behavior.

Anti-malarial prescriptions in three health care facilities after the emergence of chloroquine resistance in Niakhar, Senegal (1992–2004)

PubMed Central

Munier, Aline; Diallo, Aldiouma; Cot, Michel; Ndiaye, Ousmane; Arduin, Pascal; Chippaux, Jean-Philippe

2009-01-01

Background In the rural zone of Niakhar in Senegal, the first therapeutic failures for chloroquine (CQ) were observed in 1992. In 2003, the national policy regarding first-line treatment of uncomplicated malaria was modified, replacing CQ by a transitory bi-therapy amodiaquine/sulphadoxine-pyrimethamine (AQ/SP), before the implementation of artemisinin-based combination therapy (ACT) in 2006. The aims of the study were to assess the evolution of anti-malarial prescriptions in three health care facilities between 1992 and 2004, in parallel with increasing CQ resistance in the region. Methods The study was conducted in the area of Niakhar, a demographic surveillance site located in a sahelo-sudanese region of Senegal, with mesoendemic and seasonal malaria transmission. Health records of two public health centres and a private catholic dispensary were collected retrospectively to cover the period 1992–2004. Results Records included 110,093 consultations and 292,965 prescribed treatments. Twenty-five percent of treatments were anti-malarials, prescribed to 49% of patients. They were delivered all year long, but especially during the rainy season, and 20% of patients with no clinical malaria diagnosis received anti-malarials. Chloroquine and quinine represented respectively 55.7% and 34.6% of prescribed anti-malarials. Overall, chloroquine prescriptions rose from 1992 to 2000, in parallel with clinical malaria; then the CQ prescription rate decreased from 2000 and was concomitant with the rise of SP and the persistence of quinine use. AQ and SP were mainly used as bi-therapy after 2003, at the time of national treatment policy change. Conclusion The results show the overall level of anti-malarial prescription in the study area for a considerable number of patients over a large period of time. Even though resistance to CQ rapidly increased from 1992 to 2001, no change in CQ prescription was observed until the early 2000s, possibly due to the absence of an obvious decrease in CQ effectiveness, a lack of therapeutic options or a blind follow-up of national guidelines. PMID:19397797

Evaluation and Selection of Appropriate Reference Genes for Real-Time Quantitative PCR Analysis of Gene Expression in Nile Tilapia (Oreochromis niloticus) during Vaccination and Infection

PubMed Central

Wang, Erlong; Wang, Kaiyu; Chen, Defang; Wang, Jun; He, Yang; Long, Bo; Yang, Lei; Yang, Qian; Geng, Yi; Huang, Xiaoli; Ouyang, Ping; Lai, Weimin

2015-01-01

qPCR as a powerful and attractive methodology has been widely applied to aquaculture researches for gene expression analyses. However, the suitable reference selection is critical for normalizing target genes expression in qPCR. In the present study, six commonly used endogenous controls were selected as candidate reference genes to evaluate and analyze their expression levels, stabilities and normalization to immune-related gene IgM expression during vaccination and infection in spleen of tilapia with RefFinder and GeNorm programs. The results showed that all of these candidate reference genes exhibited transcriptional variations to some extent at different periods. Among them, EF1A was the most stable reference with RefFinder, followed by 18S rRNA, ACTB, UBCE, TUBA and GAPDH respectively and the optimal number of reference genes for IgM normalization under different experiment sets was two with GeNorm. Meanwhile, combination the Cq (quantification cycle) value and the recommended comprehensive ranking of reference genes, EF1A and ACTB, the two optimal reference genes, were used together as reference genes for accurate analysis of immune-related gene expression during vaccination and infection in Nile tilapia with qPCR. Moreover, the highest IgM expression level was at two weeks post-vaccination when normalized to EF1A, 18S rRNA, ACTB, and EF1A together with ACTB compared to one week post-vaccination before normalizing, which was also consistent with the IgM antibody titers detection by ELISA. PMID:25941937

Developmental Toxicity (Segments II) Study of WR238605 Succinate in Rabbits

DTIC Science & Technology

1995-08-08

HHHHHH HHHHHH V U O U U U M M M H M M HHHHHH M M H M M M a a...a a a a CQ CO CO CO CQ CO M • H M M M HHHHHH HHHHHH HHHHHH J J J J J J ooobbb 2 Z 2 2 2 2 • a to n o CQ o o o o o o 222222 >< < a O...M H M H M M M O D Q D Q Q D a S S| o o 2 2 TO TO CO TO CO TO QTOTOCOCOTOCOCOCQTOCO HMHHHHnHHMHMHHHHH MMMMHM HHMHMMMMMH HHHHHH

Spectral Line-Shape Model to Replace the Voigt Profile in Spectroscopic Databases

NASA Astrophysics Data System (ADS)

Lisak, Daniel; Ngo, Ngoc Hoa; Tran, Ha; Hartmann, Jean-Michel

2014-06-01

The standard description of molecular line shapes in spectral databases and radiative transfer codes is based on the Voigt profile. It is well known that its simplified assumptions of absorber free motion and independence of collisional parameters from absorber velocity lead to systematic errors in analysis of experimental spectra, and retrieval of gas concentration. We demonstrate1,2 that the partially correlated quadratic speed-dependent hardcollision profile3. (pCqSDHCP) is a good candidate to replace the Voigt profile in the next generations of spectroscopic databases. This profile takes into account the following physical effects: the Doppler broadening, the pressure broadening and shifting of the line, the velocity-changing collisions, the speed-dependence of pressure broadening and shifting, and correlations between velocity- and phase/state-changing collisions. The speed-dependence of pressure broadening and shifting is incorporated into the pCqSDNGP in the so-called quadratic approximation. The velocity-changing collisions lead to the Dicke narrowing effect; however in many cases correlations between velocityand phase/state-changing collisions may lead to effective reduction of observed Dicke narrowing. The hard-collision model of velocity-changing collisions is also known as the Nelkin-Ghatak model or Rautian model. Applicability of the pCqSDHCP for different molecular systems was tested on calculated and experimental spectra of such molecules as H2, O2, CO2, H2O in a wide span of pressures. For all considered systems, pCqSDHCP is able to describe molecular spectra at least an order of magnitude better than the Voigt profile with all fitted parameters being linear with pressure. In the most cases pCqSDHCP can reproduce the reference spectra down to 0.2% or better, which fulfills the requirements of the most demanding remote-sensing applications. An important advantage of pCqSDHCP is that a fast algorithm for its computation was developedab4,5 and allows for its calculation only a few times slower than the standard Voigt profile. Moreover, the pCqSDHCP reduces to many simpler models commonly used in experimental spectra analysis simply by setting some parameters to zero, and it can be easily extended to incorporate the line-mixing effect in the first-order approximation. The idea of using pCqSDHCP as a standard profile to go beyond the Voigt profile for description of H2O line shapes was recently supported by the IUPAC task group6 which also recommended to call this profile with fast computation algorithm the HTP profile (for Hartmann-Tran).

A high current pulsed power generator CQ-3-MMAF with co-axial cable transmitting energy for material dynamics experiments

NASA Astrophysics Data System (ADS)

Wang, Guiji; Chen, Xuemiao; Cai, Jintao; Zhang, Xuping; Chong, Tao; Luo, Binqiang; Zhao, Jianheng; Sun, Chengwei; Tan, Fuli; Liu, Cangli; Wu, Gang

2016-06-01

A high current pulsed power generator CQ-3-MMAF (Multi-Modules Assembly Facility, MMAF) was developed for material dynamics experiments under ramp wave and shock loadings at the Institute of Fluid Physics (IFP), which can deliver 3 MA peak current to a strip-line load. The rise time of the current is 470 ns (10%-90%). Different from the previous CQ-4 at IFP, the CQ-3-MMAF energy is transmitted by hundreds of co-axial high voltage cables with a low impedance of 18.6 mΩ and low loss, and then hundreds of cables are reduced and converted to tens of cables into a vacuum chamber by a cable connector, and connected with a pair of parallel metallic plates insulated by Kapton films. It is composed of 32 capacitor and switch modules in parallel. The electrical parameters in short circuit are with a capacitance of 19.2 μF, an inductance of 11.7 nH, a resistance of 4.3 mΩ, and working charging voltage of 60 kV-90 kV. It can be run safely and stable when charged from 60 kV to 90 kV. The vacuum of loading chamber can be up to 10-2 Pa, and the current waveforms can be shaped by discharging in time sequences of four groups of capacitor and switch modules. CQ-3-MMAF is an adaptive machine with lower maintenance because of its modularization design. The COMSOL Multi-physics® code is used to optimize the structure of some key components and calculate their structural inductance for designs, such as gas switches and cable connectors. Some ramp wave loading experiments were conducted to check and examine the performances of CQ-3-MMAF. Two copper flyer plates were accelerated to about 3.5 km/s in one shot when the working voltage was charged to 70 kV. The velocity histories agree very well. The dynamic experiments of some polymer bonded explosives and phase transition of tin under ramp wave loadings were also conducted. The experimental data show that CQ-3-MMAF can be used to do material dynamics experiments in high rate and low cost shots. Based on this design concept, the peak current of new generators can be increased to 5-6 MA and about 100 GPa ramp stress can be produced on the metallic samples for high pressure physics, and a conceptual design of CQ-5-MMAF was given.

A high current pulsed power generator CQ-3-MMAF with co-axial cable transmitting energy for material dynamics experiments.

PubMed

Wang, Guiji; Chen, Xuemiao; Cai, Jintao; Zhang, Xuping; Chong, Tao; Luo, Binqiang; Zhao, Jianheng; Sun, Chengwei; Tan, Fuli; Liu, Cangli; Wu, Gang

2016-06-01

A high current pulsed power generator CQ-3-MMAF (Multi-Modules Assembly Facility, MMAF) was developed for material dynamics experiments under ramp wave and shock loadings at the Institute of Fluid Physics (IFP), which can deliver 3 MA peak current to a strip-line load. The rise time of the current is 470 ns (10%-90%). Different from the previous CQ-4 at IFP, the CQ-3-MMAF energy is transmitted by hundreds of co-axial high voltage cables with a low impedance of 18.6 mΩ and low loss, and then hundreds of cables are reduced and converted to tens of cables into a vacuum chamber by a cable connector, and connected with a pair of parallel metallic plates insulated by Kapton films. It is composed of 32 capacitor and switch modules in parallel. The electrical parameters in short circuit are with a capacitance of 19.2 μF, an inductance of 11.7 nH, a resistance of 4.3 mΩ, and working charging voltage of 60 kV-90 kV. It can be run safely and stable when charged from 60 kV to 90 kV. The vacuum of loading chamber can be up to 10(-2) Pa, and the current waveforms can be shaped by discharging in time sequences of four groups of capacitor and switch modules. CQ-3-MMAF is an adaptive machine with lower maintenance because of its modularization design. The COMSOL Multi-physics® code is used to optimize the structure of some key components and calculate their structural inductance for designs, such as gas switches and cable connectors. Some ramp wave loading experiments were conducted to check and examine the performances of CQ-3-MMAF. Two copper flyer plates were accelerated to about 3.5 km/s in one shot when the working voltage was charged to 70 kV. The velocity histories agree very well. The dynamic experiments of some polymer bonded explosives and phase transition of tin under ramp wave loadings were also conducted. The experimental data show that CQ-3-MMAF can be used to do material dynamics experiments in high rate and low cost shots. Based on this design concept, the peak current of new generators can be increased to 5-6 MA and about 100 GPa ramp stress can be produced on the metallic samples for high pressure physics, and a conceptual design of CQ-5-MMAF was given.

Autophagy promotes escape from phosphatidylinositol 3-kinase inhibition in estrogen receptor-positive breast cancer.

PubMed

Yang, Wei; Hosford, Sarah R; Traphagen, Nicole A; Shee, Kevin; Demidenko, Eugene; Liu, Stephanie; Miller, Todd W

2018-03-01

Hyperactivation of the PI3K pathway has been implicated in resistance to antiestrogen therapies in estrogen receptor α (ER)-positive breast cancer, prompting the development of therapeutic strategies to inhibit this pathway. Autophagy has tumor-promoting and -suppressing roles and has been broadly implicated in resistance to anticancer therapies, including antiestrogens. Chloroquine (CQ) is an antimalarial and amebicidal drug that inhibits autophagy in mammalian cells and human tumors. Herein, we observed that CQ inhibited proliferation and autophagy in ER + breast cancer cells. PI3K inhibition with GDC-0941 (pictilisib) induced autophagy. Inhibition of autophagy using CQ or RNA interference potentiated PI3K inhibitor-induced apoptosis. Combined inhibition of PI3K and autophagy effectively induced mitochondrial membrane depolarization, which required the BH3-only proapoptotic proteins Bim and PUMA. Treatment with GDC-0941, CQ, or the combination, significantly suppressed the growth of ER + breast cancer xenografts in mice. In an antiestrogen-resistant xenograft model, GDC-0941 synergized with CQ to provide partial, but durable, tumor regression. These findings warrant clinical evaluation of therapeutic strategies to target ER, PI3K, and autophagy for the treatment of ER + breast cancer.-Yang, W., Hosford, S. R., Traphagen, N. A., Shee, K., Demidenko, E., Liu, S., Miller, T. W. Autophagy promotes escape from phosphatidylinositol 3-kinase inhibition in estrogen receptor-positive breast cancer.

River mixing in the Amazon as a driver of concentration-discharge relationships

NASA Astrophysics Data System (ADS)

Moquet, Jean-Sébastien; Bouchez, Julien; Carlo Espinoza, Jhan; Martinez, Jean-Michel; Guyot, Jean-Loup; Lagane, Christelle; Filizola, Naziano; Aniceto, Keila; Noriega, Luis; Hidalgo Sanchez, Liz; Pombosa, Rodrigo; Fraizy, Pascal; Santini, William; Timouk, Franck; Vauchel, Philippe

2017-04-01

Large hydrological systems such as continental-scale river basins aggregate water from compositionally different tributaries. Here we explore how such aggregation can affect solute concentration-discharge (C-Q) relationships and thus obscure the message carried by these relationships in terms of weathering properties of the Critical Zone. We compute 10 day-frequency time series of Q and major solute (Si, Ca2+, Mg2+, K+, Na+, Cl-, SO42-) C and fluxes (F) for 13 gauging stations of the SNO-HYBAM Monitoring Program (Geodynamical, hydrological and Biogeochemical control of erosion/weathering and material transport in the Amazon, Orinoco and Congo basins) located throughout the Amazon basin, the largest river basin in the world. Concentration-discharge relationships vary in a systematic manner, shifting for most solutes from a nearly "chemostatic" behavior (constant C) at the Andean mountain front to a more "dilutional" pattern (negative C-Q relationship) towards the system mouth. Associated to this shift in trend is a shift in shape: C-Q hysteresis becomes more prominent at the most downstream stations. A simple model of tributary mixing allows us to identify the important parameters controlling C-Q trends and shapes in the mixture, and we show that for the Amazon case, the model results are in qualitative agreement with the observations. Altogether, this study suggests that mixing of water and solutes between different flowpaths leads to altered C-Q relationships.

Inhibiting Autophagy During Interleukin 2 (IL-2) Immunotherapy Promotes Long Term Tumor Regression

PubMed Central

Liang, Xiaoyan; De Vera, Michael E.; Buchser, William J.; Romo de Vivar Chavez, Antonio; Loughran, Patricia; Stolz, Donna Beer; Basse, Per; Wang, Tao; Van Houten, Bennett; Zeh, Herbert J.; Lotze, Michael T.

2012-01-01

Administration of high dose interleukin 2 (HDIL-2) has durable antitumor effects in 5-10% patients with melanoma and renal cell carcinoma. However, treatment is often limited by side effects, including reversible, multi-organ dysfunction and characterized by a cytokine-induced ‘systemic autophagic syndrome’. Here we hypothesized that the autophagy inhibitor chloroquine (CQ) would enhance IL-2 immunotherapeutic efficacy and limit toxicity. In an advanced murine metastatic liver tumor model, IL-2 inhibited tumor growth in a dose-dependent fashion, and these anti-tumor effects were significantly enhanced upon addition of CQ. The combination of IL-2 with CQ increased long term survival, decreased toxicity associated with vascular leakage, and enhanced immune cell proliferation and infiltration in the liver and spleen. HDIL-2 alone increased serum levels of IFN-γ, IL-6 and IL-18 and also induced autophagy within the liver and translocation of HMGB1 from the nucleus to the cytosol in hepatocytes, effects that were inhibited by combined administration with CQ. In tumor cells, CQ increased autophagic vacuoles and LC3-II levels inhibited oxidative phosphorylation and ATP production and promoted apoptosis, which was associated with increased Annexin V+/PI- cells, cleaved-PARP, cleaved-caspase 3, and cytochrome C release from mitochondria. Taken together, our findings provide a novel clinical strategy to enhance the efficacy of HDIL-2 immunotherapy for cancer patients. PMID:22472122

Chloroquine induced pruritus--questionnaire based epidemiological study.

PubMed

George, Adekunle O

2004-01-01

Chloroquine (CQ) is a very useful drug with a broad spectrum of uses (as anti malarial, anti amoebiasis and for connective tissue diseases). A major side effect preventing or limiting its utilization in blacks is chloroquine induced pruritus (CP). A descriptive cross sectional questionnaire based epidemiological study of medical and nursing students, medical doctors and other workers with historic CP in a Nigerian tertiary (teaching) hospital was carried out to determine factors and features related to the development of CP. From the study the intensity of CP was not reduced by taking less CQ. About 92% of the subjects had close relations who suffered from CP. 84.5% of responders itched for 1-3 days. The longest duration for CP was 7 days. The sites of itching in descending order were generalized (49.2%) hands (46%), legs and feet (46%), perineum/genitalia (28.5%). Relieving factor/drug was identified in 66.6% of responders. Itching with oral CQ occurred in 100%. Intramuscular injection of CQ caused 49% of itching. 19% had pre-chloroquine itch. 28.5% had CP with other antimalarials notably Amodiaquine (23.8%). 50.7% took other antimalarials when down with malaria. There is a need for the identification of a cheap and readily available antidote for CP to enable CQ remain useful/relevant in Nigeria and in the West African sub-region.

Biomedical applications of SPION@APTES@PEG-folic acid@carboxylated quercetin nanodrug on various cancer cells

NASA Astrophysics Data System (ADS)

Akal, Z. Ü.; Alpsoy, L.; Baykal, A.

2016-08-01

In this study, carboxylated quercetin (CQ) was conjugated to superparamagnetic iron oxide nanoparticles (SPIONs) which were modified by (3-aminopropyl) triethoxysilane (APTES), Folic acid (FA) and carboxylated Polyethylene glycol (PEG); (SPION@APTES@FA-PEG@CQ), nanodrug has been synthesized via polyol and accompanying by various chemical synthesis routes. The characterization of the final product was done via X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Thermal gravimetric analysis (TGA), Transmission electron spectroscopy (TEM) and Vibrating sample magnetometer (VSM). Its cytotoxic and apoptotic activities on over expressed folic acid receptor (FR +) (MCF-7, HeLa) and none expressed folic acid receptor (FR-) (A549) cancer cell lines were determined by using MTT assay, Real-Time Cell Analysis, TUNEL assay, Annexin assay and RT-PCR analysis for Caspase3/7 respectively. SPION@APTES@FA-PEG@CQ nanodrug showed higher cytotoxicity against HeLa and MCF-7 cell lines as compared with A549 cell line. Moreover, SPION@APTES@FA-PEG@CQ nanodrug also caused higher apoptotic and necrotic effects in 100 μg/mL HeLa and MCF-7 cells than A549 cells. The findings showed that SPION@APTES@FA-PEG@CQ nanodrug has cytotoxic, apoptotic and necrotic effects on HeLa and MCF-7 which are FR over expressed cell lines and can be potentially used for the delivery of quercetin to cervical and breast cancer cells.

Plasmodium falciparum chloroquine resistance transporter (PfCRT) isoforms PH1 and PH2 perturb vacuolar physiology.

PubMed

Callaghan, Paul S; Siriwardana, Amila; Hassett, Matthew R; Roepe, Paul D

2016-03-31

Recent work has perfected yeast-based methods for measuring drug transport by the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT). The approach relies on inducible heterologous expression of PfCRT in Saccharomyces cerevisiae yeast. In these experiments selecting drug concentrations are not toxic to the yeast, nor is expression of PfCRT alone toxic. Only when PfCRT is expressed in the presence of CQ is the growth of yeast impaired, due to inward transport of chloroquine (CQ) via the transporter. During analysis of all 53 known naturally occurring PfCRT isoforms, two isoforms (PH1 and PH2 PfCRT) were found to be intrinsically toxic to yeast, even in the absence of CQ. Additional analysis of six very recently identified PfCRT isoforms from Malaysia also showed some toxicity. In this paper the nature of this yeast toxicity is examined. Data also show that PH1 and PH2 isoforms of PfCRT transport CQ with an efficiency intermediate to that catalyzed by previously studied CQR conferring isoforms. Mutation of PfCRT at position 160 is found to perturb vacuolar physiology, suggesting a fitness cost to position 160 amino acid substitutions. These data further define the wide range of activities that exist for PfCRT isoforms found in P. falciparum isolates from around the globe.

Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3.

PubMed Central

Crowle, A J; May, M H

1990-01-01

Intracellular tubercle bacilli (TB) reside in vacuoles in infected human macrophages (MPs). The relative impotency of streptomycin against TB in MPs and the contrary greatly increased potency of pyrazinamide (PZA) have been attributed to the fact that these vacuoles are phagolysosomes and, therefore, acidic. Chloroquine (CQ) is a lysomotropic base which can be used to raise phagolysosomal pH. Consequently, it was tested for its ability to increase the anti-TB effectiveness of streptomycin and decrease that of PZA in cultured human MPs. MPs infected with virulent Erdman strain TB were incubated in medium with various combinations of the drugs. Samples were taken at 0, 4, and 7 days and lysed for CFU counts of viable TB on nutrient agar. As expected, CQ increased the effectiveness of SM, but unexpectedly, it did not decrease that of PZA. CQ alone was found to be able to inhibit intracellular TB. Because of this, it was also tested with isoniazid, 1,25(OH)2-vitamin D3, and 25-OH-vitamin D3. It significantly enhanced the anti-TB protectiveness of both isoniazid and 25-OH-vitamin D3. Some combinations of CQ and the various drugs tested were able to kill intracellular TB. These results suggest that CQ may be useful in the treatment of tuberculosis. PMID:2127346

The Culturally Intelligent Negotiator: The Impact of Cultural Intelligence (CQ) on Negotiation Sequences and Outcomes

ERIC Educational Resources Information Center

Imai, Lynn; Gelfand, Michele J.

2010-01-01

Although scholars and practitioners have repeatedly touted the importance of negotiating effectively across cultures, paradoxically, little research has addressed what predicts intercultural negotiation effectiveness. In this research, we examined the impact of cultural intelligence (CQ) on intercultural negotiation processes and outcomes,…

Cultural Intelligence (CQ) in MBA Curricula

ERIC Educational Resources Information Center

Ahn, Mark J.; Ettner, Larry

2013-01-01

Purpose: The purpose of this paper is to investigate the role of cultural intelligence in MBA curricula. Shaping global corporate culture that manifests itself in powerful-shared values, group behavior, and persists despite changes in-group membership is decisive to organizational performance. In turn, cultural intelligence (CQ), defined, as an…

Transforming classroom questioning using emerging technology.

PubMed

Mahon, Paul; Lyng, Colette; Crotty, Yvonne; Farren, Margaret

2018-04-12

Classroom questioning is a common teaching and learning strategy in postgraduate nurse education. Technologies such as audience response systems (ARS) may offer advantage over traditional approaches to classroom questioning. However, despite being available since the 1960s, ARSs are still considered novel in many postgraduate nurse education classroom settings. This article aims to explicate the attitudes of postgraduate nursing students in an Irish academic teaching hospital towards classroom questioning (CQ) and the use of ARSs as an alternative to traditional CQ techniques. The results of this small-scale study demonstrate that ARSs have a role to play in CQ in the postgraduate setting, being regarded by students as beneficial to learning, psychological safety and classroom interaction.

In-vitro transdentinal diffusion of monomers from adhesives.

PubMed

Putzeys, Eveline; Duca, Radu Corneliu; Coppens, Lieve; Vanoirbeek, Jeroen; Godderis, Lode; Van Meerbeek, Bart; Van Landuyt, Kirsten L

2018-06-01

Biocompatibility of adhesives is important since adhesives may be applied on dentin near the pulp. Accurate knowledge of the quantity of monomers reaching the pulp is important to determine potential side effects. The aim of this study was to assess the transdentinal diffusion of residual monomers from dental adhesive systems using an in-vitro pulp chamber model. Dentin disks with a thickness of 300 µm were produced from human third molars. These disks were fixed between two open-ended glass tubes, representing an in-vitro pulp chamber. The etch-and-rinse adhesive OptiBond FL and the self-etch adhesive Clearfil SE Bond were applied to the dentin side of the disks, while on in the pulpal side, the glass tube was filled with 600 µL water. The transdentinal diffusion of different monomers was quantified using ultra-performance liquid chromatography-tandem mass spectrometry. The monomers HEMA, CQ, BisGMA, GPDM, 10-MDP and UDMA eluted from the dental materials and were able to diffuse through the dentin disks to a certain extent. Compounds with a lower molecular weight (uncured group: HEMA 7850 nmol and CQ 78.2 nmol) were more likely to elute and diffuse compared to monomers with a higher molecular weight (uncured group: BisGMA 0.42 nmol). When the adhesives were left uncured, diffusion was up to 10 times higher compared to the cured conditions. This in-vitro research resulted in the quantification of various monomers able to diffuse through dentin and therefore contributes to a more detailed understanding about the potential exposure of the dental pulp to monomers from dental adhesives. Biocompatibility of adhesives is important since adhesives may be applied on dentin near the pulp, where tubular density and diameter are greatest. Copyright © 2018. Published by Elsevier Ltd.

Winning the Future: An Investigation into the Creativity Capacity across the Levels of Education in Ireland

ERIC Educational Resources Information Center

Leahy, Keelin

2016-01-01

This research investigated the creativity capacity across the levels of education in Ireland, involving 702 participants. Creative capacity was investigated through a comparative analysis of creativity quotient (CQ). A divergent thinking task comprising the "how many uses" activity was assessed using the criteria for determining CQ;…

Evaluating the Impact of Two Globalization Projects on College Students' Cultural Competence and Cultural Intelligence (CQ)

ERIC Educational Resources Information Center

Lopes-Murphy, Solange A.

2013-01-01

Cultural competence and CQ involve awareness of cultural similarities and differences, knowledge of differences in cultural values, and intercultural encounters. To assess college students' cultural competence and cultural intelligence gains, this experimental study evaluated the impact of two globalization projects on these two constructs. The…

Using a Cultural Intelligence Assessment to Teach Global Leadership

ERIC Educational Resources Information Center

Whitaker, Brett L.; Greenleaf, Justin P.

2017-01-01

This paper describes the practice of students enrolled in an undergraduate Global Leadership course taking a Cultural Intelligence (CQ) assessment. The results of the assessment provided insight into the students' development across various dimensions of CQ, as well as their scores relative to their peers and global averages. This information was…

Transient increase of interferon-stimulated genes and no clinical benefit by chloroquine treatment during acute simian immunodeficiency virus infection of macaques.

PubMed

Vaccari, Monica; Fenizia, Claudio; Ma, Zhong-Min; Hryniewicz, Anna; Boasso, Adriano; Doster, Melvin N; Miller, Christopher J; Lindegardh, Niklas; Tarning, Joel; Landay, Alan L; Shearer, Gene M; Franchini, Genoveffa

2014-04-01

Simian immunodeficiency virus (SIV) infection leads to AIDS in experimentally infected Rhesus macaques similarly to HIV-infected humans. In contrast, SIV infection of natural hosts is characterized by a down-regulation of innate acute responses to the virus within a few weeks of infection and results in limited pathology. Chloroquine (CQ) has been used in the treatment or prevention of malaria and has recently been shown to cause a decrease of immune activation and CD4 cell loss in HIV-infected individuals treated with antiretroviral therapy. Here, we treated Rhesus macaques with CQ during the acute phase of SIVmac251 infection with the intent to decrease viral-induced immune activation and possibly limit disease progression. Contrary to what was expected, CQ treatment resulted in a temporary increased expression of interferon (IFN)-stimulating genes and it worsened the recovery of CD4(+) T cells in the blood. Our findings confirm recent results observed in asymptomatic HIV-infected patients and suggest that CQ does not provide an obvious benefit in the absence of antiretroviral therapy.

Chloroquine, a FDA-approved Drug, Prevents Zika Virus Infection and its Associated Congenital Microcephaly in Mice.

PubMed

Li, Chunfeng; Zhu, Xingliang; Ji, Xue; Quanquin, Natalie; Deng, Yong-Qiang; Tian, Min; Aliyari, Roghiyh; Zuo, Xiangyang; Yuan, Ling; Afridi, Shabbir Khan; Li, Xiao-Feng; Jung, Jae U; Nielsen-Saines, Karin; Qin, Frank Xiao-Feng; Qin, Cheng-Feng; Xu, Zhiheng; Cheng, Genhong

2017-10-01

Zika virus (ZIKV) has become a global public health emergency due to its rapidly expanding range and its ability to cause severe congenital defects such as microcephaly. However, there are no FDA-approved therapies or vaccines against ZIKV infection. Through our screening of viral entry inhibitors, we found that chloroquine (CQ), a commonly used antimalarial and a FDA-approved drug that has also been repurposed against other pathogens, could significantly inhibit ZIKV infection in vitro, by blocking virus internalization. We also demonstrated that CQ attenuates ZIKV-associated morbidity and mortality in mice. Finally, we proved that CQ protects fetal mice from microcephaly caused by ZIKV infection. Our methodology of focusing on previously identified antivirals in screens for effectiveness against ZIKV proved to be a rapid and efficient means of discovering new ZIKV therapeutics. Selecting drugs that were previously FDA-approved, such as CQ, also improves the likelihood that they may more quickly reach stages of clinical testing and use by the public. Copyright © 2017. Published by Elsevier B.V.

Effect of chitosan, O-carboxymethyl chitosan, and N-[(2-hydroxy-3-N,N-dimethylhexadecyl ammonium)propyl] chitosan chloride on overweight and insulin resistance in a murine diet-induced obesity.

PubMed

Liu, Xiaofei; Zhi, Xiaona; Liu, Yunfei; Wu, Bo; Sun, Zhong; Shen, Jun

2012-04-04

Two water-soluble chitosan derivatives, O-carboxymethyl chitosan (O-CM-chitosan) and N-[(2-hydroxy-3-N,N-dimethylhexadecyl ammonium)propyl] chitosan chloride (N-CQ-chitosan), were prepared, and the therapeutic effects of chitosan, O-CM-chitosan, and N-CQ-chitosan on insulin resistance were simultaneously evaluated by rats fed on a high-fat diet. The parameters of high-fat diet-induced rats indicated that chitosan and its two derivatives not only have low cytotoxicity but can control overnutrition by fat and achieve insulin resistance therapy. However, the results in experiment in vivo showed that the therapeutic degree varied by the molecular weight and surface charge of chitosan, O-CM-chitosan, and N-CQ-chitosan. N-CQ-chitosan with a MW of 5 × 10(4) decreased body weight, the ratio of fat to body weight, triglyceride, fasting plasma glucose, fasting plasma insulin, free fatty acid, and leptin by 11, 17, 44, 46, 44, 87, and 64% and increased fecal lipid by 95%, respectively.

Single-Nucleotide Polymorphism and Copy Number Variation of the Multidrug Resistance-1 Locus of Plasmodium vivax: Local and Global Patterns

PubMed Central

Vargas-Rodríguez, Rosa del Carmen Miluska; da Silva Bastos, Melissa; Menezes, Maria José; Orjuela-Sánchez, Pamela; Ferreira, Marcelo U.

2012-01-01

Emerging resistance to chloroquine (CQ) poses a major challenge for Plasmodium vivax malaria control, and nucleotide substitutions and copy number variation in the P. vivax multidrug resistance 1 (pvmdr-1) locus, which encodes a digestive vacuole membrane transporter, may modulate this phenotype. We describe patterns of genetic variation in pvmdr-1 alleles from Acre and Amazonas in northwestern Brazil, and compare then with those reported in other malaria-endemic regions. The pvmdr-1 mutation Y976F, which is associated with CQ resistance in Southeast Asia and Oceania, remains rare in northwestern Brazil (1.8%) and its prevalence mirrors that of CQ resistance worldwide. Gene amplification of pvmdr-1, which is associated with mefloquine resistance but increased susceptibility to CQ, remains relatively rare in northwestern Brazil (0.9%) and globally (< 4%), but became common (> 10%) in Tak Province, Thailand, possibly because of drug-mediated selection. The global database we have assembled provides a baseline for further studies of genetic variation in pvmdr-1 and drug resistance in P. vivax malaria. PMID:22949516

Single-nucleotide polymorphism and copy number variation of the multidrug resistance-1 locus of Plasmodium vivax: local and global patterns.

PubMed

Vargas-Rodríguez, Rosa del Carmen Miluska; da Silva Bastos, Melissa; Menezes, Maria José; Orjuela-Sánchez, Pamela; Ferreira, Marcelo U

2012-11-01

Emerging resistance to chloroquine (CQ) poses a major challenge for Plasmodium vivax malaria control, and nucleotide substitutions and copy number variation in the P. vivax multidrug resistance 1 (pvmdr-1) locus, which encodes a digestive vacuole membrane transporter, may modulate this phenotype. We describe patterns of genetic variation in pvmdr-1 alleles from Acre and Amazonas in northwestern Brazil, and compare then with those reported in other malaria-endemic regions. The pvmdr-1 mutation Y976F, which is associated with CQ resistance in Southeast Asia and Oceania, remains rare in northwestern Brazil (1.8%) and its prevalence mirrors that of CQ resistance worldwide. Gene amplification of pvmdr-1, which is associated with mefloquine resistance but increased susceptibility to CQ, remains relatively rare in northwestern Brazil (0.9%) and globally (< 4%), but became common (> 10%) in Tak Province, Thailand, possibly because of drug-mediated selection. The global database we have assembled provides a baseline for further studies of genetic variation in pvmdr-1 and drug resistance in P. vivax malaria.

Magnetic nanoparticles are highly toxic to chloroquine-resistant Plasmodium falciparum, dengue virus (DEN-2), and their mosquito vectors.

PubMed

Murugan, Kadarkarai; Wei, Jiang; Alsalhi, Mohamad Saleh; Nicoletti, Marcello; Paulpandi, Manickam; Samidoss, Christina Mary; Dinesh, Devakumar; Chandramohan, Balamurugan; Paneerselvam, Chellasamy; Subramaniam, Jayapal; Vadivalagan, Chithravel; Wei, Hui; Amuthavalli, Pandiyan; Jaganathan, Anitha; Devanesan, Sandhanasamy; Higuchi, Akon; Kumar, Suresh; Aziz, Al Thabiani; Nataraj, Devaraj; Vaseeharan, Baskaralingam; Canale, Angelo; Benelli, Giovanni

2017-02-01

A main challenge in parasitology is the development of reliable tools to prevent or treat mosquito-borne diseases. We investigated the toxicity of magnetic nanoparticles (MNP) produced by Magnetospirillum gryphiswaldense (strain MSR-1) on chloroquine-resistant (CQ-r) and sensitive (CQ-s) Plasmodium falciparum, dengue virus (DEN-2), and two of their main vectors, Anopheles stephensi and Aedes aegypti, respectively. MNP were studied by Fourier-transform infrared spectroscopy and transmission electron microscopy. They were toxic to larvae and pupae of An. stephensi, LC 50 ranged from 2.563 ppm (1st instar larva) to 6.430 ppm (pupa), and Ae. aegypti, LC 50 ranged from 3.231 ppm (1st instar larva) to 7.545 ppm (pupa). MNP IC 50 on P. falciparum were 83.32 μg ml -1 (CQ-s) and 87.47 μg ml -1 (CQ-r). However, the in vivo efficacy of MNP on Plasmodium berghei was low if compared to CQ-based treatments. Moderate cytotoxicity was detected on Vero cells post-treatment with MNP doses lower than 4 μg ml -1 . MNP evaluated at 2-8 μg ml -1 inhibited DEN-2 replication inhibiting the expression of the envelope (E) protein. In conclusion, our findings represent the first report about the use of MNP in medical and veterinary entomology, proposing them as suitable materials to develop reliable tools to combat mosquito-borne diseases.

Concentration-discharge responses to storm events in coastal California watersheds

NASA Astrophysics Data System (ADS)

Aguilera, R.; Melack, J. M.

2017-12-01

Storm events in montane catchments are the main cause of mobilization of solutes and particulates into and within stream channels in coastal California. Non-linear behavior of nutrients and suspended sediments during storms is evident in the hysteresis that arises in concentration-discharge (C-Q) relationships. We examined patterns in the C-Q hysteresis of nutrients (NO3-, NH4+, DON and PO43-) and total suspended solids (TSS) during storms across ten sites and water years 2002 to 2015 by quantifying the slope of the C-Q relationship and the rotational pattern of the hysteresis loop. We observed several hysteresis types: constituents associated with sediment transport (PO43- and TSS) were flushed during storm events, whereas nitrogen species had hysteretic responses such as dilution with clockwise rotation in urban sites and enrichment with anti-clockwise rotation in undeveloped sites. The wide range of C-Q responses that occurred among sites and seasons reflected the variable hydrological and biogeochemical characteristics of catchments and storms. Storm responses for nitrate in nested catchments differed in slope and rotation of C-Q hysteresis. Upland undeveloped and lowland urban sites had anti-clockwise rotation at the onset of the rainy season following a dry year, which implied a delay in the transport of this solute to the streams. By the middle of the season, the urban site switched from dilution to enrichment, and then again to dilution with clockwise rotation, which implied high initial concentrations and proximal sources by the end of the season.

Catchment heterogeneity controls emergent archetype concentration-discharge relationships

NASA Astrophysics Data System (ADS)

Musolff, A.; Fleckenstein, J. H.; Rao, P. S.; Jawitz, J. W.

2017-12-01

Relationships between in-stream dissolved solute concentrations (C) and discharge (Q) are often-used indicators of catchment-scale processes and their interference with human activities. Here we analyze observational C-Q relationships from 61 catchments and 8 different solutes across a wide range of land-uses and discharge regimes. This analysis is combined with a parsimonious stochastic modeling approach to test how C-Q relationships arise from spatial heterogeneity in catchment solute sources coupled with different timescales of biogeochemical reactions. The observational data exhibit archetypical dilution, enrichment, and constant C-Q patterns. Moreover, with land-use intensification we find decreasing C variability relative to Q variability (chemostatic export regime). Our model indicates that the dominant driver of emergent C-Q patterns was structured heterogeneity of solute sources implemented as correlation of source concentration to travel time. Regardless of the C-Q pattern, with decreasing source heterogeneity we consistently find lower variability in C than in Q and a dominance of chemostatic export regimes. Here, the variance in exported loads is determined primarily by variance of Q. We conclude that efforts to improve stream water quality and ecological integrity in intensely managed catchments should lead away from landscape homogenization by introducing structured source heterogeneity. References: Musolff, A., J. H. Fleckenstein, P. S. C. Rao, and J. W. Jawitz (2017), Emergent archetype patterns of coupled hydrologic and biogeochemical responses in catchments, Geophys. Res. Lett., 44(9), 4143-4151, doi: 10.1002/2017GL072630.

The lysosome among targets of metformin: new anti-inflammatory uses for an old drug?

PubMed

Lockwood, Thomas D

2010-05-01

Rheumatoid arthritis and type-2 diabetes exhibit progressive co-morbidity. Chloroquine (CQ) reportedly improves both. CQ inhibits lysosomal function in cultured cells at supra-therapeutic concentration; however, this is doubted as target mechanism. Some anti-diabetic biguanides are metal-interactive lysosomal inhibitors; and all bind Zn(2+). i) To bioassay the potency of CQ using (3)H-leucine release from perfused myocardial tissue. ii) To determine whether metformin (MET) is CQ-mimetic, and interactive with Zn(2+). Therapeutic CQ concentration (0.1 - 0.5 microM) clearly does cause lysosomal inhibition although delayed and submaximal. MET alone (10 microM) caused sub-maximal inhibition. Supra-physiological extracellular Zn(2+) (5 - 50 microM) alone increased tissue Zn(2+) content, and inhibited lysosomal proteolysis. Physiological equivalent Zn(2+) (approximately 1 microM) had no effect. MET (

Usefulness of an ad hoc questionnaire (Acro-CQ) for the systematic assessment of acromegaly comorbidities at diagnosis and their management at follow-up.

PubMed

Guaraldi, F; Gori, D; Beccuti, G; Prencipe, N; Giordano, R; Mints, Y; Di Giacomo, V S; Berton, A; Lorente, M; Gasco, V; Ghigo, E; Salvatori, R; Grottoli, S

2016-11-01

To determine the validity of a self-administered questionnaire (Acro-CQ) developed to systematically assess the presence, type and time of onset of acromegaly comorbidities. This is a cross-sectional study; 105 acromegaly patients and 147 controls with other types of pituitary adenoma, referred to a specialized Italian Center, autonomously compiled Acro-CQ in an outpatient clinical setting. To test its reliability in a different setting, Acro-CQ was administered via mail to 78 patients with acromegaly and 100 with other pituitary adenomas, referred to a specialized US Center. Data obtained from questionnaires in both settings were compared with medical records (gold standard). Demographics of patients and controls from both countries were similar. In both settings, >95 % of the questionnaires were completely filled; only one item was missed in the others. Concordance with medical record was excellent (k > 0.85) for most of the items, independently from the way of administration, patient age, gender and nationality, pituitary adenoma type and disease activity. Acro-CQ is an inexpensive, highly accepted from patients and reliable tool recommended to expedite systematic collection of relevant clinical data in acromegaly at diagnosis, to be replicated at follow-ups. This tool may guide a targeted, cost-effective management of complications. Moreover, it could be applied to retrieve data for survey studies in both acromegaly and other pituitary adenomas, as information is easily and rapidly accessible for statistical analysis.

H2O2 treatment or serum deprivation induces autophagy and apoptosis in naked mole-rat skin fibroblasts by inhibiting the PI3K/Akt signaling pathway.

PubMed

Zhao, Shanmin; Li, Li; Wang, Shiyong; Yu, Chenlin; Xiao, Bang; Lin, Lifang; Cong, Wei; Cheng, Jishuai; Yang, Wenjing; Sun, Wei; Cui, Shufang

2016-12-20

Naked mole-rats (NMR; Heterocephalus glaber) display extreme longevity and resistance to cancer. Here, we examined whether autophagy contributes to the longevity of NMRs by assessing the effects of the PI3K/Akt pathway inhibitor LY294002 and the autophagy inhibitor chloroquine (CQ) on autophagy and apoptosis in NMR skin fibroblasts. Serum starvation, H2O2 treatment, and LY294002 treatment all increased the LC3-II/LC3-I ratio and numbers of double-membraned autophagosomes and autophagic vacuoles, and decreased levels of p70S6K, p-AktSer473, and p-AktThr308. By contrast, CQ treatment decreased p70S6K, AktSer473, and AktThr308 levels. The Bax/Bcl-2 ratio increased after 12 h of exposure to LY294002 or CQ. These data show that inhibiting the Akt pathway promotes autophagy and apoptosis in NMR skin fibroblasts. Furthermore, LY294002 or CQ treatment decreased caspase-3, p53, and HIF1-α levels, suggesting that serum starvation or H2O2 treatment increase autophagy and apoptosis in NMR skin fibroblasts by inhibiting the PI3K/Akt pathway. CQ-induced inhibition of late autophagy stages also prevented Akt activation and induced apoptosis. Finally, the HIF-1α and p53 pathways were involved in serum starvation- or H2O2-induced autophagy in NMR skin fibroblasts.

The concentration-discharge slope as a tool for water quality management.

PubMed

Bieroza, M Z; Heathwaite, A L; Bechmann, M; Kyllmar, K; Jordan, P

2018-07-15

Recent technological breakthroughs of optical sensors and analysers have enabled matching the water quality measurement interval to the time scales of stream flow changes and led to an improved understanding of spatially and temporally heterogeneous sources and delivery pathways for many solutes and particulates. This new ability to match the chemograph with the hydrograph has promoted renewed interest in the concentration-discharge (c-q) relationship and its value in characterizing catchment storage, time lags and legacy effects for both weathering products and anthropogenic pollutants. In this paper we evaluated the stream c-q relationships for a number of water quality determinands (phosphorus, suspended sediments, nitrogen) in intensively managed agricultural catchments based on both high-frequency (sub-hourly) and long-term low-frequency (fortnightly-monthly) routine monitoring data. We used resampled high-frequency data to test the uncertainty in water quality parameters (e.g. mean, 95th percentile and load) derived from low-frequency sub-datasets. We showed that the uncertainty in water quality parameters increases with reduced sampling frequency as a function of the c-q slope. We also showed that different sources and delivery pathways control c-q relationship for different solutes and particulates. Secondly, we evaluated the variation in c-q slopes derived from the long-term low-frequency data for different determinands and catchments and showed strong chemostatic behaviour for phosphorus and nitrogen due to saturation and agricultural legacy effects. The c-q slope analysis can provide an effective tool to evaluate the current monitoring networks and the effectiveness of water management interventions. This research highlights how improved understanding of solute and particulate dynamics obtained with optical sensors and analysers can be used to understand patterns in long-term water quality time series, reduce the uncertainty in the monitoring data and to manage eutrophication in agricultural catchments. Copyright © 2018 Elsevier B.V. All rights reserved.

Evaluation of Senna singueana leaf extract as an alternative or adjuvant therapy for malaria

PubMed Central

Hiben, Mebrahtom Gebrelibanos; Sibhat, Gereziher Gebremedhin; Fanta, Biruk Sintayehu; Gebrezgi, Haile Desta; Tesema, Shewaye Belay

2015-01-01

The emergence of malarial resistance to most antimalarial drugs is the main factor driving the continued effort to identify/discover new agents for combating the disease. Moreover, the unacceptably high mortality rate in severe malaria has led to the consideration of adjuvant therapies. Senna singueana leaves are traditionally used against malaria and fever. Extracts from the leaves of this plant demonstrated in vitro and in vivo antioxidant activities, which in turn could reduce the severity of malaria. Extracts from the root bark of this plant exhibited antiplasmodial activity; however, the leaves are the more sustainable resource. Thus, S. singueana leaf was selected for in vivo evaluation as a potential alternative or adjuvant therapy for malaria. Using malaria [Plasmodium berghei ANKA, chloroquine (CQ) sensitive]-infected Swiss albino mice of both sexes, 70% ethanol extract of S. singueana leaves (alone and in combination with CQ) was tested for antimalarial activity and adjuvancy potential. The 4-day suppressive test was used to evaluate antimalarial activity. The dose of S. singueana extract administered was safe to mice and exhibited some parasite suppression effect: extract doses of 200 mg/kg/d, 400 mg/kg/d, and 800 mg/kg/d caused 34.54%, 44.52%, and 47.32% parasite suppression, respectively. Concurrent administration of the extract with CQ phosphate at varied dose levels indicated that the percentage of parasite suppression of this combination was higher than administering CQ alone, but less than the sum of the effects of the extract and CQ acting separately. In conclusion, the study indicated that 70% ethanol extract of S. singueana leaf was safe to mice and possessed some parasite suppression effect. Coadministration of the extract with CQ appeared to boost the overall antimalarial effect, indicating that the combination may have a net health benefit if used as an adjuvant therapy. PMID:26870688

Evaluation of Senna singueana leaf extract as an alternative or adjuvant therapy for malaria.

PubMed

Hiben, Mebrahtom Gebrelibanos; Sibhat, Gereziher Gebremedhin; Fanta, Biruk Sintayehu; Gebrezgi, Haile Desta; Tesema, Shewaye Belay

2016-01-01

The emergence of malarial resistance to most antimalarial drugs is the main factor driving the continued effort to identify/discover new agents for combating the disease. Moreover, the unacceptably high mortality rate in severe malaria has led to the consideration of adjuvant therapies. Senna singueana leaves are traditionally used against malaria and fever. Extracts from the leaves of this plant demonstrated in vitro and in vivo antioxidant activities, which in turn could reduce the severity of malaria. Extracts from the root bark of this plant exhibited antiplasmodial activity; however, the leaves are the more sustainable resource. Thus, S. singueana leaf was selected for in vivo evaluation as a potential alternative or adjuvant therapy for malaria. Using malaria [Plasmodium berghei ANKA, chloroquine (CQ) sensitive]-infected Swiss albino mice of both sexes, 70% ethanol extract of S. singueana leaves (alone and in combination with CQ) was tested for antimalarial activity and adjuvancy potential. The 4-day suppressive test was used to evaluate antimalarial activity. The dose of S. singueana extract administered was safe to mice and exhibited some parasite suppression effect: extract doses of 200 mg/kg/d, 400 mg/kg/d, and 800 mg/kg/d caused 34.54%, 44.52%, and 47.32% parasite suppression, respectively. Concurrent administration of the extract with CQ phosphate at varied dose levels indicated that the percentage of parasite suppression of this combination was higher than administering CQ alone, but less than the sum of the effects of the extract and CQ acting separately. In conclusion, the study indicated that 70% ethanol extract of S. singueana leaf was safe to mice and possessed some parasite suppression effect. Coadministration of the extract with CQ appeared to boost the overall antimalarial effect, indicating that the combination may have a net health benefit if used as an adjuvant therapy.

Nonradioactive heteroduplex tracking assay for the detection of minority-variant chloroquine-resistant Plasmodium falciparum in Madagascar

PubMed Central

Juliano, Jonathan J; Randrianarivelojosia, Milijaona; Ramarosandratana, Benjamin; Ariey, Frédéric; Mwapasa, Victor; Meshnick, Steven R

2009-01-01

Background Strains of Plasmodium falciparum genetically resistant to chloroquine (CQ) due to the presence of pfcrt 76T appear to have been recently introduced to the island of Madagascar. The prevalence of such resistant genotypes is reported to be low (< 3%) when evaluated by conventional PCR. However, these methods are insensitive to low levels of mutant parasites present in patients with polyclonal infections. Thus, the current estimates may be an under representation of the prevalence of the CQ-resistant P. falciparum isolates on the island. Previously, minority variant chloroquine resistant parasites were described in Malawian patients using an isotopic heteroduplex tracking assay (HTA), which can detect pfcrt 76T-bearing P. falciparum minority variants in individual patients that were undetectable by conventional PCR. However, as this assay required a radiolabeled probe, it could not be used in many resource-limited settings. Methods This study describes a digoxigenin (DIG)-labeled chemiluminescent heteroduplex tracking assay (DIG-HTA) to detect pfcrt 76T-bearing minority variant P. falciparum. This assay was compared to restriction fragment length polymorphism (RFLP) analysis and to the isotopic HTA for detection of genetically CQ-resistant parasites in clinical samples. Results Thirty one clinical P. falciparum isolates (15 primary isolates and 16 recurrent isolates) from 17 Malagasy children treated with CQ for uncomplicated malaria were genotyped for the pfcrt K76T mutation. Two (11.7%) of 17 patients harboured genetically CQ-resistant P. falciparum strains after therapy as detected by HTA. RFLP analysis failed to detect any pfcrt K76T-bearing isolates. Conclusion These findings indicate that genetically CQ-resistant P. falciparum are more common than previously thought in Madagascar even though the fitness of the minority variant pfcrt 76T parasites remains unclear. In addition, HTAs for malaria drug resistance alleles are promising tools for the surveillance of anti-malarial resistance. The use of a non-radioactive label allows for the use of HTAs in malaria endemic countries. PMID:19291288

Expression of Plasmodium vivax crt-o Is Related to Parasite Stage but Not Ex Vivo Chloroquine Susceptibility.

PubMed

Pava, Zuleima; Handayuni, Irene; Wirjanata, Grennady; To, Sheren; Trianty, Leily; Noviyanti, Rintis; Poespoprodjo, Jeanne Rini; Auburn, Sarah; Price, Ric N; Marfurt, Jutta

2016-01-01

Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o (pvcrt-o) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5; P < 0.001). Twenty-nine isolates fulfilled the criteria for ex vivo drug susceptibility testing and showed high variability in CQ responses (median, 107.9 [range, 6.5 to 345.7] nM). After controlling for the parasite stage, we found that pvcrt-o expression levels did not correlate with the ex vivo response to CQ or with that to any of the other antimalarials tested. Our results highlight the importance of development-stage composition for measuring pvcrt-o expression and suggest that pvcrt-o transcription is not a primary determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivax drug resistance. Copyright © 2015 Pava et al.

Confirmed Plasmodium vivax Resistance to Chloroquine in Central Vietnam.

PubMed

Thanh, Pham Vinh; Hong, Nguyen Van; Van, Nguyen Van; Louisa, Melva; Baird, Kevin; Xa, Nguyen Xuan; Peeters Grietens, Koen; Hung, Le Xuan; Duong, Tran Thanh; Rosanas-Urgell, Anna; Speybroeck, Niko; D'Alessandro, Umberto; Erhart, Annette

2015-12-01

Plasmodium vivax resistance to chloroquine (CQ) is currently reported in almost all countries where P. vivax is endemic. In Vietnam, despite a first report on P. vivax resistance to chloroquine published in the early 2000s, P. vivax was still considered sensitive to CQ. Between May 2009 and December 2011, a 2-year cohort study was conducted in central Vietnam to assess the recommended radical cure regimen based on a 10-day course of primaquine (0.5 mg/kg/day) together with 3 days of CQ (25 mg/kg). Here we report the results of the first 28-day follow-up estimating the cumulative risk of P. vivax recurrences together with the corresponding CQ blood concentrations, among other endpoints. Out of 260 recruited P. vivax patients, 240 completed treatment and were followed up to day 28 according to the WHO guidelines. Eight patients (3.45%) had a recurrent P. vivax infection, at day 14 (n = 2), day 21 (n = 1), and day 28 (n = 5). Chloroquine blood concentrations, available for 3/8 recurrent infections (days 14, 21, and 28), were above the MIC (>100 ng/ml whole blood) in all of these cases. Fever and parasitemia (both sexual and asexual stages) were cleared by day 3. Anemia was common at day 0 (35.8%), especially in children under 10 years (50%), and hemoglobin (Hb) recovery at day 28 was substantial among anemic patients (median change from day 0 to 28, +1.7 g/dl; interquartile range [IQR], +0.7 to +3.2). This report, based on CQ blood levels measured at the time of recurrences, confirms for the first time P. vivax CQ resistance in central Vietnam and calls for further studies using standardized protocols for accurately monitoring the extent and evolution of P. vivax resistance to chloroquine in Vietnam. These results, together with the mounting evidence of artemisinin resistance in central Vietnam, further highlight the increasing threat of antimalarial drug resistance to malaria elimination in Vietnam. Copyright © 2015 Thanh et al.

A Numerical Analysis of the Air Distribution System for the Ventilation of the Crew Quarters on board of the International Space Station

NASA Astrophysics Data System (ADS)

Bode, Florin; Nastase, Ilinca; Croitoru, Cristiana Verona; Sandu, Mihnea; Dogeanu, Angel

2018-02-01

Quality of life on the International Space Station (ISS) has become more and more important, since the time spent by astronauts outside the terrestrial atmosphere has increased in the last years. The actual concept for the Crew Quarters (CQ) have demonstrated the possibility of a personal space for sleep and free time activities in which the noise levels are lower, but not enough, compared to the noisy ISS isle way. However, there are several issues that needs to be improved to increase the performance of CQ. Our project QUEST is intended to propose a new concept of CQ in which we will correct these issues, like the noise levels will be lower, more space for astronaut, increased thermal comfort, reduce the CQ total weight, higher efficiency for the air distribution, personalized ventilation system in CQ for the crew members in order to remove CO2 from the breathing zone. This paper presents a CFD study in which we are comparing the actual and a proposed ventilation solution for introducing the air in CQ. A preliminary numerical model of the present configuration of the air distribution system of the Crew Quarters on board of the ISS, shows the need for an improved air distribution inside these enclosures. Lower velocity values at the inlet diffuser, distributed over a larger surface, as well as diffusers with improved induction would appear to be a better choice. This was confirmed through the development of a new model including linear diffusers with a larger discharge surface. In this new configuration, the regions of possible draught are dramatically reduced. The overall distributions of the velocity magnitudes displaying more uniform, lower values, in the same time with more uniform temperatures. All these observations allow us to consider a better mixing of the air inside the enclosure.

CONCURRENT WHOLE BRAIN RADIOTHERAPY AND SHORT-COURSE CHLOROQUINE IN PATIENTS WITH BRAIN METASTASES: A PILOT TRIAL.

PubMed

Eldredge, Harriet Belding; Denittis, Albert; Duhadaway, James B; Chernick, Michael; Metz, Richard; Prendergast, George C

2013-09-01

The immune modulatory drug chloroquine (CQ) has been demonstrated to enhance survival following radiotherapy in patients with high-grade glioma in a clinical trial, but the efficacy in patients with brain metastases is unknown. We hypothesized that short-course CQ during whole brain radiotherapy (WBRT) would improve response to local therapy in patients with brain metastases. A prospective, single-cohort study was performed combining WBRT with concurrent CQ to assess both the feasibility of and intracranial response to combined therapy in patients with brain metastases. Safety, tolerability and overall survival of this combination was also examined, along with allelic status of IDO2 (indoleamine 2,3-dioxygenase 2), an immune modulatory enzyme inhibited by chloroquine that may affect survival outcomes. CQ therapy (250 mg by mouth daily) was initiated 1 week before WBRT (37.5 Gy in 2.5 Gy daily fractions) in patients with newly diagnosed brain metastases from biopsy-proven, primary lung, breast or ovarian solid tumors (n=20). The primary endpoint was radiologic response 3 months after combined CQ and WBRT therapy. Secondary endpoints included toxicity and overall survival. Patients were stratified by IDO2 allelic status. After a median clinical follow up of 5 months (range, 0.5-31), 16 patients were evaluable for radiologic response which was complete response in two patients, partial response in 13 patients and stable disease in one patient. There were no treatment-related grade≥3 toxicities or treatment interruption due to toxicity. Median and mean overall survival was 5.7 and 8.9 months, respectively (range, 0.8-31). A trend toward increased overall survival was observed in patients with wild-type IDO2 compared to patients with heterozygous or homozygous configurations that ablate IDO2 enzyme activity (10.4 mos vs. 4.1 mos.; p=0.07). WBRT with concurrent, short-course CQ is well tolerated in patients with brain metastases. The high intracranial disease control rate warrants additional study.

Influenza A/H1N1 vaccination of patients with SLE: can antimalarial drugs restore diminished response under immunosuppressive therapy?

PubMed

Borba, Eduardo F; Saad, Carla G S; Pasoto, Sandra G; Calich, Ana L G; Aikawa, Nadia E; Ribeiro, Ana C M; Moraes, Julio C B; Leon, Elaine P; Costa, Luciana P; Guedes, Lissiane K N; Silva, Clovis A A; Goncalves, Celio R; Fuller, Ricardo; Oliveira, Suzimara A; Ishida, Maria A; Precioso, Alexander R; Bonfa, Eloisa

2012-06-01

To assess the efficacy and safety of pandemic 2009 influenza A (H1N1) in SLE under different therapeutic regimens. A total of 555 SLE patients and 170 healthy controls were vaccinated with a single dose of a non-adjuvanted preparation. According to current therapy, patients were initially classified as SLE No Therapy (n = 75) and SLE with Therapy (n = 480). Subsequent evaluations included groups under monotherapy: chloroquine (CQ) (n = 105), prednisone (PRED) ≥20 mg (n = 76), immunosuppressor (IS) (n = 95) and those with a combination of these drugs. Anti-H1N1 titres and seroconversion (SC) rate were evaluated at entry and 21 days post-vaccination. The SLE with Therapy group had lower SC compared with healthy controls (59.0 vs 80.0%; P < 0.0001), whereas the SLE No Therapy group had equivalent SC (72 vs 80.0%; P = 0.18) compared with healthy controls. Further comparison revealed that the SC of SLE No Therapy (72%) was similar to the CQ group (69.5%; P = 0.75), but it was significantly reduced in PRED ≥20 mg (53.9%; P = 0.028), IS (55.7%; P = 0.035) and PRED ≥20 mg + IS (45.4%; P = 0.038). The concomitant use of CQ in each of these later regimens was associated with SC responses comparable with SLE No Therapy group (72%): PRED ≥20 mg + CQ (71.4%; P = 1.00), IS + CQ (65.2%; P = 0.54) and PRED ≥20 mg + IS + CQ (57.4%; P = 0.09). Pandemic influenza A H1N1/2009 vaccine response is diminished in SLE under immunosuppressive therapy and antimalarials seems to restore this immunogenicity. Trial registration. www.clinicaltrials.gov, NCT01151644.

Is Time the Best Metric to Measure Carbon-Related Climate Change Potential and Tune the Economy Toward Reduced Fossil Carbon Extraction?

NASA Astrophysics Data System (ADS)

DeGroff, F. A.

2016-12-01

Anthropogenic changes to non-anthropogenic carbon fluxes are a primary driver of climate change. There currently exists no comprehensive metric to measure and value anthropogenic changes in carbon flux between all states of carbon. Focusing on atmospheric carbon emissions as a measure of anthropogenic activity on the environment ignores the fungible characteristics of carbon that are crucial in both the biosphere and the worldwide economy. Focusing on a single form of inorganic carbon as a proxy metric for the plethora of anthropogenic activity and carbon compounds will prove inadequate, convoluted, and unmanageable. A broader, more basic metric is needed to capture the entirety of carbon activity, particularly in an economic, profit-driven environment. We propose a new metric to measure changes in the temporal distance of any form or state of carbon from one state to another. Such a metric would be especially useful to measure the temporal distance of carbon from sinks such as the atmosphere or oceans. The effect of changes in carbon flux as a result of any human activity can be measured by the difference between the anthropogenic and non-anthropogenic temporal distance. The change in the temporal distance is a measure of the climate change potential much like voltage is a measure of electrical potential. The integral of the climate change potential is proportional to the anthropogenic climate change. We also propose a logarithmic vector scale for carbon quality, cq, as a measure of anthropogenic changes in carbon flux. The distance between the cq vector starting and ending temporal distances represents the change in cq. A base-10 logarithmic scale would allow the addition and subtraction of exponents to calculate changes in cq. As anthropogenic activity changes the temporal distance of carbon, the change in cq is measured as: cq = ß ( log10 [mean carbon temporal distance] ) where ß represents the carbon price coefficient for a particular country. For any country, cq measures the climate change potential for any domestic anthropogenic activity that results in a change in temporal distance of any carbon. The greater the carbon fees for a country, the larger the ß coefficient would be, and the greater the import fees would be to achieve carbon parity on imports from countries with lower carbon fees.

Effective symptomatic treatment for severe and intractable pruritus associated with severe burn-induced hypertrophic scars: A prospective, multicenter, controlled trial.

PubMed

Wu, Jun; Xu, Rui; Zhan, Rixing; Luo, Gaoxing; Niu, Xihua; Liu, Yi; Lee, Benjamin Tak-Kwong; Flury, Meinrad; Wong, Chun-Ho; Fok, Manson; Lau, Johnson Yiu-Nam

2016-08-01

Burn-induced hypertrophic scars are disfiguring and can be associated with severe and intractable pruritus. No effective treatment modalities are currently available for symptomatic control of pruritus for most patients. We assessed the effect of the Antipruritic Hydrogel (CQ-01) in the symptomatic treatment of severe and intractable pruritus associated with burn-induced hypertrophic scars in a prospective, multicenter, controlled trial. A pilot study was conducted in healthy adult volunteers to identify the most appropriate hydrogel formulation. A selected preparation called Chongqing No. 1 (CQ-01; a guar gum-based hydrogel impregnated with peppermint oil, menthol, and methyl salicylate by a nanoemulsion), showed an excellent symptomatic relief in an exploratory study in 2 patients with intractable pruritus. A statistically powered, prospective, multicenter, controlled study was then conducted in 74 patients to evaluate the efficacy and safety of a 24-h application of CQ-01 compared to a gel control and a negative control on three separate areas in each patient. Symptom assessment was based on our visual analog JW scale (ranging from 0 to 100) at baseline and various time points up to 7 days after application. Follow-up studies were conducted to determine the reproducibility of CQ-01 in repeated applications. Of the 74 enrolled subjects, the only observed adverse event was skin irritation reported in 6 patients (8%) and resolved shortly after gel removal. Compared to the baseline, the gauze negative control had a mean JW score reduction of 7; while the gel control and CQ-01 had a drop of 18 (p<0.001) and 36 (p<0.001), respectively. The CQ-01 clinical effect was significant for up to 3 days and waned slowly from 3 to 7 days. There was no statistical correlation between the treatment response and any of the demographic, patient or burn-related factors. Further studies showed a trend that repeated applications might be more effective, suggesting the absence of tachyphylaxis. This prospective, multicenter, controlled study showed that this novel hydrogel CQ-01 is safe and provides significant symptomatic relief for severe and intractable pruritus associated with hypertrophic scars, an unmet medical need for these patients. This effect is independent of the etiology of the burn trauma, extent of the scarring, and duration of the scar formation. Copyright © 2016. Published by Elsevier Ltd.

Green-synthesized CdS nano-pesticides: Toxicity on young instars of malaria vectors and impact on enzymatic activities of the non-target mud crab Scylla serrata.

PubMed

Sujitha, Vasu; Murugan, Kadarkarai; Dinesh, Devakumar; Pandiyan, Amuthvalli; Aruliah, Rajasekar; Hwang, Jiang-Shiou; Kalimuthu, Kandasamy; Panneerselvam, Chellasamy; Higuchi, Akon; Aziz, Al Thabiani; Kumar, Suresh; Alarfaj, Abdullah A; Vaseeharan, Baskaralingam; Canale, Angelo; Benelli, Giovanni

2017-07-01

Currently, nano-formulated mosquito larvicides have been widely proposed to control young instars of malaria vector populations. However, the fate of nanoparticles in the aquatic environment is scarcely known, with special reference to the impact of nanoparticles on enzymatic activity of non-target aquatic invertebrates. In this study, we synthesized CdS nanoparticles using a green protocol relying on the cheap extract of Valoniopsis pachynema algae. CdS nanoparticles showed high toxicity on young instars of the malaria vectors Anopheles stephensi and A. sundaicus. The antimalarial activity of the nano-synthesized product against chloroquine-resistant (CQ-r) Plasmodium falciparum parasites was investigated. From a non-target perspective, we focused on the impact of this novel nano-pesticide on antioxidant enzymes acetylcholinesterase (AChE) and glutathione S-transferase (GST) activities of the mud crab Scylla serrata. The characterization of nanomaterials was carried out by UV-vis and FTIR spectroscopy, as well as SEM and XRD analyses. In mosquitocidal assays, LC 50 of V. pachynema-synthesized CdS nanoparticles on A. stephensi ranged from 16.856 (larva I), to 30.301μg/ml (pupa), while for An. sundaicus they ranged from 13.584 to 22.496μg/ml. The antiplasmodial activity of V. pachynema extract and CdS nanoparticles was evaluated against CQ-r and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. IC 50 of V. pachynema extract was 58.1μg/ml (CQ-s) and 71.46μg/ml (CQ-r), while nano-CdS IC 50 was 76.14μg/ml (CQ-s) and 89.21μg/ml (CQ-r). In enzymatic assays, S. serrata crabs were exposed to sub-lethal concentrations, i.e. 4, 6 and 8μg/ml of CdS nanoparticles, assessing changes in GST and AChE activity after 16days. We observed significantly higher activity of GST, if compared to the control, during the whole experiment period. In addition, a single treatment with CdS nanoparticles led to a significant decrease in AChE activity over time. The toxicity of CdS nanoparticles and Cd ions in aqueous solution was also assessed in mud crabs, showing higher toxicity of aqueous Cd ions if compared to nano-CdS. Overall, our results underlined the efficacy of green-synthesized CdS nanoparticles in malaria vector control, outlining also significant impacts on the enzymatic activity of non-target aquatic organisms, with special reference to mud crabs. Copyright © 2017 Elsevier B.V. All rights reserved.

Does Cultural Intelligence Matter? Effects of Principal and Teacher Cultural Intelligence on Latino Student Achievement

ERIC Educational Resources Information Center

Collins, Kathy S.; Duyar, Ibrahim; Pearson, Carolyn L.

2016-01-01

Purpose: The purpose of this study was to examine whether the levels of cultural intelligence (CQ) of principals and teachers influence Latino students' achievement. The study first tested the applicability of Ang and Van Dyne's (2008) Cultural Intelligence Questionnaire (CQS) for the measurement of principals and teachers' CQ levels by construct…

Anisotropic Responses of Mechanical and Thermal Processed Cast Al-Si-Mg-Cu Alloy

NASA Astrophysics Data System (ADS)

Adeosun, S. O.; Akpan, E. I.; Balogun, S. A.; Onoyemi, O. K.

2015-05-01

The effects of ambient directional rolling and heat treatments on ultimate tensile strength (UTS), hardness (HD), percent elongation (PE), and impact energy (IE) on Al-Si-Mg-Cu alloy casting with reference to inclination to rolling direction are discussed in this article. The results show that rolled and quenched (CQ) sample possess superior UTS and HD to as-cast and those of rolled and aged samples (CA). Improved IE resistance with ductility is shown by both CQ and CA samples. However, these mechanical properties are enhanced as changes in the test sample direction moved away from rolling direction for all heat-treated samples. The CQ samples displayed highest tensile strength (108 MPa) and PE (19.8%) in the 90° direction.

Measurement of glottal cycle characteristics between children and adults: Physiological Variations

PubMed Central

Patel, Rita R.; Dubrovskiy, Denis; Döllinger, Michael

2014-01-01

Objective The aim of this study is to quantify phases of the vibratory cycle using measurements of glottal cycle quotients and glottal cycle derivatives, in typically developing pre-pubertal children and young adults with use of high speed digital imaging (HSDI). Method Vocal fold vibrations were recorded from 27 children (age range 5–9 years) and 35 adults (age range 21–45 years), with HSDI at 4000 frames per second for sustained phonation. Glottal area waveform (GAW) measures of Open Quotient (OQ), Closing Quotient (CQ), Speed Index (SI), Rate Quotient (RQ) and Asymmetry Quotient (AsyQ) were computed. Glottal cycle derivatives of Amplitude Quotient (AQ) and Maximum Area Declination Rate (MADR) were also computed. Group differences (adult females, adult males, and children) were statistically investigated for mean and standard deviation values of the glottal cycle quotients and glottal cycle derivatives. Results Children exhibited higher values of Speed Index, Asymmetry Quotient and lower MADR compared to adult males. Children exhibited the highest mean value and lowest variability in Amplitude Quotient compared to adult males and females. Adult males showed lower values of Speed Index, Asymmetry Quotient, Amplitude Quotient and higher values of MADR compared to adult females. Conclusion Glottal cycle vibratory motion in children is functionally different compared to adult males and females; suggesting the need for development of children specific norms for both normal and disordered voice qualities. PMID:24629646

Multiple Cytochrome P450 genes: their constitutive overexpression and permethrin induction in insecticide resistant mosquitoes, Culex quinquefasciatus.

PubMed

Liu, Nannan; Li, Ting; Reid, William R; Yang, Ting; Zhang, Lee

2011-01-01

Four cytochrome P450 cDNAs, CYP6AA7, CYP9J40, CYP9J34, and CYP9M10, were isolated from mosquitoes, Culex quinquefasciatus. The P450 gene expression and induction by permethrin were compared for three different mosquito populations bearing different resistance phenotypes, ranging from susceptible (S-Lab), through intermediate (HAmCq(G0), the field parental population) to highly resistant (HAmCq(G8), the 8(th) generation of permethrin selected offspring of HAmCq(G0)). A strong correlation was found for P450 gene expression with the levels of resistance and following permethrin selection at the larval stage of mosquitoes, with the highest expression levels identified in HAmCq(G8), suggesting the importance of CYP6AA7, CYP9J40, CYP9J34, and CYP9M10 in the permethrin resistance of larva mosquitoes. Only CYP6AA7 showed a significant overexpression in HAmCq(G8) adult mosquitoes. Other P450 genes had similar expression levels among the mosquito populations tested, suggesting different P450 genes may be involved in the response to insecticide pressure in different developmental stages. The expression of CYP6AA7, CYP9J34, and CYP9M10 was further induced by permethrin in resistant mosquitoes. Taken together, these results indicate that multiple P450 genes are up-regulated in insecticide resistant mosquitoes through both constitutive overexpression and induction mechanisms, thus increasing the overall expression levels of P450 genes.

Concentration-Discharge Responses to Storm Events in Coastal California Watersheds

NASA Astrophysics Data System (ADS)

Aguilera, Rosana; Melack, John M.

2018-01-01

Storm events in montane catchments are the main cause of mobilization of solutes and particulates into and within stream channels in coastal California. Nonlinear behavior of nutrients and suspended sediments during storms is evident in the hysteresis that arises in concentration-discharge (C-Q) relationships. We examined patterns in the C-Q hysteresis of nutrients (NO3-, NH4+, DON, and PO43-) and total suspended solids (TSS) during storms across 10 sites and water years 2002-2015 by quantifying the slope of the C-Q relationship and the rotational pattern of the hysteresis loop. We observed several hysteresis types in the ˜400 storms included in our study. Concentrations of constituents associated with sediment transport (PO43- and TSS) peaked during high flows. Conversely, nitrogen species had hysteretic responses such as dilution with clockwise rotation in urban sites and enrichment with anticlockwise rotation in undeveloped sites. The wide range of C-Q responses that occurred among sites and seasons reflected the variable hydrological and biogeochemical characteristics of catchments and storms. Responses for nitrate in nested catchments differed in slope and rotation of C-Q hysteresis. Upland undeveloped and lowland urban sites had anticlockwise rotation at the onset of the rainy season following a dry year, which implied a delay in the transport of this solute to the streams. Slopes by the middle of the rainy season showed that the urban site switched from dilution to enrichment, and then again to dilution with clockwise rotation at the end of the season, which implied high initial concentrations and proximal sources.

Oral administration of metal chelator ameliorates motor dysfunction after a small hemorrhage near the internal capsule in rat.

PubMed

Masuda, Tadashi; Hida, Hideki; Kanda, Yoshie; Aihara, Noritaka; Ohta, Kengo; Yamada, Kazuo; Nishino, Hitoo

2007-01-01

Cerebral hemorrhage leads to local production of free iron, radicals, cytokines, etc. To investigate whether a decrease of iron-mediated radical production influences functional recovery after intracerebral hemorrhage (ICH), a modified ICH rat model with a small hemorrhage near the internal capsule (IC) accompanied with relatively severe motor dysfunction was first developed. Then clioquinol (CQ), an iron chelator that reduces hydroxyl radical production, was orally administrated. Injection of different doses of Type IV collagenase (1.4 mul 1-200 U/ml) into the left striatum near the IC in Wistar rats showed that injection of 7.5 U/ml collagenase resulted in a small hemorrhoidal lesion near the IC with relatively severe motor dysfunction (IC model). Retrograde labeling of neurons in the sensory-motor cortex and axons in the corticospinal tract using Fluoro-gold (FG) injection into the spinal cord (C3-C4) showed that few labeled neurons in the sensory-motor cortex were detected in the IC model, FG-labeled axons disappeared, and FG-including ED-1-positive cells appeared within 24 hr in the IC. Assessments of behavior and histologic analysis after oral administration of CQ in the IC model indicated that oral administration of CQ prevented a decrease of FG-labeled neurons, and resulted in better motor-function recovery. CQ inhibited hydrogen peroxide-induced cell toxicity in oligodendrocytes in vitro, but not in neurons. Our data suggests that CQ ameliorated motor dysfunction after a small hemorrhage near the IC by a mechanism that is related to reduction of chain-reactive hydroxyl radical production in oligodendrocytes.

Characterizing hyporheic exchange processes using high-frequency electrical conductivity-discharge relationships on subhourly to interannual timescales

NASA Astrophysics Data System (ADS)

Singley, Joel G.; Wlostowski, Adam N.; Bergstrom, Anna J.; Sokol, Eric R.; Torrens, Christa L.; Jaros, Chris; Wilson, Colleen E.; Hendrickson, Patrick J.; Gooseff, Michael N.

2017-05-01

Concentration-discharge (C-Q) relationships are often used to quantify source water contributions and biogeochemical processes occurring within catchments, especially during discrete hydrological events. Yet, the interpretation of C-Q hysteresis is often confounded by complexity of the critical zone, such as numerous source waters and hydrochemical nonstationarity. Consequently, researchers must often ignore important runoff pathways and geochemical sources/sinks, especially the hyporheic zone because it lacks a distinct hydrochemical signature. Such simplifications limit efforts to identify processes responsible for the transience of C-Q hysteresis over time. To address these limitations, we leverage the hydrologic simplicity and long-term, high-frequency Q and electrical conductivity (EC) data from streams in the McMurdo Dry Valleys, Antarctica. In this two end-member system, EC can serve as a proxy for the concentration of solutes derived from the hyporheic zone. We utilize a novel approach to decompose loops into subhysteretic EC-Q dynamics to identify individual mechanisms governing hysteresis across a wide range of timescales. We find that hydrologic and hydraulic processes govern EC response to diel and seasonal Q variability and that the effects of hyporheic mixing processes on C-Q transience differ in short and long streams. We also observe that variable hyporheic turnover rates govern EC-Q patterns at daily to interannual timescales. Last, subhysteretic analysis reveals a period of interannual freshening of glacial meltwater streams related to the effects of unsteady flow on hyporheic exchange. The subhysteretic analysis framework we introduce may be applied more broadly to constrain the processes controlling C-Q transience and advance understanding of catchment evolution.

Augmentation of the Differentiation Response to Antitumor Antimalarials

DTIC Science & Technology

2004-07-01

Release; Distribution Unlimited 13. ABSTRACT (Maximum 200 Words) We have shown that the quinoline antimalarials chloroquine (CQ) and hydroxychloroquine (HCQ...Introduction: Preliminary studies showed that two of the quinoline antimalarials, chloroquine (CQ) and hydroxychloroquine (HCQ), displayed selective... hydroxychloroquine upon pretreatment with ATRA or Aza on tumor cell survival (Figures 1 and 2, respectively). Clonogenic survival of MDA-MB-231 cells exposed to

Ex Vivo Drug Susceptibility of Ferroquine against Chloroquine-Resistant Isolates of Plasmodium falciparum and P. vivax▿

PubMed Central

Marfurt, Jutta; Chalfein, Ferryanto; Prayoga, Pak; Wabiser, Frans; Kenangalem, Enny; Piera, Kim A.; MacHunter, Barbara; Tjitra, Emiliana; Anstey, Nicholas M.; Price, Ric N.

2011-01-01

Ferroquine (FQ; SSR97193), a ferrocene-containing 4-aminoquinoline derivate, has potent in vitro efficacy against chloroquine (CQ)-resistant Plasmodium falciparum and CQ-sensitive P. vivax. In the current study, ex vivo FQ activity was tested in multidrug-resistant P. falciparum and P. vivax field isolates using a schizont maturation assay. Although FQ showed excellent activity against CQ-sensitive and -resistant P. falciparum and P. vivax (median 50% inhibitory concentrations [IC50s], 9.6 nM and 18.8 nM, respectively), there was significant cross-susceptibility with the quinoline-based drugs chloroquine, amodiaquine, and piperaquine (for P. falciparum, r = 0.546 to 0.700, P < 0.001; for P. vivax, r = 0.677 to 0.821, P < 0.001). The observed ex vivo cross-susceptibility is likely to reflect similar mechanisms of drug uptake/efflux and modes of drug action of this drug class. However, the potent activity of FQ against resistant isolates of both P. falciparum and P. vivax highlights a promising role for FQ as a lead antimalarial against CQ-resistant Plasmodium and a useful partner drug for artemisinin-based combination therapy. PMID:21730116

Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases.

PubMed

Rainsford, K D; Parke, Ann L; Clifford-Rashotte, Matthew; Kean, W F

2015-10-01

This review examines the pharmacokinetics, modes of action and therapeutic properties of the anti-malarial drugs, hydroxychloroquine (HCQ) and chloroquine (CQ), in the treatment of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and related conditions, as well as osteoarthritis (OA). Both HCQ and CQ have historically been employed successfully for the treatment of SLE and RA for over 70 years. HCQ has been used extensively for SLE where it has a good reputation for controlling the dermatological complications in SLE. It has also been reported to effectively control the symptoms of Sjøgren's syndrome, as well as preventing thrombosis in phospholipid antibody (aPL) syndrome. In RA and SLE, HCQ is preferred because of the lower incidence of gastrointestinal adverse reactions compared with CQ and it might have a lower risk of ocular adverse reactions. There is increasing evidence that HCQ may reduce atherosclerosis and risks of cardiovascular disease in rheumatic patients. Both HCQ and CQ have been shown to improve glycaemia and reduce the risks of type II diabetes mellitus. Although both HCQ and CQ are effective in low-moderate RA, HCQ is now preferred as part of combination therapy for more severe disease. The advantages of combination therapy are that the doses of the individual drugs may be lowered so reducing adverse reactions. Both HCQ and CQ are diastereoisomers, have basic properties and are given as the sulphate and phosphate salts. While being relatively well absorbed orally and with good bioavailability, they have long and variable plasma terminal elimination half-lives (approximately 40-60 days). This reflects their high volume of distribution, V D (HCQ 44,000L; CQ 65,000L) which extends into aqueous compartments, long mean residence time (HCQ 1300 h; CQ 900 h) and with about half the drugs (metabolites) undergoing renal clearance. The strong binding to melanin reflects the ocular injury and dermatological properties of these drugs. The consensus is that the occurrence of ocular adverse reactions can be minimised by close attention to the dose (which should be set on a body weight basis) with regular (e.g. quarterly) retinal examination. Although HCQ and CQ can pass through the placenta, the use of these drugs during pregnancy does not appear to risk harm to the baby and might be beneficial to the mother with SLE and her child by controlling the SLE disease activity, which is known to be an important factor affecting pregnancy outcome. The modes of action of HCQ and CQ in these arthritides represent somewhat of an enigma. Undoubtedly, these drugs have multiple actions related, in part, their ability to accumulate in lysosomes and autophagosomes of phagocytic cells as well as affecting MHC Class II expression and antigen presentation; actions of the production of pro-inflammatory cytokines [e.g. interleukin-1 (IL-1) tumour necrosis factor-α (TNFα)]; control of toll-like receptor-9 activation; and leucocyte generation of reactive oxygen species (ROS); i.e. antioxidant activity. The actions of these drugs on T and B cells are less clear but may depend on these leucocyte-mediated actions. Anti-malarials also protect against cytokine-mediated cartilage resorption. This and other actions may underlie the potential benefits in treating OA. The exact relationships of these various actions, mostly determined in vitro, have not been specifically defined in vivo or ex vivo in relation to clinical efficacy. HCQ and CQ have a good reputation for being effective and relatively safe treatments in SLE, mild-moderate RA and Sjøgren's syndrome. There is need for (a) more information on their mode of action in relation to the control of these diseases, (b) scope for developing formulations that have improved pharmacokinetic and therapeutic properties and safety, and (c) further exploring their use in drug combinations not only with other disease modifying agents but also with biologics. (c) further exploring their use in drug combinations not only with other disease-modifying agents but also with biologics.

MiRNA Analysis by Quantitative PCR in Preterm Human Breast Milk Reveals Daily Fluctuations of hsa-miR-16-5p.

PubMed

Floris, Ilaria; Billard, Hélène; Boquien, Clair-Yves; Joram-Gauvard, Evelyne; Simon, Laure; Legrand, Arnaud; Boscher, Cécile; Rozé, Jean-Christophe; Bolaños-Jiménez, Francisco; Kaeffer, Bertrand

2015-01-01

Human breast milk is an extremely dynamic fluid containing many biologically-active components which change throughout the feeding period and throughout the day. We designed a miRNA assay on minimized amounts of raw milk obtained from mothers of preterm infants. We investigated changes in miRNA expression within month 2 of lactation and then over the course of 24 hours. Analyses were performed on pooled breast milk, made by combining samples collected at different clock times from the same mother donor, along with time series collected over 24 hours from four unsynchronized mothers. Whole milk, lipids or skim milk fractions were processed and analyzed by qPCR. We measured hsa-miR-16-5p, hsa-miR-21-5p, hsa-miR-146-5p, and hsa-let-7a, d and g (all -5p). Stability of miRNA endogenous controls was evaluated using RefFinder, a web tool integrating geNorm, Normfinder, BestKeeper and the comparative ΔΔCt method. MiR-21 and miR-16 were stably expressed in whole milk collected within month 2 of lactation from four mothers. Analysis of lipids and skim milk revealed that miR-146b and let-7d were better references in both fractions. Time series (5H-23H) allowed the identification of a set of three endogenous reference genes (hsa-let-7d, hsa-let-7g and miR-146b) to normalize raw quantification cycle (Cq) data. We identified a daily oscillation of miR-16-5p. Our assay allows exploring miRNA levels of breast milk from mother with preterm baby collected in time series over 48-72 hours.

The electromagnetic multipole moments of the charged open-flavor {Z}_{\\bar{c}q} states

NASA Astrophysics Data System (ADS)

Azizi, K.; Özdem, U.

2018-05-01

The electromagnetic multipole moments of the open-flavor {Z}\\bar{cq} states are investigated by assuming a diquark–antidiquark picture for their internal structure and quantum numbers {J}{PC}={1}+- for their spin-parity. In particular, their magnetic and quadrupole moments are extracted in the framework of light-cone QCD sum rule by the help of the photon distribution amplitudes. The electromagnetic multipole moments of the open-flavor {Z}\\bar{cq} states are important dynamical observables, which encode valuable information on their underlying structure. The results obtained for the magnetic moments of different structures are considerably large and can be measured in future experiments. We obtain very small values for the quadrupole moments of {Z}\\bar{cq} states indicating a nonspherical charge distribution.

Fern-synthesized nanoparticles in the fight against malaria: LC/MS analysis of Pteridium aquilinum leaf extract and biosynthesis of silver nanoparticles with high mosquitocidal and antiplasmodial activity.

PubMed

Panneerselvam, Chellasamy; Murugan, Kadarkarai; Roni, Mathath; Aziz, Al Thabiani; Suresh, Udaiyan; Rajaganesh, Rajapandian; Madhiyazhagan, Pari; Subramaniam, Jayapal; Dinesh, Devakumar; Nicoletti, Marcello; Higuchi, Akon; Alarfaj, Abdullah A; Munusamy, Murugan A; Kumar, Suresh; Desneux, Nicolas; Benelli, Giovanni

2016-03-01

Malaria remains a major public health problem due to the emergence and spread of Plasmodium falciparum strains resistant to chloroquine. There is an urgent need to investigate new and effective sources of antimalarial drugs. This research proposed a novel method of fern-mediated synthesis of silver nanoparticles (AgNP) using a cheap plant extract of Pteridium aquilinum, acting as a reducing and capping agent. AgNP were characterized by UV-vis spectrophotometry, Fourier transform infrared (FTIR) spectroscopy, energy-dispersive X-ray spectroscopy (EDX), and X-ray diffraction (XRD). Phytochemical analysis of P. aquilinum leaf extract revealed the presence of phenols, alkaloids, tannins, flavonoids, proteins, carbohydrates, saponins, glycosides, steroids, and triterpenoids. LC/MS analysis identified at least 19 compounds, namely pterosin, hydroquinone, hydroxy-acetophenone, hydroxy-cinnamic acid, 5, 7-dihydroxy-4-methyl coumarin, trans-cinnamic acid, apiole, quercetin 3-glucoside, hydroxy-L-proline, hypaphorine, khellol glucoside, umbelliferose, violaxanthin, ergotamine tartrate, palmatine chloride, deacylgymnemic acid, methyl laurate, and palmitoyl acetate. In DPPH scavenging assays, the IC50 value of the P. aquilinum leaf extract was 10.04 μg/ml, while IC50 of BHT and rutin were 7.93 and 6.35 μg/ml. In mosquitocidal assays, LC50 of P. aquilinum leaf extract against Anopheles stephensi larvae and pupae were 220.44 ppm (larva I), 254.12 ppm (II), 302.32 ppm (III), 395.12 ppm (IV), and 502.20 ppm (pupa). LC50 of P. aquilinum-synthesized AgNP were 7.48 ppm (I), 10.68 ppm (II), 13.77 ppm (III), 18.45 ppm (IV), and 31.51 ppm (pupa). In the field, the application of P. aquilinum extract and AgNP (10 × LC50) led to 100 % larval reduction after 72 h. Both the P. aquilinum extract and AgNP reduced longevity and fecundity of An. stephensi adults. Smoke toxicity experiments conducted against An. stephensi adults showed that P. aquilinum leaf-, stem-, and root-based coils evoked mortality rates comparable to the permethrin-based positive control (57, 50, 41, and 49 %, respectively). Furthermore, the antiplasmodial activity of P. aquilinum leaf extract and green-synthesized AgNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of P. falciparum. IC50 of P. aquilinum were 62.04 μg/ml (CQ-s) and 71.16 μg/ml (CQ-r); P. aquilinum-synthesized AgNP achieved IC50 of 78.12 μg/ml (CQ-s) and 88.34 μg/ml (CQ-r). Overall, our results highlighted that fern-synthesized AgNP could be candidated as a new tool against chloroquine-resistant P. falciparum and different developmental instars of its primary vector An. stephensi. Further research on nanosynthesis routed by the LC/MS-identified constituents is ongoing.

Asiago spectroscopic classification of ASAS-SN18ck, ASAS-SN18cp, ASAS-SN18cq and ASASSN-18cj

NASA Astrophysics Data System (ADS)

Tomasella, L.; Benetti, S.; Cappellaro, E.; Turatto, M.

2018-02-01

The Asiago Transient Classification Program (Tomasella et al. 2014, AN, 335, 841) reports the spectroscopic classification of ASAS-SN18ck, ASAS-SN18cp, ASAS-SN18cq and ASASSN-18cj, discovered during the ongoing All Sky Automated Survey for SuperNovae (ASAS-SN, Shappee et al. 2014, Atel #11178).

Synthesis of nutrient and sediment export patterns in the Chesapeake Bay watershed: Complex and non-stationary concentration-discharge relationships.

PubMed

Zhang, Qian

2018-03-15

Derived from river monitoring data, concentration-discharge (C-Q) relationships are useful indicators of riverine export dynamics. A top-down synthesis of C-Q patterns was conducted for suspended sediment (SS), total phosphorus (TP), and total nitrogen (TN) for nine major tributaries (15 monitoring sites) to Chesapeake Bay, which represent diverse characteristics in terms of land use, physiography, and hydrological settings. Model coefficients from the recently-developed Weighted Regressions on Time, Discharge, and Season (WRTDS) method were used to make informative interpretation of C-Q relationships. Unlike many previous C-Q studies that focused on stormflow conditions, this approach allows simultaneous examination of various discharge conditions within an uncertainty framework. This synthesis on WRTDS coefficients (i.e., the sensitivity of concentration to discharge) has offered new insights on the complexity of watershed function. Results show that watershed export has been dominated by mobilization patterns for SS and TP (particulate-dominated species) and chemostasis patterns for TN (dissolved-dominated species) under many river discharge conditions. Among nine possible modalities of low-flow vs. high-flow patterns, the three most frequent modalities are mobilization vs. mobilization (17 cases), chemostasis vs. mobilization (13 cases), and chemostasis vs. chemostasis (7 cases), representing 82% of all 45 watershed-constituent pairs. The general lack of dilution patterns may suggest that none of these constituents has been supply-limited in these watersheds. For many watershed-constituent combinations, results show clear temporal non-stationarity in C-Q relationships under selected time-invariant discharges, reflecting major changes in dominant watershed sources due to anthropogenic actions. These results highlight the potential pitfalls of assuming fixed C-Q relationships in the record. Overall, this work demonstrates the utility of WRTDS model coefficients for interpretation of river water-quality data and for generation of sensible hypotheses on dominant processes in different watersheds. The approach is readily adaptable to other river systems, where long-term discretely-sampled data are available, to decipher complex interactions between hydrological and biogeochemical processes. Copyright © 2017 Elsevier B.V. All rights reserved.

Legal rights of client councils and their role in policy of long-term care organisations in the Netherlands

PubMed Central

2011-01-01

Background Legislation demands the establishment of client councils in Dutch nursing homes and residential care facilities. The members of those councils are residents or their representatives. Client councils have the right to participate in the strategic management of long-term care facilities. More specifically, they need to be consulted regarding organisational issues and a right to consent on issues regarding daily living of residents, including CQ-index research. CQ-index research concerns a method that measures, analyses and report clients' experiences about the quality of care. Research questions were: 'Do client councils exercise their rights to be consulted and to give their consent?' and 'What is the role of client councils in the process of measuring clients' experiences with the CQ-index and what is their opinion about the CQ-index?' Methods Postal questionnaires were sent to members of 1,540 client councils of Dutch nursing homes and residential care facilities. The questionnaire focussed on background information and client councils' involvement in decision-making and strategic management. Results The response rate was 34% (n = 524). Most councils consisted of seven members (range: 5 to 12 members). One out of four members participating in the client councils were clients themselves. Although councils have a legal right to be consulted for organisational issues like finance, vision, annual report, and accommodation, less than half the councils (31-46%) reported that they exercised this right. The legal right to consent was perceived by 18 to 36% of the councils regarding client care issues like food and drink, complaints registration, respectful treatment, and activities. For CQ-index research, only 18% of the client councils perceived a right to consent. Their rights to choose an approved contractor -who performs CQ-index research- and indicating improvement priorities, were hardly used. Conclusions Client councils play a rather passive role in determining the policy on quality of long-term care. Therefore, specific attention and actions are needed to create a more proactive attitude in councils towards exercising their rights, which are already supported by legislation. PMID:21910899

A Neuroprotective Effect of the Glutamate Receptor Antagonist MK801 on Long-Term Cognitive and Behavioral Outcomes Secondary to Experimental Cerebral Malaria.

PubMed

de Miranda, Aline Silva; Brant, Fátima; Vieira, Luciene Bruno; Rocha, Natália Pessoa; Vieira, Érica Leandro Marciano; Rezende, Gustavo Henrique Souza; de Oliveira Pimentel, Pollyana Maria; Moraes, Marcio F D; Ribeiro, Fabíola Mara; Ransohoff, Richard M; Teixeira, Mauro Martins; Machado, Fabiana Simão; Rachid, Milene Alvarenga; Teixeira, Antônio Lúcio

2017-11-01

Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum infection, which can result in long-term cognitive and behavioral deficits despite successful anti-malarial therapy. Due to the substantial social and economic burden of CM, the development of adjuvant therapies is a scientific goal of highest priority. Apart from vascular and immune responses, changes in glutamate system have been reported in CM pathogenesis suggesting a potential therapeutic target. Based on that, we hypothesized that interventions in the glutamatergic system induced by blockage of N-methyl-D-aspartate (NMDA) receptors could attenuate experimental CM long-term cognitive and behavioral outcomes. Before the development of evident CM signs, susceptible mice infected with Plasmodium berghei ANKA (PbA) strain were initiated on treatment with dizocilpine maleate (MK801, 0.5 mg/kg), a noncompetitive NMDA receptor antagonist. On day 5 post-infection, mice were treated orally with a 10-day course chloroquine (CQ, 30 mg/kg). Control mice also received saline, CQ or MK801 + CQ therapy. After 10 days of cessation of CQ treatment, magnetic resonance images (MRI), behavioral and immunological assays were performed. Indeed, MK801 combined with CQ prevented long-term memory impairment and depressive-like behavior following successful PbA infection resolution. In addition, MK801 also modulated the immune system by promoting a balance of TH1/TH2 response and upregulating neurotrophic factors levels in the frontal cortex and hippocampus. Moreover, hippocampus abnormalities observed by MRI were partially prevented by MK801 treatment. Our results indicate that NMDA receptor antagonists can be neuroprotective in CM and could be a valuable adjuvant strategy for the management of the long-term impairment observed in CM.

Seasonal characteristics, formation mechanisms and source origins of PM2.5 in two megacities in Sichuan Basin, China

NASA Astrophysics Data System (ADS)

Wang, Huanbo; Tian, Mi; Chen, Yang; Shi, Guangming; Liu, Yuan; Yang, Fumo; Zhang, Leiming; Deng, Liqun; Yu, Jiayan; Peng, Chao; Cao, Xuyao

2018-01-01

To investigate the characteristics of PM2.5 and its major chemical components, formation mechanisms, and geographical origins in the two megacities, Chengdu (CD) and Chongqing (CQ), in Sichuan Basin of southwest China, daily PM2.5 samples were collected simultaneously at one urban site in each city for four consecutive seasons from autumn 2014 to summer 2015. Annual mean concentrations of PM2.5 were 67.0 ± 43.4 and 70.9 ± 41.4 µg m-3 at CD and CQ, respectively. Secondary inorganic aerosol (SNA) and organic matter (OM) accounted for 41.1 and 26.1 % of PM2.5 mass at CD, and 37.4 and 29.6 % at CQ, respectively. Seasonal variations of PM2.5 and major chemical components were significant, usually with the highest mass concentration in winter and the lowest in summer. Daily PM2.5 concentration exceeded the national air quality standard on 30 % of the sampling days at both sites, and most of the pollution events were at the regional scale within the basin formed under stagnant meteorological conditions. The concentrations of carbonaceous components were higher at CQ than CD, likely partially caused by emissions from the large number of motorcycles and the spraying processes used during automobile production in CQ. Heterogeneous reactions probably played an important role in the formation of SO42-, while both homogeneous and heterogeneous reactions contributed to the formation of NO3-. Geographical origins of emissions sources contributing to high PM2.5 masses at both sites were identified to be mainly distributed within the basin based on potential source contribution function (PSCF) analysis.

Correlation between in vitro and in vivo antimalarial activity of compounds using CQ-sensitive and CQ-resistant strains of Plasmodium falciparum and CQ-resistant strain of P. yoelii.

PubMed

Srivastava, Kumkum; Agarwal, Pooja; Soni, Awakash; Puri, S K

2017-07-01

Present efforts have been made to establish a correlation between in vitro and in vivo antimalarial activity using MIC, IC 50 and IC 90 values against CQ-sensitive (3D7) and CQ-resistant (K1) strains of Plasmodium falciparum and in vivo activity against Plasmodium yoelii. The method of discriminant function analysis (DFA) was applied to analyze the data. It was observed that in vitro IC 90 values against both 3D7 and K1 strains (p < 0.001) have strong correlation with in vivo curative activity. The respective IC 50 and IC 90 values of compounds, which cured mice (i.e., animals did not show recrudescence of parasitemia even after 60 days posttreatment), ranged between 3 and 14 nM and 14 and 186 nM against 3D7 and between 9 and 65 nM and 24 and 359 nM against the K1 strain of P. falciparum. Whereas the IC 50 and IC 90 values of compounds which exhibited in vivo suppressive activity in mice ranged between 10 and 307 nm and 61 and >965 nM, respectively, against 3D7 and 75 and >806 nm and 241 and >1232 nM against the K1 strain of P. falciparum. The findings suggest that IC 90 values against both 3D7 and K1 strains (p < 0.02) are the main contributors for the prediction of in vivo curative activity of a new molecule. Apart from this, a reasonable correlation between MIC and IC 50 values of compounds has also been established.

Distribution of Mutations Associated with Antifolate and Chloroquine Resistance among Imported Plasmodium vivax in the State of Qatar.

PubMed

Bansal, Devendra; Acharya, Anushree; Bharti, Praveen K; Abdelraheem, Mohamed H; Elmalik, Ashraf; Abosalah, Salem; Khan, Fahmi Y; ElKhalifa, Mohamed; Kaur, Hargobinder; Mohapatra, Pradyumna K; Sehgal, Rakesh; Idris, Mohammed A; Mahanta, Jagadish; Singh, Neeru; Babiker, Hamza A; Sultan, Ali A

2017-12-01

Plasmodium vivax is the most prevalent parasite worldwide, escalating by spread of drug resistance. Currently, in Qatar, chloroquine (CQ) plus primaquine are recommended for the treatment of P. vivax malaria. The present study examined the prevalence of mutations in dihydrofolate reductase ( dhfr ), dihydropteroate synthase ( dhps ) genes and CQ resistance transporter ( crt-o ) genes, associated with sulphadoxine-pyrimethamine (SP) and chloroquine resistance, among imported P. vivax cases in Qatar. Blood samples were collected from patients positive for P. vivax and seeking medical treatment at Hamad General Hospital, Doha, during 2013-2016. The Sanger sequencing method was performed to examine the single nucleotide polymorphisms in Pvdhfr , Pvdhps , and Pvcrt-o genes. Of 314 examined P. vivax isolates, 247 (78.7%), 294 (93.6%) and 261 (83.1%) were successfully amplified and sequenced for Pvdhfr , Pvdhps , and Pvcrt-o , respectively. Overall, 53.8% ( N = 133) carried mutant alleles (58R/117N) in Pvdhfr , whereas 77.2% ( N = 227) and 90% ( N = 235) isolates possessed wild type allele in Pvdhps and Pvcrt-o genes, respectively. In addition, a total of eleven distinct haplotypes were detected in Pvdhfr / Pvdhps genes. Interestingly, K10 insertion in the Pvcrt-o gene was observed only in patients originating from the Indian subcontinent. The results suggested that CQ remains an acceptable treatment regimen but further clinical data are required to assess the effectiveness of CQ and SP in Qatar to support the current national treatment guidelines. In addition, limited distribution of genetic polymorphisms associated with CQ and SP resistance observed in imported P. vivax infections, necessitates regular monitoring of drug resistant P. vivax malaria in Qatar.

The detection of pfcrt and pfmdr1 point mutations as molecular markers of chloroquine drug resistance, Pahang, Malaysia

PubMed Central

2012-01-01

Background Malaria is still a public health problem in Malaysia with chloroquine (CQ) being the first-line drug in the treatment policy of uncomplicated malaria. There is a scarcity in information about the magnitude of Plasmodium falciparum CQ resistance. This study aims to investigate the presence of single point mutations in the P. falciparum chloroquine-resistance transporter gene (pfcrt) at codons 76, 271, 326, 356 and 371 and in P. falciparum multi-drug resistance-1 gene (pfmdr1) at codons 86 and 1246, as molecular markers of CQ resistance. Methods A total of 75 P. falciparum blood samples were collected from different districts of Pahang state, Malaysia. Single nucleotide polymorphisms in pfcrt gene (codons 76, 271, 326, 356 and 371) and pfmdr1 gene (codons 86 and 1246) were analysed by using mutation-specific nested PCR and restriction fragment length polymorphism (PCR-RFLP) methods. Results Mutations of pfcrt K76T and pfcrt R371I were the most prevalent among pfcrt gene mutations reported by this study; 52% and 77%, respectively. Other codons of the pfcrt gene and the positions 86 and 1246 of the pfmdr1 gene were found mostly of wild type. Significant associations of pfcrt K76T, pfcrt N326S and pfcrt I356T mutations with parasitaemia were also reported. Conclusion The high existence of mutant pfcrt T76 may indicate the low susceptibility of P. falciparum isolates to CQ in Peninsular Malaysia. The findings of this study establish baseline data on the molecular markers of P. falciparum CQ resistance, which may help in the surveillance of drug resistance in Peninsular Malaysia. PMID:22853645

The antimalarial activity of Ru–chloroquine complexes against resistant Plasmodium falciparum is related to lipophilicity, basicity, and heme aggregation inhibition ability near water/n-octanol interfaces

PubMed Central

Martínez, Alberto; Rajapakse, Chandima S. K.; Jalloh, Dalanda; Dautriche, Cula

2012-01-01

We have measured water/n-octanol partition coefficients, pKa values, heme binding constants, and heme aggregation inhibition activity of a series of ruthenium–πarene–chloroquine (CQ) complexes recently reported to be active against CQ-resistant strains of Plasmodium falciparum. Measurements of heme aggregation inhibition activity of the metal complexes near water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ; we conclude that this modified method may be a better predictor of antimalarial potency than standard tests in aqueous acidic buffer. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied. PMID:19343380

The antimalarial activity of Ru-chloroquine complexes against resistant Plasmodium falciparum is related to lipophilicity, basicity, and heme aggregation inhibition ability near water/n-octanol interfaces.

PubMed

Martínez, Alberto; Rajapakse, Chandima S K; Jalloh, Dalanda; Dautriche, Cula; Sánchez-Delgado, Roberto A

2009-08-01

We have measured water/n-octanol partition coefficients, pK(a) values, heme binding constants, and heme aggregation inhibition activity of a series of ruthenium-pi-arene-chloroquine (CQ) complexes recently reported to be active against CQ-resistant strains of Plasmodium falciparum. Measurements of heme aggregation inhibition activity of the metal complexes near water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ; we conclude that this modified method may be a better predictor of antimalarial potency than standard tests in aqueous acidic buffer. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied.

Combating Piracy in the Gulf of Guinea

DTIC Science & Technology

2015-02-01

stretching from Cape Verde to An- gola (Figure 1), is the main transit hub and facilitator to the region’s rapid economic growth which has averaged...tio n in 1 5 yr s Sm al l C ra ft A cq ui si tio n in 1 0 yr s So ur ce s of A cq ui si tio n Benin 65 7 7 China, France Cabo Verde 530 2 3

Joint Service Aircrew Mask (JSAM) Extended Wear Comfort Evaluation

DTIC Science & Technology

2009-10-01

JSAM eyeglass frames containing his optical prescription. Comfort Questionnaire (CQ). The CQ was completed ten times as scheduled by the USAF...and comfort of the JSAM while wearing eyeglass frames was very acceptable. Their ability to see was reported as acceptable. No fogging of the...Performance Wing acceleration and altitude test subject panels. The subjects were male, ranged in age from 28-39 years, physically fit , and considered

Role of G-protein-coupled receptor-related genes in insecticide resistance of the mosquito, Culex quinquefasciatus.

PubMed

Li, Ting; Liu, Lena; Zhang, Lee; Liu, Nannan

2014-09-29

G-protein-coupled receptors regulate signal transduction pathways and play diverse and pivotal roles in the physiology of insects, however, the precise function of GPCRs in insecticide resistance remains unclear. Using quantitative RT-PCR and functional genomic methods, we, for the first time, explored the function of GPCRs and GPCR-related genes in insecticide resistance of mosquitoes, Culex quinquefasciatus. A comparison of the expression of 115 GPCR-related genes at a whole genome level between resistant and susceptible Culex mosquitoes identified one and three GPCR-related genes that were up-regulated in highly resistant Culex mosquito strains, HAmCq(G8) and MAmCq(G6), respectively. To characterize the function of these up-regulated GPCR-related genes in resistance, the up-regulated GPCR-related genes were knockdown in HAmCq(G8) and MAmCq(G6) using RNAi technique. Knockdown of these four GPCR-related genes not only decreased resistance of the mosquitoes to permethrin but also repressed the expression of four insecticide resistance-related P450 genes, suggesting the role of GPCR-related genes in resistance is involved in the regulation of resistance P450 gene expression. This results help in understanding of molecular regulation of resistance development in Cx. quinquefasciatus.

Uncertainty quantification metrics for whole product life cycle cost estimates in aerospace innovation

NASA Astrophysics Data System (ADS)

Schwabe, O.; Shehab, E.; Erkoyuncu, J.

2015-08-01

The lack of defensible methods for quantifying cost estimate uncertainty over the whole product life cycle of aerospace innovations such as propulsion systems or airframes poses a significant challenge to the creation of accurate and defensible cost estimates. Based on the axiomatic definition of uncertainty as the actual prediction error of the cost estimate, this paper provides a comprehensive overview of metrics used for the uncertainty quantification of cost estimates based on a literature review, an evaluation of publicly funded projects such as part of the CORDIS or Horizon 2020 programs, and an analysis of established approaches used by organizations such NASA, the U.S. Department of Defence, the ESA, and various commercial companies. The metrics are categorized based on their foundational character (foundations), their use in practice (state-of-practice), their availability for practice (state-of-art) and those suggested for future exploration (state-of-future). Insights gained were that a variety of uncertainty quantification metrics exist whose suitability depends on the volatility of available relevant information, as defined by technical and cost readiness level, and the number of whole product life cycle phases the estimate is intended to be valid for. Information volatility and number of whole product life cycle phases can hereby be considered as defining multi-dimensional probability fields admitting various uncertainty quantification metric families with identifiable thresholds for transitioning between them. The key research gaps identified were the lacking guidance grounded in theory for the selection of uncertainty quantification metrics and lacking practical alternatives to metrics based on the Central Limit Theorem. An innovative uncertainty quantification framework consisting of; a set-theory based typology, a data library, a classification system, and a corresponding input-output model are put forward to address this research gap as the basis for future work in this field.

Electroglottographic parameterization of the effects of gender, vowel and phonatory registers on vocal fold vibratory patterns: an Indian perspective.

PubMed

Paul, Nilanjan; Kumar, Suman; Chatterjee, Indranil; Mukherjee, Biswarup

2011-01-01

In-depth study on laryngeal biomechanics and vocal fold vibratory patterns reveal that a single vibratory cycle can be divided into two major phases, the closed and open phase, which is subdivided into opening and closing phases. Studies reveal that the relative time course of abduction and adduction, which in turn is dependent on the relative relaxing and tensing of the vocal fold cover and body, to be the determining factor in production of a particular vocal register like the modal (or chest), falsetto, glottal fry registers. Studies further point out Electroglottography to be particularly suitable for the study of vocal vibratory patterns during register changes. However, to date, there has been limited study on quantitative parameterization of EGG wave form in vocal fry register. Moreover, contradictory findings abound in literature regarding effects of gender and vowel types on vocal vibratory patterns, especially during phonation at different registers. The present study endeavors to find out the effects of vowel and gender differences on the vocal fold vibratory patterns in different registers and how these would be reflected in standard EGG parameters of Contact Quotient (CQ) and Contact Index (CI), taking into consideration the Indian sociolinguistic context. Electroglottographic recordings of 10 young adults (5 males and 5 females) were taken while the subjects phonated the three vowels /a/,/i/,/u/ each in two vocal registers, modal and vocal fry. Obtained raw EGG were further normalized using the Derived EGG algorithm and theCQ and CI values were derived. Obtained data were subject to statistical analysis using the 3-way ANOVA with gender, vowel and vocal register as the three variables. Post-hoc Dunnett C multiple comparison analysis were also performed. Results reveal that CQ values are significantly higher in vocal fry than modal phonation for both males and females, indicating a relatively hyperconstricted vocal system during vocal fry. The males have significantly greater CQ values than females both at modal and vocal fry phonations which indicate that the males are predisposed to greater vocal fold constriction. Females demonstrated no significant increase in CI values in vocal fry state; and in some cases actually decrease in the CI values which suggest an inherently distinct vocal fold physiological adjustment from that in males. No vowel effects were found in any conditions. Perturbation values (CQP and CIP) are significantly more in vocal fry register than in modal register, and the increase was more in case of females than males. The findings give strong evidence to certain hypotheses in literature regarding effects of vowel, gender and phonatory register on vocal fold vibratory patterns.

Neuropsychological profiles of children with cerebral palsy.

PubMed

Stadskleiv, Kristine; Jahnsen, Reidun; Andersen, Guro L; von Tetzchner, Stephen

2018-02-01

To explore factors contributing to variability in cognitive functioning in children with cerebral palsy (CP). A geographical cohort of 70 children with CP was assessed with tests of language comprehension, visual-spatial reasoning, attention, working memory, memory, and executive functioning. Mean age was 9;9 years (range 5;1-17;7), 54.3% were girls, and 50.0% had hemiplegic, 25.7% diplegic, 12.9% quadriplegic, and 11.4% dyskinetic CP. For the participants with severe motor impairments, assessments were adapted for gaze pointing. A cognitive quotient (CQ) was computed. Mean CQ was 78.5 (range 19-123). Gross motor functioning, epilepsy, and type of brain injury explained 35.5% of the variance in CQ (F = 10.643, p = .000). Twenty-four percent had an intellectual disability, most of them were children with quadriplegic CP. Verbal comprehension and perceptual reasoning scores did only differ for the 21% with an uneven profile, of whom two-thirds had challenges with perceptual reasoning.

Measuring patients' experiences with rheumatic care: the consumer quality index rheumatoid arthritis.

PubMed

Zuidgeest, Marloes; Sixma, Herman; Rademakers, Jany

2009-12-01

Rheumatologists and other caregivers can learn from patients’ experiences with the quality of care that can be measured with the CQ-index Rheumatoid Arthritis (CQ-index RA) survey. Patients with RA (n = 590) received this survey were they rated their actual experiences and what they find important in rheumatic healthcare. Descriptive analyses and psychometric methods were used to test the reliability. The response rate was 69%. The items in the pilot instrument could be grouped into 10 scales (α ranged from 0.77 to 0.94). The most important quality aspects according to patients concerned the alertness when prescribing medication. Providing patients with information on a special website of the hospital about RA was the highest quality improvement aspect. The results of this study show that the CQ-index RA is a reliable instrument for quality assessment from the patients’ perspective. The instrument provides rheumatologists and other caregivers with feedback for service improvement initiatives.

Electric double-layer capacitance between an ionic liquid and few-layer graphene.

PubMed

Uesugi, Eri; Goto, Hidenori; Eguchi, Ritsuko; Fujiwara, Akihiko; Kubozono, Yoshihiro

2013-01-01

Ionic-liquid gates have a high carrier density due to their atomically thin electric double layer (EDL) and extremely large geometrical capacitance Cg. However, a high carrier density in graphene has not been achieved even with ionic-liquid gates because the EDL capacitance CEDL between the ionic liquid and graphene involves the series connection of Cg and the quantum capacitance Cq, which is proportional to the density of states. We investigated the variables that determine CEDL at the molecular level by varying the number of graphene layers n and thereby optimising Cq. The CEDL value is governed by Cq at n < 4, and by Cg at n > 4. This transition with n indicates a composite nature for CEDL. Our finding clarifies a universal principle that determines capacitance on a microscopic scale, and provides nanotechnological perspectives on charge accumulation and energy storage using an ultimately thin capacitor.

Electric double-layer capacitance between an ionic liquid and few-layer graphene

PubMed Central

Uesugi, Eri; Goto, Hidenori; Eguchi, Ritsuko; Fujiwara, Akihiko; Kubozono, Yoshihiro

2013-01-01

Ionic-liquid gates have a high carrier density due to their atomically thin electric double layer (EDL) and extremely large geometrical capacitance Cg. However, a high carrier density in graphene has not been achieved even with ionic-liquid gates because the EDL capacitance CEDL between the ionic liquid and graphene involves the series connection of Cg and the quantum capacitance Cq, which is proportional to the density of states. We investigated the variables that determine CEDL at the molecular level by varying the number of graphene layers n and thereby optimising Cq. The CEDL value is governed by Cq at n < 4, and by Cg at n > 4. This transition with n indicates a composite nature for CEDL. Our finding clarifies a universal principle that determines capacitance on a microscopic scale, and provides nanotechnological perspectives on charge accumulation and energy storage using an ultimately thin capacitor. PMID:23549208

Biological and haematological safety profile of oral amodiaquine and chloroquine in healthy volunteers with or without Plasmodium falciparum infection in northeast Tanzania.

PubMed

Massaga, J J; Lusingu, J P; Makunde, R; Malebo, H M; Chile, M M; Akida, J A; Lemnge, M M; Rønn, A M; Theander, T G; Bygbjerg, I C; Kitua, A Y

2008-07-01

Amodiaquine (AQ), an effective antimalarial drug for uncomplicated malaria, has been greatly restricted after cases of life-threatening agranulocytosis and hepatic toxicity during prophylactic use. We conducted a hospital based open-label randomised clinical trial in 40 indigenous semi-immune healthy adult male volunteers with and without malaria parasites. The objective was to collect data on biological and haematological safety, tolerability, and parasitological efficacy to serve as baseline in the evaluation of the effectiveness of AQ preventive intermittent treatment against malaria morbidity in infants. Volunteers were stratified according to parasitaemia status and randomly assigned 20 participants each arm to three days treatment with either AQ or chloroquine (CQ). The level of difference of selected haematological and hepatological values pre-and post-trial were marginal and within the normal limits. Clinical adverse effects mostly mild and transient were noticed in 33.3% CQ treated-aparasitaemic, 23.8% of CQ treated-parasitaemic, 28.6% ofAQ-treated parasitaemic and 14.3% of aparasitaemic receiving AQ. Amodiaquine attained 100% parasitological clearance rate versus 70% in CQ-treated volunteers. The findings indicate that there was no agranulocytosis or hepatic toxicity suggesting that AQ may pose no public health risk in its wide therapeutic dosage uses. Larger studies are needed to exclude rare adverse effects.

Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains.

PubMed

Tasso, Bruno; Novelli, Federica; Tonelli, Michele; Barteselli, Anna; Basilico, Nicoletta; Parapini, Silvia; Taramelli, Donatella; Sparatore, Anna; Sparatore, Fabio

2015-09-01

Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria-related deaths, has developed resistance against this drug. Twenty-seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro-2H-quinolizine and 1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one, were synthesized and tested for activity against D-10 (CQ-susceptible) and W-2 (CQ-resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub-micromolar IC50 values. Eleven compounds were found to be 2.7- to 13.4-fold more potent than CQ against the W-2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC-1 and HepG2) along with easier synthetic accessibility. Replacement of the 4-NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites.

PubMed

Hunt, Paul; Afonso, Ana; Creasey, Alison; Culleton, Richard; Sidhu, Amar Bir Singh; Logan, John; Valderramos, Stephanie G; McNae, Iain; Cheesman, Sandra; do Rosario, Virgilio; Carter, Richard; Fidock, David A; Cravo, Pedro

2007-07-01

Artemisinin- and artesunate-resistant Plasmodium chabaudi mutants, AS-ART and AS-ATN, were previously selected from chloroquine-resistant clones AS-30CQ and AS-15CQ respectively. Now, a genetic cross between AS-ART and the artemisinin-sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS-30CQ and AS-ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS-ATN to artemisinin derivates, the other cannot account solely for the resistance of AS-ART, relative to the responses of its sensitive progenitor AS-30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug-response phenotype was not genetically stable. No mutations in the UBP-1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed.

Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites§

PubMed Central

Hunt, Paul; Afonso, Ana; Creasey, Alison; Culleton, Richard; Sidhu, Amar Bir Singh; Logan, John; Valderramos, Stephanie G; McNae, Iain; Cheesman, Sandra; do Rosario, Virgilio; Carter, Richard; Fidock, David A; Cravo, Pedro

2007-01-01

Artemisinin- and artesunate-resistant Plasmodium chabaudi mutants, AS-ART and AS-ATN, were previously selected from chloroquine-resistant clones AS-30CQ and AS-15CQ respectively. Now, a genetic cross between AS-ART and the artemisinin-sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS-30CQ and AS-ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS-ATN to artemisinin derivates, the other cannot account solely for the resistance of AS-ART, relative to the responses of its sensitive progenitor AS-30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug-response phenotype was not genetically stable. No mutations in the UBP-1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed. PMID:17581118

Military to civilian questionnaire: a measure of postdeployment community reintegration difficulty among veterans using Department of Veterans Affairs medical care.

PubMed

Sayer, Nina A; Frazier, Patricia; Orazem, Robert J; Murdoch, Maureen; Gravely, Amy; Carlson, Kathleen F; Hintz, Samuel; Noorbaloochi, Siamak

2011-12-01

The primary objective of this study was to describe the development, reliability, and construct validity of scores on the Military to Civilian Questionnaire (M2C-Q), a 16-item self-report measure of postdeployment community reintegration difficulty. We surveyed a national, stratified sample of 1,226 Iraq and Afghanistan veterans who used U.S. Department of Veterans Affairs (VA) medical care; 745 completed the M2C-Q and validated mental health screening measures. All analyses were based on weighted estimates. The internal consistency of the M2C-Q was .95 in this sample. Factor analyses indicated a single total score was the best-fitting model. Total scores were associated with measures theoretically related to reintegration difficulties including perception of overall difficulty readjusting back into civilian life (R(2) = .49), probable PTSD (d = 1.07), probable problem drug or alcohol use (d = 0.34), and overall mental health (r = -.83). Subgroup analyses revealed a similar pattern of findings in those who screened negative for PTSD. Nonwhite and unemployed veterans reported greater community reintegration difficulty (d = 0.20 and 0.45, respectively). Findings offer preliminary support for the reliability and construct validity of M2C-Q scores. Published 2011. This article is a US Government work and is in the public domain in the USA.

Comparison of intermittent preventive treatment with chemoprophylaxis for the prevention of malaria during pregnancy in Mali.

PubMed

Kayentao, Kassoum; Kodio, Mamoudou; Newman, Robert D; Maiga, Hamma; Doumtabe, Didier; Ongoiba, Aissata; Coulibaly, Drissa; Keita, Abdoul Salam; Maiga, Bouboucar; Mungai, Mary; Parise, Monica E; Doumbo, Ogobara

2005-01-01

Malaria during pregnancy contributes to maternal anemia and low birth weight. In East Africa, several studies have demonstrated that intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) is more efficacious than weekly chloroquine (CQ) chemoprophylaxis in preventing these adverse consequences. To our knowledge, there are no published trials evaluating IPT in West Africa. We undertook a randomized controlled trial of weekly CQ chemoprophylaxis, 2-dose IPT with CQ, and 2-dose IPT with SP; 1163 women were enrolled. In multivariate analyses, when compared with weekly CQ, IPT/SP was associated with a reduction in third-trimester anemia (adjusted odds ratio [AOR], 0.49; P<.001), placental parasitemia (AOR, 0.69; P=.04), and low birth weight (<2500 g) (AOR, 0.69; P=.04). The prevalence of placental infection remained unexpectedly high, even in the IPT/SP group (24.5%), possibly because of the intensity of seasonal transmission. There were no significant differences in stillbirths, spontaneous abortions, or neonatal deaths among the 3 groups. In Mali, IPT with SP appears more efficacious than weekly chloroquine chemoprophylaxis in preventing malaria during pregnancy. These data support World Health Organization recommendations to administer at least 2 doses of IPT during pregnancy. In intensely seasonal transmission settings in Mali, >2 doses may be required to prevent placental reinfection prior to delivery.

Method-Unifying View of Loop-Formation Kinetics in Peptide and Protein Folding.

PubMed

Jacob, Maik H; D'Souza, Roy N; Schwarzlose, Thomas; Wang, Xiaojuan; Huang, Fang; Haas, Elisha; Nau, Werner M

2018-04-26

Protein folding can be described as a probabilistic succession of events in which the peptide chain forms loops closed by specific amino acid residue contacts, herein referred to as loop nodes. To measure loop rates, several photophysical methods have been introduced where a pair of optically active probes is incorporated at selected chain positions and the excited probe undergoes contact quenching (CQ) upon collision with the second probe. The quenching mechanisms involved triplet-triplet energy transfer, photoinduced electron transfer, and collision-induced fluorescence quenching, where the fluorescence of Dbo, an asparagine residue conjugated to 2,3-diazabicyclo[2.2.2]octane, is quenched by tryptophan. The discrepancy between the loop rates afforded from these three CQ techniques has, however, remained unresolved. In analyzing this discrepancy, we now report two short-distance FRET methods where Dbo acts as an energy acceptor in combination with tryptophan and naphtylalanine, two donors with largely different fluorescence lifetimes of 1.3 and 33 ns, respectively. Despite the different quenching mechanisms, the rates from FRET and CQ methods were, surprisingly, of comparable magnitude. This combination of FRET and CQ data led to a unifying physical model and to the conclusion that the rate of loop formation in folding reactions varies not only with the kind and number of residues that constitute the chain but also in particular with the size and properties of the residues that constitute the loop node.

Expression of Geochemical Controls on Water Quality in Loch Vale, Rocky Mountain National Park

NASA Astrophysics Data System (ADS)

Podzorski, H.; Navarre-Sitchler, A.; Stets, E.; Clow, D. W.

2017-12-01

Relationships between concentrations of rock weathering products and discharge provide insight into the interactions between climate and solute dynamics. This concentration-discharge (C-Q) relationship is especially interesting in high alpine regions, due to their susceptibility to changes in the timing and magnitude of snowmelt. Previous studies looking at C-Q relationships have concluded that concentrations of conservative solutes remain relatively constant as discharge varies; however, these results may be due to relatively small sample sizes, especially at higher discharge values. Using water chemistry data collected regularly by the U.S. Geological Survey from Loch Vale, a high-elevation catchment in Rocky Mountain National Park, C-Q relationships were examined to determine possible geochemical controls on stream solute concentrations. A record of over 20 years of C-Q data resulted in a pattern that shows little variation in conservative solute concentrations during base flow and larger variations in concentrations around peak discharge. This observed pattern is consistent with accumulation of solutes in pore water during base flow, which are then flushed out and diluted by snowmelt. Further evidence of this flushing out mechanism is found in patterns of hysteresis that are present in annual C-Q relationships. Before peak discharge, concentrations of weathering products are higher than after peak discharge at similar values of discharge. Based on these observations, we hypothesize that the geochemical processes controlling stream chemistry vary by season. During the winter, solute concentrations are transport-limited due to slow subsurface flushing resulting in concentrations that are effectively constant and close to equilibrium. During the spring and summer, concentrations drop sharply after peak discharge due to a combination of dilution and reaction-limited processes under conditions with faster subsurface flow and continued snowmelt. This study provides insight into seasonal geochemical controls on conservative solute concentrations that can be overlooked with small, or seasonally biased, data sets.

Effect of different photoinitiators and reducing agents on cure efficiency and color stability of resin-based composites using different LED wavelengths.

PubMed

de Oliveira, Dayane Carvalho Ramos Salles; Rocha, Mateus Garcia; Gatti, Alexandre; Correr, Americo Bortolazzo; Ferracane, Jack Liborio; Sinhoret, Mario Alexandre Coelho

2015-12-01

To evaluate the effect of photoinitiators and reducing agents on cure efficiency and color stability of resin-based composites using different LED wavelengths. Model resin-based composites were associated with diphenyl(2,4,6-trimethylbenzoyl) phosphine oxide (TPO), phenylbis(2,4,6-trimethylbenzoyl) phosphine oxide (BAPO) or camphorquinone (CQ) associated with 2-(dimethylamino) ethyl methacrylate (DMAEMA), ethyl 4-(dimethyamino) benzoate (EDMAB) or 4-(N,N-dimethylamino) phenethyl alcohol (DMPOH). A narrow (Smartlite, Dentisply) and a broad spectrum (Bluephase G2, Ivoclar Vivadent) LEDs were used for photo-activation (20 J/cm(2)). Fourier transform infrared spectroscopy (FT-IR) was used to evaluate the cure efficiency for each composite, and CIELab parameters to evaluated color stability (ΔE00) after aging. The UV-vis absorption spectrophotometric analysis of each photoinitiator and reducing agent was determined. Data were analyzed using two-way ANOVA and Tukey's test for multiple comparisons (α=0.05). Higher cure efficiency was found for type-I photoinitiators photo-activated with a broad spectrum light, and for CQ-systems with a narrow band spectrum light, except when combined with an aliphatic amine (DMAEMA). Also, when combined with aromatic amines (EDMAB and DMPOH), similar cure efficiency with both wavelength LEDs was found. TPO had no cure efficiency when light-cured exclusively with a blue narrowband spectrum. CQ-systems presented higher color stability than type-I photoinitiators, especially when combined with DMPOH. After aging, CQ-based composites became more yellow and BAPO and TPO lighter and less yellow. However, CQ-systems presented higher color stability than type-I photoinitiators, as BAPO- and TPO-, despite their higher cure efficiency when photo-activated with corresponding wavelength range. Color matching is initially important, but color change over time will be one of the major reasons for replacing esthetic restorations; despite the less yellowing of these alternative photoinitiators, camphorquinone presented higher color stability. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evolution of Fitness Cost-Neutral Mutant PfCRT Conferring P. falciparum 4-Aminoquinoline Drug Resistance Is Accompanied by Altered Parasite Metabolism and Digestive Vacuole Physiology

PubMed Central

Gabryszewski, Stanislaw J.; Dhingra, Satish K.; Lewis, Ian A.; Callaghan, Paul S.; Hassett, Matthew R.; Siriwardana, Amila; Henrich, Philipp P.; Lee, Andrew H.; Gnädig, Nina F.; Musset, Lise; Llinás, Manuel; Egan, Timothy J.; Roepe, Paul D.

2016-01-01

Southeast Asia is an epicenter of multidrug-resistant Plasmodium falciparum strains. Selective pressures on the subcontinent have recurrently produced several allelic variants of parasite drug resistance genes, including the P. falciparum chloroquine resistance transporter (pfcrt). Despite significant reductions in the deployment of the 4-aminoquinoline drug chloroquine (CQ), which selected for the mutant pfcrt alleles that halted CQ efficacy decades ago, the parasite pfcrt locus is continuously evolving. This is highlighted by the presence of a highly mutated allele, Cam734 pfcrt, which has acquired the singular ability to confer parasite CQ resistance without an associated fitness cost. Here, we used pfcrt-specific zinc-finger nucleases to genetically dissect this allele in the pathogenic setting of asexual blood-stage infection. Comparative analysis of drug resistance and growth profiles of recombinant parasites that express Cam734 or variants thereof, Dd2 (the most common Southeast Asian variant), or wild-type pfcrt, revealed previously unknown roles for PfCRT mutations in modulating parasite susceptibility to multiple antimalarial agents. These results were generated in the GC03 strain, used in multiple earlier pfcrt studies, and might differ in natural isolates harboring this allele. Results presented herein show that Cam734-mediated CQ resistance is dependent on the rare A144F mutation that has not been observed beyond Southeast Asia, and reveal distinct impacts of this and other Cam734-specific mutations on CQ resistance and parasite growth rates. Biochemical assays revealed a broad impact of mutant PfCRT isoforms on parasite metabolism, including nucleoside triphosphate levels, hemoglobin catabolism and disposition of heme, as well as digestive vacuole volume and pH. Results from our study provide new insights into the complex molecular basis and physiological impact of PfCRT-mediated antimalarial drug resistance, and inform ongoing efforts to characterize novel pfcrt alleles that can undermine the efficacy of first-line antimalarial drug regimens. PMID:27832198

Chloroquine-Primaquine versus Chloroquine Alone to Treat Vivax Malaria in Afghanistan: An Open Randomized Superiority Trial.

PubMed

Awab, Ghulam Rahim; Imwong, Mallika; Bancone, Germana; Jeeyapant, Atthanee; Day, Nicholas P J; White, Nicholas J; Woodrow, Charles J

2017-12-01

Afghanistan's national guidelines recommend primaquine (PQ) for radical treatment of Plasmodium vivax malaria, but this is rarely implemented because of concerns over potential hemolysis in patients who have G6PD deficiency. Between August 2009 and February 2014, we conducted an open-label, randomized controlled trial of chloroquine (CQ) alone versus chloroquine plus primaquine (0.25 mg base/kg/day for 14 days) (CQ+PQ) in patients aged 6 months and older with microscopy confirmed P. vivax infection. In the CQ+PQ group, G6PD deficiency was excluded by fluorescent spot testing. The primary outcome was P. vivax recurrence assessed by survival analysis over one year follow-up. Of 593 patients enrolled, 570 attended at or after 14 days of follow-up. Plasmodium vivax recurrences occurred in 37 (13.1%) of 282 patients in the CQ+PQ arm versus 86 (29.9%) of 288 in the CQ arm (Cox proportional hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.25-0.54) (intention-to-treat analysis). Protection against recurrence was greater in the first 6 months of follow-up (HR 0.082; 95% CI 0.029-0.23) than later (HR 0.65, 95% CI 0.41-1.03). Five of seven patients requiring hospital admission were considered possible cases of PQ-related hemolysis, and PQ was stopped in a further six; however, in none of these cases did hemoglobin fall by ≥ 2 g/dL or to below 7 g/dL, and genotyping did not detect any cases of Mediterranean variant G6PD deficiency. PQ 0.25 mg/kg/day for 14 days prevents relapse of P. vivax in Afghanistan. Patient visits during the first week may improve adherence. Implementation will require deployment of point-of-care phenotypic tests for G6PD deficiency.

Chloroquine–Primaquine versus Chloroquine Alone to Treat Vivax Malaria in Afghanistan: An Open Randomized Superiority Trial

PubMed Central

Awab, Ghulam Rahim; Imwong, Mallika; Bancone, Germana; Jeeyapant, Atthanee; Day, Nicholas P. J.; White, Nicholas J.; Woodrow, Charles J.

2017-01-01

Abstract. Afghanistan’s national guidelines recommend primaquine (PQ) for radical treatment of Plasmodium vivax malaria, but this is rarely implemented because of concerns over potential hemolysis in patients who have G6PD deficiency. Between August 2009 and February 2014, we conducted an open-label, randomized controlled trial of chloroquine (CQ) alone versus chloroquine plus primaquine (0.25 mg base/kg/day for 14 days) (CQ+PQ) in patients aged 6 months and older with microscopy confirmed P. vivax infection. In the CQ+PQ group, G6PD deficiency was excluded by fluorescent spot testing. The primary outcome was P. vivax recurrence assessed by survival analysis over one year follow-up. Of 593 patients enrolled, 570 attended at or after 14 days of follow-up. Plasmodium vivax recurrences occurred in 37 (13.1%) of 282 patients in the CQ+PQ arm versus 86 (29.9%) of 288 in the CQ arm (Cox proportional hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.25–0.54) (intention-to-treat analysis). Protection against recurrence was greater in the first 6 months of follow-up (HR 0.082; 95% CI 0.029–0.23) than later (HR 0.65, 95% CI 0.41–1.03). Five of seven patients requiring hospital admission were considered possible cases of PQ-related hemolysis, and PQ was stopped in a further six; however, in none of these cases did hemoglobin fall by ≥ 2 g/dL or to below 7 g/dL, and genotyping did not detect any cases of Mediterranean variant G6PD deficiency. PQ 0.25 mg/kg/day for 14 days prevents relapse of P. vivax in Afghanistan. Patient visits during the first week may improve adherence. Implementation will require deployment of point-of-care phenotypic tests for G6PD deficiency. PMID:29141719

Real-time polymerase chain reaction assay for the rapid detection and characterization of chloroquine-resistant Plasmodium falciparum malaria in returned travelers.

PubMed

Farcas, Gabriella A; Soeller, Rainer; Zhong, Kathleen; Zahirieh, Alireza; Kain, Kevin C

2006-03-01

Imported drug-resistant malaria is a growing problem in industrialized countries. Rapid and accurate diagnosis is essential to prevent malaria-associated mortality in returned travelers. However, outside of a limited number of specialized centers, the microscopic diagnosis of malaria is slow, unreliable, and provides little information about drug resistance. Molecular diagnostics have the potential to overcome these limitations. We developed and evaluated a rapid, real-time polymerase chain reaction (PCR) assay to detect Plasmodium falciparum malaria and chloroquine (CQ)-resistance determinants in returned travelers who are febrile. A real-time PCR assay based on detection of the K76T mutation in PfCRT (K76T) of P. falciparum was developed on a LightCycler platform (Roche). The performance characteristics of the real-time assay were compared with those of the nested PCR-restriction fragment-length polymorphism (RFLP) and the sequence analyses of samples obtained from 200 febrile returned travelers, who included 125 infected with P. falciparum (48 of whom were infected CQ-susceptible [K76] and 77 of whom were CQ-resistant [T76] P. falciparum), 22 infected with Plasmodium vivax, 10 infected with Plasmodium ovale, 3 infected with Plasmodium malariae malaria, and 40 infected with other febrile syndromes. All patient samples were coded, and all analyses were performed blindly. The real-time PCR assay detected multiple pfcrt haplotypes associated with CQ resistance in geographically diverse malaria isolates acquired by travelers. Compared with nested-PCR RFLP (the reference standard), the real-time assay was 100% sensitive and 96.2% specific for detection of the P. falciparum K76T mutation. This assay is rapid, sensitive, and specific for the detection and characterization of CQ-resistant P. falciparum malaria in returned travelers. This assay is automated, standardized, and suitable for routine use in clinical diagnostic laboratories.

The effects of chloroquine and verapamil on digestive vacuolar pH of P. falciparum either sensitive or resistant to chloroquine.

PubMed

Ursos, L M; Dzekunov, S M; Roepe, P D

2000-09-01

In the preceding paper, we present a novel method for measuring the digestive vacuolar pH (pH(vac)) of the malarial parasite Plasmodium falciparum, and show that, surprisingly, pH(vac) is lower for chloroquine resistant (CQR) Dd2 parasites relative to chloroquine sensitive (CQS) HB3. These data may have important consequences for elucidating mechanisms of antimalarial drug resistance and for developing new antimalarial therapy. Additional issues central to a better understanding of antimalarial pharmacology and antimalarial drug resistance require detailed comparative data on the effects of key drugs and other compounds on parasite biophysical parameters such as pH(vac), measured under close-to-physiologic conditions. Since the methods we develop in the previous paper allow us to record fluorescence signals from spatially well-defined regions of the living parasite while they are under continuous perfusion, it is relatively straightforward for us to test how antimalarial drugs (e. g. chloroquine, CQ) and other compounds (e.g. the chemoreversal agent verapamil [VPL]) affect pH(vac). In this paper, we measure both short term (i.e. initial perfusion conditions) and longer-term effects of CQ and VPL for living, intraerythrocytic CQS (HB3) and CQR (Dd2) malarial parasites under constant perfusion with physiologically relevant buffers. We find that VPL normalizes pH(vac) for Dd2 to a value near that measured for HB3, but has no effect on pH(vac) for HB3. Longer term CQ exposure is found to alter pH(vac) for HB3 but not Dd2, and short-term exposure to the drug has no significant effect in either strain. The results may help resolve longstanding debate regarding the effects of CQ and VPL on parasite physiology, and further support our evolving hypothesis for the mechanism of CQ resistance.

New quinoline derivatives demonstrate a promising antimalarial activity against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.

PubMed

Soares, Roberta Reis; da Silva, José Marcio Fernandes; Carlos, Bianca Cecheto; da Fonseca, Camila Campos; de Souza, Laila Salomé Araújo; Lopes, Fernanda Valério; de Paula Dias, Rafael Mafra; Moreira, Paulo Otávio Lourenço; Abramo, Clarice; Viana, Gustavo Henrique Ribeiro; de Pila Varotti, Fernando; da Silva, Adilson David; Scopel, Kézia Katiani Gorza

2015-06-01

Malaria continues to be an important public health problem in the world. Nowadays, the widespread parasite resistance to many drugs used in antimalarial therapy has made the effective treatment of cases and control of the disease a constant challenge. Therefore, the discovery of new molecules with good antimalarial activity and tolerance to human use can be really important in the further treatment of the disease. In this study we have investigated the antiplasmodial activity of 10 synthetic compounds derived from quinoline, five of them combined to sulfonamide and five to the hydrazine or hydrazide group. The compounds were evaluated according to their cytotoxicity against HepG2 and HeLa cell lines, their antimalarial activity against CQ-sensitive and CQ-resistant Plasmodium falciparum strains and, finally, their schizonticide blood action in mice infected with Plasmodium berghei NK65. The compounds exhibited no cytotoxic action in HepG2 and HeLa cell lines when tested up to a concentration of 100 μg/mL. In addition, the hydrazine or hydrazide derivative compounds were less cytotoxic against cell lines and more active against CQ-sensitive and CQ-resistant P. falciparum strains, showing high SI (>1000 when SI was calculated using the CC50 from the 3D7 strain as reference). When tested in vivo, the hydrazine derivative 1f compound showed activity against the development of blood parasites similar to that observed with CQ, the reference drug. Interestingly, the 1f compound demonstrated the best LipE value (4.84) among all those tested in vivo. Considering the in vitro and in vivo activities of the compounds studied here and the LipE values, we believe the 1f compound to be the most promising molecule for further studies in antimalarial chemotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Molecular Mechanisms for Drug Hypersensitivity Induced by the Malaria Parasite’s Chloroquine Resistance Transporter

PubMed Central

Baker, Eileen S.; Webster, Michael W.; Lehane, Adele M.; Shafik, Sarah H.; Martin, Rowena E.

2016-01-01

Mutations in the Plasmodium falciparum ‘chloroquine resistance transporter’ (PfCRT) confer resistance to chloroquine (CQ) and related antimalarials by enabling the protein to transport these drugs away from their targets within the parasite’s digestive vacuole (DV). However, CQ resistance-conferring isoforms of PfCRT (PfCRTCQR) also render the parasite hypersensitive to a subset of structurally-diverse pharmacons. Moreover, mutations in PfCRTCQR that suppress the parasite’s hypersensitivity to these molecules simultaneously reinstate its sensitivity to CQ and related drugs. We sought to understand these phenomena by characterizing the functions of PfCRTCQR isoforms that cause the parasite to become hypersensitive to the antimalarial quinine or the antiviral amantadine. We achieved this by measuring the abilities of these proteins to transport CQ, quinine, and amantadine when expressed in Xenopus oocytes and complemented this work with assays that detect the drug transport activity of PfCRT in its native environment within the parasite. Here we describe two mechanistic explanations for PfCRT-induced drug hypersensitivity. First, we show that quinine, which normally accumulates inside the DV and therewithin exerts its antimalarial effect, binds extremely tightly to the substrate-binding site of certain isoforms of PfCRTCQR. By doing so it likely blocks the normal physiological function of the protein, which is essential for the parasite’s survival, and the drug thereby gains an additional killing effect. In the second scenario, we show that although amantadine also sequesters within the DV, the parasite’s hypersensitivity to this drug arises from the PfCRTCQR-mediated transport of amantadine from the DV into the cytosol, where it can better access its antimalarial target. In both cases, the mutations that suppress hypersensitivity also abrogate the ability of PfCRTCQR to transport CQ, thus explaining why rescue from hypersensitivity restores the parasite’s sensitivity to this antimalarial. These insights provide a foundation for understanding clinically-relevant observations of inverse drug susceptibilities in the malaria parasite. PMID:27441371

Prevalence of Plasmodium falciparum Molecular Markers of Antimalarial Drug Resistance in a Residual Malaria Focus Area in Sabah, Malaysia

PubMed Central

Mohd Abd Razak, Mohd Ridzuan; Abdullah, Noor Rain; Sastu, Umi Rubiah; Imwong, Mallika; Muniandy, Prem Kumar; Saat, Muhammad Nor Farhan; Muhammad, Amirrudin; Jelip, Jenarun; Tikuson, Moizin; Yusof, Norsalleh; Rundi, Christina; Mudin, Rose Nani; Syed Mohamed, Ami Fazlin

2016-01-01

Chloroquine (CQ) and fansidar (sulphadoxine-pyrimethamine, SP) were widely used for treatment of Plasmodium falciparum for several decades in Malaysia prior to the introduction of Artemisinin-based Combination Therapy (ACT) in 2008. Our previous study in Kalabakan, located in south-east coast of Sabah showed a high prevalence of resistance to CQ and SP, suggesting the use of the treatment may no longer be effective in the area. This study aimed to provide a baseline data of antimalarial drug resistant markers on P. falciparum isolates in Kota Marudu located in the north-east coast of Sabah. Mutations on genes associated with CQ (pfcrt and pfmdr1) and SP (pfdhps and pfdhfr) were assessed by PCR amplification and restriction fragment length polymorphism. Mutations on the kelch13 marker (K13) associated with artemisinin resistance were determined by DNA sequencing technique. The assessment of pfmdr1 copy number variation associated with mefloquine resistant was done by real-time PCR technique. A low prevalence (6.9%) was indicated for both pfcrt K76T and pfmdr1 N86Y mutations. All P. falciparum isolates harboured the pfdhps A437G mutation. Prevalence of pfdhfr gene mutations, S108N and I164L, were 100% and 10.3%, respectively. Combining the different resistant markers, only two isolates were conferred to have CQ and SP treatment failure markers as they contained mutant alleles of pfcrt and pfmdr1 together with quintuple pfdhps/pfdhfr mutation (combination of pfdhps A437G+A581G and pfdhfr C59R+S108N+I164L). All P. falciparum isolates carried single copy number of pfmdr1 and wild type K13 marker. This study has demonstrated a low prevalence of CQ and SP resistance alleles in the study area. Continuous monitoring of antimalarial drug efficacy is warranted and the findings provide information for policy makers in ensuring a proper malaria control. PMID:27788228

Role of Pfmdr1 in In Vitro Plasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

PubMed Central

Wurtz, Nathalie; Fall, Bécaye; Pascual, Aurélie; Fall, Mansour; Baret, Eric; Camara, Cheikhou; Nakoulima, Aminata; Diatta, Bakary; Fall, Khadidiatou Ba; Mbaye, Pape Saliou; Diémé, Yaya; Bercion, Raymond; Wade, Boubacar

2014-01-01

The involvement of Pfmdr1 (Plasmodium falciparum multidrug resistance 1) polymorphisms in antimalarial drug resistance is still debated. Here, we evaluate the association between polymorphisms in Pfmdr1 (N86Y, Y184F, S1034C, N1042D, and D1246Y) and Pfcrt (K76T) and in vitro responses to chloroquine (CQ), mefloquine (MQ), lumefantrine (LMF), quinine (QN), monodesethylamodiaquine (MDAQ), and dihydroartemisinin (DHA) in 174 Plasmodium falciparum isolates from Dakar, Senegal. The Pfmdr1 86Y mutation was identified in 14.9% of the samples, and the 184F mutation was identified in 71.8% of the isolates. No 1034C, 1042N, or 1246Y mutations were detected. The Pfmdr1 86Y mutation was significantly associated with increased susceptibility to MDAQ (P = 0.0023), LMF (P = 0.0001), DHA (P = 0.0387), and MQ (P = 0.00002). The N86Y mutation was not associated with CQ (P = 0.214) or QN (P = 0.287) responses. The Pfmdr1 184F mutation was not associated with various susceptibility responses to the 6 antimalarial drugs (P = 0.168 for CQ, 0.778 for MDAQ, 0.324 for LMF, 0.961 for DHA, 0.084 for QN, and 0.298 for MQ). The Pfmdr1 86Y-Y184 haplotype was significantly associated with increased susceptibility to MDAQ (P = 0.0136), LMF (P = 0.0019), and MQ (P = 0.0001). The additional Pfmdr1 86Y mutation increased significantly the in vitro susceptibility to MDAQ (P < 0.0001), LMF (P < 0.0001), MQ (P < 0.0001), and QN (P = 0.0026) in wild-type Pfcrt K76 parasites. The additional Pfmdr1 86Y mutation significantly increased the in vitro susceptibility to CQ (P = 0.0179) in Pfcrt 76T CQ-resistant parasites. PMID:25199781

Emergent Archetype Hydrological-Biogeochemical Response Patterns in Heterogeneous Catchments

NASA Astrophysics Data System (ADS)

Jawitz, J. W.; Gall, H. E.; Rao, P.

2013-12-01

What can spatiotemporally integrated patterns observed in stream hydrologic and biogeochemical signals generated in response to transient hydro-climatic and anthropogenic forcing tell us about the interactions between spatially heterogeneous soil-mediated hydrological and biogeochemical processes? We seek to understand how the spatial structure of solute sources coupled with hydrologic responses affect observed concentration-discharge (C-Q) patterns. These patterns are expressions of the spatiotemporal structure of solute loads exported from managed catchments, and their likely ecological consequences manifested in receiving water bodies (e.g., wetlands, rivers, lakes, and coastal waters). We investigated the following broad questions: (1) How does the correlation between flow-generating areas and biogeochemical source areas across a catchment evolve under stochastic hydro-climatic forcing? (2) What are the feasible hydrologic and biogeochemical responses that lead to the emergence of the observed archetype C-Q patterns? and; (3) What implications do these coupled dynamics have for catchment monitoring and implementation of management practices? We categorize the observed temporal signals into three archetypical C-Q patterns: dilution; accretion, and constant concentration. We introduce a parsimonious stochastic model of heterogeneous catchments, which act as hydrologic and biogeochemical filters, to examine the relationship between spatial heterogeneity and temporal history of solute export signals. The core concept of the modeling framework is considering the types and degree of spatial correlation between solute source zones and flow generating zones, and activation of different portions of the catchments during rainfall events. Our overarching hypothesis is that each of the archetype C-Q patterns can be generated by explicitly linking landscape-scale hydrologic responses and spatial distributions of solute source properties within a catchment. The model simulations reproduce the three major C-Q patterns observed in published data, offering valuable insight into coupled catchment processes. The findings have important implications for effective catchment management for water quality improvement, and stream monitoring strategies.

Weather, AFSCs 1W0X1/A and 15WX/A

DTIC Science & Technology

1998-04-01

their observing tasks. Finally, a small group of Keesler instructors are also included within this job who are teaching in the basic Observer course...CQ CQ Ü 00 00 o ON C- NO 00 «r> m vo vo »-i <-< vo <o c- NO >n PH ’S* a Efl 2 £ a & tu ^ *o £ «a -a .a I3 «.2 g 5 ^3 o 1 fa fa "i s

Autophagy inhibitors reduce avian-reovirus-mediated apoptosis in cultured cells and in chicken embryos.

PubMed

Duan, Shipeng; Cheng, Jinghua; Li, Chenxi; Yu, Liping; Zhang, Xiaorong; Jiang, Ke; Wang, Yupeng; Xu, Jiansheng; Wu, Yantao

2015-07-01

Avian reovirus (ARV)-induced apoptosis contributes to the pathogenesis of reovirus in infected chickens. However, methods for effectively reducing ARV-triggered apoptosis remain to be explored. Here, we show that pretreatment with chloroquine (CQ) or E64d plus pepstatin A decreases ARV-mediated apoptosis in chicken DF-1 cells. By acting as autophagy inhibitors, CQ and E64d plus pepstatin A increase microtubule-associated protein 1 light chain 3-II (LC3II) accumulation in ARV-infected cells, which results in decreased ARV protein synthesis and virus yield and thereby contributes to the reduction of apoptosis. Furthermore, ARV-mediated apoptosis in the bursa, heart and intestines of chicken embryos is attenuated by CQ and E64d plus pepstatin A treatment. Importantly, treatment with these autophagy inhibitors increases the survival of infected chicken embryos. Together, our data suggest that pharmacological inhibition of autophagy might represent a novel strategy for reducing ARV-mediated apoptosis.

Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria

PubMed Central

Peng, Linyuan; Tang, Xiaolong; Meng, Fanbiao; Ao, Ying; Zhou, Mingyan; Wang, Ming; Cao, Xinyue; Qin, Baoming; Wang, Zimei; Zhou, Zhongjun; Wang, Guangming; Gao, Zhengliang; Xu, Jun

2018-01-01

DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans, but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases. PMID:29717979

Local and integral disruption forces on the tokamak wall

NASA Astrophysics Data System (ADS)

Pustovitov, V. D.; Kiramov, D. I.

2018-04-01

The disruption-induced forces on the tokamak wall are evaluated analytically within the standard large-aspect-ratio model that implies axisymmetry, circular plasma and wall, and absence of halo currents. Additionally, the ideal-wall reaction is assumed. The disruptions are modelled as rapid changes in the plasma pressure (thermal quench (TQ)) and net current (current quench (CQ)). The force distribution over the poloidal angle is found as a function of these inputs. The derived formulas allow comparison of the TQ- and CQ-produced forces calculated differently, with and without account of the poloidal current induced in the wall. The latter variant represents the inherent property of the codes treating the wall as a set of toroidal filaments. It is proved here that such a simplification leads to unacceptably large errors in the simulated forces for both TQs and CQs. It is also shown that the TQ part of the force must prevail over that due to CQ in the high-β scenarios developed for JT-60SA and ITER.

Synthesis, Antiplasmodial Activity, and β-Hematin Inhibition of Hydroxypyridone–Chloroquine Hybrids

PubMed Central

2013-01-01

A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor N-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of Plasmodium falciparum. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were 8c (0.13, 0.004, and 0.1 μM); 8d (0.08, 0.01, and 0.02 μM); and 7g (0.07, 0.03, and 0.08 μM). PMID:24900724

Blood Stage of Plasmodium vivax in Central China Is Still Susceptible to Chloroquine Plus Primaquine Combination Therapy

PubMed Central

Zhu, Guoding; Lu, Feng; Cao, Jun; Zhou, Huayun; Liu, Yaobao; Han, Eun-Taek; Gao, Qi

2013-01-01

In central China, Plasmodium vivax accounts for all of the native reported cases of malaria. Chloroquine (CQ) plus primaquine (PQ) have been used for more than 60 years as the frontline drugs, but the risk of treatment failure remains unknown. To measure the effectiveness and safety of CQ-PQ among vivax malaria patients, a total of 39 subjects with monoinfection vivax malaria was enrolled in a study from 2008 to 2009. There were no recrudescence or danger signs observed within the 28-day follow-up period, showing that blood stage of P. vivax isolates from central China is still susceptible to CQ plus PQ combination therapy. However, the antirelapse efficacy of PQ is difficult to assess because of the high rate of loss to follow-up after 28 days; also, parasites persisted in a single case at 3 days post-antimalarial drug treatment, indicating that continuous annual monitoring is needed in central China. PMID:23669232

Insights into the Role of Heme in the Mechanism of Action of Antimalarials

PubMed Central

Combrinck, Jill M.; Mabotha, Tebogo E.; Ncokazi, Kanyile K.; Ambele, Melvin A.; Taylor, Dale; Smith, Peter J.; Hoppe, Heinrich C.; Egan, Timothy J.

2012-01-01

Using cell fractionation and measurement of Fe(III)heme-pyridine, the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent decrease in hemozoin and concomitant increase in toxic “free” heme in cultured Plasmodium falciparum that is directly correlated with parasite survival. Transmission electron microscopy techniques have further shown that heme is redistributed from the parasite digestive vacuole to the cytoplasm and that CQ disrupts hemozoin crystal growth, resulting in mosaic boundaries in the crystals formed in the parasite. Extension of the cell fractionation study to other drugs has shown that artesunate, amodiaquine, lumefantrine, mefloquine and quinine, all clinically important antimalarials, also inhibit hemozoin formation in the parasite cell, while the antifolate pyrimethamine and its combination with sulfadoxine do not. This study finally provides direct evidence in support of the hemozoin inhibition hypothesis for the mechanism of action of CQ and shows that other quinoline and related antimalarials inhibit cellular hemozoin formation. PMID:23043646

Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria.

PubMed

Qian, Minxian; Liu, Zuojun; Peng, Linyuan; Tang, Xiaolong; Meng, Fanbiao; Ao, Ying; Zhou, Mingyan; Wang, Ming; Cao, Xinyue; Qin, Baoming; Wang, Zimei; Zhou, Zhongjun; Wang, Guangming; Gao, Zhengliang; Xu, Jun; Liu, Baohua

2018-05-02

DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans , but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases. © 2018, Qian et al.

Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review.

PubMed

Parhizgar, Arezoo Rafiee; Tahghighi, Azar

2017-03-01

Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold.

Chloroquine inhibits autophagy and deteriorates the mitochondrial dysfunction and apoptosis in hypoxic rat neurons.

PubMed

Li, Peng; Hao, Lei; Guo, Yan-Yan; Yang, Guang-Lu; Mei, Hua; Li, Xiao-Hua; Zhai, Qiong-Xiang

2018-06-01

Mitochondrial dysfunction (MD) and apoptosis in the neurons are associated with neonatal hypoxic-ischemic (HI) encephalopathy (HIE). The present study was to explore the influence of autophagy on the induction of MD and apoptosis in the neurons in a neonatal HIE rats and in hypoxia-treated neurons in vitro. Ten-day-old HI rat pups were sacrificed for brain pathological examination and immunohistochemical analysis. The induction of autophagy, apoptosis and MD were also determined in the neurons under hypoxia, with or without autophagy inhibitor, chloroquine (CQ) treatment. HI treatment caused atrophy and apoptosis of neurons, with a significantly increased levels of apoptosis- and autophagy-associated proteins, such as cleaved caspase 3 and the B subunit of autophagy-related microtubule-associated protein 1 light chain 3 (LC3-B). in vitro experiments demonstrated that the hypoxia induced autophagy in neurons, as was inhibited by CQ. The hypoxia-induced cytochrome c release, cleaved caspase 3 and cleaved caspase 9 were aggravated by CQ. Moreover, there were higher levels of reactive oxygen species, more mitochondrial superoxide and less mitochondrial membrane potential in the CQ-treated neurons under hypoxia than in the neurons singularly under hypoxia. Apoptosis and autophagy were induced in HI neonatal rat neurons, autophagy inhibition deteriorates the hypoxia-induced neuron MD and apoptosis. It implies a neuroprotection of autophagy in the hypoxic-ischemic encephalopathy. Administration of autophagy inducer agents might be promising in HIE treatment. Copyright © 2018. Published by Elsevier Inc.

Fabrication and efficacy evaluation of chloroquine nanoparticles in CFA-induced arthritic rats using TNF-α ELISA.

PubMed

Bhalekar, Mangesh R; Upadhaya, Prashant G; Madgulkar, Ashwini R

2016-03-10

Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, stimulates various immune cells especially macrophages, causing release of various proinflammatory cytokines such as TNF-α leading to persistent synovitis. Chloroquine, an anti-malarial drug inhibits the production of TNF-α, thus, halting the disease progression. The aim of the present study was fabrication, characterization and demonstration of kinetic and dynamic efficacy of chloroquine loaded solid lipid nanoparticles (CQ-SLNs) in arthritic rats and in lowering TNF-α levels. CQ-SLNs were prepared using melt homogenization method and subjected to lyophilization. The particle size, zeta potential, PDI and entrapment efficiency were found to be 113.6±0.15nm, -27.8±1.21mV, 0.125±0.03 and 93.45±0.43% respectively. Ex vivo endocytic uptake studies revealed engrossment of endocytic pathways in the uptake of SLN from intestine. Plasma drug profile upon pharmacokinetic evaluation demonstrated increased AUC, half-life and decreased elimination rate of the drug. Pharmacodynamic studies revealed reduction in the paw volume, bone erosion and cartilage destruction, the same was also reflected in histopathological studies. The TNF-α ELISA concluded that the TNF-α level was significantly reduced in the synovial fluid upon treatment with CQ-SLN, thus, leading to the conclusion that CQ-SLN could be used as a potential in reducing inflammatory TNF-α at the arthritic site and halting the disease progression. Copyright © 2016 Elsevier B.V. All rights reserved.

A strategy for acquisition and analysis of complex natural abundance (33)S solid-state NMR spectra of a disordered tetrathio transition-metal anion.

PubMed

Jakobsen, Hans J; Bildsøe, Henrik; Skibsted, Jørgen; Brorson, Michael; Gor'kov, Peter; Gan, Zhehong

2010-02-01

A strategy, involving (i) sensitivity enhancement for the central transition (CT) by population transfer (PT) employing WURST inversion pulses to the satellite transitions (STs) in natural abundance (33)S MAS NMR for two different MAS frequencies (nu(r)=5.0 and 10.0kHz) at 14.1T and (ii) a (33)S static QCPMG experiment at 19.6T, has allowed acquisition and analysis of very complex solid-state (33)S CT NMR spectra for the disordered tetrathioperrhenate anion ReS(4)(-) in [(C(2)H(5))(4)N][ReS(4)]. This strategy of different NMR experiments combined with spectral analysis/simulations has allowed determination of precise values for two sets of quadrupole coupling parameters (C(Q) and eta(Q)) assigned to the two different S sites for the four sulfur atoms in the ReS(4)(-) anion in the ratio S1:S2=1:3. These sets of C(Q), eta(Q) values for the S1 and S2 site are quite similar and the magnitudes of the quadrupole coupling constants (C(Q)=2.2-2.5MHz) are a factor of about three larger than observed for other tetrathiometalates A(2)MS(4) (A=NH(4), Cs, Rb and M=W, Mo). In addition, the spectral analysis also leads to a determination of the chemical shift anisotropy (CSA) parameters (delta(sigma) and eta(sigma)) for the S1 and S2 site, however, with much lower precisions (about 20% error margins) compared to those for C(Q), eta(Q), because the magnitudes of the two CSAs (i.e., delta(sigma)=60-90ppm) are about a factor of six smaller than observed for the other tetrathiometalates mentioned above. This large difference in the magnitudes of the anisotropic parameters C(Q) and delta(sigma) for the ReS(4)(-) anion, compared to those for the WS(4)(2-) and MoS(4)(2-) anions determined previously under identical experimental conditions, accounts for the increased complexity of the PT-enhanced (33)S MAS spectra observed for the ReS(4)(-) anion in this study. This difference in C(Q) also contributes significantly to the intensity distortions observed in the outer wings of the CTs when employing PT from the STs under conditions of slow-speed MAS. Copyright 2009 Elsevier Inc. All rights reserved.

The Impact of Repeated Freeze-Thaw Cycles on the Quality of Biomolecules in Four Different Tissues.

PubMed

Ji, Xiaoli; Wang, Min; Li, Lingling; Chen, Fang; Zhang, Yanyang; Li, Qian; Zhou, Junmei

2017-10-01

High-quality biosamples are valuable resources for biomedical research. However, some tissues are stored without being sectioned into small aliquots and have to undergo repeated freeze-thaw cycles throughout prolonged experimentation. Little is known regarding the effects of repeated freeze-thaw cycles on the quality of biomolecules in tissues. The aim of this study was to evaluate the impact of repeated freeze-thaw (at room temperature or on ice) cycles on biomolecules and gene expression in four different types of tissues. Each fresh tissue was sectioned into seven aliquots and snap-frozen before undergoing repeated freeze-thaw cycles at room temperature or on ice. Biomolecules were extracted and analyzed. Both relative and absolute quantification were used to detect the changes in gene expression. The results indicated that the impact of repeated freeze-thaw cycles on RNA integrity varied by tissue type. Gene expression, including the housekeeping gene, was affected in RNA-degraded samples according to absolute quantification rather than relative quantification. Furthermore, our results suggest that thawing on ice could protect RNA integrity compared with thawing at room temperature. No obvious degradation of protein or DNA was observed with repeated freeze-thaw cycles either at room temperature or on ice. This research provides ample evidence for the necessity of sectioning fresh tissues into small aliquots before snap-freezing, thus avoiding degradation of RNA and alteration of gene expression resulting from repeated freeze-thaw cycles. For frozen tissue samples that were already in storage and had to be used repeatedly during their lifecycle, thawing on ice or sectioned at ultralow temperature is recommended.

A statistical approach to quantification of genetically modified organisms (GMO) using frequency distributions.

PubMed

Gerdes, Lars; Busch, Ulrich; Pecoraro, Sven

2014-12-14

According to Regulation (EU) No 619/2011, trace amounts of non-authorised genetically modified organisms (GMO) in feed are tolerated within the EU if certain prerequisites are met. Tolerable traces must not exceed the so-called 'minimum required performance limit' (MRPL), which was defined according to the mentioned regulation to correspond to 0.1% mass fraction per ingredient. Therefore, not yet authorised GMO (and some GMO whose approvals have expired) have to be quantified at very low level following the qualitative detection in genomic DNA extracted from feed samples. As the results of quantitative analysis can imply severe legal and financial consequences for producers or distributors of feed, the quantification results need to be utterly reliable. We developed a statistical approach to investigate the experimental measurement variability within one 96-well PCR plate. This approach visualises the frequency distribution as zygosity-corrected relative content of genetically modified material resulting from different combinations of transgene and reference gene Cq values. One application of it is the simulation of the consequences of varying parameters on measurement results. Parameters could be for example replicate numbers or baseline and threshold settings, measurement results could be for example median (class) and relative standard deviation (RSD). All calculations can be done using the built-in functions of Excel without any need for programming. The developed Excel spreadsheets are available (see section 'Availability of supporting data' for details). In most cases, the combination of four PCR replicates for each of the two DNA isolations already resulted in a relative standard deviation of 15% or less. The aims of the study are scientifically based suggestions for minimisation of uncertainty of measurement especially in -but not limited to- the field of GMO quantification at low concentration levels. Four PCR replicates for each of the two DNA isolations seem to be a reasonable minimum number to narrow down the possible spread of results.

The Dubai Community Psychiatric Survey: II. Development of the Socio-cultural Change Questionnaire.

PubMed

Bebbington, P; Ghubash, R; Hamdi, E

1993-04-01

The Dubai Community Psychiatric Survey was carried out to assess the effect of very rapid social change on the mental health of women in Dubai, one of the United Arab Emirates. In order to measure social change at an individual level, we developed a questionnaire covering behaviour and attitudes in a wide range of situations, the Socio-cultural Change Questionnaire (ScCQ). In this paper we give an account of the considerations that determined the form of the ScCQ, its structural characteristics, and its validity.

Competitive light absorbers in photoactive dental resin-based materials.

PubMed

Hadis, Mohammed A; Shortall, Adrian C; Palin, William M

2012-08-01

The absorbance profile of photoinitiators prior to, during and following polymerization of light curable resin-based materials will have a significant effect on the cure and color properties of the final material. So-called "colorless" photoinitiators are used in some light-activated resin-based composite restorative materials to lessen the yellowing effect of camphoroquinone (CQ) in order to improve the esthetic quality of dental restorations. This work characterizes absorption properties of commonly used photoinitiators, an acylphosphine oxide (TPO) and CQ, and assesses their influence on material discoloration. Dimethacrylate resin formulations contained low (0.0134 mol/dm(3)), intermediate (0.0405 mol/dm(3)) or high (0.0678 mol/dm(3)) concentrations of the photoinitiators and the inhibitor, butylated hydroxytoluene (BHT) at 0, 0.1 or 0.2% by mass. Disc shaped specimens (n = 3) of each resin were polymerized for 60s using a halogen light curing unit. Dynamic measurements of photoinitiator absorption, polymer conversion and reaction temperature were performed. A spectrophotometer was used to measure the color change before and after cure. GLM three-way analysis of variance revealed significant differences (p<0.001), where photoinitiator concentration (df = 2; F = 618.83)>photoinitiator type (df = 1; F = 176.12)>% BHT (df = 2, F = 13.17). BHT concentration affected the rate of polymerization and produced lower conversion in some of the CQ-based resins. Significant differences between photoinitiator type and concentrations were seen in color (where TPO resins became yellower and camphoroquinone resins became less yellow upon irradiation). Reaction temperature, kinetics and conversion also differed significantly for both initiators (p<0.001). Despite TPO-based resins producing a visually perceptible color change upon polymerization, the color change was significantly less than that produced with CQ-based resins. Although some photoinitiators such as TPO may be a more esthetic alternative to CQ, they may actually cause significant color contamination when used in high concentrations and therefore manufacturers should limit its concentration in order to improve its esthetic quality. Copyright © 2012 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Effective treatment with a tetrandrine/chloroquine combination for chloroquine-resistant falciparum malaria in Aotus monkeys

PubMed Central

2013-01-01

Background In vitro evidence indicates that tetrandrine (TT) can potentiate the action of chloroquine 40-fold against choloquine-resistant Plasmodium falciparum. The key question emanating from that study is “would tetrandine and chloroquine be highly effective in a live Aotus monkey model with chloroquine-resistant parasites”. This study was designed to closely mimic the pharmacological/anti-malarial activity in man. Methods The Vietnam Smith/RE strain of P. falciparum, which is chloroquine-resistant was used in this study. Previous experimental procedures were followed. Panamanian owl monkeys (Aotus) were inoculated with 5×106 erythrocytes parasitized with the CQ-resistant strain of P. falciparum. Oral drug treatment was with CQ (20 mg/kg) and/or tetrandrine at 15 mg/Kg, 30 mg/Kg or 60 mg/Kg or 25 mg/Kg depending on experimental conditions. Results and Discussion Parasitaemia was cleared rapidly with CQ and TT while CQ treatment alone was ineffective. Recrudescence of malaria occurred after seven days post-infection. However, four animals were treated orally with TT and CQ parasites were cleared. It is likely that monkeys were cured via a combination of both drug and host immune responses. A single Aotus monkey infected with P. falciparum and untreated with drugs, died. No side effects were observed with these drug treatments. Conclusions This combination of chloroquine and tetrandrine forms the basis of a new attack on chloroquine-resistant malaria - one based upon inhibition of the basis of chloroquine resistance, the multiple drug resistance pump. Previous studies demonstrated that the parasite MDR pump was found on parasite membranes using 3H azidopine photoaffinity labelling. Since MDR-based choloroquine resistance is induced by chloroquine, the basis of the action of tetrandrine is the following: 1) tetrandrine inhibits the MDR pump by stimulating MDR ATPase which limits the energy of the pump by depletion of parasite ATP, 2) tetrandrine blocks the genetic factor which controls the induction of the pump. Therefore, it appears that the parasite cannot outsmart these mechanisms and produce a new mode of resistance. Only time will tell if this is correct. PMID:23547773

High Density Linkage Map Construction and QTL Detection for Three Silique-Related Traits in Orychophragmus violaceus Derived Brassica napus Population.

PubMed

Yang, Yi; Shen, Yusen; Li, Shunda; Ge, Xianhong; Li, Zaiyun

2017-01-01

Seeds per silique (SS), seed weight (SW), and silique length (SL) are important determinant traits of seed yield potential in rapeseed ( Brassica napus L.), and are controlled by naturally occurring quantitative trait loci (QTLs). Mapping QTLs to narrow chromosomal regions provides an effective means of characterizing the genetic basis of these complex traits. Orychophragmus violaceus is a crucifer with long siliques, many SS, and heavy seeds. A novel B. napus introgression line with many SS was previously selected from multiple crosses ( B. rapa ssp. chinesis × O. violaceus ) × B. napus . In present study, a doubled haploid (DH) population with 167 lines was established from a cross between the introgression line and a line with far fewer SS, in order to detect QTLs for silique-related traits. By screening with a Brassica 60K single nucleotide polymorphism (SNP) array, a high-density linkage map consisting of 1,153 bins and spanning a cumulative length of 2,209.1 cM was constructed, using 12,602 high-quality polymorphic SNPs in the DH population. The average recombination bin densities of the A and C subgenomes were 1.7 and 2.4 cM, respectively. 45 QTLs were identified for the three traits in all, which explained 4.0-34.4% of the total phenotypic variation; 20 of them were integrated into three unique QTLs by meta-analysis. These unique QTLs revealed a significant positive correlation between SS and SL and a significant negative correlation between SW and SS, and were mapped onto the linkage groups A05, C08, and C09. A trait-by-trait meta-analysis revealed eight, four, and seven consensus QTLs for SS, SW, and SL, respectively, and five major QTLs ( cqSS.A09b, cqSS.C09, cqSW.A05, cqSW.C09 , and cqSL.C09 ) were identified. Five, three, and four QTLs for SS, SW, and SL, respectively, might be novel QTLs because of the existence of alien genetic loci for these traits in the alien introgression. Thirty-eight candidate genes underlying nine QTLs for silique-related traits were identified.

Dopamine receptor antagonists as new mode-of-action insecticide leads for control of Aedes and Culex mosquito vectors.

PubMed

Nuss, Andrew B; Ejendal, Karin F K; Doyle, Trevor B; Meyer, Jason M; Lang, Emma G; Watts, Val J; Hill, Catherine A

2015-03-01

New mode-of-action insecticides are sought to provide continued control of pesticide resistant arthropod vectors of neglected tropical diseases (NTDs). We previously identified antagonists of the AaDOP2 D1-like dopamine receptor (DAR) from the yellow fever mosquito, Aedes aegypti, with toxicity to Ae. aegypti larvae as leads for novel insecticides. To extend DAR-based insecticide discovery, we evaluated the molecular and pharmacological characteristics of an orthologous DAR target, CqDOP2, from Culex quinquefasciatus, the vector of lymphatic filariasis and West Nile virus. CqDOP2 has 94.7% amino acid identity to AaDOP2 and 28.3% identity to the human D1-like DAR, hD1. CqDOP2 and AaDOP2 exhibited similar pharmacological responses to biogenic amines and DAR antagonists in cell-based assays. The antagonists amitriptyline, amperozide, asenapine, chlorpromazine and doxepin were between 35 to 227-fold more selective at inhibiting the response of CqDOP2 and AaDOP2 in comparison to hD1. Antagonists were toxic to both C. quinquefasciatus and Ae. aegypti larvae, with LC50 values ranging from 41 to 208 μM 72 h post-exposure. Orthologous DOP2 receptors identified from the African malaria mosquito, Anopheles gambiae, the sand fly, Phlebotomus papatasi and the tsetse fly, Glossina morsitans, had high sequence similarity to CqDOP2 and AaDOP2. DAR antagonists represent a putative new insecticide class with activity against C. quinquefasciatus and Ae. aegypti, the two most important mosquito vectors of NTDs. There has been limited change in the sequence and pharmacological properties of the DOP2 DARs of these species since divergence of the tribes Culicini and Aedini. We identified antagonists selective for mosquito versus human DARs and observed a correlation between DAR pharmacology and the in vivo larval toxicity of antagonists. These data demonstrate that sequence similarity can be predictive of target potential. On this basis, we propose expanded insecticide discovery around orthologous DOP2 targets from additional dipteran vectors.

Genetic mutations in pfcrt and pfmdr1 at the time of artemisinin combination therapy introduction in South Pacific islands of Vanuatu and Solomon Islands.

PubMed

Gresty, Karryn J; Gray, Karen-Ann; Bobogare, Albino; Taleo, George; Hii, Jeffrey; Wini, Lyndes; Cheng, Qin; Waters, Norman C

2014-10-15

Chloroquine (CQ), alone or in combination with sulphadoxine-pyrimethamine, was widely used for the treatment of Plasmodium falciparum and Plasmodium vivax for several decades in both Vanuatu and Solomon Islands prior to the introduction of artemether-lumefantrine (AL) in 2008. However, the effect of chloroquine selection on parasite population, which may affect the efficacy of lumefantrine or other partner drugs of artemisinin, has not been well assessed. This study aims to provide baseline data on molecular markers (pfcrt and pfmdr1), along with the origins of pfcrt, prior to the introduction of AL. Blood spots were obtained from epidemiological surveys conducted on Tanna Island, Tafea Province, Vanuatu and Temotu Province, Solomon Islands in 2008. Additional samples from Malaita Province, Solomon Islands were collected as part of an artemether-lumefantrine efficacy study in 2008. Plasmodium falciparum pfcrt and pfmdr1 genes were examined for polymorphisms. Microsatellite markers flanking pfcrt were also examined to ascertain origins of CQ resistance. Pfcrt analysis revealed 100% of parasites from Tafea Province, Vanuatu and Malaita Province, Solomon Islands and 98% of parasites from Temotu Province, Solomon Islands carried the K76T polymorphism that confers CQ resistance. Comparison of pfcrt allelic patterns and microsatellite markers flanking pfcrt revealed six haplotypes with more than 70% of isolates possessing haplotypes very similar to those observed in Papua New Guinea. The dominant (98.5%) pfmdr1 allele across all island groups was YYCND. Prior to the introduction of AL in the Solomon Islands and Vanuatu, P. falciparum isolates possessed point mutations known to confer CQ resistance and possibly associated with a decreased susceptibility to quinine and halofantrine, but an increased susceptibility to artemisinin and lumefantrine. Overall, pfcrt allelic types and the flanking microsatellite markers exhibited similarities to those of Papua New Guinea, suggesting these parasites share a common ancestry. The current use of AL for both P. falciparum and P. vivax infections will enable changes in these markers, in the absence of CQ pressure, to be monitored.

FUSE Spectroscopy of the Accreting Hot Components in Symbiotic Variables.

PubMed

Sion, Edward M; Godon, Patrick; Mikolajewska, Joanna; Sabra, Bassem; Kolobow, Craig

2017-04-01

We have conducted a spectroscopic analysis of the far ultraviolet archival spectra of four symbiotic variables, EG And, AE Ara, CQ Dra and RW Hya. RW Hya and EG And have never had a recorded outburst while CQ Dra and AE Ara have outburst histories. We analyze these systems while they are in quiescence in order to help reveal the physical properties of their hot components via comparisons of the observations with optically thick accretion disk models and NLTE model white dwarf photospheres. We have extended the wavelength coverage down to the Lyman Limit with FUSE spectra. We find that the hot component in RW Hya is a low mass white dwarf with a surface temperature of 160,000K. We re-examine whether or not the symbiotic system CQ Dra is a triple system with a red giant transferring matter to a hot component made up of a cataclysmic variable in which the white dwarf has a surface temperature as low as ∼20,000K. The very small size of the hot component contributing to the shortest wavelengths of the FUSE spectrum of CQ Dra agrees with an optically thick and geometrically thin (∼4% of the WD surface) hot (∼ 120, 000K) boundary layer. Our analysis of EG And reveals that its hot component is a hot, bare, low mass white dwarf with a surface temperature of 80-95,000K, with a surface gravity log( g ) = 7.5. For AE Ara, we also find that a low gravity (log( g ) ∼ 6) hot ( T ∼ 130, 000K) WD accounts for the hot component.

A 3D QSAR pharmacophore model and quantum chemical structure--activity analysis of chloroquine(CQ)-resistance reversal.

PubMed

Bhattacharjee, Apurba K; Kyle, Dennis E; Vennerstrom, Jonathan L; Milhous, Wilbur K

2002-01-01

Using CATALYST, a three-dimensional QSAR pharmacophore model for chloroquine(CQ)-resistance reversal was developed from a training set of 17 compounds. These included imipramine (1), desipramine (2), and 15 of their analogues (3-17), some of which fully reversed CQ-resistance, while others were without effect. The generated pharmacophore model indicates that two aromatic hydrophobic interaction sites on the tricyclic ring and a hydrogen bond acceptor (lipid) site at the side chain, preferably on a nitrogen atom, are necessary for potent activity. Stereoelectronic properties calculated by using AM1 semiempirical calculations were consistent with the model, particularly the electrostatic potential profiles characterized by a localized negative potential region by the side chain nitrogen atom and a large region covering the aromatic ring. The calculated data further revealed that aminoalkyl substitution at the N5-position of the heterocycle and a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two or three carbon bridge to the heteroaromatic nitrogen (N5) are required for potent "resistance reversal activity". Lowest energy conformers for 1-17 were determined and optimized to afford stereoelectronic properties such as molecular orbital energies, electrostatic potentials, atomic charges, proton affinities, octanol-water partition coefficients (log P), and structural parameters. For 1-17, fairly good correlation exists between resistance reversal activity and intrinsic basicity of the nitrogen atom at the tricyclic ring system, frontier orbital energies, and lipophilicity. Significantly, nine out of 11 of a group of structurally diverse CQ-resistance reversal agents mapped very well on the 3D QSAR pharmacophore model.

Importation of chloroquine-resistant Plasmodium falciparum by Guatemalan peacekeepers returning from the Democratic Republic of the Congo

PubMed Central

2013-01-01

Background Malaria elimination is being pursued in five of seven Central American countries. Military personnel returning from peacekeeping missions in sub-Saharan Africa could import chloroquine-resistant Plasmodium falciparum, posing a threat to elimination and to the continued efficacy of first-line chloroquine (CQ) treatment in these countries. This report describes the importation of P. falciparum from among 150 Guatemalan army special forces and support staff who spent ten months on a United Nations’ peacekeeping mission in the Democratic Republic of the Congo (DRC) in 2010. Methods Investigators reviewed patients’ medical charts and interviewed members of the contingent to identify malaria cases and risk factors for malaria acquisition. Clinical specimens were tested for malaria; isolated parasites were characterized molecularly for CQ resistance. Results Investigators identified 12 cases (8%) of laboratory-confirmed P. falciparum infection within the contingent; one case was from a soldier infected with a CQ-resistant pfcrt genotype resulting in his death. None of the contingent used an insecticide-treated bed net (ITN) or completely adhered to malaria chemoprophylaxis while in the DRC. Conclusion This report highlights the need to promote use of malaria prevention measures, in particular ITNs and chemoprophylaxis, among peacekeepers stationed in malaria-endemic areas. Countries attempting to eliminate malaria should consider appropriate methods to screen peacekeepers returning from endemic areas for malaria infections. Cases of malaria in travellers, immigrants and soldiers returning to Central America from countries with CQ-resistant malaria should be assumed to be carry resistant parasites and receive appropriate anti-malarial therapy to prevent severe disease and death. PMID:24060234

Quantitative trait locus analysis of plasma cholesterol and triglyceride levels in C57BL/6J x RR F2 mice.

PubMed

Suto, Jun-ichi; Takahashi, Yuji; Sekikawa, Kenji

2004-10-01

A highly significant cholesterol quantitative trait locus (QTL) (Cq6) was identified on chromosome 1 in C57BL/6J x RR F2 mice. The Cq6 was located over the gene for apolipoprotein A-Il (Apoa2), and the RR allele was associated with increased plasma cholesterol. C57BL/6J has Apoa2a alleles and RR has Apoa2b alleles. Three different Apoa2 alleles are known on the basis of amino acid substitutions at four residues. Analysis with partial Apoa2 congenic strains possessing Apoa2a, Apoa2b, and Apoa2C alleles revealed that the Apoa2b allele is unique in the ability to increase cholesterol among the three Apoa2 alleles, and that the Ala-to-Val substitution at residue 61 may be crucial as far as cholesterol metabolism is concerned. We also investigated the question of whether the Apoa1 gene is responsible for the cholesterol QTLs (Cq4 and Cq5) that had been identified previously on chromosome 9 in C57BL/6J x KK-Ay/a F2 and in KK x RR F2, but not in C57BL/6J x RR F2 mice. Similar to Apoa2 alleles, three different Apoal alleles with two successive amino acid substitutions were revealed among the strains. However, we could not correlate Apoal polymorphisms with the occurrence of QTLs in these three sets of F2 mice.

Development and Validation of a Real-Time PCR Assay for Rapid Detection of Two-Spotted Spider Mite, Tetranychus urticae (Acari: Tetranychidae)

PubMed Central

Li, Dongmei; Fan, Qing-Hai; Waite, David W.; Gunawardana, Disna; George, Sherly; Kumarasinghe, Lalith

2015-01-01

Spider mites of the genus Tetranychus are difficult to identify due to their limited diagnostic characters. Many of them are morphologically similar and males are needed for species-level identification. Tetranychus urticae is a common interception and non-regulated pest at New Zealand’s borders, however, most of the intercepted specimens are females and the identification was left at Tetranychus sp. Consequently, the shipments need to be fumigated. DNA sequencing and PCR-restriction fragment length polymorphism (PCR-RFLP) protocols could be used to facilitate the accurate identification. However, in the context of border security practiced in New Zealand, insect identifications are required to be provided within four hours of receiving the samples; thus, those molecular methods are not sufficient to meet this requirement. Therefore, a real-time PCR TaqMan assay was developed for identification of T. urticae by amplification of a 142 bp Internal Transcribed Spacer (ITS) 1 sequence. The developed assay is rapid, detects all life stages of T. urticae within three hours, and does not react with closely related species. Plasmid DNA containing ITS1 sequence of T. uritcae was serially diluted and used as standards in the real-time PCR assay. The quantification cycle (Cq) value of the assay depicted a strong linear relationship with T. urticae DNA content, with a regression coefficient of 0.99 and efficiency of 98%. The detection limit was estimated to be ten copies of the T. urticae target region. The assay was validated against a range of T. urticae specimens from various countries and hosts in a blind panel test. Therefore the application of the assay at New Zealand will reduce the unnecessary fumigation and be beneficial to both the importers and exporters. It is expected that the implementation of this real-time PCR assay would have wide applications in diagnostic and research agencies worldwide. PMID:26147599

MiRNA Analysis by Quantitative PCR in Preterm Human Breast Milk Reveals Daily Fluctuations of hsa-miR-16-5p

PubMed Central

Floris, Ilaria; Billard, Hélène; Boquien, Clair-Yves; Joram-Gauvard, Evelyne; Simon, Laure; Legrand, Arnaud; Boscher, Cécile; Rozé, Jean-Christophe; Bolaños-Jiménez, Francisco; Kaeffer, Bertrand

2015-01-01

Background and Aims Human breast milk is an extremely dynamic fluid containing many biologically-active components which change throughout the feeding period and throughout the day. We designed a miRNA assay on minimized amounts of raw milk obtained from mothers of preterm infants. We investigated changes in miRNA expression within month 2 of lactation and then over the course of 24 hours. Materials and Methods Analyses were performed on pooled breast milk, made by combining samples collected at different clock times from the same mother donor, along with time series collected over 24 hours from four unsynchronized mothers. Whole milk, lipids or skim milk fractions were processed and analyzed by qPCR. We measured hsa-miR-16-5p, hsa-miR-21-5p, hsa-miR-146-5p, and hsa-let-7a, d and g (all -5p). Stability of miRNA endogenous controls was evaluated using RefFinder, a web tool integrating geNorm, Normfinder, BestKeeper and the comparative ΔΔCt method. Results MiR-21 and miR-16 were stably expressed in whole milk collected within month 2 of lactation from four mothers. Analysis of lipids and skim milk revealed that miR-146b and let-7d were better references in both fractions. Time series (5H-23H) allowed the identification of a set of three endogenous reference genes (hsa-let-7d, hsa-let-7g and miR-146b) to normalize raw quantification cycle (Cq) data. We identified a daily oscillation of miR-16-5p. Perspectives Our assay allows exploring miRNA levels of breast milk from mother with preterm baby collected in time series over 48–72 hours. PMID:26474056

On uniform constants of strong uniqueness in Chebyshev approximations and fundamental results of N. G. Chebotarev

NASA Astrophysics Data System (ADS)

Marinov, Anatolii V.

2011-06-01

In the problem of the best uniform approximation of a continuous real-valued function f\\in C(Q) in a finite-dimensional Chebyshev subspace M\\subset C(Q), where Q is a compactum, one studies the positivity of the uniform strong uniqueness constant \\gamma(N)=\\inf\\{\\gamma(f)\\colon f\\in N\\}. Here \\gamma(f) stands for the strong uniqueness constant of an element f_M\\in M of best approximation of f, that is, the largest constant \\gamma>0 such that the strong uniqueness inequality \\Vert f-\\varphi\\Vert\\ge\\Vert f-f_M\\Vert+\\gamma\\Vert f_M-\\varphi\\Vert holds for any \\varphi\\in M. We obtain a characterization of the subsets N\\subset C(Q) for which there is a neighbourhood O(N) of N satisfying the condition \\gamma(O(N))>0. The pioneering results of N. G. Chebotarev were published in 1943 and concerned the sharpness of the minimum in minimax problems and the strong uniqueness of algebraic polynomials of best approximation. They seem to have been neglected by the specialists, and we discuss them in detail.

International Space Station USOS Crew Quarters Development

NASA Technical Reports Server (NTRS)

Broyan, James Lee, Jr.; Borrego, Melissa Ann; Bahr, Juergen F.

2008-01-01

The International Space Station (ISS) United States Operational Segment (USOS) currently provides a Temporary Sleep Station (TeSS) as crew quarters for one crewmember in the Laboratory Module. The Russian Segment provides permanent crew quarters (Kayutas) for two crewmembers in the Service Module. The TeSS provides limited electrical, communication, and ventilation functionality. A new permanent rack sized USOS ISS Crew Quarters (CQ) is being developed. Up to four CQs can be installed into the Node 2 element to increase the ISS crewmember size to six. The new CQs will provide private crewmember space with enhanced acoustic noise mitigation, integrated radiation reduction material, controllable airflow, communication equipment, redundant electrical systems, and redundant caution and warning systems. The rack sized CQ is a system with multiple crewmember restraints, adjustable lighting, controllable ventilation, and interfaces that allow each crewmember to personalize their CQ workspace. Providing an acoustically quiet and visually isolated environment, while ensuring crewmember safety, is critical for obtaining crewmember rest and comfort to enable long term crewmember performance. The numerous human factor, engineering, and program considerations during the concept, design, and prototyping are outlined in the paper.

LC3 and p62 as diagnostic markers of drug-induced autophagic vacuolar cardiomyopathy: a study of 3 cases.

PubMed

Daniels, Brianne H; McComb, Rodney D; Mobley, Bret C; Gultekin, Sakir Humayun; Lee, Han S; Margeta, Marta

2013-07-01

Autophagic vacuolar cardiomyopathy is an underrecognized, but potentially fatal, complication of treatment with chloroquine (CQ) and its derivative hydroxychloroquine (HCQ), which are used as therapy for malaria and common connective tissue disorders. Currently, the diagnosis of autophagic vacuolar cardiomyopathy is established through an endomyocardial biopsy and requires electron microscopy, which is not widely available and has a significant potential for sampling error. Recently, we have reported that immunohistochemistry for autophagic markers LC3 and p62 can replace electron microscopy in the diagnosis of HCQ-induced and colchicine-induced autophagic vacuolar skeletal myopathies. In the current study, we use 3 cases of CQ-induced or HCQ-induced cardiomyopathy and 1 HCQ-treated control case to show that the same two markers can be used to diagnose autophagic vacuolar cardiomyopathies by light microscopy. CQ-induced or HCQ-induced autophagic vacuolar cardiomyopathy is not universally fatal, but successful treatment requires early detection. By lowering the barriers to diagnosis, the application of these immunohistochemical markers will decrease the number of misdiagnosed patients, thus increasing the likelihood of favorable clinical outcomes.

Dynamic Behaviors of Materials under Ramp Wave Loading on Compact Pulsed Power Generators

NASA Astrophysics Data System (ADS)

Zhao, Jianheng; Luo, Binqiang; Wang, Guiji; Chong, Tao; Tan, Fuli; Liu, Cangli; Sun, Chengwei

The technique using intense current to produce magnetic pressure provides a unique way to compress matter near isentrope to high density without obvious temperature increment, which is characterized as ramp wave loading, and firstly developed by Sandia in 1998. Firstly recent advances on compact pulsed power generators developed in our laboratory, such as CQ-4, CQ-3-MMAF and CQ-7 devices, are simply introduced here, which devoted to ramp wave loading from 50GPa to 200 GPa, and to ultrahigh-velocity flyer launching up to 30 km/s. And then, we show our progress in data processing methods and experiments of isentropic compression conducted on these devices mentioned above. The suitability of Gruneisen EOS and Vinet EOS are validated by isentropic experiments of tantalum, and the parameters of SCG constitutive equation of aluminum and copper are modified to give better prediction under isentropic compression. Phase transition of bismuth and tin are investigated under different initial temperatures, parameters of Helmholtz free energy and characteristic relaxation time in kinetic phase transition equation are calibrated. Supported by NNSF of China under Contract No.11327803 and 11176002

Natural products as potential anticonvulsants: caffeoylquinic acids.

PubMed

Kim, Hyo Geun; Oh, Myung Sook

2012-03-01

Current anticonvulsant therapies are generally directed at symptomatic treatment by suppressing excitability within the brain. Consequently, they have adverse effects such as cognitive impairment, dependence, and abuse. The need for more effective and less toxic anticonvulsants has generated renewed interest in natural products for the treatment of convulsions. Caffeoylquinic acids (CQs) are naturally occurring phenolic acids that are distributed widely in plants. There has been increasing interest in the biological activities of CQs in diseases of the central nervous system. In this issue, Nugroho et al. give evidence for the anticonvulsive effect of a CQ-rich extract from Aster glehni Franchet et Sckmidt. They optimized the extract solvent conditions, resulting in high levels of CQs and peroxynitrite-scavenging activity. Then, they investigated the sedative and anticonvulsive effects in pentobarbital- and pentylenetetrazole-induced models in mice. The CQ-rich extract significantly inhibited tonic convulsions as assessed by onset time, tonic extent, and mortality. They suggested that the CQ-rich extract from A. glehni has potential for treating convulsions. This report provides preclinical data which may be used for the development of anticonvulsants from natural products.

The determination and quantification of photosynthetic pigments by reverse phase high-performance liquid chromatography, thin-layer chromatography, and spectrophotometry.

PubMed

Pocock, Tessa; Król, Marianna; Huner, Norman P A

2004-01-01

Chorophylls and carotenoids are functionally important pigment molecules in photosynthetic organisms. Methods for the determination of chlorophylls a and b, beta-carotene, neoxanthin, and the pigments that are involved in photoprotective cycles such as the xanthophylls are discussed. These cycles involve the reversible de-epoxidation of violaxanthin into antheraxanthin and zeaxanthin, as well as the reversible de-epoxidation of lutein-5,6-epoxide into lutein. This chapter describes pigment extraction procedures from higher plants and green algae. Methods for the determination and quantification using high-performance liquid chromatograpy (HPLC) are described as well as methods for the separation and purification of pigments for use as standards using thin-layer chromatography (TLC). In addition, several spectrophotometric methods for the quantification of chlorophylls a and b are described.

Insights into hydrologic and hydrochemical processes based on concentration-discharge and end-member mixing analyses in the mid-Merced River Basin, Sierra Nevada, California

NASA Astrophysics Data System (ADS)

Liu, Fengjing; Conklin, Martha H.; Shaw, Glenn D.

2017-01-01

Both concentration-discharge relation and end-member mixing analysis were explored to elucidate the connectivity of hydrologic and hydrochemical processes using chemical data collected during 2006-2008 at Happy Isles (468 km2), Pohono Bridge (833 km2), and Briceburg (1873 km2) in the snowmelt-fed mid-Merced River basin, augmented by chemical data collected by the USGS during 1990-2014 at Happy Isles. Concentration-discharge (C-Q) in streamflow was dominated by a well-defined power law relation, with the magnitude of exponent (0.02-0.6) and R2 values (p < 0.001) lower on rising than falling limbs. Concentrations of conservative solutes in streamflow resulted from mixing of two end-members at Happy Isles and Pohono Bridge and three at Briceburg, with relatively constant solute concentrations in end-members. The fractional contribution of groundwater was higher on rising than falling limbs at all basin scales. The relationship between the fractional contributions of subsurface flow and groundwater and streamflow (F-Q) followed the same relation as C-Q as a result of end-member mixing. The F-Q relation was used as a simple model to simulate subsurface flow and groundwater discharges to Happy Isles from 1990 to 2014 and was successfully validated by solute concentrations measured by the USGS. It was also demonstrated that the consistency of F-Q and C-Q relations is applicable to other catchments where end-members and the C-Q relationships are well defined, suggesting hydrologic and hydrochemical processes are strongly coupled and mutually predictable. Combining concentration-discharge and end-member mixing analyses could be used as a diagnostic tool to understand streamflow generation and hydrochemical controls in catchment hydrologic studies.

Comparative study of autophagy inhibition by 3MA and CQ on Cytarabine‑induced death of leukaemia cells.

PubMed

Palmeira dos Santos, Caroline; Pereira, Gustavo J S; Barbosa, Christiano M V; Jurkiewicz, Aron; Smaili, Soraya S; Bincoletto, Claudia

2014-06-01

As the molecular mechanisms of Cytarabine,one of the most important drugs used in the leukaemia’s treatment, are only partially understood and the role of autophagy on leukaemia development and treatment is only recently being investigated, in this study, by using Chloroquine (CQ) and 3-methyladenine (3MA) as autophagy inhibitors, we aim to evaluate the contribution of an autophagic mechanism to Cytarabine (AraC)-induced death of HL60 leukaemia cells. Trypan blue exclusion and AnnexinV/PI assays were used to evaluate HL60 cell death under AraC treatment in the presence or absence of 3MA and CQ. Western blotting and immunofluorescence experiments were performed to show the involvement of apoptosis and autophagy protein expressions. Phenotypic characterization of HL60-treated cells was performed by using immunophenotyping. Clonogenic assays were applied to analyse clonal function of HL60-treated cells. We observed that although autophagy inhibition by 3MA, but not CQ, increased the death of HL60 AraC cells after 24 h of treatment, no significant differences between AraC and AraC + 3MA-treated groups were observed by using clonogenic assay. In addition, increased number of immature (CD34(+)/CD38(−)Lin(−/low)) HL60 cells was found in AraC and AraC-3MA groups when compared with control untreated cells. Although AraC anti-leukaemia effects could be potentiated by 3MA autophagy inhibition after 24 h of exposure, leukaemia cell resistance, the main causes of treatment failure, is also promoted by autophagy initial stage impairment by 3MA, denoting the complex role of autophagy in leukaemia cells’ response to chemotherapy.

Therapeutic efficacy test in malaria falciparum in Antioquia, Colombia

PubMed Central

Blair, Silvia; Carmona-Fonseca, Jaime; Piñeros, Juan G; Ríos, Alexandra; Álvarez, Tania; Álvarez, Gonzalo; Tobón, Alberto

2006-01-01

Objective Evaluate the frequency of failure of eight treatments for non-complicated malaria caused by Plasmodium falciparum in patients from Turbo (Urabá region), El Bagre and Zaragoza (Bajo Cauca region), applying the 1998 protocol of the World Health Organization (WHO). Monotherapies using chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ) and sulphadoxine-pyrimethamine (SP), and combinations using chloroquine-sulphadoxine-pyrimethamine (CQ-SP), amodiaquine-sulphadoxine-pyrimethamine (AQ-SP), mefloquine-sulphadoxine-pyrimethamine (MQ-SP) and artesunate-sulphadoxine-pyrimethamine (AS-SP), were examined. Methodology A balanced experimental design with eight groups. Samples were selected based on statistical and epidemiological criteria. Patients were followed for 21 to 28 days, including seven or eight parasitological and clinical evaluations, with an active search for defaulting patients. A non-blinded evaluation of the antimalarial treatment response (early failure, late failure, adequate response) was performed. Results Initially, the loss of patients to follow-up was higher than 40%, but the immediate active search for the cases and the monetary help for transportation expenses of patients, reduced the loss to 6%. The treatment failure was: CQ 82%, AQ 30%, MQ 4%, SP 24%, CQ-SP 17%, AQ-SP 2%, MQ-S-P 0%, AS-SP 3%. Conclusion The characteristics of an optimal epidemiological monitoring system of antimalarial treatment response in Colombia are discussed. It is proposed to focus this on early failure detection, by applying a screening test every two to three years, based on a seven to 14-day follow-up. Clinical and parasitological assessment would be carried out by a general physician and a field microscopist from the local hospital, with active measures to search for defaulter patients at follow-up. PMID:16504002

Photopolymerization of highly filled dimethacrylate-based composites using Type I or Type II photoinitiators and varying co-monomer ratios.

PubMed

Randolph, Luc D; Steinhaus, Johannes; Möginger, Bernhard; Gallez, Bernard; Stansbury, Jeffrey; Palin, William M; Leloup, Gaëtane; Leprince, Julian G

2016-02-01

The use of a Type I photoinitiator (monoacylphosphine oxide, MAPO) was described as advantageous in a model formulation, as compared to the conventional Type II photoinitiator (Camphorquinone, CQ). The aim of the present work was to study the kinetics of polymerization of various composite mixtures (20-40-60-80 mol%) of bisphenol A glycidyl dimethacrylate/triethylene glycol dimethacrylate (BisGMA/TegDMA) containing either CQ or MAPO, based on real-time measurements and on the characterization of various post-cure characteristics. Polymerization kinetics were monitored by Fourier-transform near-infrared spectroscopy (FT-NIRS) and dielectric analysis (DEA). A range of postcure properties was also investigated. FT-NIRS and DEA proved complementary to follow the fast kinetics observed with both systems. Autodecceleration occurred after ≈1 s irradiation for MAPO-composites and ≈5-10 s for CQ-composites. Conversion decreased with increasing initial viscosity for both photoinitiating systems. However despite shorter light exposure (3s for MAPO vs 20s for CQ-composites), MAPO-composites yielded higher conversions for all co-monomer mixtures, except at 20 mol% BisGMA, the less viscous material. MAPO systems were associated with increased amounts of trapped free radicals, improved flexural strength and modulus, and reduced free monomer release for all co-monomer ratios, except at 20 mol% BisGMA. This work confirms the major influence of the initiation system both on the conversion and network cross-linking of highly-filled composites, and further highlights the advantages of using MAPO photoinitiating systems in highly-filled dimethacrylate-based composites provided that sufficient BisGMA content (>40 mol%) and adapted light spectrum are used. Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Hydroxychloroquine binding to cytoplasmic domain of Band 3 in human erythrocytes: Novel mechanistic insights into drug structure, efficacy and toxicity.

PubMed

Nakagawa, Mizuki; Sugawara, Kotomi; Goto, Tatsufumi; Wakui, Hideki; Nunomura, Wataru

2016-05-13

Hydroxychloroquine (HCQ) is a widely used drug in the treatment of autoimmune diseases, such as arthritis and systemic lupus erythematosus. It has also been prescribed for the treatment of malaria owing to its lower toxicity compared to its closely related compound chloroquine (CQ). However, the mechanisms of action of HCQ in erythrocytes (which bind preferentially this drug) have not been documented and the reasons underlying the lower side effects of HCQ compared to CQ remain unclear. Here we show that, although the activity of erythrocyte lactate dehydrogenase (LDH), but not GAPDH, was inhibited by both HCQ and CQ in vitro, LDH activity in erythrocytes incubated with 20 mM HCQ was not significantly reduced within 5 h in contrast to CQ did. Using HCQ coupled Sepharose chromatography (HCQ-Sepharose), we identified Band 3, spectrin, ankyrin, protein 4.1R and protein 4.2 as HCQ binding proteins in human erythrocyte plasma membrane. Recombinant cytoplasmic N-terminal 43 kDa domain of Band 3 bound to HCQ-Sepharose and was eluted with 40 mM (but not 20 mM) HCQ. Band 3 transport activity was reduced by only 23% in the presence of 20 mM HCQ. Taken together, these data demonstrate that HCQ binds to the cytoplasmic N-terminal domain of Band 3 in human erythrocytes but does not inhibit dramatically its transport activity. We hypothesize that the trapping of HCQ on Band 3 contributes to the lower side effects of the drug on energy production in erythrocytes. Copyright © 2016 Elsevier Inc. All rights reserved.

Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency.

PubMed

Romero-Moya, Damià; Santos-Ocaña, Carlos; Castaño, Julio; Garrabou, Gloria; Rodríguez-Gómez, José A; Ruiz-Bonilla, Vanesa; Bueno, Clara; González-Rodríguez, Patricia; Giorgetti, Alessandra; Perdiguero, Eusebio; Prieto, Cristina; Moren-Nuñez, Constanza; Fernández-Ayala, Daniel J; Victoria Cascajo, Maria; Velasco, Iván; Canals, Josep Maria; Montero, Raquel; Yubero, Delia; Jou, Cristina; López-Barneo, José; Cardellach, Francesc; Muñoz-Cánoves, Pura; Artuch, Rafael; Navas, Plácido; Menendez, Pablo

2017-07-01

Coenzyme Q 10 (CoQ 10 ) plays a crucial role in mitochondria as an electron carrier within the mitochondrial respiratory chain (MRC) and is an essential antioxidant. Mutations in genes responsible for CoQ 10 biosynthesis (COQ genes) cause primary CoQ 10 deficiency, a rare and heterogeneous mitochondrial disorder with no clear genotype-phenotype association, mainly affecting tissues with high-energy demand including brain and skeletal muscle (SkM). Here, we report a four-year-old girl diagnosed with minor mental retardation and lethal rhabdomyolysis harboring a heterozygous mutation (c.483G > C (E161D)) in COQ4. The patient's fibroblasts showed a decrease in [CoQ 10 ], CoQ 10 biosynthesis, MRC activity affecting complexes I/II + III, and respiration defects. Bona fide induced pluripotent stem cell (iPSCs) lines carrying the COQ4 mutation (CQ4-iPSCs) were generated, characterized and genetically edited using the CRISPR-Cas9 system (CQ4 ed -iPSCs). Extensive differentiation and metabolic assays of control-iPSCs, CQ4-iPSCs and CQ4 ed -iPSCs demonstrated a genotype association, reproducing the disease phenotype. The COQ4 mutation in iPSC was associated with CoQ 10 deficiency, metabolic dysfunction, and respiration defects. iPSC differentiation into SkM was compromised, and the resulting SkM also displayed respiration defects. Remarkably, iPSC differentiation in dopaminergic or motor neurons was unaffected. This study offers an unprecedented iPSC model recapitulating CoQ 10 deficiency-associated functional and metabolic phenotypes caused by COQ4 mutation. Stem Cells 2017;35:1687-1703. © 2017 AlphaMed Press.

Development and validation of the Consumer Quality index instrument to measure the experience and priority of chronic dialysis patients.

PubMed

van der Veer, Sabine N; Jager, Kitty J; Visserman, Ella; Beekman, Robert J; Boeschoten, Els W; de Keizer, Nicolette F; Heuveling, Lara; Stronks, Karien; Arah, Onyebuchi A

2012-08-01

Patient experience is an established indicator of quality of care. Validated tools that measure both experiences and priorities are lacking for chronic dialysis care, hampering identification of negative experiences that patients actually rate important. We developed two Consumer Quality (CQ) index questionnaires, one for in-centre haemodialysis (CHD) and the other for peritoneal dialysis and home haemodialysis (PHHD) care. The instruments were validated using exploratory factor analyses, reliability analysis of identified scales and assessing the association between reliable scales and global ratings. We investigated opportunities for improvement by combining suboptimal experience with patient priority. Sixteen dialysis centres participated in our study. The pilot CQ index for CHD care consisted of 71 questions. Based on data of 592 respondents, we identified 42 core experience items in 10 scales with Cronbach's α ranging from 0.38 to 0.88; five were reliable (α ≥ 0.70). The instrument identified information on centres' fire procedures as the aspect of care exhibiting the biggest opportunity for improvement. The pilot CQ index PHHD comprised 56 questions. The response of 248 patients yielded 31 core experience items in nine scales with Cronbach's α ranging between 0.53 and 0.85; six were reliable. Information on kidney transplantation during pre-dialysis showed most room for improvement. However, for both types of care, opportunities for improvement were mostly limited. The CQ index reliably and validly captures dialysis patient experience. Overall, most care aspects showed limited room for improvement, mainly because patients participating in our study rated their experience to be optimal. To evaluate items with high priority, but with which relatively few patients have experience, more qualitative instruments should be considered.

Residual Stresses and Sliding Wear.

DTIC Science & Technology

1982-05-25

case of rolling contact, taking into account strain hardening during plastic deformation. ..-s calculations (forSAE 52100 at a hardness level of 58.5 R...can reach -800- 1000 MPa. If 033 was comparable to these values, it would indeed effect the wear rate. It is evident that an experimental deter...cc o 40 1 °2 00 I I +A ) S l~lll0 44MUK I CQ E3 e0 El 0 Uc 00 E3 (3 80 j40 c (vclq) SSHHI +ce ce mCQ ce (2E e0 4El EJ) E - 0 El 0 E0 .. t El 0 (vdNp

Thermal quench mitigation and current quench control by injection of mixed species shattered pellets in DIII-D

DOE PAGES

Shiraki, D.; Commaux, N.; Baylor, L. R.; ...

2016-06-27

Injection of large shattered pellets composed of variable quantities of the main ion species (deuterium) and high-Z impurities (neon) in the DIII-D tokamak demonstrate control of thermal quench (TQ) and current quench (CQ) properties in mitigated disruptions. As the pellet composition is varied, TQ radiation fractions increase continuously with the quantity of radiating impurity in the pellet, with a corresponding decrease in divertor heating. Post-TQ plasma resistivities increase as a result of the higher radiation fraction, allowing control of current decay timescales based on the pellet composition. Magnetic reconstructions during the CQ show that control of the current decay ratemore » allows continuous variation of the minimum safety factor during the vertically unstable disruption, reducing the halo current fraction and resulting vessel displacement. Both TQ and CQ characteristics are observed to saturate at relatively low quantities of neon, indicating that effective mitigation of disruption loads by shattered pellet injection (SPI) can be achieved with modest impurity quantities, within injection quantities anticipated for ITER. In conclusion, this mixed species SPI technique provides apossible approach for tuning disruption properties to remain within the limited ranges allowed in the ITER design.« less

Thermal quench mitigation and current quench control by injection of mixed species shattered pellets in DIII-D

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

Shiraki, D.; Commaux, N.; Baylor, L. R.

Injection of large shattered pellets composed of variable quantities of the main ion species (deuterium) and high-Z impurities (neon) in the DIII-D tokamak demonstrate control of thermal quench (TQ) and current quench (CQ) properties in mitigated disruptions. As the pellet composition is varied, TQ radiation fractions increase continuously with the quantity of radiating impurity in the pellet, with a corresponding decrease in divertor heating. Post-TQ plasma resistivities increase as a result of the higher radiation fraction, allowing control of current decay timescales based on the pellet composition. Magnetic reconstructions during the CQ show that control of the current decay ratemore » allows continuous variation of the minimum safety factor during the vertically unstable disruption, reducing the halo current fraction and resulting vessel displacement. Both TQ and CQ characteristics are observed to saturate at relatively low quantities of neon, indicating that effective mitigation of disruption loads by shattered pellet injection (SPI) can be achieved with modest impurity quantities, within injection quantities anticipated for ITER. In conclusion, this mixed species SPI technique provides apossible approach for tuning disruption properties to remain within the limited ranges allowed in the ITER design.« less

Thermal quench mitigation and current quench control by injection of mixed species shattered pellets in DIII-D

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

Shiraki, D.; Commaux, N.; Baylor, L. R.

Injection of large shattered pellets composed of variable quantities of the main ion species (deuterium) and high-Z impurities (neon) in the DIII-D tokamak demonstrates control of thermal quench (TQ) and current quench (CQ) properties in mitigated disruptions. As the pellet composition is varied, TQ radiation fractions increase continuously with the quantity of radiating impurity in the pellet, with a corresponding decrease in divertor heating. Post-TQ plasma resistivities increase as a result of the higher radiation fraction, allowing control of current decay timescales based on the pellet composition. Magnetic reconstructions during the CQ show that control of the current decay ratemore » allows continuous variation of the minimum safety factor during the vertically unstable disruption, reducing the halo current fraction and resulting vessel displacement. Both TQ and CQ characteristics are observed to saturate at relatively low quantities of neon, indicating that effective mitigation of disruption loads by shattered pellet injection (SPI) can be achieved with modest impurity quantities, within injection quantities anticipated for ITER. This mixed species SPI technique provides a possible approach for tuning disruption properties to remain within the limited ranges allowed in the ITER design.« less

Correlating cytotoxicity to elution behaviors of composite resins in term of curing kinetic.

PubMed

Meng, Junquan; Yang, Huichuan; Cao, Man; Li, Lei; Cai, Qing

2017-09-01

Cytotoxicity of photocurable composite resins is a key issue for their safe use in dental restoration. Curing kinetic and elution behaviors of the composite resin would have decisive effects on its cytotoxicity. In this study, composite resins composed of bisphenol-glycidyl dimethacrylate (Bis-GMA), triethyleneglycol dimethacrylate (TEGDMA), camphorquinone (CQ), N,N-dimethylaminoethyl methacrylate (DMAEMA) and barium glass powders were prepared by setting the photoinitiators CQ/DMAEMA at 0.5wt%, 1wt% or 3wt% of the total weight of Bis-GMA/TEGDMA. The ratio of Bis-GMA/TEGDMA was 6:4, the ratio of CQ/DMAEMA was 1:1, and the incorporated inorganic powder was 75wt%. Then, curing kinetics were studied by using real-time Fourier transform infrared spectroscopy (FTIR) and photo-DSC (differential scanning calorimeter). Elution behaviors in both ethanol solution and deionized water were monitored by using liquid chromatogram/mass spectrometry (LC/MS). Cytotoxicity was evaluated by in vitro culture of L929 fibroblasts. Finally, they were all analyzed and correlated in terms of initiator contents. It was found that the commonly used 0.5wt% of photoinitiators was somewhat insufficient in obtaining composite resin with low cytotoxicity. Copyright © 2017. Published by Elsevier B.V.

Position-based coding and convex splitting for private communication over quantum channels

NASA Astrophysics Data System (ADS)

Wilde, Mark M.

2017-10-01

The classical-input quantum-output (cq) wiretap channel is a communication model involving a classical sender X, a legitimate quantum receiver B, and a quantum eavesdropper E. The goal of a private communication protocol that uses such a channel is for the sender X to transmit a message in such a way that the legitimate receiver B can decode it reliably, while the eavesdropper E learns essentially nothing about which message was transmitted. The ɛ -one-shot private capacity of a cq wiretap channel is equal to the maximum number of bits that can be transmitted over the channel, such that the privacy error is no larger than ɛ \\in (0,1). The present paper provides a lower bound on the ɛ -one-shot private classical capacity, by exploiting the recently developed techniques of Anshu, Devabathini, Jain, and Warsi, called position-based coding and convex splitting. The lower bound is equal to a difference of the hypothesis testing mutual information between X and B and the "alternate" smooth max-information between X and E. The one-shot lower bound then leads to a non-trivial lower bound on the second-order coding rate for private classical communication over a memoryless cq wiretap channel.

Preliminary Study on a Reduced Scaled Model Regarding the Air Diffusion inside a Crew Quarter on Board of the ISS

NASA Astrophysics Data System (ADS)

Sandu, Mihnea; Nastase, Ilinca; Bode, Florin; Croitoru, CristianaVerona; Tacutu, Laurentiu

2018-02-01

The paper focus on the air quality inside the Crew Quarters on board of the International Space Station. Several issues to improve were recorded by NASA and ESA and most important of them are the following: noise level reduction, CO2 accumulation reduction and dust accumulation reduction. The study in this paper is centred on a reduced scaled model used to provide simulations related to the air diffusion inside the CQ. It is obvious that a new ventilation system is required to achieve the three issues mentioned above, and the solutions obtained by means of numerical simulation need to be validated by experimental approach. First of all we have built a reduced scaled physical model to simulate the flow pattern inside the CQ and the equipment inside the CQ has been reproduced using a geometrical scale ratio. The flow pattern was considered isothermal and incompressible. The similarity criteria used was the Reynolds number to characterize the flow pattern and the length scale was set at value 1/4. Water has been used inside the model to simulate air. Velocity magnitude vectors have been obtained using PIV measurement techniques.

Phosphorus Export Model Development in a Terminal Lake Basin using Concentration-Streamflow Relationship

NASA Astrophysics Data System (ADS)

Jeannotte, T.; Mahmood, T. H.; Matheney, R.; Hou, X.

2017-12-01

Nutrient export to streams and lakes by anthropogenic activities can lead to eutrophication and degradation of surface water quality. In Devils Lake, ND, the only terminal lake in the Northern Great Plains, the algae boom is of great concern due to the recent increase in streamflow and consequent rise in phosphorus (P) export from prairie agricultural fields. However, to date, very few studies explored the concentration (c) -streamflow (q) relationship in the headwater catchments of the Devils Lake basin. A robust watershed-scale quantitative framework would aid understanding of the c-q relationship, simulating P concentration and load. In this study, we utilize c-q relationships to develop a simple model to estimate phosphorus concentration and export from two headwater catchments of different size (Mauvais Coulee: 1032 km2 and Trib 3: 160 km2) draining to Devils Lake. Our goal is to link the phosphorus export model with a physically based hydrologic model to identify major drivers of phosphorus export. USGS provided the streamflow measurements, and we collected water samples (filtered and unfiltered) three times daily during the spring snowmelt season (March 31, 2017- April 12, 2017) at the outlets of both headwater catchments. Our results indicate that most P is dissolved and very little is particulate, suggesting little export of fine-grained sediment from agricultural fields. Our preliminary analyses in the Mauvais Coulee catchment show a chemostatic c-q relationship in the rising limb of the hydrograph, while the recession limb shows a linear and positive c-q relationship. The poor correlation in the rising limb of the hydrograph suggests intense flushing of P by spring snowmelt runoff. Flushing then continues in the recession limb of the hydrograph, but at a more constant rate. The estimated total P load for the Mauvais Coulee basin is 193 kg/km2, consistent with other catchments of similar size across the Red River of the North basin to the east. We expect our P measurements at Trib 3 basin, a considerably smaller basin compared to Mauvais Coulee, provide an opportunity to investigate the impacts of watershed scales on nutrient exports and c-q relationship. Finally, our study will lay a strong foundation for future nutrient modeling studies in the Devils Lake basin.

The consumer quality index anthroposophic healthcare: a construction and validation study.

PubMed

Koster, Evi B; Ong, Rob R S; Heybroek, Rachel; Delnoij, Diana M J; Baars, Erik W

2014-04-02

Accounting for the patients' perspective on quality of care has become increasingly important in the development of Evidence Based Medicine as well as in governmental policies. In the Netherlands the Consumer Quality (CQ) Index has been developed to measure the quality of care from the patients' perspective in different healthcare sectors in a standardized manner. Although the scientific accountability of anthroposophic healthcare as a form of integrative medicine is growing, patient experiences with anthroposophic healthcare have not been measured systematically. In addition, the specific anthroposophic aspects are not measured by means of existing CQ Indexes. To enable accountability of quality of the anthroposophic healthcare from the patients' perspective the aim of this study is the construction and validation of a CQ Index for anthroposophic healthcare. Construction in three phases: Phase 1. Determining anthroposophic quality aspects: literature study and focus groups. Phase 2. Adding new questions and validating the new questionnaire. Research population: random sample from 7910 patients of 22 anthroposophic GPs. survey, mixed mode by means of the Dillman method. Measuring instrument: experience questionnaire: CQ Index General Practice (56 items), added with 27 new anthroposophic items added and an item-importance questionnaire (anthroposophic items only). Factor analysis, scale construction, internal consistency (Chronbach's Alpha), inter-item-correlation, discriminative ability (Intra Class Correlation) and inter-factor-correlations. Phase 3. Modulation and selection of new questions based on results. Criteria of retaining items: general: a limited amount of items, statistical: part of a reliable scale and inter-item-correlation <0,7, and theoretical. Phase 1. 27 anthroposophic items. Phase 2. Two new anthroposophic scales: Scale AntroposophicTreatmentGP: seven items, Alpha=0,832, ICC=4,2 Inter-factor-correlation with existing GP-scales range from r=0,24 (Accessibility) to r=0,56 (TailoredCare). Scale InteractionalStyleGP: five items, Alpha=0,810, ICC=5,8, Inter-factor-correlation with existing GP-scales range from r=0,32 (Accessibility) to r=0,76 (TailoredCare). Inter-factor-correlation between new scales: r=0,50. Phase 3: Adding both scales and four single items. Removing eleven items and reformulating two items. The CQ Index Anthroposophic Healthcare measures patient experiences with anthroposophic GP's validly and reliably. Regarding the inter-factor-correlations anthroposophic quality aspects from the patients' perspective are mostly associated with individually tailored care and patient centeredness.

Cytostatic versus Cytocidal Activities of Chloroquine Analogues and Inhibition of Hemozoin Crystal Growth

PubMed Central

Gorka, Alexander P.; Alumasa, John N.; Sherlach, Katy S.; Jacobs, Lauren M.; Nickley, Katherine B.; Brower, Jonathan P.; de Dios, Angel C.

2013-01-01

We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365–374, 2013). PMID:23114783

Cytostatic versus cytocidal activities of chloroquine analogues and inhibition of hemozoin crystal growth.

PubMed

Gorka, Alexander P; Alumasa, John N; Sherlach, Katy S; Jacobs, Lauren M; Nickley, Katherine B; Brower, Jonathan P; de Dios, Angel C; Roepe, Paul D

2013-01-01

We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365-374, 2013).

Monitoring Theileria orientalis (Ikeda)-associated bovine anaemia in affected cattle over time.

PubMed

McFadden, Amj; Hart, M; Bueno, I M; Ha, H J; Heath, Acg; Pulford, D J

2017-10-15

The aim of the study was to observe changes in haematocrit (HCT) over time in a New Zealand South Island dairy herd affected by an outbreak of Theileria-associated bovine anaemia (TABA; Ikeda). A secondary aim was to relate individual cow HCTs to the amount of Theileria orientalis Ikeda DNA present in the blood, as measured by cycle threshold values, using a quantitative PCR (qPCR). Over a 6 month period, blood samples from 19 randomly selected cattle were monitored from a herd of 600 dairy cows. The sampling interval was approximately fortnightly for the first six weeks, followed by sampling at between four and six week intervals. At the initial report of the outbreak, two from six cattle were anaemic (HCT<0.25L/L). Blood collected from 14 cattle 11 days later showed that 57% (95% CI 33-77%) of the cattle sampled were anaemic. Of the 19 cattle that went on to be monitored, 12 (63% 95% CI=41-81%) developed anaemia at some point during the period of monitoring. One of the anaemic animals did not meet the case definition for TABA Ikeda. For individual cattle, the average number of days between when cattle were first detected as anaemic and when HCT returned to normal was 53days (median=47 days, range=6-92 days). At the point of notification the amount of T. orientalis Ikeda DNA in the blood of the six cattle tested was low (Cq median=36), but 11days later the amount of DNA in blood of 14 additional cows tested was relatively high (Cq median=24). Levels of all 19 cows monitored continued to remain moderately high through the period of testing (Cq median=29). This was despite a general improvement in the HCT of affected cattle. In four of the 15 cattle positive to T. orientalis Ikeda where blood fractions (plasma and whole blood) were tested, it appeared that T. orientalis Ikeda (as measured by qPCR) dropped more rapidly in plasma fractions than in whole blood at the point that HCT started to return to normal levels. Despite the assumption that tick populations were low in the Canterbury region of the South Island the impact of TABA (proportion of herd affected and the average period that animals remained anaemic) on the case herd was still relatively high. Copyright © 2017 Elsevier B.V. All rights reserved.

Landscape and flux reveal a new global view and physical quantification of mammalian cell cycle

PubMed Central

Li, Chunhe; Wang, Jin

2014-01-01

Cell cycles, essential for biological function, have been investigated extensively. However, enabling a global understanding and defining a physical quantification of the stability and function of the cell cycle remains challenging. Based upon a mammalian cell cycle gene network, we uncovered the underlying Mexican hat landscape of the cell cycle. We found the emergence of three local basins of attraction and two major potential barriers along the cell cycle trajectory. The three local basins of attraction characterize the G1, S/G2, and M phases. The barriers characterize the G1 and S/G2 checkpoints, respectively, of the cell cycle, thus providing an explanation of the checkpoint mechanism for the cell cycle from the physical perspective. We found that the progression of a cell cycle is determined by two driving forces: curl flux for acceleration and potential barriers for deceleration along the cycle path. Therefore, the cell cycle can be promoted (suppressed), either by enhancing (suppressing) the flux (representing the energy input) or by lowering (increasing) the barrier along the cell cycle path. We found that both the entropy production rate and energy per cell cycle increase as the growth factor increases. This reflects that cell growth and division are driven by energy or nutrition supply. More energy input increases flux and decreases barrier along the cell cycle path, leading to faster oscillations. We also identified certain key genes and regulations for stability and progression of the cell cycle. Some of these findings were evidenced from experiments whereas others lead to predictions and potential anticancer strategies. PMID:25228772

Crew Quarters (CQ) and Electromagnetic Interference (EMI) Measurement Facility Combined Impedance Study

NASA Technical Reports Server (NTRS)

Scully, Robert C.

2011-01-01

This report documents an investigation into observed failures associated with conducted susceptibility testing of Crew Quarters (CQ) hardware in the Johnson Space Center (JSC) Electromagnetic Interference (EMI) Measurement Facility, and the work accomplished to identify the source of the observed behavior. Investigation led to the conclusion that the hardware power input impedance was interacting with the facility power impedance leading to instability at the observed frequencies of susceptibility. Testing performed in other facilities did not show this same behavior, pointing back to the EMI Measurement Facility power as the potential root cause. A LISN emulating the Station power bus impedance was inserted into the power circuit, and the susceptibility was eliminated from the measurements.

Potential antimalarial activity of Methyl Jasmonate and its effect on lipid profiles in Plasmodium Berghei infected mice.

PubMed

Oyinloye, Oladapo E; Kosoko, Ayokulehin M; Emikpe, Benjamin; Falade, Catherine O; Ademowo, Olusegun G

2015-09-01

The antimalarial activity and lipid profiles of Methyl Jasmonate (MJ) were investigated against established malaria infection in vivo using BALB/c mice. Arteether (AE) and chloroquine (CQ) were used as reference drugs while ethanol was used as the vehicle for drug delivery for MJ. Mice treated with 10 and 25 mg/kg MJ showed a remarkable reduction in percentage parasitemia by 68.3% and 78.2% on day 10(post treatment) respectively while 45.4% and 87.2% reduction in percentage parasitemia were observed in the group treated with 50 mg/kg on day 3 and 10 (post treatment) respectively. The highest mean survival time was observed in CQ followed by AE and MJ in dose-dependent manner. A progressive decrease in packed cell volume (PCV) was observed in infected untreated mice which led to the death of all the mice by day 9 (post treatment). Infected mice treated with MJ showed reduced level of HDL and LDL compared with infected untreated group. As the dose of MJ increased in infected mice cholesterol levels increased while there was reduction in triglyceride. Overall there was marked decrease in parasitemia in Plasmodium berghei infected mice treated with graded doses of MJ but appears to have reduced antimalarial activity compared with CQ and AE.

Effect of Heat Treatment Technique on the Low Temperature Impact Toughness of Steel EQ70 for Offshore Structure

NASA Astrophysics Data System (ADS)

Tao, Su-Fen; Xia, Yun-Jin; Wang, Fu-Ming; Li, Jie; Fan, Ding-Dong

2017-09-01

Circle quenching and tempering (CQ&T), intercritical quenching and tempering (IQ&T) and regular quenching and tempering (Q&T) were used to study the influence of heat treatment techniques on the low temperature impact toughness of steel EQ70 for offshore structure. The steels with 2.10 wt. % Ni (steel A) and 1.47 wt. % Ni (steel B) were chosen to analyze the effect of Ni content on the low temperature impact toughness of steel EQ70 for offshore structure. The fracture morphologies were examined by using a scanning electron microscope (SEM, JSM-6480LV), and microstructures etched by 4 vol. % nitric acid were observed on a type 9XB-PC optical microscope. The results show that the impact toughness of steel A is higher than that of steel B at the same test temperature and heat treatment technique. For steel B, the energy absorbed is, in descending order, CQ&T, Q&T and IQ&T, while for steel A, that is CQ&T, IQ&T and Q&T. The effects of heat treatment on the low temperature impact toughness are different for steels A and B, the absorbed energy changes more obviously for steel A. The results can be significant references for actual heat treatment techniques in steel plant.

New adaptive color quantization method based on self-organizing maps.

PubMed

Chang, Chip-Hong; Xu, Pengfei; Xiao, Rui; Srikanthan, Thambipillai

2005-01-01

Color quantization (CQ) is an image processing task popularly used to convert true color images to palletized images for limited color display devices. To minimize the contouring artifacts introduced by the reduction of colors, a new competitive learning (CL) based scheme called the frequency sensitive self-organizing maps (FS-SOMs) is proposed to optimize the color palette design for CQ. FS-SOM harmonically blends the neighborhood adaptation of the well-known self-organizing maps (SOMs) with the neuron dependent frequency sensitive learning model, the global butterfly permutation sequence for input randomization, and the reinitialization of dead neurons to harness effective utilization of neurons. The net effect is an improvement in adaptation, a well-ordered color palette, and the alleviation of underutilization problem, which is the main cause of visually perceivable artifacts of CQ. Extensive simulations have been performed to analyze and compare the learning behavior and performance of FS-SOM against other vector quantization (VQ) algorithms. The results show that the proposed FS-SOM outperforms classical CL, Linde, Buzo, and Gray (LBG), and SOM algorithms. More importantly, FS-SOM achieves its superiority in reconstruction quality and topological ordering with a much greater robustness against variations in network parameters than the current art SOM algorithm for CQ. A most significant bit (MSB) biased encoding scheme is also introduced to reduce the number of parallel processing units. By mapping the pixel values as sign-magnitude numbers and biasing the magnitudes according to their sign bits, eight lattice points in the color space are condensed into one common point density function. Consequently, the same processing element can be used to map several color clusters and the entire FS-SOM network can be substantially scaled down without severely scarifying the quality of the displayed image. The drawback of this encoding scheme is the additional storage overhead, which can be cut down by leveraging on existing encoder in an overall lossy compression scheme.

Comparative Study of the Fatty Acid Binding Process of a New FABP from Cherax quadricarinatus by Fluorescence Intensity, Lifetime and Anisotropy

PubMed Central

Li, Jiayao; Henry, Etienne; Wang, Lanmei; Delelis, Olivier; Wang, Huan; Simon, Françoise; Tauc, Patrick; Brochon, Jean-Claude; Zhao, Yunlong; Deprez, Eric

2012-01-01

Fatty acid-binding proteins (FABPs) are small cytosolic proteins, largely distributed in invertebrates and vertebrates, which accomplish uptake and intracellular transport of hydrophobic ligands such as fatty acids. Although long chain fatty acids play multiple crucial roles in cellular functions (structural, energy metabolism, regulation of gene expression), the precise functions of FABPs, especially those of invertebrate species, remain elusive. Here, we have identified and characterized a novel FABP family member, Cq-FABP, from the hepatopancreas of red claw crayfish Cherax quadricarinatus. We report the characterization of fatty acid-binding affinity of Cq-FABP by four different competitive fluorescence-based assays. In the two first approaches, the fluorescent probe 8-Anilino-1-naphthalenesulfonate (ANS), a binder of internal cavities of protein, was used either by directly monitoring its fluorescence emission or by monitoring the fluorescence resonance energy transfer occurring between the single tryptophan residue of Cq-FABP and ANS. The third and the fourth approaches were based on the measurement of the fluorescence emission intensity of the naturally fluorescent cis-parinaric acid probe or the steady-state fluorescence anisotropy measurements of a fluorescently labeled fatty acid (BODIPY-C16), respectively. The four methodologies displayed consistent equilibrium constants for a given fatty acid but were not equivalent in terms of analysis. Indeed, the two first methods were complicated by the existence of non specific binding modes of ANS while BODIPY-C16 and cis-parinaric acid specifically targeted the fatty acid binding site. We found a relationship between the affinity and the length of the carbon chain, with the highest affinity obtained for the shortest fatty acid, suggesting that steric effects primarily influence the interaction of fatty acids in the binding cavity of Cq-FABP. Moreover, our results show that the binding affinities of several fatty acids closely parallel their prevalences in the hepatopancreas of C. quadricarinatus as measured under specific diet conditions. PMID:23284658

Area of Concern: a new paradigm in life cycle assessment for the development of footprint metrics

EPA Science Inventory

Purpose: As a class of environmental metrics, footprints have been poorly defined, have shared an unclear relationship to life cycle assessment (LCA), and the variety of approaches to quantification have sometimes resulted in confusing and contradictory messages in the marketplac...

Molecular markers associated with resistance to commonly used antimalarial drugs among Plasmodium falciparum isolates from a malaria-endemic area in Taiz governorate-Yemen during the transmission season.

PubMed

Alareqi, Lina M Q; Mahdy, Mohammed A K; Lau, Yee-Ling; Fong, Mun-Yik; Abdul-Ghani, Rashad; Mahmud, Rohela

2016-10-01

Since 2005, artesunate (AS) plus sulfadoxine/pyrimethamine (SP) combination has been adopted as the first-line treatment for uncomplicated malaria in Yemen in response to the high level of Plasmodium falciparum resistance to chloroquine (CQ). Therefore, the aim of the present study was to determine the frequency distribution of molecular markers associated with resistance to CQ and AS plus SP combination among P. falciparum isolates from a malaria-endemic area in Taiz governorate, Yemen. Fifty P. falciparum isolates were collected during a cross-sectional study in Mawza district, Taiz, in the period from October 2013 to April 2014. The isolates were investigated for drug resistance-associated molecular markers in five genes, including P. falciparum CQ resistance transporter (pfcrt) 76T and P. falciparum multidrug resistance 1 (pfmdr1) 86Y as markers of resistance to CQ, mutations in the Kelch 13 (K13) propeller domain for resistance to AS, and P. falciparum dihydrofolate reductase (pfdhfr) and P. falciparum dihydropteroate synthase (pfdhps) genes for resistance to SP. Nested polymerase chain reaction was used to amplify target genes in DNA extracts of the isolates followed by restriction fragment length polymorphism for detecting 76T and 86Y mutations in pfcrt and pfmdr1, respectively, and by DNA sequencing for detecting mutations in K13, pfdhfr and pfdhps. All the investigated isolates from Mawza district were harboring the pfcrt 76T mutant and the pfmdr1 N86 wild-type alleles. The pfdhfr 51I/108N double mutant allele was found in 2.2% (1/45) of the isolates; however, no mutations were detected at codons 436, 437, 540, 581 and 613 of pfdhps. All P. falciparum isolates that were successfully sequenced (n=47) showed the K13 Y493, R539, I543 and C580 wild-type alleles. In conclusion, the pfcrt 76T mutant allele is fixed in the study area about six years after the official withdrawal of CQ, possibly indicating its over-the-counter availability and continued use as a self-medication in the study area. However, the almost predominant wild-type alleles of the genes associated with resistance to AS and SP among P. falciparum isolates in the present study indicates the sustained efficacy of the currently adopted first-line treatment of AS plus SP in the study area. Copyright © 2016 Elsevier B.V. All rights reserved.

Role of Autophagy in Glycogen Breakdown and Its Relevance to Chloroquine Myopathy

PubMed Central

Zirin, Jonathan; Nieuwenhuis, Joppe; Perrimon, Norbert

2013-01-01

Several myopathies are associated with defects in autophagic and lysosomal degradation of glycogen, but it remains unclear how glycogen is targeted to the lysosome and what significance this process has for muscle cells. We have established a Drosophila melanogaster model to study glycogen autophagy in skeletal muscles, using chloroquine (CQ) to simulate a vacuolar myopathy that is completely dependent on the core autophagy genes. We show that autophagy is required for the most efficient degradation of glycogen in response to starvation. Furthermore, we show that CQ-induced myopathy can be improved by reduction of either autophagy or glycogen synthesis, the latter possibly due to a direct role of Glycogen Synthase in regulating autophagy through its interaction with Atg8. PMID:24265594

Sensitive determination of THC and main metabolites in human plasma by means of microextraction in packed sorbent and gas chromatography-tandem mass spectrometry.

PubMed

Rosado, T; Fernandes, L; Barroso, M; Gallardo, E

2017-02-01

Cannabis is one of the most available and consumed illicit drug in the world and its identification and quantification in biological specimens can be a challenge given its low concentrations in body fluids. The present work describes a fast and fully validated procedure for the simultaneous detection and quantification of ▵ 9 -tetrahydrocannabinol (▵ 9_ THC) and its two main metabolites 11-hydroxy ▵ 9_ tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-▵ 9 - tetrahydrocannbinol (THC-COOH) in plasma samples using microextraction by packed sorbent (MEPS) and gas chromatography-tandem mass spectrometry (GC-MS/MS). A small plasma volume (0.25mL) pre-diluted (1:20), was extracted with MEPS M1 sorbent as follows: conditioning (4 cycles of 250μL methanol and 4 cycles of 250μL 0.1% formic acid in water); sample load (26 cycles of 250μL); wash (100μL of 3% acetic acid in water followed by 100μL 5% methanol in water); and elution (6 cycles of 100μL of 10% ammonium hydroxide in methanol). The procedure allowed the quantification of all analytes in the range of 0.1-30ng/mL. Recoveries ranged from 53 to 78% (THC), 57 to 66% (11-OH-THC) and 62 to 65% (THC-COOH), allowing the limits of detection and quantification to be set at 0.1ng/mL for all compounds. Intra-day precision and accuracy revealed coefficients of variation (CVs) lower than 10% at the studied concentrations, with a mean relative error within±9%, while inter-day precision and accuracy showed CVs lower than 15% for all analytes at the tested concentrations, with an inaccuracy within±8%. Copyright © 2016 Elsevier B.V. All rights reserved.

Visualization of endothelial cell cycle dynamics in mouse using the Flt-1/eGFP-anillin system.

PubMed

Herz, Katia; Becker, Alexandra; Shi, Chenyue; Ema, Masatsugo; Takahashi, Satoru; Potente, Michael; Hesse, Michael; Fleischmann, Bernd K; Wenzel, Daniela

2018-05-01

Endothelial cell proliferation is a key process during vascular growth but its kinetics could only be assessed in vitro or ex vivo so far. To enable the monitoring and quantification of cell cycle kinetics in vivo, we have generated transgenic mice expressing an eGFP-anillin construct under control of the endothelial-specific Flt-1 promoter. This construct labels the nuclei of endothelial cells in late G1, S and G2 phase and changes its localization during the different stages of M phase, thereby enabling the monitoring of EC proliferation and cytokinesis. In Flt-1/eGFP-anillin mice, we found eGFP + signals specifically in Ki67 + /PECAM + endothelial cells during vascular development. Quantification using this cell cycle reporter in embryos revealed a decline in endothelial cell proliferation between E9.5 to E12.5. By time-lapse microscopy, we determined the length of different cell cycle phases in embryonic endothelial cells in vivo and found a M phase duration of about 80 min with 2/3 covering karyokinesis and 1/3 cytokinesis. Thus, we have generated a versatile transgenic system for the accurate assessment of endothelial cell cycle dynamics in vitro and in vivo.

Artemyev post-EVA

NASA Image and Video Library

2014-06-19

Cosmonaut Oleg Artemyev, Expedition 40 flight engineer, is photographed still wearing his liquid cooling and ventilation garment after a Russian Extravehicular Activity (EVA). Artemyev is standing in his crew quarters (CQ).

Effect of different photo-initiators and light curing units on degree of conversion of composites.

PubMed

Brandt, William Cunha; Schneider, Luis Felipe Jochims; Frollini, Elisabete; Correr-Sobrinho, Lourenço; Sinhoreti, Mário Alexandre Coelho

2010-01-01

The aim of this study was to evaluate: (i) the absorption of photo-initiators and emission spectra of light curing units (LCUs); and (ii) the degree of conversion (DC) of experimental composites formulated with different photo-initiators when activated by different LCUs. Blends of BisGMA, UDMA, BisEMA and TEGDMA with camphorquinone (CQ) and/ or 1-phenyl-1,2-propanedione (PPD) were prepared. Dimethylaminoethyl methacrylate (DMAEMA) was used as co-initiator. Each mixture was loaded with 65 wt% of silanated filler particles. One quartz-tungsten-halogen - QTH (XL 2500, 3M/ESPE) and two lightemitting diode (LED) LCUs (UltraBlue IS, DMC and UltraLume LED 5, Ultradent) were used for activation procedures. Irradiance (mW/cm²) was calculated by the ratio of the output power by the area of the tip, and spectral distribution with a spectrometer (USB 2000). The absorption curve of each photo-initiator was determined using a spectrophotometer (Varian Cary 5G). DC was assessed by Fourier transformed infrared spectroscopy. Data were submitted to two-way ANOVA and Tukey's test (5%). No significant difference was found for DC values when using LED LCUs regardless of the photo-initiator type. However, PPD showed significantly lower DC values than composites with CQ when irradiated with QTH. PPD produced DC values similar to those of CQ, but it was dependent on the LCU type.

Vocal economy in vocally trained actresses and untrained female subjects.

PubMed

Master, Suely; Guzman, Marco; Dowdall, Jayme

2013-11-01

Vocally trained actresses are expected to have more vocal economy than nonactresses. Therefore, we hypothesize that there will be differences in the electroglottogram-based voice economy parameter quasi-output cost ratio (QOCR) between actresses and nonactresses. This difference should remain across different levels of intensity. A total of 30 actresses and 30 nonactresses were recruited for this study. Participants from both groups were required to sustain the vowels /a/, /i/, and /u/, in habitual, moderate, and high intensity levels. Acoustic variables such as sound pressure level (SPL), fundamental frequency (F0), and glottal contact quotient (CQ) were obtained. The QOCR was then calculated. There were no significant differences among the groups for QOCR. Positive correlations were observed for QOCR versus SPL and QOCR versus F0 in all intensity levels. Negative correlation was found between QOCR and CQ in all intensity levels. Considering the differences among intensity levels, from habitual to moderate and from moderate to loud, only the CQ did not differ significantly. The QOCR, SPL, and F0 presented significant differences throughout the different intensity levels. The QOCR did not reflect the level of vocal training when comparing trained and nontrained female subjects in the present study. Both groups demonstrated more vocal economy in moderate and high intensity levels owing to more voice output without an increase in glottal adduction. Copyright © 2013 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

Insight into magnesium coordination environments in benzoate and salicylate complexes through 25Mg solid-state NMR spectroscopy.

PubMed

Burgess, Kevin M N; Xu, Yang; Leclerc, Matthew C; Bryce, David L

2013-08-01

We report on the (25)Mg solid-state nuclear magnetic resonance (NMR) characterization of a series of magnesium complexes featuring Mg(2+) ions in organic coordination environments. Six compounds have been synthesized with benzoate and salicylate ligands, which are typically used as linkers in metal organic frameworks (MOFs). The use of ultrahigh-field solid-state NMR has revealed a relatively large range of values for the (25)Mg quadrupolar coupling constant, CQ((25)Mg), in these compounds. In contrast to some previously studied inorganic Mg(2+) complexes, the values of CQ((25)Mg) in organic Mg(2+) complexes are well rationalized by the degree of octahedral strain of the "MgO6" coordination polyhedra. (13)C and (25)Mg isotropic chemical shifts were also found to be sensitive to the binding mode of the carboxylate ligands. The experimental findings are corroborated by gauge-including projector-augmented-wave (GIPAW) density functional theory (DFT) computations, and these have allowed for an interpretation of the experimentally observed trend in the CQ((25)Mg) values and for the visualization of the EFG tensor principal components with respect to the molecular structure. These new insights may prove to be valuable for the understanding and interpretation of (25)Mg NMR data for Mg(2+) ions in organic binding environments such as those found in MOFs and protein-divalent metal binding sites.

A Variant PfCRT Isoform Can Contribute to Plasmodium falciparum Resistance to the First-Line Partner Drug Piperaquine

PubMed Central

Dhingra, Satish K.; Redhi, Devasha; Combrinck, Jill M.; Yeo, Tomas; Okombo, John; Henrich, Philipp P.; Cowell, Annie N.; Gupta, Purva; Stegman, Matthew L.; Hoke, Jonathan M.; Cooper, Roland A.; Winzeler, Elizabeth; Mok, Sachel; Egan, Timothy J.

2017-01-01

ABSTRACT Current efforts to reduce the global burden of malaria are threatened by the rapid spread throughout Asia of Plasmodium falciparum resistance to artemisinin-based combination therapies, which includes increasing rates of clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nuclease-based gene editing, we report that addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC90) or 50% parasite killing (50% lethal dose [LD50]). This mutation also reversed Dd2-mediated CQ resistance, sensitized parasites to amodiaquine, quinine, and artemisinin, and conferred amantadine and blasticidin resistance. Using heme fractionation assays, we demonstrate that PPQ causes a buildup of reactive free heme and inhibits the formation of chemically inert hemozoin crystals. Our data evoke inhibition of heme detoxification in the parasite’s acidic digestive vacuole as the primary mode of both the bis-aminoquinoline PPQ and the related 4-aminoquinoline CQ. Both drugs also inhibit hemoglobin proteolysis at elevated concentrations, suggesting an additional mode of action. Isogenic lines differing in their pfmdr1 copy number showed equivalent PPQ susceptibilities. We propose that mutations in PfCRT could contribute to a multifactorial basis of PPQ resistance in field isolates. PMID:28487425

Une méthode de quantification de la dégradation d'un escarpement de faille au cours des cycles climatiques du Quaternaire : la faille de Jobourg (Nord Cotentin, France)Quantification of a fault-scarp degradation through Quaternary: the Jobourg fault (North Cotentin, France)

NASA Astrophysics Data System (ADS)

Font, Marianne; Lagarde, Jean-Louis; Amorese, Daniel; Coutard, Jean-Pierre; Ozouf, Jean-Claude

The degradation of the Jobourg fault-scarp occurred by cryoclastic processes in a periglacial environment during a part of Quaternary time. An attempt of quantification indicates a bulk scarp erosion of about 39 m 3 m -2, while the head accumulated at the bottom of the fault scarp only represents 4.6 m 3 m -2. To cite this article: M. Font et al., C. R. Geoscience 334 (2002) 171-178.

Cycling transport safety quantification

NASA Astrophysics Data System (ADS)

Drbohlav, Jiri; Kocourek, Josef

2018-05-01

Dynamic interest in cycling transport brings the necessity to design safety cycling infrastructure. In las few years, couple of norms with safety elements have been designed and suggested for the cycling infrastructure. But these were not fully examined. The main parameter of suitable and fully functional transport infrastructure is the evaluation of its safety. Common evaluation of transport infrastructure safety is based on accident statistics. These statistics are suitable for motor vehicle transport but unsuitable for the cycling transport. Cycling infrastructure evaluation of safety is suitable for the traffic conflicts monitoring. The results of this method are fast, based on real traffic situations and can be applied on any traffic situations.

New evidence for the potential role of Culex pipiens mosquitoes in the transmission cycle of West Nile virus in Tunisia.

PubMed

Krida, G; Rhim, A; Daaboub, J; Failloux, A-B; Bouattour, A

2015-06-01

Physiological and molecular characteristics of natural populations of Culex pipiens Linnaeus, 1758 (Diptera: Culicidae) were investigated to elucidate how this species is potentially involved in the transmission of West Nile virus in Tunisia. A total of 215 Cx. pipiens females from 11 breeding habitats were analysed in the laboratory to estimate autogeny and stenogamy rates. They were tested individually for the locus CQ11 to distinguish between the two Cx. pipiens forms, pipiens and molestus. All tested Cx. pipiens populations were stenogamous. Females from underground breeding sites were all autogeneous, whereas females from above-ground habitats were mostly anautogeneous. Of all the females tested, 59.7% were identified as pipiens, 22.4% as molestus, and 17.9% as hybrid pipiens/molestus. Furthermore, both Cx. pipiens forms and their hybrids were found to co-occur in sympatry in all sites. The results of this study represent the first evidence that both Cx. pipiens forms and their hybrids are present in Tunisia. Because hybrids able to act as bridge vectors are present in all studied habitats, Tunisia can be considered to have a high degree of receptivity for the establishment of West Nile virus zoonotic cycles. © 2015 The Royal Entomological Society.

Automatic detection of cardiac cycle and measurement of the mitral annulus diameter in 4D TEE images

NASA Astrophysics Data System (ADS)

Graser, Bastian; Hien, Maximilian; Rauch, Helmut; Meinzer, Hans-Peter; Heimann, Tobias

2012-02-01

Mitral regurgitation is a wide spread problem. For successful surgical treatment quantification of the mitral annulus, especially its diameter, is essential. Time resolved 3D transesophageal echocardiography (TEE) is suitable for this task. Yet, manual measurement in four dimensions is extremely time consuming, which confirms the need for automatic quantification methods. The method we propose is capable of automatically detecting the cardiac cycle (systole or diastole) for each time step and measuring the mitral annulus diameter. This is done using total variation noise filtering, the graph cut segmentation algorithm and morphological operators. An evaluation took place using expert measurements on 4D TEE data of 13 patients. The cardiac cycle was detected correctly on 78% of all images and the mitral annulus diameter was measured with an average error of 3.08 mm. Its full automatic processing makes the method easy to use in the clinical workflow and it provides the surgeon with helpful information.

Molecular evaluation of pvdhfr and pvmdr-1 mutants in Plasmodium vivax isolates after treatment with sulfadoxine/pyrimethamine and chloroquine in Iran during 2001-2016.

PubMed

Parsaei, Mahdi; Raeisi, Ahmad; Spotin, Adel; Shahbazi, Abbas; Mahami-Oskouei, Mahmoud; Hazratian, Teimour; Khorashad, Alireza Salimi; Zaman, Jalal; Bazmani, Ahad; Sarafraz, Sedighe

2018-06-19

The rising use of sulfadoxine/pyrimethamine (SP) in the treatment of chloroquine (CQ)-resistant Plasmodium falciparum has resulted in increased exposure to P. vivax isolates in Iran, where both species are being circulated. In this investigation, the frequency of pvdhfr and pvmdr-1 mutants was assessed in P. vivax strains during 2001-2016 after the introduction of SP/CQ in malarious areas of Iran. The P. vivax isolates (n, 52) were obtained from autochthonous samples in Southeast Iran during 2015-2016. The genomic DNA was extracted and examined using nested polymerase chain reaction-(PCR) and sequencing. Mutations were detected in pvdhfr codons P33L (21.2%), T61 M (25%), S93H (3.9%), and S117 T (1.9%) and 5 isolates showed double mutations (33 L/61 M, 7.7%; 33 L/117 T, 1.9%). No mutation was identified in pvdhfr codons F57 and S58. The pvmdr-1 1076 L mutation was detected in 93.3% of P. vivax isolates. The findings indicated that the frequency of three codons of pvdhfr F57/S58/S117 has decreased from 2001 (1.05%/7.0%/16.9%) to 2016 (0%/0%/1.9%). Genomic analysis of pvmdr-1 showed that the frequency of 1076 L has gradually increased from 2013 (93%) to 2016 (93.3%) (P > .05). The results demonstrated that P. vivax isolates are probably being exited under SP pressure, which reflects the appropriate level of training for field microscopists, as established by Iranian policymakers. Emergent pvdhfr codons 33L, 61M, and 93H should be noticed in plausible drug tolerance and treatment plans. The high prevalence of pvmdr-1 1076L mutation shows that efficacy of CQ combination with primaquine may be in danger of being compromised, however further investigations are needed to evaluate the clinical importance of CQ-resistant P. vivax isolates. Copyright © 2018 Elsevier B.V. All rights reserved.

The effect of resonance tubes on glottal contact quotient with and without task instruction: a comparison of trained and untrained voices.

PubMed

Gaskill, Christopher S; Quinney, Dana M

2012-05-01

Phonation into narrow tubes or straws has been used as a voice training and voice therapy technique and belongs to a group of techniques known as semi-occluded vocal tract exercises. The use of what are called resonance tubes has received renewed attention in the voice research literature, in both theoretical and empirical studies. The assumption is that the partially occluded and lengthened vocal tract alters supraglottal acoustics in such a way as to allow phonation near a lowered first vocal tract formant, which has been suggested as a way to bring about a more efficient glottal closure pattern for sustained oscillation. In this study, two groups of male participants, 10 with no vocal training and 10 with classical vocal training, phonated into a resonance tube for approximately 1 minute. Electroglottography was used to estimate glottal contact quotient (CQ) during spoken /a/ vowels before tube phonation, during tube phonation, and again during spoken /a/ vowels after tube phonation. Half of each group of participants was made to keep pitch and loudness consistent for all phases of the experiment, replicating the method of a previous study by this author. The other half was instructed to practice phonating into the resonance tube before collecting data and was encouraged to find a pitch and loudness combination that maximized ease of phonation and a sense of forward oral resonance. Glottal CQ altered considerably from baseline for almost all participants during tube phonation, with a larger variability than that during vowel production. Small differences in glottal CQ were found as a function of training and instruction, with most participants' CQ increasing during tube phonation. A small post-tube phonation effect was found primarily for the trained and instructed group. Secondary single-subject analyses revealed large intersubject variation, highlighting the highly individualized response to the resonance tube task. Continued study of resonance tubes is recommended, comparing both male and female as well as vocally trained and untrained participants. Future studies should continue to examine systematic variations in task instruction, length of practice, and resonance tube dimensions. Copyright © 2012 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

Evaluation of dihydrofolate reductase and dihydropteroate synthetase genotypes that confer resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum in Haiti

PubMed Central

2012-01-01

Background Malaria caused by Plasmodium falciparum infects roughly 30,000 individuals in Haiti each year. Haiti has used chloroquine (CQ) as a first-line treatment for malaria for many years and as a result there are concerns that malaria parasites may develop resistance to CQ over time. Therefore it is important to prepare for alternative malaria treatment options should CQ resistance develop. In many other malaria-endemic regions, antifolates, particularly pyrimethamine (PYR) and sulphadoxine (SDX) treatment combination (SP), have been used as an alternative when CQ resistance has developed. This study evaluated mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes that confer PYR and SDX resistance, respectively, in P. falciparum to provide baseline data in Haiti. This study is the first comprehensive study to examine PYR and SDX resistance genotypes in P. falciparum in Haiti. Methods DNA was extracted from dried blood spots and genotyped for PYR and SDX resistance mutations in P. falciparum using PCR and DNA sequencing methods. Sixty-one samples were genotyped for PYR resistance in codons 51, 59, 108 and 164 of the dhfr gene and 58 samples were genotyped for SDX resistance codons 436, 437, 540 of the dhps gene in P. falciparum. Results Thirty-three percent (20/61) of the samples carried a mutation at codon 108 (S108N) of the dhfr gene. No mutations in dhfr at codons 51, 59, 164 were observed in any of the samples. In addition, no mutations were observed in dhps at the three codons (436, 437, 540) examined. No significant difference was observed between samples collected in urban vs rural sites (Welch’s T-test p-value = 0.53 and permutations p-value = 0.59). Conclusion This study has shown the presence of the S108N mutation in P. falciparum that confers low-level PYR resistance in Haiti. However, the absence of SDX resistance mutations suggests that SP resistance may not be present in Haiti. These results have important implications for ongoing discussions on alternative malaria treatment options in Haiti. PMID:22889367

Synthesis and antimalarial activity of new 4-amino-7-chloroquinolyl amides, sulfonamides, ureas and thioureas.

PubMed

Ekoue-Kovi, Kekeli; Yearick, Kimberly; Iwaniuk, Daniel P; Natarajan, Jayakumar K; Alumasa, John; de Dios, Angel C; Roepe, Paul D; Wolf, Christian

2009-01-01

We report the synthesis and in vitro antimalarial activities of more than 50 7-chloro-4-aminoquinolyl-derived sulfonamides 3-8 and 11-26, ureas 19-22, thioureas 23-26, and amides 27-54. Many of the CQ analogues prepared for this study showed submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strains of Plasmodium falciparum) and low resistance indices were obtained in most cases. Systematic variation of the side chain length and introduction of fluorinated aliphatic and aromatic termini revealed promising leads that overcome CQ resistance. In particular, sulfonamide 3 exhibiting a short side chain with a terminal dansyl moiety combined high antiplasmodial potency with a low resistance index and showed IC(50)s of 17.5 and 22.7 nM against HB3 and Dd2 parasites.

Syntheses and in Vitro Antiplasmodial Activity of Aminoalkylated Chalcones and Analogues.

PubMed

Wilhelm, Anke; Kendrekar, Pravin; Noreljaleel, Anwar E M; Abay, Efrem T; Bonnet, Susan L; Wiesner, Lubbe; de Kock, Carmen; Swart, Kenneth J; van der Westhuizen, Jan Hendrik

2015-08-28

A series of readily synthesized and inexpensive aminoalkylated chalcones and diarylpropane analogues (1-55) were synthesized and tested against chloroquinone-sensitive (D10 and NF54) and -resistant (Dd2 and K1) strains of Plasmodium falciparum. Hydrogenation of the enone to a diarylpropane moiety increased antiplasmodial bioactivity significantly. The influence of the structure of the amine moiety, A-ring substituents, propyl vs ethyl linker, and chloride salt formation on further enhancing antiplasmodial activity was investigated. Several compounds have IC₅₀ values similar to or better than chloroquine (CQ). The most active compound (26) had an IC₅₀ value of 0.01 μM. No signs of resistance were detected, as can be expected from compounds with structures unrelated to CQ and other currently used antimalarial drugs. Toxicity tests (in vitro CHO cell assay) gave high SI indices.

Influence of Photoinitiator on Accelerated Artificial Aging and Bond Strength of Experimental Resin Cements.

PubMed

Righi, Helouise; Costa, Ana Rosa; Oliveira, Dayane Carvalho Ramos Salles de; Abuna, Gabriel Flores; Sinhoreti, Mario Alexandre Coelho; Naufel, Fabiana Scarparo

2018-01-01

The goal of this study was to evaluate in vitro the effect of the photoinitiator phenylpropanedione (PPD), alone or combined with camphorquinone (CQ), on color stability of photoactivated resin cements and their bond strength to ceramics using a micro-shear test. Four resin cements were used: a commercial brand cement (RelyX Veneer®) and 3 experimental cements with different types and concentration of photoinitiators. For color analysis, ceramic discs were cemented on bovine dentin specimens to simulate indirect restorations (n=8) and were exposed to UV for 120 h and tested for color alteration using a reflectance spectrophotometer and the CIEL*a*b* system. Data were analyzed by Anova and Tukey's test at 5% significance level. The color test results did not present statistically significant difference for the ∆E for all the studied cements, neither for ∆L, ∆a and ∆b. For the bond strength, all the studied cements showed statistically significant differences to each other, with the highest result for the RelyX Veneer® (29.07 MPa) cement, followed by the cement with CQ (21.74 MPa) and CQ+PPD (19.09 MPa) cement; the lowest result was obtained by the cement using only PPD as a photoinitiator (13.99 MPa). So, based on the studied parameters, PPD was not advantageous as photoinitiator of resin cements, because it showed a low value of bond strength to the ceramics and no superior color stability.

Sensitive fluorescence HPLC assay for AQ-13, a candidate aminoquinoline antimalarial, that also detects chloroquine and N-dealkylated metabolites.

PubMed

Deng, Haiyan; Liu, Huayin; Krogstad, Frances M; Krogstad, Donald J

2006-04-03

A sensitive, specific and reproducible fluorescence high performance liquid chromatography (HPLC) assay has been developed for the separate or simultaneous measurement of AQ-13 (a candidate 4-aminoquinoline antimalarial), chloroquine (CQ), and their metabolites in whole blood. After liquid-solid extraction using commercially available extraction cartridges, these two aminoquinolines (AQs) and their metabolites were separated on C18 (Xterra RP18) columns using a mobile phase containing 60% borate buffer (20 mM, pH 9.0) and 40% acetonitrile with isocratic elution at a flow-rate of 1.0 ml/min. The assay uses a biologically inactive 8-chloro-4-aminoquinoline (AQ-18) as its internal standard (IS). There is a linear relationship between the concentrations of these AQs and the peak area ratio (ratio between the peak area of the AQ or metabolite and the peak area of the IS) on the chromatogram. Linear calibration curves with correlation coefficients > or = 0.997 (r2 > or = 0.995, p < 0.001) were obtained for AQ-13, CQ and their N-dealkylated metabolites. Reproducibility of the assay was excellent with coefficients of variation (CVs) < or = 3.8% for AQ-13 and its metabolites, and < or =2.5% for CQ and its metabolites. The sensitivity of the assay is 5 nM using 1.0 ml of blood and a 20 microl injection volume, and can be increased by using 5.0 ml of blood with an injection volume of 40 microl.

Measuring patients' experiences with palliative care: the Consumer Quality Index Palliative Care.

PubMed

Claessen, Susanne J J; Francke, Anneke L; Sixma, Herman J; de Veer, Anke J E; Deliens, Luc

2012-12-01

The Consumer Quality Index Palliative Care (CQ-index PC) is a structured questionnaire for measuring the quality of palliative care from the perspective of care users. CQ-indices assess which care aspects need quality improvement by relating answers about actual care experiences to answers about the importance of certain aspects of care. To improve the chance that the new instrument has good content validity, a literature study and individual and group discussions were performed, and a steering committee was consulted to establish the instrument's face and content validity. The questionnaire was administered to patients with a life expectancy of 6 months or less and/or who were receiving palliative treatment. Descriptive analyses were carried out on the items about actual care experiences and the importance of care aspects, and on 'need for improvement' scores. 15 care organisations participated. 133 patients met the inclusion criteria (net response n=85). Patients considered the following aspects the most important: 'offering help in good time in acute situations', 'caregivers having the necessary expertise' and 'caregivers taking the patient seriously'. The three care aspects with the highest 'need for improvement' scores were: 'support when the patient feels depressed', 'support when the patient is anxious' and 'support when the patient has shortness of breath'. The CQ-index PC provides opportunities for care organisations to assess which care aspects have the highest priority for quality improvement within their organisation. Further research is needed to assess whether the instrument has enough discriminative power to assess differences between organisations.

In vitro antimalarial activity of novel semisynthetic nocathiacin I antibiotics.

PubMed

Sharma, Indu; Sullivan, Margery; McCutchan, Thomas F

2015-01-01

Presently, the arsenal of antimalarial drugs is limited and needs to be replenished. We evaluated the potential antimalarial activity of two water-soluble derivatives of nocathiacin (BMS461996 and BMS411886) against the asexual blood stages of Plasmodium falciparum. Nocathiacins are a thiazolyl peptide group of antibiotics, are structurally related to thiostrepton, have potent activity against a wide spectrum of multidrug-resistant Gram-positive bacteria, and inhibit protein synthesis. The in vitro growth inhibition assay was done using three laboratory strains of P. falciparum displaying various levels of chloroquine (CQ) susceptibility. Our results indicate that BMS461996 has potent antimalarial activity and inhibits parasite growth with mean 50% inhibitory concentrations (IC50s) of 51.55 nM for P. falciparum 3D7 (CQ susceptible), 85.67 nM for P. falciparum Dd2 (accelerated resistance to multiple drugs [ARMD]), and 99.44 nM for P. falciparum K1 (resistant to CQ, pyrimethamine, and sulfadoxine). Similar results at approximately 7-fold higher IC50s were obtained with BMS411886 than with BMS461996. We also tested the effect of BMS491996 on gametocytes; our results show that at a 20-fold excess of the mean IC50, gametocytes were deformed with a pyknotic nucleus and growth of stage I to IV gametocytes was arrested. This preliminary study shows a significant potential for nocathiacin analogues to be developed as antimalarial drug candidates and to warrant further investigation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Concentration-discharge relationships to understand the interplay between hydrological and biogeochemical processes: insights from data analysis and numerical experiments in headwater catchments.

NASA Astrophysics Data System (ADS)

De Dreuzy, J. R.; Marçais, J.; Moatar, F.; Minaudo, C.; Courtois, Q.; Thomas, Z.; Longuevergne, L.; Pinay, G.

2017-12-01

Integration of hydrological and biogeochemical processes led to emerging patterns at the catchment scale. Monitoring in rivers reflects the aggregation of these effects. While discharge time series have been measured for decades, high frequency water quality monitoring in rivers now provides prominent measurements to characterize the interplay between hydrological and biogeochemical processes, especially to infer the processes that happen in the heterogeneous subsurface. However, we still lack frameworks to relate observed patterns to specific processes, because of the "organized complexity" of hydrological systems. Indeed, it is unclear what controls, for example, patterns in concentration-discharge (C/Q) relationships due to non-linear processes and hysteresis effects. Here we develop a non-intensive process-based model to test how the integration of different landforms (i.e. geological heterogeneities and structures, topographical features) with different biogeochemical reactivity assumptions (e.g. reactive zone locations) can shape the overall water quality time series. With numerical experiments, we investigate typical patterns in high frequency C/Q relationships. In headwater basins, we found that typical hysteretic patterns in C/Q relationships observed in data time series can be attributed to differences in water and solute locations stored across the hillslope. At the catchment scale though, these effects tend to average out by integrating contrasted hillslopes' landforms. Together these results suggest that information contained in headwater water quality monitoring can be used to understand how hydrochemical processes determine downstream conditions.

Malaria prophylaxis in the French armed forces: evolution of concepts.

PubMed

Touze, J E; Paule, P; Baudon, D; Boutin, J P

2001-01-01

Malaria is still a serious public health problem in the world and control remains a major priority for the approximately 25.000 French troops deployed, mostly on permanent assignment, in malaria transmission regions. Epidemiological surveillance of malaria provides data necessary to assess morbidity, monitor changing patterns of Plasmodium falciparum drug-sensitivity, and evaluate the efficacy of malaria control measures. About 540 cases were observed in 1999 for an incidence of 4.1 p. 100 men. year. Since 1991, strong emphasis has been placed on prophylaxis. In addition to vector control measures and individual protection against mosquito bites (impregnated bednets, protective clothing, application of repellents, and indoor insecticide spraying), drug prophylaxis has been recommended using a combination of 100 mg of chloroquine and 200 mg of proguanil chlorhydrate (CQ + PG) in a single capsule manufactured by the French Health Army Service. Initially this policy led to a significant decrease in malaria cases among French soldiers. However the incidence of malaria rose in 1995 and 1996. This recrudescence was attributed to poor compliance with chemoprophylaxis and to the declining efficacy of the CQ + PG combination. In response to these problems, a new policy was implemented especially in countries where cycloguanil-resistant Plasmodium falciparum incidence rate is increasing. The new chemoprophylactic regimen calls for a personal prescription of mefloquine. Doxycycline monohydrate is used in case of mefloquine contra-indication or intolerance. Combination of CQ + PG delivered in a single capsule remains a suitable chemoprophylactic regimen in Sahel countries as well as Horn of Africa.

Exploring the Underlying Mechanisms of the Xenopus laevis Embryonic Cell Cycle.

PubMed

Zhang, Kun; Wang, Jin

2018-05-31

The cell cycle is an indispensable process in proliferation and development. Despite significant efforts, global quantification and physical understanding are still challenging. In this study, we explored the mechanisms of the Xenopus laevis embryonic cell cycle by quantifying the underlying landscape and flux. We uncovered the Mexican hat landscape of the Xenopus laevis embryonic cell cycle with several local basins and barriers on the oscillation path. The local basins characterize the different phases of the Xenopus laevis embryonic cell cycle, and the local barriers represent the checkpoints. The checkpoint mechanism of the cell cycle is revealed by the landscape basins and barriers. While landscape shape determines the stabilities of the states on the oscillation path, the curl flux force determines the stability of the cell cycle flow. Replication is fundamental for biology of living cells. We quantify the input energy (through the entropy production) as the thermodynamic requirement for initiation and sustainability of single cell life (cell cycle). Furthermore, we also quantify curl flux originated from the input energy as the dynamical requirement for the emergence of a new stable phase (cell cycle). This can provide a new quantitative insight for the origin of single cell life. In fact, the curl flux originated from the energy input or nutrition supply determines the speed and guarantees the progression of the cell cycle. The speed of the cell cycle is a hallmark of cancer. We characterized the quality of the cell cycle by the coherence time and found it is supported by the flux and energy cost. We are also able to quantify the degree of time irreversibility by the cross correlation function forward and backward in time from the stochastic traces in the simulation or experiments, providing a way for the quantification of the time irreversibility and the flux. Through global sensitivity analysis upon landscape and flux, we can identify the key elements for controlling the cell cycle speed. This can help to design an effective strategy for drug discovery against cancer.

Comparison of deterministic and stochastic approaches for isotopic concentration and decay heat uncertainty quantification on elementary fission pulse

NASA Astrophysics Data System (ADS)

Lahaye, S.; Huynh, T. D.; Tsilanizara, A.

2016-03-01

Uncertainty quantification of interest outputs in nuclear fuel cycle is an important issue for nuclear safety, from nuclear facilities to long term deposits. Most of those outputs are functions of the isotopic vector density which is estimated by fuel cycle codes, such as DARWIN/PEPIN2, MENDEL, ORIGEN or FISPACT. CEA code systems DARWIN/PEPIN2 and MENDEL propagate by two different methods the uncertainty from nuclear data inputs to isotopic concentrations and decay heat. This paper shows comparisons between those two codes on a Uranium-235 thermal fission pulse. Effects of nuclear data evaluation's choice (ENDF/B-VII.1, JEFF-3.1.1 and JENDL-2011) is inspected in this paper. All results show good agreement between both codes and methods, ensuring the reliability of both approaches for a given evaluation.

Quantification of Training and Competition Loads in Endurance Sports: Methods and Applications.

PubMed

Mujika, Iñigo

2017-04-01

Training quantification is basic to evaluate an endurance athlete's responses to training loads, ensure adequate stress/recovery balance, and determine the relationship between training and performance. Quantifying both external and internal workload is important, because external workload does not measure the biological stress imposed by the exercise sessions. Generally used quantification methods include retrospective questionnaires, diaries, direct observation, and physiological monitoring, often based on the measurement of oxygen uptake, heart rate, and blood lactate concentration. Other methods in use in endurance sports include speed measurement and the measurement of power output, made possible by recent technological advances such as power meters in cycling and triathlon. Among subjective methods of quantification, rating of perceived exertion stands out because of its wide use. Concurrent assessments of the various quantification methods allow researchers and practitioners to evaluate stress/recovery balance, adjust individual training programs, and determine the relationships between external load, internal load, and athletes' performance. This brief review summarizes the most relevant external- and internal-workload-quantification methods in endurance sports and provides practical examples of their implementation to adjust the training programs of elite athletes in accordance with their individualized stress/recovery balance.

Facile Quantification and Identification Techniques for Reducing Gases over a Wide Concentration Range Using a MOS Sensor in Temperature-Cycled Operation.

PubMed

Schultealbert, Caroline; Baur, Tobias; Schütze, Andreas; Sauerwald, Tilman

2018-03-01

Dedicated methods for quantification and identification of reducing gases based on model-based temperature-cycled operation (TCO) using a single commercial MOS gas sensor are presented. During high temperature phases the sensor surface is highly oxidized, yielding a significant sensitivity increase after switching to lower temperatures (differential surface reduction, DSR). For low concentrations, the slope of the logarithmic conductance during this low-temperature phase is evaluated and can directly be used for quantification. For higher concentrations, the time constant for reaching a stable conductance during the same low-temperature phase is evaluated. Both signals represent the reaction rate of the reducing gas on the strongly oxidized surface at this low temperature and provide a linear calibration curve, which is exceptional for MOS sensors. By determining these reaction rates on different low-temperature plateaus and applying pattern recognition, the resulting footprint can be used for identification of different gases. All methods are tested over a wide concentration range from 10 ppb to 100 ppm (4 orders of magnitude) for four different reducing gases (CO, H₂, ammonia and benzene) using randomized gas exposures.

Facile Quantification and Identification Techniques for Reducing Gases over a Wide Concentration Range Using a MOS Sensor in Temperature-Cycled Operation

PubMed Central

Schultealbert, Caroline; Baur, Tobias; Schütze, Andreas; Sauerwald, Tilman

2018-01-01

Dedicated methods for quantification and identification of reducing gases based on model-based temperature-cycled operation (TCO) using a single commercial MOS gas sensor are presented. During high temperature phases the sensor surface is highly oxidized, yielding a significant sensitivity increase after switching to lower temperatures (differential surface reduction, DSR). For low concentrations, the slope of the logarithmic conductance during this low-temperature phase is evaluated and can directly be used for quantification. For higher concentrations, the time constant for reaching a stable conductance during the same low-temperature phase is evaluated. Both signals represent the reaction rate of the reducing gas on the strongly oxidized surface at this low temperature and provide a linear calibration curve, which is exceptional for MOS sensors. By determining these reaction rates on different low-temperature plateaus and applying pattern recognition, the resulting footprint can be used for identification of different gases. All methods are tested over a wide concentration range from 10 ppb to 100 ppm (4 orders of magnitude) for four different reducing gases (CO, H2, ammonia and benzene) using randomized gas exposures. PMID:29494545

Quantification of cell cycle kinetics by EdU (5-ethynyl-2′-deoxyuridine)-coupled-fluorescence-intensity analysis

PubMed Central

Cabrita, Marisa; Bekman, Evguenia; Braga, José; Rino, José; Santus, Renè; Filipe, Paulo L.; Sousa, Ana E.; Ferreira, João A.

2017-01-01

We propose a novel single-deoxynucleoside-based assay that is easy to perform and provides accurate values for the absolute length (in units of time) of each of the cell cycle stages (G1, S and G2/M). This flow-cytometric assay takes advantage of the excellent stoichiometric properties of azide-fluorochrome detection of DNA substituted with 5-ethynyl-2′-deoxyuridine (EdU). We show that by pulsing cells with EdU for incremental periods of time maximal EdU-coupled fluorescence is reached when pulsing times match the length of S phase. These pulsing times, allowing labelling for a full S phase of a fraction of cells in asynchronous populations, provide accurate values for the absolute length of S phase. We characterized additional, lower intensity signals that allowed quantification of the absolute durations of G1 and G2 phases. Importantly, using this novel assay data on the lengths of G1, S and G2/M phases are obtained in parallel. Therefore, these parameters can be estimated within a time frame that is shorter than a full cell cycle. This method, which we designate as EdU-Coupled Fluorescence Intensity (E-CFI) analysis, was successfully applied to cell types with distinctive cell cycle features and shows excellent agreement with established methodologies for analysis of cell cycle kinetics. PMID:28465489

Pre-amplification in the context of high-throughput qPCR gene expression experiment.

PubMed

Korenková, Vlasta; Scott, Justin; Novosadová, Vendula; Jindřichová, Marie; Langerová, Lucie; Švec, David; Šídová, Monika; Sjöback, Robert

2015-03-11

With the introduction of the first high-throughput qPCR instrument on the market it became possible to perform thousands of reactions in a single run compared to the previous hundreds. In the high-throughput reaction, only limited volumes of highly concentrated cDNA or DNA samples can be added. This necessity can be solved by pre-amplification, which became a part of the high-throughput experimental workflow. Here, we focused our attention on the limits of the specific target pre-amplification reaction and propose the optimal, general setup for gene expression experiment using BioMark instrument (Fluidigm). For evaluating different pre-amplification factors following conditions were combined: four human blood samples from healthy donors and five transcripts having high to low expression levels; each cDNA sample was pre-amplified at four cycles (15, 18, 21, and 24) and five concentrations (equivalent to 0.078 ng, 0.32 ng, 1.25 ng, 5 ng, and 20 ng of total RNA). Factors identified as critical for a success of cDNA pre-amplification were cycle of pre-amplification, total RNA concentration, and type of gene. The selected pre-amplification reactions were further tested for optimal Cq distribution in a BioMark Array. The following concentrations combined with pre-amplification cycles were optimal for good quality samples: 20 ng of total RNA with 15 cycles of pre-amplification, 20x and 40x diluted; and 5 ng and 20 ng of total RNA with 18 cycles of pre-amplification, both 20x and 40x diluted. We set up upper limits for the bulk gene expression experiment using gene expression Dynamic Array and provided an easy-to-obtain tool for measuring of pre-amplification success. We also showed that variability of the pre-amplification, introduced into the experimental workflow of reverse transcription-qPCR, is lower than variability caused by the reverse transcription step.

A Philosophical Rationale and Practical Guide to Raising the "CQ" - Caring Quality - in Education ... A Moral Imperative.

ERIC Educational Resources Information Center

Kobak, Dorothy

1987-01-01

Argues that successful education must include teaching children to care. Outlines how a caring capacity can be developed and incorporated into educational methodology through action oriented projects. (BSR)

A Molecular Survey of Tick-Borne Pathogens from Ticks Collected in Central Queensland, Australia.

PubMed

Chalada, Melissa Judith; Stenos, John; Vincent, Gemma; Barker, Dayana; Bradbury, Richard Stewart

2018-03-01

Central Queensland (CQ) is a large and isolated, low population density, remote tropical region of Australia with a varied environment. The region has a diverse fauna and several species of ticks that feed upon that fauna. This study examined 518 individual ticks: 177 Rhipicephalus sanguineus (brown dog tick), 123 Haemaphysalis bancrofti (wallaby tick), 102 Rhipicephalus australis (Australian cattle tick), 47 Amblyomma triguttatum (ornate kangaroo tick), 57 Ixodes holocyclus (paralysis tick), 9 Bothriocroton tachyglossi (CQ short-beaked echidna tick), and 3 Ornithodoros capensis (seabird soft tick). Tick midguts were pooled by common host or environment and screened for four genera of tick-borne zoonoses by PCR and sequencing. The study examined a total of 157 midgut pools of which 3 contained DNA of Coxiella burnetii, 13 Rickettsia gravesii, 1 Rickettsia felis, and 4 other Rickettsia spp. No Borrelia spp. or Babesia spp. DNA were recovered.

The effect of a voiced lip trill on estimated glottal closed quotient.

PubMed

Gaskill, Christopher S; Erickson, Molly L

2008-11-01

The use of lip trills has been advocated for both vocal habilitation and rehabilitation. A voiced lip trill requires continuous vibration of the lips while simultaneously maintaining phonation. The mechanism of any effects of a lip trill on vocal fold vibration is still unknown. While other techniques that either constrict or artificially lengthen the vocal tract have been investigated, no studies thus far have systematically examined the effect of lip trills on vocal fold vibration. Classically trained singers and vocally untrained participants produced a lip trill for approximately 1 minute, and vocal fold closed quotient (CQ) was calculated both during the lip trill and on a sustained spoken vowel before and after the trill. Data are reported for both a group design and a single-subject design. Most participants showed a tendency for a reduction in CQ during the lip trill, with a more pronounced change in the untrained participants.

Antiplasmodial, beta-haematin inhibition, antitrypanosomal and cytotoxic activity in vitro of novel 4-aminoquinoline 2-imidazolines.

PubMed

Musonda, Chitalu C; Yardley, Vanessa; de Souza, Renata C Carvalho; Ncokazi, Kanyile; Egan, Timothy J; Chibale, Kelly

2008-12-07

A novel series of 4-aminoquinoline-containing 2-imidazolines were synthesized via a one-pot 3-component condensation reaction of amine, aldehyde and isocyanoacetate. The products were obtained in high yield as well as purity and were evaluated directly against two strains of Plasmodium falciparum and Trypanosoma brucei. Compound was the most active across all parasites with ED(50) = 3.3 nM against a chloroquine (CQ)-sensitive 3D7 strain, ED(50) = 33 nM against a CQ-resistant K1 strain and ED(50) = 70 nM against T. brucei. Several compounds were able to inhibit formation of beta-haematin in vitro, suggesting haemozoin formation in the malaria parasite as a possible target. On the other hand, evaluation against a human KB cell line revealed that the compounds were generally non-cytotoxic to the host cells.

Synthesis, antimalarial activity, heme binding and docking studies of N-substituted 4-aminoquinoline-pyrimidine molecular hybrids.

PubMed

Maurya, Shiv Shyam; Khan, Shabana I; Bahuguna, Aparna; Kumar, Deepak; Rawat, Diwan S

2017-03-31

A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

4-Aminoquinoline-pyrimidine hybrids: synthesis, antimalarial activity, heme binding and docking studies.

PubMed

Kumar, Deepak; Khan, Shabana I; Tekwani, Babu L; Ponnan, Prija; Rawat, Diwan S

2015-01-07

A series of novel 4-aminoquinoline-pyrimidine hybrids has been synthesized and evaluated for their antimalarial activity. Several compounds showed promising in vitro antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. Selected compound 7g exhibited significant suppression of parasitemia in the in vivo assay. The heme binding studies were conducted to determine the mode of action of these hybrid molecules. These compounds form a stable 1:1 complex with hematin suggesting that heme may be one of the possible targets of these hybrids. The interaction of these conjugate hybrids was also investigated by the molecular docking studies in the binding site of PfDHFR. The pharmacokinetic property analysis of best active compounds was also studied using ADMET prediction. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Solid-state (55)Mn NMR spectroscopy of bis(μ-oxo)dimanganese(IV) [Mn(2)O(2)(salpn)(2)], a model for the oxygen evolving complex in photosystem II.

PubMed

Ellis, Paul D; Sears, Jesse A; Yang, Ping; Dupuis, Michel; Boron, Thaddeus T; Pecoraro, Vincent L; Stich, Troy A; Britt, R David; Lipton, Andrew S

2010-12-01

We have examined the antiferromagneticly coupled bis(μ-oxo)dimanganese(IV) complex [Mn(2)O(2)(salpn)(2)] (1) with (55)Mn solid-state NMR at cryogenic temperatures and first-principle theory. The extracted values of the (55)Mn quadrupole coupling constant, C(Q), and its asymmetry parameter, η(Q), for 1 are 24.7 MHz and 0.43, respectively. Further, there was a large anisotropic contribution to the shielding of each Mn(4+), i.e. a Δσ of 3375 ppm. Utilizing broken symmetry density functional theory, the predicted values of the electric field gradient (EFG) or equivalently the C(Q) and η(Q) at ZORA, PBE QZ4P all electron level of theory are 23.4 MHz and 0.68, respectively, in good agreement with experimental observations.

Transient increase in Zn2+ in hippocampal CA1 pyramidal neurons causes reversible memory deficit.

PubMed

Takeda, Atsushi; Takada, Shunsuke; Nakamura, Masatoshi; Suzuki, Miki; Tamano, Haruna; Ando, Masaki; Oku, Naoto

2011-01-01

The translocation of synaptic Zn(2+) to the cytosolic compartment has been studied to understand Zn(2+) neurotoxicity in neurological diseases. However, it is unknown whether the moderate increase in Zn(2+) in the cytosolic compartment affects memory processing in the hippocampus. In the present study, the moderate increase in cytosolic Zn(2+) in the hippocampus was induced with clioquinol (CQ), a zinc ionophore. Zn(2+) delivery by Zn-CQ transiently attenuated CA1 long-term potentiation (LTP) in hippocampal slices prepared 2 h after i.p. injection of Zn-CQ into rats, when intracellular Zn(2+) levels was transiently increased in the CA1 pyramidal cell layer, followed by object recognition memory deficit. Object recognition memory was transiently impaired 30 min after injection of ZnCl(2) into the CA1, but not after injection into the dentate gyrus that did not significantly increase intracellular Zn(2+) in the granule cell layer of the dentate gyrus. Object recognition memory deficit may be linked to the preferential increase in Zn(2+) and/or the preferential vulnerability to Zn(2+) in CA1 pyramidal neurons. In the case of the cytosolic increase in endogenous Zn(2+) in the CA1 induced by 100 mM KCl, furthermore, object recognition memory was also transiently impaired, while ameliorated by co-injection of CaEDTA to block the increase in cytosolic Zn(2+). The present study indicates that the transient increase in cytosolic Zn(2+) in CA1 pyramidal neurons reversibly impairs object recognition memory.

Transient Increase in Zn2+ in Hippocampal CA1 Pyramidal Neurons Causes Reversible Memory Deficit

PubMed Central

Takeda, Atsushi; Takada, Shunsuke; Nakamura, Masatoshi; Suzuki, Miki; Tamano, Haruna; Ando, Masaki; Oku, Naoto

2011-01-01

The translocation of synaptic Zn2+ to the cytosolic compartment has been studied to understand Zn2+ neurotoxicity in neurological diseases. However, it is unknown whether the moderate increase in Zn2+ in the cytosolic compartment affects memory processing in the hippocampus. In the present study, the moderate increase in cytosolic Zn2+ in the hippocampus was induced with clioquinol (CQ), a zinc ionophore. Zn2+ delivery by Zn-CQ transiently attenuated CA1 long-term potentiation (LTP) in hippocampal slices prepared 2 h after i.p. injection of Zn-CQ into rats, when intracellular Zn2+ levels was transiently increased in the CA1 pyramidal cell layer, followed by object recognition memory deficit. Object recognition memory was transiently impaired 30 min after injection of ZnCl2 into the CA1, but not after injection into the dentate gyrus that did not significantly increase intracellular Zn2+ in the granule cell layer of the dentate gyrus. Object recognition memory deficit may be linked to the preferential increase in Zn2+ and/or the preferential vulnerability to Zn2+ in CA1 pyramidal neurons. In the case of the cytosolic increase in endogenous Zn2+ in the CA1 induced by 100 mM KCl, furthermore, object recognition memory was also transiently impaired, while ameliorated by co-injection of CaEDTA to block the increase in cytosolic Zn2+. The present study indicates that the transient increase in cytosolic Zn2+ in CA1 pyramidal neurons reversibly impairs object recognition memory. PMID:22163318

A CHANDRA OBSERVATION OF THE ECLIPSING WOLF-RAYET BINARY CQ Cep

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

Skinner, Stephen L.; Zhekov, Svetozar A.; Güdel, Manuel

The short-period (1.64 d) near-contact eclipsing WN6+O9 binary system CQ Cep provides an ideal laboratory for testing the predictions of X-ray colliding wind shock theory at close separation where the winds may not have reached terminal speeds before colliding. We present results of a Chandra X-ray observation of CQ Cep spanning ∼1 day during which a simultaneous Chandra optical light curve was acquired. Our primary objective was to compare the observed X-ray properties with colliding wind shock theory, which predicts that the hottest shock plasma (T ≳ 20 MK) will form on or near the line-of-centers between the stars. The X-raymore » spectrum is strikingly similar to apparently single WN6 stars such as WR 134 and spectral lines reveal plasma over a broad range of temperatures T ∼ 4-40 MK. A deep optical eclipse was seen as the O star passed in front of the Wolf-Rayet star and we determine an orbital period P {sub orb} = 1.6412400 d. Somewhat surprisingly, no significant X-ray variability was detected. This implies that the hottest X-ray plasma is not confined to the region between the stars, at odds with the colliding wind picture and suggesting that other X-ray production mechanisms may be at work. Hydrodynamic simulations that account for such effects as radiative cooling and orbital motion will be needed to determine if the new Chandra results can be reconciled with the colliding wind picture.« less

A Study and Review of Effects of Botulinum Toxins on Mast Cell Dependent and Independent Pruritus

PubMed Central

Ramachandran, Roshni; Marino, Marc J.; Paul, Snighdha; Wang, Zhenping; Mascarenhas, Nicholas L.; Pellett, Sabine; Johnson, Eric A.; DiNardo, Anna; Yaksh, Tony L.

2018-01-01

Pruriceptive itch originates following activation of peripheral sensory nerve terminals when pruritogens come in contact with the skin. The ability of botulinum neurotoxins (BoNTs) to attenuate transmitter release from afferent terminals provides a rationale for studying its effect on pruritus. This study investigated the effects of BoNT/A1 and BoNT/B1 on mast cell dependent (Compound 48/80:48/80) and independent (Chloroquine:CQ) scratching. C57Bl/6 male mice received intradermal injection of 1.5 U of BoNT/A1, BoNT/B1 or saline 2, 7, 14 and 21 days prior to ipsilateral 48/80 or CQ at the nape of the neck. Ipsilateral hind paw scratching was determined using an automated recording device. The effect of BoNTs on 48/80 mediated mast cell degranulation was analyzed in human and murine mast cells and the presence of SNAREs was determined using qPCR, immunostaining and Western blot. Pre-treatment with BoNT/A1 and BoNT/B1 reduced 48/80 and CQ induced scratching behavior starting on day 2 with reversal by day 21. Both serotypes inhibited 48/80 induced mast cell degranulation. qPCR and immunostaining detected SNAP-25 mRNA and protein, respectively, in mast cells, however, Western blots did not. This study demonstrates the long-lasting anti-pruritic effects of two BoNT serotypes, in a murine pruritus model using two different mechanistically driven pruritogens. These data also indicate that BoNTs may have a direct effect upon mast cell degranulation. PMID:29570628

Measuring client experiences in long-term care in the Netherlands: a pilot study with the Consumer Quality Index Long-term Care.

PubMed

Triemstra, Mattanja; Winters, Sjenny; Kool, Rudolf B; Wiegers, Therese A

2010-04-12

This study aims to describe the development, testing and optimization of a new standard instrument, the Consumer Quality Index (CQ-index) Long-term Care, for measuring client experiences with long-term care in the Netherlands. Three versions of the CQ-index questionnaires and protocols for study sampling and data collection were developed, designed for interviews with residents of nursing or residential care homes and postal surveys among representatives of psychogeriatric residents and homecare clients. From July to November 2006 a pilot study was conducted among 2,697 clients of 68 nursing or residential care homes, 2,164 representatives of clients in 57 psychogeriatric care institutions, and 1,462 clients of 19 homecare organizations. We performed psychometric analyses and descriptive analyses, and evaluated the pilot study. The pilot study showed the feasibility and usability of the instruments, supported the multidimensionality of the questionnaires and showed first findings on client experiences and possibilities for quality improvement. Nine scales applied to all care settings: shared decision making, attitude and courtesy, information, body care, competence and safety of care, activities, autonomy, mental well-being, and availability of personnel. The pilot resulted in three optimized questionnaires and recommendations for nationwide implementation. The CQ-index Long-term Care provides a good basis to investigate the quality of nursing homes, residential care homes and homecare from the clients' perspective. This standardized instrument enables a nationwide comparison of the quality of long-term care for the purpose of transparency and quality assurance.

Therapeutic assessment of chloroquine-primaquine combined regimen in adult cohort of Plasmodium vivax malaria from a tertiary care hospital in southwestern India.

PubMed

Rishikesh, Kumar; Kamath, Asha; Hande, Manjunatha H; Vidyasagar, Sudha; Acharya, Raviraja V; Acharya, Vasudeva; Belle, Jayaprakash; Shastry, Ananthakrishna B; Saravu, Kavitha

2015-08-11

Of late there have been accounts of therapeutic failure and chloroquine resistance in Plasmodium vivax malaria especially from Southeast Asian regions. The present study was conducted to assess the therapeutic efficacy of chloroquine-primaquine (CQ-PQ) combined regimen in a cohort of uncomplicated P. vivax mono-infection. A tertiary care hospital-based prospective study was conducted among adult cohort with mono-infection P. vivax malaria as per the World Health Organization's protocol of in vivo assessment of anti-malarial therapeutic efficacy. Participants were treated with CQ 25 mg/kg body weight divided over 3 days and PQ 0.25 mg/kg body weight daily for 2 weeks. Of a total of 125 participants recruited, 122 (97.6%) completed day 28 follow up, three (2.4%) participants were lost to follow-up. Eight patients (6.4%) were ascertained to have mixed P. vivax and Plasmodium falciparum infection by nested polymerase chain reaction test. The majority of subjects (56.8%, 71/125) became aparasitaemic on day 2 followed by 35.2% (44/125) on day 3, and 8% (10/125) on day 7, and remained so thereafter. Overall only one therapeutic failure (0.8%, 1/125) occurred on day 3 due to persistence of fever and parasitaemia. CQ-PQ combined regimen remains outstandingly effective for uncomplicated P. vivax malaria and should be retained as treatment of choice in the study region. One case of treatment failure indicates possible resistance which warrants constant vigilance and periodic surveillance.

Mixing as a driver of temporal variations in river hydrochemistry: 1. Insights from conservative tracers in the Andes-Amazon transition

NASA Astrophysics Data System (ADS)

Torres, Mark A.; Baronas, J. Jotautas; Clark, Kathryn E.; Feakins, Sarah J.; West, A. Joshua

2017-04-01

The response of hillslope processes to changes in precipitation may drive the observed changes in the solute geochemistry of rivers with discharge. This conjecture is most robust when variations in the key environmental factors that affect hillslope processes (e.g., lithology, erosion rate, and climate) are minimal across a river's catchment area. For rivers with heterogenous catchments, temporal variations in the relative contributions of different tributary subcatchments may modulate variations in solute geochemistry with runoff. In the absence of a dense network of hydrologic gauging stations, alternative approaches are required to distinguish between the different drivers of temporal variability in river solute concentrations. In this contribution, we apportion the water and solute fluxes of a reach of the Madre de Dios River (Peru) between its four major tributary subcatchments during two sampling campaigns (wet and dry seasons) using spatial variations in conservative tracers. Guided by the results of a mixing model, we identify temporal variations in solute concentrations of the main stem Madre de Dios that are due to changes in the relative contributions of each tributary. Our results suggest that variations in tributary mixing are, in part, responsible for the observed concentration-discharge (C-Q) relationships. The implications of these results are further explored by reanalyzing previously published C-Q data from this region, developing a theoretical model of tributary mixing, and, in a companion paper, comparing the C-Q behavior of a suite of major and trace elements in the Madre de Dios River system.

Tris(trimethylsilyl)silane as a co-initiator for dental adhesive: Photo-polymerization kinetics and dynamic mechanical property

PubMed Central

Song, Linyong; Ye, Qiang; Ge, Xueping; Misra, Anil; Spencer, Paulette

2017-01-01

Objectives The purpose of this study was to evaluate the polymerization behavior of a model dentin adhesive with tris(trimethylsilyl)silane (TTMSS) as a co-initiator, and to investigate the polymerization kinetics and mechanical properties of copolymers in dry and wet conditions. Methods A co-monomer mixture based on HEMA/BisGMA (45/55, w/w) was used as a model dentin adhesive. The photoinitiator system included camphorquinone (CQ) as the photosensitizer and the co-initiator was ethyl-4-(dimethylamino) benzoate (EDMAB) or TTMSS. Iodonium salt, diphenyliodonium hexafluorophosphate (DPIHP) serving as a catalyst, was selectively added into the adhesive formulations. The control and the experimental formulations were characterized with regard to the degree of conversion (DC) and dynamic mechanical properties under dry and wet conditions. Results In two-component photoinitiator system (CQ/TTMSS), with an increase of TTMSS concentration, the polymerization rate and DC of C═C double bond increased, and showed a dependence on the irradiation time and curing light intensity. The copolymers that contained the three-component photoinitiator system (CQ/TTMSS/DPIHP) showed similar dynamic mechanical properties, under both dry and wet conditions, to the EDMAB-containing system. Significance The DC of formulations using TTMSS as co-initiator showed a strong dependence on irradiation time. With the addition of TTMSS, the maximum polymerization rate can be adjusted and the network structure became more homogenous. The results indicated that the TTMSS could be used as a substitute for amine-type co-initiator in visible-light induced free radical polymerization of methacrylate-based dentin adhesives. PMID:26616688

Prevalence of mutations associated with antimalarial drugs in Plasmodium falciparum isolates prior to the introduction of sulphadoxine-pyrimethamine as first-line treatment in Iran

PubMed Central

Zakeri, Sedigheh; Afsharpad, Mandana; Raeisi, Ahmad; Djadid, Navid Dinparast

2007-01-01

Background This work was carried out to assess the patterns and prevalence of resistance to chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) in Iran. Methods The prevalence of pfcrt K76T, pfmdr1 N86Y, pfdhfr N51I, C59R, S108N/T and I164L and codons S436F/A, A437G, K540E, A581E, and A613S/T in pfdhps genes were genotyped by PCR/RFLP methods in 206 Plasmodium falciparum isolates from Chabahar and Sarbaz districts in Sistan and Baluchistan province, Iran, during 2003–2005. Results All P. falciparum isolates carried the 108N, while 98.5% parasite isolates carried the 59R mutation. 98.5% of patients carried both 108N and 59R. The prevalence of pfdhps 437G mutation was 17% (Chabahar) and 33% (Sarbaz) isolates. 20.4% of samples presented the pfdhfr 108N, 59R with pfdhps 437G mutations. The frequency of allele pfcrt 76T was 98%, while 41.4% (Chabahar) and 27.7% (Sarbaz) isolates carried pfmdr1 86Y allele. Eight distinct haplotypes were identified in all 206 samples, while the most prevalent haplotype was T76/N86/N51R59N108/A437 among both study areas. Conclusion Finding the fixed level of CQ resistance polymorphisms (pfcrt 76T) suggests that CQ must be withdrawn from the current treatment strategy in Iran, while SP may remain the treatment of choice for uncomplicated malaria. PMID:17999755

A Study and Review of Effects of Botulinum Toxins on Mast Cell Dependent and Independent Pruritus.

PubMed

Ramachandran, Roshni; Marino, Marc J; Paul, Snighdha; Wang, Zhenping; Mascarenhas, Nicholas L; Pellett, Sabine; Johnson, Eric A; DiNardo, Anna; Yaksh, Tony L

2018-03-23

Pruriceptive itch originates following activation of peripheral sensory nerve terminals when pruritogens come in contact with the skin. The ability of botulinum neurotoxins (BoNTs) to attenuate transmitter release from afferent terminals provides a rationale for studying its effect on pruritus. This study investigated the effects of BoNT/A1 and BoNT/B1 on mast cell dependent (Compound 48/80:48/80) and independent (Chloroquine:CQ) scratching. C57Bl/6 male mice received intradermal injection of 1.5 U of BoNT/A1, BoNT/B1 or saline 2, 7, 14 and 21 days prior to ipsilateral 48/80 or CQ at the nape of the neck. Ipsilateral hind paw scratching was determined using an automated recording device. The effect of BoNTs on 48/80 mediated mast cell degranulation was analyzed in human and murine mast cells and the presence of SNAREs was determined using qPCR, immunostaining and Western blot. Pre-treatment with BoNT/A1 and BoNT/B1 reduced 48/80 and CQ induced scratching behavior starting on day 2 with reversal by day 21. Both serotypes inhibited 48/80 induced mast cell degranulation. qPCR and immunostaining detected SNAP-25 mRNA and protein, respectively, in mast cells, however, Western blots did not. This study demonstrates the long-lasting anti-pruritic effects of two BoNT serotypes, in a murine pruritus model using two different mechanistically driven pruritogens. These data also indicate that BoNTs may have a direct effect upon mast cell degranulation.

Life Cycle Inventory of Biodiesel and Petroleum Diesel for Use in an Urban Bus

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

Sheehan, John; Camobreco, Vince; Duffield, James

1998-05-01

This report presents the findings from a study of the life cycle inventories (LCIs) for petroleum diesel and biodiesel. An LCI is a comprehensive quantification of all the energy and environmental flows associated with a product from “cradle to grave.” It provides information on raw materials extracted from the environment; energy resources consumed; air, water, and solid waste emissions generated.

The antiplasmodial activity of norcantharidin analogs

USDA-ARS?s Scientific Manuscript database

Despite the availability of many antimalarial drugs, including chloroquine (CQ), artemisinin, atovaquone, proguanil and sulphadoxine-pyrimethamine (SP), malaria remains a serious disease. Malaria is especially dangerous due to the ability of Plasmodium falciparum to evolve resistance to the most com...

MicroRNA-196a-5p is a potential prognostic marker of delayed lymph node metastasis in early-stage tongue squamous cell carcinoma

PubMed Central

Maruyama, Tessho; Nishihara, Kazuhide; Umikawa, Masato; Arasaki, Akira; Nakasone, Toshiyuki; Nimura, Fumikazu; Matayoshi, Akira; Takei, Kimiko; Nakachi, Saori; Kariya, Ken-Ichi; Yoshimi, Naoki

2018-01-01

MicroRNAs (miRs) are expected to serve as prognostic tools for cancer. However, many miRs have been reported as prognostic markers of recurrence or metastasis in oral squamous cell carcinoma patients. We aimed to determine the prognostic markers in early-stage tongue squamous cell carcinoma (TSCC). Based on previous studies, we hypothesized that miR-10a, 10b, 196a-5p, 196a-3p, and 196b were prognostic markers and we retrospectively performed miR expression analyses using formalin-fixed paraffin-embedded sections of surgical specimens. Total RNA was isolated from cancer tissues and adjacent normal tissue as control, and samples were collected by laser-capture microdissection. After cDNA synthesis, reverse transcription-quantitative polymerase chain reaction was performed. Statistical analyses for patient clinicopathological characteristics, recurrence/metastasis, and survival rates were performed to discern their relationships with miR expression levels, and the 2−ΔΔCq method was used. miR-196a-5p levels were significantly upregulated in early-stage TSCC, particularly in the lymph node metastasis (LNM) group. The LNM-free survival rate in the low miR-196a-5p ΔΔCq value regulation group was found to be lower than that in the high ΔΔCq value regulation group (P=0.0079). Receiver operating characteristic analysis of ΔΔCq values revealed that miR-196a-5p had a P-value=0.0025, area under the curve=0.740, and a cut-off value=−0.875 for distinguishing LNM. To our knowledge, this is the first study to examine LNM-related miRs in early-stage TSCC as well as miRs and ‘delayed LNM’ in head and neck cancer. miR-196a-5p upregulation may predict delayed LNM. Our data serve as a foundation for future studies to evaluate miR levels and facilitate the prediction of delayed LNM during early-stage TSCC, which prevent metastasis when combined with close follow-up and aggressive adjuvant therapy or elective neck dissection. Moreover, our data will serve as a foundation for future studies to evaluate whether miR-196a-5p can serve as a therapeutic marker for preventing metastasis. PMID:29434944

Effectiveness of combined chloroquine and primaquine treatment in 14 days versus intermittent single dose regimen, in an open, non-randomized, clinical trial, to eliminate Plasmodium vivax in southern Mexico.

PubMed

Gonzalez-Ceron, Lilia; Rodriguez, Mario H; Sandoval, Marco A; Santillan, Frida; Galindo-Virgen, Sonia; Betanzos, Angel F; Rosales, Angel F; Palomeque, Olga L

2015-10-30

In Mexico, combined chloroquine (CQ) and primaquine (PQ) treatment has been used since the late 1950s to treat Plasmodium vivax infections. Although malaria transmission has declined, current treatment strategies must be evaluated to advance towards malaria elimination. The clinical and parasitological outcome of treating symptomatic P. vivax with the 14-day (T14) treatment or intermittent single dose (ISD) regimen was evaluated in southern Mexico between February 2008 and September 2010. Patients over 12 months old with P. vivax mono-infection and asexual parasitaemia ≥500 parasites/µl were treated under supervision. After diagnosis (day 0), treatment began immediately. T14 patients received CQ for 3 days (10, 10 and 5 mg/kg) and PQ daily for 14 days (0.25 mg/kg), while ISD patients received a single dose of CQ (10 mg/kg) and PQ (0.75 mg/kg) on days 0, 30, 60, 180, 210, and 240. Follow-up was done by observing clinical and laboratory (by microscopy, serology and PCR) outcome, considering two endpoints: primary blood infection clearance and clinical response at ~28 days, and the incidence of recurrent blood infection during 12 months. Parasite genotypes of primary/recurrent blood infections were analysed. During the first 28 days, no differences in parasite clearance or clinical outcome were observed between T14 (86 patients) and ISD (67 patients). On day 3, 95 % of patients in both groups showed no blood parasites, and no recurrences were detected on days 7-28. Contrarily, the therapeutic effectiveness (absence of recurrent parasitaemia) was distinct for T14 versus ISD at 12 months: 83.7 versus 50 %, respectively (p = 0.000). Symptomatic and asymptomatic infections were recorded on days 31-352. Some parasite recurrences were detected by PCR and/or serological testing. T14 was effective for opportune elimination of the primary blood infection and preventing relapse episodes. The first single dose of CQ-PQ eliminated primary blood infection as efficiently as the initial three-dose scheme of T14, but the ISD regimen should be abandoned. A single combined dose administered to symptomatic patients in remote areas while awaiting parasitological diagnosis may contribute to halting P. vivax transmission. Alternatives for meeting the challenge of T14 supervision are discussed. NIH-USA, ClinicalTrial.gov Identifier: NCT02394197.

Solid-state (127)I NMR and GIPAW DFT study of metal iodides and their hydrates: structure, symmetry, and higher-order quadrupole-induced effects.

PubMed

Widdifield, Cory M; Bryce, David L

2010-10-14

Central-transition (127)I solid-state nuclear magnetic resonance (SSNMR) spectra are presented for several anhydrous group 2 metal iodides (MgI(2), CaI(2), SrI(2), and BaI(2)), hydrates (BaI(2)·2H(2)O and SrI(2)·6H(2)O), and CdI(2) (4H polytype). Variable offset cumulative spectrum data acquisition coupled with echo pulse sequences and an 'ultrahigh' applied field of 21.1 T were usually suitable to acquire high-quality spectra. Spectral analysis revealed iodine-127 nuclear quadrupole coupling constants (C(Q)((127)I)) ranging in magnitude from 43.5 (CaI(2)) to 214 MHz (one site in SrI(2)). For very large C(Q), analytical second-order perturbation theory could not be used to reliably extract chemical shifts and a treatment which includes quadrupolar effects exactly was required (Bain, A. D. Mol. Phys. 2003, 101, 3163). Differences between second-order and exact modeling allowed us to observe 'higher-order' quadrupole-induced effects for the first time. This finding will have implications for the interpretation of SSNMR spectra of quadrupolar nuclei with large quadrupole moments. In favorable situations (i.e., C(Q)((127)I) < 120 MHz), measurements were also performed at 11.75 T which when combined with the 21.1 T data allowed us to measure iodine chemical shift (CS) tensor spans in the range from 60 (BaI(2)·2H(2)O) to 300 ppm (one site in BaI(2)). These measurements represent the first complete characterizations (i.e., electric field gradient and CS tensors as well as their relative orientation) of noncubic iodide sites using (127)I SSNMR. In select cases, the SSNMR data are supported with (127)I NQR measurements. We also summarize a variety of trends in the halogen SSNMR parameters for group 2 metal halides. Gauge-including projector-augmented wave DFT computations are employed to complement the experimental observations, to predict potential structures for the two hydrates, and to highlight the sensitivity of C(Q)((127)I) to minute structural changes, which has potential applications in NMR crystallography.

Solid-state lighting for the International Space Station: Tests of visual performance and melatonin regulation

NASA Astrophysics Data System (ADS)

Brainard, George C.; Coyle, William; Ayers, Melissa; Kemp, John; Warfield, Benjamin; Maida, James; Bowen, Charles; Bernecker, Craig; Lockley, Steven W.; Hanifin, John P.

2013-11-01

The International Space Station (ISS) uses General Luminaire Assemblies (GLAs) that house fluorescent lamps for illuminating the astronauts' working and living environments. Solid-state light emitting diodes (LEDs) are attractive candidates for replacing the GLAs on the ISS. The advantages of LEDs over conventional fluorescent light sources include lower up-mass, power consumption and heat generation, as well as fewer toxic materials, greater resistance to damage and long lamp life. A prototype Solid-State Lighting Assembly (SSLA) was developed and successfully installed on the ISS. The broad aim of the ongoing work is to test light emitted by prototype SSLAs for supporting astronaut vision and assessing neuroendocrine, circadian, neurobehavioral and sleep effects. Three completed ground-based studies are presented here including experiments on visual performance, color discrimination, and acute plasma melatonin suppression in cohorts of healthy, human subjects under different SSLA light exposure conditions within a high-fidelity replica of the ISS Crew Quarters (CQ). All visual tests were done under indirect daylight at 201 lx, fluorescent room light at 531 lx and 4870 K SSLA light in the CQ at 1266 lx. Visual performance was assessed with numerical verification tests (NVT). NVT data show that there are no significant differences in score (F=0.73, p=0.48) or time (F=0.14, p=0.87) for subjects performing five contrast tests (10%-100%). Color discrimination was assessed with Farnsworth-Munsell 100 Hue tests (FM-100). The FM-100 data showed no significant differences (F=0.01, p=0.99) in color discrimination for indirect daylight, fluorescent room light and 4870 K SSLA light in the CQ. Plasma melatonin suppression data show that there are significant differences (F=29.61, p<0.0001) across the percent change scores of plasma melatonin for five corneal irradiances, ranging from 0 to 405 μW/cm2 of 4870 K SSLA light in the CQ (0-1270 lx). Risk factors for the health and safety of astronauts include disturbed circadian rhythms and altered sleep-wake patterns. These studies will help determine if SSLA lighting can be used both to support astronaut vision and serve as an in-flight countermeasure for circadian desynchrony, sleep disruption and cognitive performance deficits on the ISS.

Return of chloroquine-sensitive Plasmodium falciparum parasites and emergence of chloroquine-resistant Plasmodium vivax in Ethiopia

PubMed Central

2014-01-01

Background Increased resistance by Plasmodium falciparum parasites led to the withdrawal of the antimalarial drugs chloroquine and sulphadoxine-pyrimethamine in Ethiopia. Since 2004 artemether-lumefantrine has served to treat uncomplicated P. falciparum malaria. However, increasing reports on delayed parasite clearance to artemisinin opens up a new challenge in anti-malarial therapy. With the complete withdrawal of CQ for the treatment of Plasmodium falciparum malaria, this study assessed the evolution of CQ resistance by investigating the prevalence of mutant alleles in the pfmdr1 and pfcrt genes in P. falciparum and pvmdr1 gene in Plasmodium vivax in Southern and Eastern Ethiopia. Methods Of the 1,416 febrile patients attending primary health facilities in Southern Ethiopia, 329 febrile patients positive for P. falciparum or P. vivax were recruited. Similarly of the 1,304 febrile patients from Eastern Ethiopia, 81 febrile patients positive for P. falciparum or P. vivax were included in the study. Of the 410 finger prick blood samples collected from malaria patients, we used direct sequencing to investigate the prevalence of mutations in pfcrt and pfmdr1. This included determining the gene copy number in pfmdr1 in 195 P. falciparum clinical isolates, and mutations in the pvmdr1 locus in 215 P. vivax clinical isolates. Results The pfcrt K76 CQ-sensitive allele was observed in 84.1% of the investigated P.falciparum clinical isolates. The pfcrt double mutations (K76T and C72S) were observed less than 3%. The pfcrt SVMNT haplotype was also found to be present in clinical isolates from Ethiopia. The pfcrt CVMNK-sensitive haplotypes were frequently observed (95.9%). The pfmdr1 mutation N86Y was observed only in 14.9% compared to 85.1% of the clinical isolates that carried sensitive alleles. Also, the sensitive pfmdr1 Y184 allele was more common, in 94.9% of clinical isolates. None of the investigated P. falciparum clinical isolates carried S1034C, N1042D and D1246Y pfmdr1 polymorphisms. All investigated P. falciparum clinical isolates from Southern and Eastern Ethiopia carried only a single copy of the mutant pfmdr1 gene. Conclusion The study reports for the first time the return of chloroquine sensitive P. falciparum in Ethiopia. These findings support the rationale for the use of CQ-based combination drugs as a possible future alternative. PMID:24964730

Endogenously determined cycles: empirical evidence from livestock industries.

PubMed

McCullough, Michael P; Huffaker, Ray; Marsh, Thomas L

2012-04-01

This paper applies the techniques of phase space reconstruction and recurrence quantification analysis to investigate U.S. livestock cycles in relation to recent literature on the business cycle. Results are presented for pork and cattle cycles, providing empirical evidence that the cycles themselves have slowly diminished. By comparing the evolution of production processes for the two livestock cycles we argue that the major cause for this moderation is largely endogenous. The analysis suggests that previous theoretical models relying solely on exogenous shocks to create cyclical patterns do not fully capture changes in system dynamics. Specifically, the biological constraint in livestock dynamics has become less significant while technology and information are relatively more significant. Concurrently, vertical integration of the supply chain may have improved inventory management, all resulting in a small, less deterministic, cyclical effect.

Research influence on antimalarial drug policy change in Tanzania: case study of replacing chloroquine with sulfadoxine-pyrimethamine as the first-line drug

PubMed Central

Mubyazi, Godfrey M; Gonzalez-Block, Miguel A

2005-01-01

Introduction Research is an essential tool in facing the challenges of scaling up interventions and improving access to services. As in many other countries, the translation of research evidence into drug policy action in Tanzania is often constrained by poor communication between researchers and policy decision-makers, individual perceptions or attitudes towards the drug and hesitation by some policy decision-makers to approve change when they anticipate possible undesirable repercussions should the policy change as proposed. Internationally, literature on the role of researchers on national antimalarial drug policy change is limited. Objectives To describe the (a) role of researchers in producing evidence that influenced the Tanzanian government replace chloroquine (CQ) with sulfadoxine-pyrimethamine (SP) as the first-line drug and the challenges faced in convincing policy-makers, general practitioners, pharmaceutical industry and the general public on the need for change (b) challenges ahead before a new drug combination treatment policy is introduced in Tanzania. Methods In-depth interviews were held with national-level policy-makers, malaria control programme managers, pharmaceutical officers, general medical practitioners, medical research library and publications officers, university academicians, heads of medical research institutions and district and regional medical officers. Additional data were obtained through a review of malaria drug policy documents and participant observations were also done. Results In year 2001, the Tanzanian Government officially changed its malaria treatment policy guidelines whereby CQ – the first-line drug for a long time was replaced with SP. This policy decision was supported by research evidence indicating parasite resistance to CQ and clinical CQ treatment failure rates to have reached intolerable levels as compared to SP and amodiaquine (AQ). Research also indicated that since SP was also facing rising resistance trend, the need for a more effective drug was indispensable but for an interim 5–10 year period it was justifiable to recommend SP that was relatively more cost-effective than CQ and AQ. The government launched the policy change considering that studies (ethically approved by the Ministry of Health) on therapeutic efficacy and cost-effectiveness of artemisinin drug combination therapies were underway. Nevertheless, the process of communicating research results and recommendations to policy-making authorities involved critical debates between policy makers and researchers, among the researchers themselves and between the researchers and general practitioners, the speculative media reports on SP side-effects and reservations by the general public concerning the rationale for policy change, when to change, and to which drug of choice. Conclusion Changing national drug policy will remain a sensitive issue that cannot be done overnight. However, to ensure that research findings are recognised and the recommendations emanating from such findings are effectively utilized, a systematic involvement of all the key stakeholders (including policy-makers, drug manufacturers, media, practitioners and the general public) at all stages of research is crucial. It also matters how and when research information is communicated to the stakeholders. Professional organizations such as the East African Network on Malaria Treatment have potential to bring together malaria researchers, policy-makers and other stakeholders in the research-to-drug policy change interface. PMID:16242017

Assessment of Proper Bonding Methods and Mechanical Characterization FPGA CQFPs

NASA Technical Reports Server (NTRS)

Davis, Milton C.

2008-01-01

This presentation discusses fractured leads on field-programmable gate array (FPGA) during flight vibration. Actions taken to determine root cause and resolution of the failure include finite element analysis (FEA) and vibration testing and scanning electron microscopy (with X-ray microanalysis) and energy dispersive spectrometry (SEM/EDS) failure assessment. Bonding methods for surface mount parts is assessed, including critical analysis and assessment of random fatigue damage. Regarding ceramic quad flat pack (CQFP) lead fracture, after disassembling the attitude control electronics (ACE) configuration, photographs showed six leads cracked on FPGA RTSX72SU-1 CQ208B package located on the RWIC card. An identical package (FPGA RTSX32SU-1 CQ208B) mounted on the RWIC did not results in cracked pins due to vibration. FPGA lead failure theories include workmanship issues in the lead-forming, material defect in the leads of the FPGA packages, and the insecure mounting of the board in the card guides, among other theories. Studies were conducted using simple calculations to determine the response and fatigue life of the package. Shorter packages exhibited more response when loaded by out-of-plane displacement of PCB while taller packages exhibit more response when loaded by in-plane acceleration of PCB. Additionally, under-fill did not contribute to reducing stress in leads due to out-of-plane PCB loading or from component twisting, as much as corner bonding. The combination of corner bond and under-fill is best to address mechanical and thermal S/C environment. Test results of bonded parts showed reduced (dampened) amplitude and slightly shifted peaks at the un-bonded natural frequency and an additional response at the bonded frequency. Stress due to PCBB out-of-plane loading was decreased on in the corners when only a corner bond was used. Future work may address CQFP fatigue assessment, including the investigation of discrepancy in predicted fatigue damage, as well as comparing fatigue life and fatigue damage cycle ration computed using FEA and Miner's rule to results from a fatigue assessment software program.

Dynamics of Malaria Drug Resistance Patterns in the Amazon Basin Region following Changes in Peruvian National Treatment Policy for Uncomplicated Malaria▿ †

PubMed Central

Bacon, David J.; McCollum, Andrea M.; Griffing, Sean M.; Salas, Carola; Soberon, Valeria; Santolalla, Meddly; Haley, Ryan; Tsukayama, Pablo; Lucas, Carmen; Escalante, Ananias A.; Udhayakumar, Venkatachalam

2009-01-01

Monitoring changes in the frequencies of drug-resistant and -sensitive genotypes can facilitate in vivo clinical trials to assess the efficacy of drugs before complete failure occurs. Peru changed its national treatment policy for uncomplicated malaria to artesunate (ART)-plus-mefloquine (MQ) combination therapy in the Amazon basin in 2001. We genotyped isolates collected in 1999 and isolates collected in 2006 to 2007 for mutations in the Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes, multidrug resistance gene 1 (Pfmdr-1), the chloroquine (CQ) resistance transporter gene (Pfcrt), and the Ca2+ ATPase gene (PfATP6); these have been shown to be involved in resistance to sulfadoxine-pyrimethamine (SP), MQ, CQ, and possibly ART, respectively. Microsatellite haplotypes around the Pfdhfr, Pfdhps, Pfcrt, and Pfmdr-1 loci were also determined. There was a significant decline in the highly SP resistant Pfdhfr and Pfdhps genotypes from 1999 to 2006. In contrast, a CQ-resistant Pfcrt genotype increased in frequency during the same period. Among five different Pfmdr-1 allelic forms noted in 1999, two genotypes increased in frequency while one genotype decreased by 2006. We also noted previously undescribed polymorphisms in the PfATP6 gene as well as an increase in the frequency of a deletion mutant during this period. In addition, microsatellite analysis revealed that the resistant Pfdhfr, Pfdhps, and Pfcrt genotypes have each evolved from a single founder haplotype, while Pfmdr-1 genotypes have evolved from at least two independent haplotypes. Importantly, this study demonstrates that the Peruvian triple mutant Pfdhps genotypes are very similar to those found in other parts of South America. PMID:19258269

Nitrate concentration-drainage flow (C-Q) relationship for a drained agricultural field in Eastern North Carolina Plain

NASA Astrophysics Data System (ADS)

Liu, W.; Youssef, M.; Birgand, F.; Chescheir, G. M.; Maxwell, B.; Tian, S.

2017-12-01

Agricultural drainage is a practice used to artificially enhance drainage characteristics of naturally poorly drained soils via subsurface drain tubing or open-ditch systems. Approximately 25% of the U.S. agricultural land requires improved drainage for economic crop production. However, drainage increases the transport of dissolved agricultural chemicals, particularly nitrates to downstream surface waters. Nutrient export from artificially drained agricultural landscapes has been identified as the leading source of elevated nutrient levels in major surface water bodies in the U.S. Controlled drainage has long been practiced to reduce nitrogen export from agricultural fields to downstream receiving waters. It has been hypothesized that controlled drainage reduces nitrogen losses by promoting denitrification, reducing drainage outflow from the field, and increasing plant uptake. The documented performance of the practice was widely variable as it depends on several site-specific factors. The goal of this research was to utilize high frequency measurements to investigate the effect of agricultural drainage and related management practices on nitrate fate and transport for an artificially drained agricultural field in eastern North Carolina. We deployed a field spectrophotometer to measure nitrate concentration every 45 minutes and measured drainage flow rate using a V-notch weir every 15 minutes. Furthermore, we measured groundwater level, precipitation, irrigation amount, temperature to characterize antecedent conditions for each event. Nitrate concentration-drainage flow (C-Q) relationships generated from the high frequency measurements illustrated anti-clockwise hysteresis loops and nitrate flushing mechanism in response to most precipitation and irrigation events. Statistical evaluation will be carried out for the C-Q relationships. The results of our analysis, combined with numerical modeling, will provide a better understanding of hydrological and biogeochemical processes controlling the fate and transport of nitrate in drained agricultural landscapes.

Monitoring efficacy of commonly used antimalarials by a 14-day in-vivo test in a new settler's camp in endemic zone at Cox's Bazar.

PubMed

Rahman, M R; Hassan, M R; Faiz, M A; Samad, R; Paul, B; Jalil, M A

1998-12-01

The study was done in a new settler's camp "Barachara" under Sadar thana of Cox's Bazar district. It has a total population of 784 of all age groups, registered in the middle of the study period. A prospective evaluation of all cases of fever were done over 12 months, to see the pattern of febrile illness among the population and to compare the therapeutic efficacy of two alternative drug regimens for uncomplicated falciparum malaria (UM). Blood for malarial parasite (MP) was done in all cases of fever and was treated in line with the new clinical case definitions and treatment guidelines for malaria in Bangladesh. Slide positive UM cases were subjected to a "14-day in-vivo test" for therapeutic efficacy testing of antimalarial agents. The two drug regimens were randomised by lottery--a) 3 days oral chloroquine plus single dose sulphadoxin/pyrimethamine (CQ + SP) and, b) 3 days oral quinine plus single dose sulphadoxin/pyrimethamine (Q3 + SP). Drug administration was supervised by the field assistant and was followed up on days 3, 7 and 14 for blood slide examinations and clinical assessment. Sensitive response was observed in 79% of the cases in the CQ + SP group and 84% in the Q3 + SP group. Early treatment failure (persistently febrile and parasitaemic on days 3 or 7) was observed in 16% in the CQ + SP group and 9% in the Q3 + SP group. Both the evaluated drug regimens had less than 20% failures and can be used as alternative first line agents and Q3 + SP regimens can also be used as the second line agents for treatment failure (to chloroquine and/or SP) UM cases in the study area.

Effects of an artificially lengthened vocal tract on the glottal closed quotient in untrained male voices

NASA Astrophysics Data System (ADS)

Gaskill, Christopher Somers

The use of hard-walled narrow tubes, often called resonance tubes, for the purpose of voice therapy and voice training has a historical precedent and some theoretical support, but the mechanism of any potential benefit from the application of this technique has remained poorly understood. Fifteen vocally untrained male participants produced a series of spoken /a / vowels at a modal pitch and constant loudness, followed by a minute of repeated phonation into a hard-walled glass tube at the same pitch and loudness targets. The tube parameters and tube phonation task criteria were selected according to theoretical calculations predicting an increase in the acoustic load such that phonation would occur under conditions of near-maximum inertive reactance. Following tube phonation, each participant repeated a similar series of spoken /a/ vowels. Electroglottography (EGG) was used to measure the glottal closed quotient (CQ) during each phase of the experiment. A single-subject, multiple-baseline design with direct replication across subjects was used to identify any changes in CQ across the phases of the experiment. Single-subject analysis using the method of Statistical Process Control (SPC) revealed statistically significant changes in CQ during tube phonation, but with no discernable pattern across the 15 participants. These results indicate that the use of resonance tubes can have a distinct effect on glottal closure, but the mechanism behind this change remains unclear. The implication is that vocal loading techniques such as this need to be studied further with specific attention paid to the underlying mechanism of any measured changes in glottal behavior, and especially to the role of instruction and feedback in the therapeutic and pedagogical application of these techniques.

Use of LysoTracker dyes: a flow cytometric study of autophagy.

PubMed

Chikte, Shaheen; Panchal, Neelam; Warnes, Gary

2014-02-01

The flow cytometric use of LysoTracker dyes was employed to investigate the autophagic process and to compare this with the upregulation of autophagy marker, the microtubule-associated protein LC3B. Although the mechanism of action of LysoTracker dyes is not fully understood, they have been used in microscopy to image acidic spherical organelles, and their use in flow cytometry has not been thoroughly investigated in the study of autophagy. This investigation uses numerous autophagy-inducing agents including chloroquine (CQ), rapamycin, low serum (<1%) RPMI, and nutrient starvation to induce autophagy in Jurkat T-cell leukemia and K562 erythromyeloid cell lines. LC3B showed an increase with CQ treatment although this was different to LysoTracker signals in terms of dose and time. Rapamycin, low serum (<1%) RPMI, and nutrient starvation induction of autophagy also induced an increase in LysoTracker and LC3B signals. CQ also induced apoptosis in cell lines, which was blocked by pan-caspase inhibitor z-VAD resulting in a reduction in cells undergoing apoptosis and a subsequent upregulation of autophagic markers LC3B and lysosomal dye signals. Given that LC3B and LysoTracker are measuring different biological events in the autophagic process, they surprisingly both upregulated during autophagic process. This study, however, shows that although LysoTracker dyes do not specifically label lysosomes or autophagosomes within the cell, they allow the simultaneous measurement of an autophagy-related process and other live-cell functions, which are not possible with the standard LC3B antibody-labeling technique. This method has the advantage of other live-cell LCB-GFP-tagged experiments in that be used to analyze patient cells as well as easier to use and significantly less costly. Copyright © 2013 International Society for Advancement of Cytometry.

Cost–effectiveness of artemisinin combination therapy for uncomplicated malaria in children: data from Papua New Guinea

PubMed Central

Davis, Wendy A; Clarke, Philip M; Siba, Peter M; Karunajeewa, Harin A; Davy, Carol; Mueller, Ivo

2011-01-01

Abstract Objective To compare the cost–effectiveness of conventional antimalarial therapy with that of three artemisinin combination treatment regimens in children from Papua New Guinea aged 6 to 60 months. Methods An incremental cost–effectiveness analysis was performed using data from 656 children with Plasmodium falciparum and/or P. vivax malaria who participated in a large intervention trial in two clinics in northern Papua New Guinea. The children were randomized to one of the following groups: (i) conventional treatment with chloroquine plus sulfadoxine plus pyrimethamine (CQ+S+P); (ii) artesunate plus S plus P; (iii) dihydroartemisinin plus piperaquine (DHA+PQ); and (iv) artemether plus lumefantrine (A+L). For treatment outcomes, World Health Organization definitions were used. The cost of transport between home and the clinic plus direct health-care costs served as a basis for determining each regimen’s incremental cost per incremental treatment success relative to CQ+S+P by day 42 and its cost per life year saved. Findings A+L proved to be the most effective regimen against P. falciparum malaria and was highly cost-effective at 6.97 United States dollars (US$) per treatment success (about US$ 58 per life year saved). DHA+PQ was the most effective regimen against P. vivax malaria and was more cost-effective than CQ+S+P. Conclusion A+L and DHA+PQ are highly cost-effective regimens for the treatment of paediatric P. falciparum and P. vivax malaria, respectively, in parts of Papua New Guinea. Future research will be required to determine if these findings hold true for other territories in Asia and Oceania with similar malaria epidemiology. PMID:21379417

How Stressful Is "Deep Bubbling"?

PubMed

Tyrmi, Jaana; Laukkanen, Anne-Maria

2017-03-01

Water resistance therapy by phonating through a tube into the water is used to treat dysphonia. Deep submersion (≥10 cm in water, "deep bubbling") is used for hypofunctional voice disorders. Using it with caution is recommended to avoid vocal overloading. This experimental study aimed to investigate how strenuous "deep bubbling" is. Fourteen subjects, half of them with voice training, repeated the syllable [pa:] in comfortable speaking pitch and loudness, loudly, and in strained voice. Thereafter, they phonated a vowel-like sound both in comfortable loudness and loudly into a glass resonance tube immersed 10 cm into the water. Oral pressure, contact quotient (CQ, calculated from electroglottographic signal), and sound pressure level were studied. The peak oral pressure P(oral) during [p] and shuttering of the outer end of the tube was measured to estimate the subglottic pressure P(sub) and the mean P(oral) during vowel portions to enable calculation of transglottic pressure P(trans). Sensations during phonation were reported with an open-ended interview. P(sub) and P(oral) were higher in "deep bubbling" and P(trans) lower than in loud syllable phonation, but the CQ did not differ significantly. Similar results were obtained for the comparison between loud "deep bubbling" and strained phonation, although P(sub) did not differ significantly. Most of the subjects reported "deep bubbling" to be stressful only for respiratory and lip muscles. No big differences were found between trained and untrained subjects. The CQ values suggest that "deep bubbling" may increase vocal fold loading. Further studies should address impact stress during water resistance exercises. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Signaling protein signature predicts clinical outcome of non-small-cell lung cancer.

PubMed

Jin, Bao-Feng; Yang, Fan; Ying, Xiao-Min; Gong, Lin; Hu, Shuo-Feng; Zhao, Qing; Liao, Yi-Da; Chen, Ke-Zhong; Li, Teng; Tai, Yan-Hong; Cao, Yuan; Li, Xiao; Huang, Yan; Zhan, Xiao-Yan; Qin, Xuan-He; Wu, Jin; Chen, Shuai; Guo, Sai-Sai; Zhang, Yu-Cheng; Chen, Jing; Shen, Dan-Hua; Sun, Kun-Kun; Chen, Lu; Li, Wei-Hua; Li, Ai-Ling; Wang, Na; Xia, Qing; Wang, Jun; Zhou, Tao

2018-03-06

Non-small-cell lung cancer (NSCLC) is characterized by abnormalities of numerous signaling proteins that play pivotal roles in cancer development and progression. Many of these proteins have been reported to be correlated with clinical outcomes of NSCLC. However, none of them could provide adequate accuracy of prognosis prediction in clinical application. A total of 384 resected NSCLC specimens from two hospitals in Beijing (BJ) and Chongqing (CQ) were collected. Using immunohistochemistry (IHC) staining on stored formalin-fixed paraffin-embedded (FFPE) surgical samples, we examined the expression levels of 75 critical proteins on BJ samples. Random forest algorithm (RFA) and support vector machines (SVM) computation were applied to identify protein signatures on 2/3 randomly assigned BJ samples. The identified signatures were tested on the remaining BJ samples, and were further validated with CQ independent cohort. A 6-protein signature for adenocarcinoma (ADC) and a 5-protein signature for squamous cell carcinoma (SCC) were identified from training sets and tested in testing sets. In independent validation with CQ cohort, patients can also be divided into high- and low-risk groups with significantly different median overall survivals by Kaplan-Meier analysis, both in ADC (31 months vs. 87 months, HR 2.81; P <  0.001) and SCC patients (27 months vs. not reached, HR 9.97; P <  0.001). Cox regression analysis showed that both signatures are independent prognostic indicators and outperformed TNM staging (ADC: adjusted HR 3.07 vs. 2.43, SCC: adjusted HR 7.84 vs. 2.24). Particularly, we found that only the ADC patients in high-risk group significantly benefited from adjuvant chemotherapy (P = 0.018). Both ADC and SCC protein signatures could effectively stratify the prognosis of NSCLC patients, and may support patient selection for adjuvant chemotherapy.

Photoinitiation chemistry affects light transmission and degree of conversion of curing experimental dental resin composites.

PubMed

Ogunyinka, A; Palin, W M; Shortall, A C; Marquis, P M

2007-07-01

The effect of photoinitiator and co-initiator chemistry on the setting reaction and degree of conversion of dental resin-based composites (RBCs) has rarely been determined explicitly. This work examines the effect of type and concentration of photoinitiator and co-initiator on the rate of change of light transmission throughout polymerisation and degree of conversion of model RBC formulations. Bisphenol-A diglycidyl ether dimethacrylate (bis-GMA) and triethylene glycol dimethacrylate (TEGDMA) (6:4 molar ratio) resins filled with silanized glass filler (74wt.%) and containing various photoinitiators (camphorquinone; CQ, 1-phenyl-1,2-propanedione; PPD, benzil; BZ), co-initiator types (N,N-dimethyl-p-amino benzoic acid ethyl ester; DABE, N,N-cyanoethyl methylaniline; CEMA, N,N-diethanol-p-toluidine; DEPT) and concentration (0.0-0.3% DABE) were polymerised using a halogen or LED light curing-unit (LCU) for 10, 20 and 40s. The setting reaction was monitored in real-time by measuring the light transmittance through the curing specimen and bulk degree of conversion (DC) evaluated using Fourier transform infra-red spectroscopy. Specimens containing CQ and PPD cured with the halogen LCU did not have a significant effect on DC or changes in light transmission, although a significant increase in DC was observed for CQ compared with PPD specimens cured with the LED LCU. DABE and CEMA were more effective co-initiators than DEPT. Although DC was not limited by co-initiator concentration, the absence of a co-initiator resulted in marked differences in light transmission and decreased DC throughout 40s irradiation with each LCU type. The spectral range emitted from different types of LCU and absorption characteristics of the photoinitiator chemistry of light-activated resin-based composites play a critical role in the efficiency of polymerisation.

In vitro antimalarial activity of medicinal plant extracts against Plasmodium falciparum.

PubMed

Bagavan, Asokan; Rahuman, Abdul Abdul; Kaushik, Naveen Kumar; Sahal, Dinkar

2011-01-01

Malaria is a major global public health problem, and the alarming spread of drug resistance and limited number of effective drugs now available underline how important it is to discover new antimalarial compounds. In the present study, ten plants were extracted with ethyl acetate and methanol and tested for their antimalarial activity against chloroquine (CQ)-sensitive (3D7) and CQ-resistant (Dd2 and INDO) strains of Plasmodium falciparum in culture using the fluorescence-based SYBR Green assay. Plant extracts showed moderate to good antiparasitic effects. Promising antiplasmodial activity was found in the extracts from two plants, Phyllanthus emblica leaf 50% inhibitory concentration (IC₅₀) 3D7: 7.25 μg/mL (ethyl acetate extract), 3.125 μg/mL (methanol extract), and Syzygium aromaticum flower bud, IC₅₀ 3D7:13 μg/mL, (ethyl acetate extract) and 6.25 μg/mL (methanol extract). Moderate activity (30-75 μg/mL) was found in the ethyl acetate and methanol extracts of Abrus precatorius (seed) and Gloriosa superba (leaf); leaf ethyl acetate extracts of Annona squamosa and flower of Musa paradisiaca. The above mentioned plant extracts were also found to be active against CQ-resistant strains (Dd2 and INDO). Cytotoxicity study with P. emblica leaf and S. aromaticum flower bud, extracts showed good therapeutic indices. These results demonstrate that leaf ethyl acetate and methanol extracts of P. emblica and flower bud extract of S. aromaticum may serve as antimalarial agents even in their crude form. The isolation of compounds from P. emblica and S. aromaticum seems to be of special interest for further antimalarial studies.

Effectiveness of closure of public places with time delay in disease control.

PubMed

Wang, Zhenggang; Szeto, Kwok Yip; Leung, Frederick Chi-Ching

2008-08-25

A theoretical basis for the evaluation of the effciency of quarantine measure is developed in a SIR model with time delay. In this model, the effectiveness of the closure of public places such as schools in disease control, modeled as a high degree node in a social network, is evaluated by considering the effect of the time delay in the identification of the infected. In the context of the SIR model, the relation between the number of infectious individuals who are identified with time delay and then quarantined and those who are not identified and continue spreading the virus are investigated numerically. The social network for the simulation is modeled by a scale free network. Closure measures are applied to those infected nodes with high degrees. The effectiveness of the measure can be controlled by the present value of the critical degree K(C): only those nodes with degree higher than K(C) will be quarantined. The cost C(Q) incurred for the closure measure is assumed to be proportional to the total links rendered inactive as a result of the measure, and generally decreases with K(C), while the medical cost C(Q) incurred for virus spreading increases with K(C). The total social cost (C(M) + C(Q)) will have a minimum at a critical K(*), which depends on the ratio of medical cost coeffcient alpha(M) and closure cost coeffcient alpha(Q). Our simulation results demonstrate a mathematical procedure to evaluate the effciency of quarantine measure. Although the numerical work is based on a scale free network, the procedure can be readily generalized and applied to a more realistic social network to determine the proper closure measure in future epidemics.

In Vitro Susceptibility of Plasmodium vivax to Antimalarials in Colombia

PubMed Central

Fernández, Diana; Segura, César; Arboleda, Margarita; Garavito, Giovanny; Blair, Silvia

2014-01-01

The in vitro susceptibilities of 30 isolates of Plasmodium vivax to a number of antimalarials (chloroquine [CQ], mefloquine, amodiaquine, quinine, and artesunate [AS]) were evaluated. The isolates came from the region of Urabá in Colombia, in which malaria is endemic, and were evaluated by the schizont maturation test. The 50% inhibitory concentration (IC50) was 0.6 nM (95% confidence interval [CI], 0.3 to 1.0 nM) for artesunate, 8.5 nM (95% CI, 5.6 to 13.0 nM) for amodiaquine, 23.3 nM (95% CI, 12.4 to 44.1 nM) for chloroquine, 55.6 nM (95% CI, 36.8 to 84.1 nM) for mefloquine, and 115.3 nM (95% CI, 57.7 to 230.5 nM) for quinine. The isolates were classified according to whether the initial parasites were mature or immature trophozoites (Tfz). It was found that the IC50s for chloroquine and artesunate were significantly different in the two aforementioned groups (P < 0.001). The IC50s of CQ and AS were higher in the isolates from mature Tfz (CQ, 39.3 nM versus 17 nM; AS, 1.4 nM versus 0.3 nM), and 10% of the isolates showed lower susceptibilities to one of the antimalarial drugs, 13.3% to two antimalarial drugs, and 3.3% to more than three antimalarial drugs. It should be highlighted that despite the extensive use of chloroquine in Colombia, P. vivax continues to be susceptible to antimalarials. This is the first report, to our knowledge, showing in vitro susceptibilities of P. vivax isolates to antimalarials in Colombia. PMID:25114141

Mirincamycin, an old candidate for malaria combination treatment and prophylaxis in the 21st century: in vitro interaction profiles with potential partner drugs in continuous culture and field isolates.

PubMed

Starzengruber, Peter; Fuehrer, Hans-Peter; Swoboda, Paul; Ganesh, Deepa; Haque, Rashidul; Khan, Wasif A; Graninger, Wolfgang; Noedl, Harald

2014-06-10

Spreading resistance of Plasmodium falciparum to existing drugs calls for the search for novel anti-malarial drugs and combinations for the treatment of falciparum malaria. In vitro and ex vivo investigations were conducted with fresh P. falciparum field isolates and culture-adapted P. falciparum clones to evaluate the anti-malarial potential of mirincamycin, a lincosamide, alone and in combination with tafenoquine (TQ), dihydroartemisinin (DHA), and chloroquine (CQ). All samples were tested in a histidine-rich protein 2 (HRP2) drug susceptibility assay. Interaction analysis showed additive to synergistic interaction profiles with these potential partner drugs, with an overall geometric mean fractional inhibitory concentration at 50% inhibition (FIC₅₀) of 0.78, 0.80 and 0.80 for mirincamycin with TQ, DHA, and CQ, respectively. Antagonism was not found in any of the tested field isolates or clones. The strongest tendency toward synergy (i.e. the lowest FIC) was seen with a combination ratio of 1:0.27 to 1:7.2 (mean 1:2.7) for the combination with tafenoquine. The optimal combination ratios for DHA and CQ were 1:444.4 to 1:36,000 (mean 1:10,755.5) and 1:2.7 to 1:216 (mean 1:64.5), respectively. No evidence of an activity correlation (i.e. potential cross-resistance) with DHA, mefloquine, quinine or chloroquine was seen whereas a significant correlation with the activity of clindamycin and azithromycin was detected. Mirincamycin combinations may be promising candidates for further clinical investigations in the therapy and prophylaxis of multidrug-resistant falciparum malaria or in combination with 4 or 8-aminoquinolines for the treatment and relapse prevention of vivax malaria.

Mirincamycin, an old candidate for malaria combination treatment and prophylaxis in the 21st century: in vitro interaction profiles with potential partner drugs in continuous culture and field isolates

PubMed Central

2014-01-01

Background Spreading resistance of Plasmodium falciparum to existing drugs calls for the search for novel anti-malarial drugs and combinations for the treatment of falciparum malaria. Methods In vitro and ex vivo investigations were conducted with fresh P. falciparum field isolates and culture-adapted P. falciparum clones to evaluate the anti-malarial potential of mirincamycin, a lincosamide, alone and in combination with tafenoquine (TQ), dihydroartemisinin (DHA), and chloroquine (CQ). All samples were tested in a histidine-rich protein 2 (HRP2) drug susceptibility assay. Results Interaction analysis showed additive to synergistic interaction profiles with these potential partner drugs, with an overall geometric mean fractional inhibitory concentration at 50% inhibition (FIC50) of 0.78, 0.80 and 0.80 for mirincamycin with TQ, DHA, and CQ, respectively. Antagonism was not found in any of the tested field isolates or clones. The strongest tendency toward synergy (i.e. the lowest FIC) was seen with a combination ratio of 1:0.27 to 1:7.2 (mean 1:2.7) for the combination with tafenoquine. The optimal combination ratios for DHA and CQ were 1:444.4 to 1:36,000 (mean 1:10,755.5) and 1:2.7 to 1:216 (mean 1:64.5), respectively. No evidence of an activity correlation (i.e. potential cross-resistance) with DHA, mefloquine, quinine or chloroquine was seen whereas a significant correlation with the activity of clindamycin and azithromycin was detected. Conclusions Mirincamycin combinations may be promising candidates for further clinical investigations in the therapy and prophylaxis of multidrug-resistant falciparum malaria or in combination with 4 or 8-aminoquinolines for the treatment and relapse prevention of vivax malaria. PMID:24916383

Quantitative trait locus analysis of plasma cholesterol levels and body weight by controlling the effects of the Apoa2 allele in mice.

PubMed

Suto, Jun-ichi

2007-04-01

Colleagues and I previously performed quantitative trait locus (QTL) analysis on plasma total-cholesterol (T-CHO) levels in C57BL/6J (B6) x RR F2 mice. We identified only one significant QTL (Cq6) on chromosome 1 in a region containing the Apoa2 gene locus, a convincing candidate gene for Cq6. Because Cq6 was a highly significant QTL, we considered that the detection of other potential QTLs might be hindered. In the present study, QTL analysis was performed in B6.KK-Apoa2b N(8) x RR F2 mice [B6.KK-Apoa2b N(8) is a partial congenic strain carrying the Apoa2b allele from the KK strain, and RR also has the Apoa2b allele] by controlling of the effects of the Apoa2 allele, for identifying additional QTLs. Although no significant QTLs were identified, 2 suggestive QTLs were found on chromosomes 2 and 3 in place of the effects of the Apoa2 allele. A significant body weight QTL was identified on chromosome 3 (Bwq7, peak LOD score 5.2); its effect on body weight was not significant in previously analyzed B6 x RR F2 mice. Suggestive body weight QTL that had been identified in B6 x RR F2 mice on chromosome 4 (LOD score 3.8) was not identified in B6.KK-Apoa2b N(8) x RR F2 mice. Thus, contrary to expectation, the genetic control of body weight was also altered significantly by controlling of the effects of the Apoa2 allele. The QTL mapping strategy by controlling of the effects of a major QTL facilitated the identification of additional QTLs.

Nicotinate-Curcumin Impedes Foam Cell Formation from THP-1 Cells through Restoring Autophagy Flux

PubMed Central

Gu, Hong-Feng; Li, Hai-Zhe; Tang, Ya-Ling; Tang, Xiao-Qing; Zheng, Xi-Long; Liao, Duan-Fang

2016-01-01

Our previous studies have indicated that a novel curcumin derivate nicotinate-curcumin (NC) has beneficial effects on the prevention of atherosclerosis, but the precise mechanisms are not fully understood. Given that autophagy regulates lipid metabolism, the present study was designed to investigate whether NC decreases foam cell formation through restoring autophagy flux in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 cells. Our results showed that ox-LDL (100 μg/ml) was accumulated in THP-1 cells and impaired autophagy flux. Ox-LDL-induced impairment of autophagy was enhanced by treatment with the autophagy inhibitor chloroquine (CQ) and rescued by the autophagy inducer rapamycin. The aggregation of ox-LDL was increased by CQ, but decreased by rapamycin. In addition, colocalization of lipid droplets with LC3-II was remarkably reduced in ox-LDL group. In contrast, NC (10 μM) rescued the impaired autophagy flux by significantly increasing level of LC3-II, the number of autophagolysosomes, and the degradation of p62 in ox-LDL-treated THP-1 cells. Inhibition of the PI3K-Akt-mTOR signaling was required for NC-rescued autophagy flux. Notably, our results showed that NC remarkably promoted the colocalization of lipid droplets with autophagolysosomes, increased efflux of cholesterol, and reduced ox-LDL accumulation in THP-1 cells. However, treatment with 3-methyladenine (3-MA) or CQ reduced the protective effects of NC on lipid accumulation. Collectively, the findings suggest that NC decreases lipid accumulation in THP-1 cells through restoring autophagy flux, and further implicate that NC may be a potential therapeutic reagent to reverse atherosclerosis. PMID:27128486

A comparative study of novel spectrophotometric resolution techniques applied for pharmaceutical mixtures with partially or severely overlapped spectra

NASA Astrophysics Data System (ADS)

Lotfy, Hayam M.; Tawakkol, Shereen M.; Fahmy, Nesma M.; Shehata, Mostafa A.

2015-02-01

Simultaneous determination of mixtures of lidocaine hydrochloride (LH), flucortolone pivalate (FCP), in presence of chlorquinaldol (CQ) without prior separation steps was applied using either successive or progressive resolution techniques. According to the concentration of CQ the extent of overlapping changed so it can be eliminated from the mixture to get the binary mixture of LH and FCP using ratio subtraction method for partially overlapped spectra or constant value via amplitude difference followed by ratio subtraction or constant center followed by spectrum subtraction spectrum subtraction for severely overlapped spectra. Successive ratio subtraction was coupled with extended ratio subtraction, constant multiplication, derivative subtraction coupled constant multiplication, and spectrum subtraction can be applied for the analysis of partially overlapped spectra. On the other hand severely overlapped spectra can be analyzed by constant center and the novel methods namely differential dual wavelength (D1 DWL) for CQ, ratio difference and differential derivative ratio (D1 DR) for FCP, while LH was determined by applying constant value via amplitude difference followed by successive ratio subtraction, and successive derivative subtraction. The spectra of the cited drugs can be resolved and their concentrations are determined progressively from the same ratio spectrum using amplitude modulation method. The specificity of the developed methods was investigated by analyzing laboratory prepared mixtures and were successfully applied for the analysis of pharmaceutical formulations containing the cited drugs with no interference from additives. The proposed methods were validated according to the ICH guidelines. The obtained results were statistically compared with those of the official or reported methods; using student t-test, F-test, and one way ANOVA, showing no significant difference with respect to accuracy and precision.

The chemotherapeutic potential of PEG-b-PLGA copolymer micelles that combine chloroquine as autophagy inhibitor and docetaxel as an anti-cancer drug.

PubMed

Zhang, Xudong; Zeng, Xiaowei; Liang, Xin; Yang, Ying; Li, Xiaoming; Chen, Hongbo; Huang, Laiqiang; Mei, Lin; Feng, Si-Shen

2014-11-01

Micelles may be the nanocarrier that is used most often in the area of nanomedicine due to its promising performance and technical simplicity. However, like the original drugs, micellar formulation may arouse intracellular autophagy that deteriorates their advantages for efficient drug delivery. There has been no report in the literature that involves the fate of micelles after successfully internalized into the cancer cells. In this study, we show by using docetaxel-loaded PEG-b-PLGA micelles as a micellar model that the micelles do arouse intracellular autophagy and are thus subject to degradation through the endo-lysosome pathway. Moreover, we show that co-administration of the micellar formulation with autophagy inhibitor such as chloroquine (CQ) could significantly enhance their therapeutic effects. The docetaxel-loaded PEG-b-PLGA micelles are formulated by the membrane dialysis method, which are of 7.1% drug loading and 72.8% drug encapsulation efficiency in a size range of around 40 nm with narrow size distribution. Autophagy degradation and inhibition are investigated by confocal laser scanning microscopy with various biological makers. We show that the IC50 values of the drug formulated in the PEG-b-PLGA micelles after 24 h treatment MCF-7 cancer cells with no autophagy inhibitor or in combination with CQ were 22.30 ± 1.32 and 1.75 ± 0.43 μg/mL respectively, which indicated a 12-fold more efficient treatment with CQ. The in vivo investigation further confirmed the advantages of such a strategy. The findings may provide advanced knowledge for development of nanomedicine for clinical application. Copyright © 2014 Elsevier Ltd. All rights reserved.

NEWS Climatology Project: The State of the Water Cycle at Continental to Global Scales

NASA Technical Reports Server (NTRS)

Rodell, Matthew; LEcuyer, Tristan; Beaudoing, Hiroko Kato; Olson, Bill

2011-01-01

NASA's Energy and Water Cycle Study (NEWS) program fosters collaborative research towards improved quantification and prediction of water and energy cycle consequences of climate change. In order to measure change, it is first necessary to describe current conditions. The goal of the NEWS Water and Energy Cycle Climatology project is to develop "state of the global water cycle" and "state of the global energy cycle" assessments based on data from modern ground and space based observing systems and data integrating models. The project is a multiinstitutional collaboration with more than 20 active contributors. This presentation will describe results of the first stage of the water budget analysis, whose goal was to characterize the current state of the water cycle on mean monthly, continental scales. We examine our success in closing the water budget within the expected uncertainty range and the effects of forcing budget closure as a method for refining individual flux estimates.

Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives.

PubMed

Shiraki, Hiroaki; Kozar, Michael P; Melendez, Victor; Hudson, Thomas H; Ohrt, Colin; Magill, Alan J; Lin, Ai J

2011-01-13

In an attempt to separate the antimalarial activity of tafenoquine (3) from its hemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients, a series of 5-aryl-8-aminoquinoline derivatives was prepared and assessed for antimalarial activities. The new compounds were found metabolically stable in human and mouse microsomal preparations, with t(1/2) > 60 min, and were equal to or more potent than primaquine (2) and 3 against Plasmodium falciparum cell growth. The new agents were more active against the chloroquine (CQ) resistant clone than to the CQ-sensitive clone. Analogues with electron donating groups showed better activity than those with electron withdrawing substituents. Compounds 4bc, 4bd, and 4be showed comparable therapeutic index (TI) to that of 2 and 3, with TI ranging from 5 to 8 based on IC(50) data. The new compounds showed no significant causal prophylactic activity in mice infected with Plasmodium berghei sporozoites, but are substantially less toxic than 2 and 3 in mouse tests.

Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds

PubMed Central

Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois

2016-01-01

Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria. PMID:26953199

Reversibility in Quantum Models of Stochastic Processes

NASA Astrophysics Data System (ADS)

Gier, David; Crutchfield, James; Mahoney, John; James, Ryan

Natural phenomena such as time series of neural firing, orientation of layers in crystal stacking and successive measurements in spin-systems are inherently probabilistic. The provably minimal classical models of such stochastic processes are ɛ-machines, which consist of internal states, transition probabilities between states and output values. The topological properties of the ɛ-machine for a given process characterize the structure, memory and patterns of that process. However ɛ-machines are often not ideal because their statistical complexity (Cμ) is demonstrably greater than the excess entropy (E) of the processes they represent. Quantum models (q-machines) of the same processes can do better in that their statistical complexity (Cq) obeys the relation Cμ >= Cq >= E. q-machines can be constructed to consider longer lengths of strings, resulting in greater compression. With code-words of sufficiently long length, the statistical complexity becomes time-symmetric - a feature apparently novel to this quantum representation. This result has ramifications for compression of classical information in quantum computing and quantum communication technology.

Towards more patient centred healthcare: A new Consumer Quality Index instrument to assess patients' experiences with breast care.

PubMed

Damman, Olga C; Hendriks, Michelle; Sixma, Herman J

2009-06-01

To develop a Consumer Quality Index (CQ-index) Breast Care instrument that measures quality of care from the perspective of patients with (suspicion of) breast cancer. To develop a pilot questionnaire, three focus group discussions with breast cancer patients were performed. The questionnaire was sent to 1197 patients. We performed psychometric and descriptive analyses to optimise the new instrument. Focus group discussions revealed nine main themes related to breast care quality. Psychometric analyses resulted in 15 reliable scales. The final instrument consisted of 152 items, of which 118 items regarded patients' experiences. The aspect with the highest need for quality improvement was informing patients about a second opinion. The CQ-index Breast Care (CQI-BC) instrument provides a good starting point for further research on the quality of breast care seen from the perspective of patients. The newly developed instrument can be used by different stakeholders for future quality monitoring.

Computer simulation of a cellular automata model for the immune response in a retrovirus system

NASA Astrophysics Data System (ADS)

Pandey, R. B.

1989-02-01

Immune response in a retrovirus system is modeled by a network of three binary cell elements to take into account some of the main functional features of T4 cells, T8 cells, and viruses. Two different intercell interactions are introduced, one of which leads to three fixed points while the other yields bistable fixed points oscillating between a healthy state and a sick state in a mean field treatment. Evolution of these cells is studied for quenched and annealed random interactions on a simple cubic lattice with a nearest neighbor interaction using inhomogenous cellular automata. Populations of T4 cells and viral cells oscillate together with damping (with constant amplitude) for annealed (quenched) interaction on increasing the value of mixing probability B from zero to a characteristic value B ca ( B cq). For higher B, the average number of T4 cells increases while that of the viral infected cells decreases monotonically on increasing B, suggesting a phase transition at B ca ( B cq).

17O NMR Investigation of Water Structure and Dynamics

PubMed Central

Keeler, Eric G.; Michaelis, Vladimir K.; Griffin, Robert G.

2017-01-01

The structure and dynamics of the bound water in barium chlorate monohydrate were studied with 17O nuclear magnetic resonance (NMR) spectroscopy in samples that are stationary and spinning at the magic-angle in magnetic fields ranging from 14.1 to 21.1 T. 17O NMR parameters of the water were determined, and the effects of torsional oscillations of the water molecule on the 17O quadrupolar coupling constant (CQ) were delineated with variable temperature MAS NMR. With decreasing temperature and reduction of the librational motion, we observe an increase in the experimentally measured CQ explaining the discrepancy between experiments and predictions from density functional theory. In addition, at low temperatures and in the absence of 1H decoupling, we observe a well-resolved 1H–17O dipole splitting in the spectra, which provides information on the structure of the H2O molecule. The splitting arises because of the homogeneous nature of the coupling between the two 1H–17O dipoles and the 1H–1H dipole. PMID:27454747

Oxidative Pentose Phosphate Pathway Inhibition Is A Key Determinant of Antimalarial Induced Cancer Cell Death

PubMed Central

Salas, Eduardo; Roy, Srirupa; Marsh, Timothy; Rubin, Brian; Debnath, Jayanta

2015-01-01

Despite immense interest in employing antimalarials as autophagy inhibitors to treat cancer, it remains unclear if these agents act predominantly via autophagy inhibition or whether other pathways direct their anti-cancer properties. By comparing the treatment effects of the antimalarials chloroquine (CQ) and quinacrine (Q) on KRAS mutant lung cancer cells, we demonstrate that inhibition of the oxidative arm of the pentose phosphate pathway (oxPPP) is required for antimalarial induced apoptosis. Despite inhibiting autophagy, neither CQ treatment nor RNAi against autophagy regulators (ATGs) promote cell death. In contrast, Q triggers high levels of apoptosis, both in vitro and in vivo, and this phenotype requires both autophagy inhibition and p53-dependent inhibition of the oxPPP. Simultaneous genetic targeting of the oxPPP and autophagy is sufficient to trigger apoptosis in lung cancer cells, including cells lacking p53. Thus, in addition to reduced autophagy, oxPPP inhibition serves as an important determinant of antimalarial cytotoxicity in cancer cells. PMID:26434592

A simple and fast method for extraction and quantification of cryptophyte phycoerythrin.

PubMed

Thoisen, Christina; Hansen, Benni Winding; Nielsen, Søren Laurentius

2017-01-01

The microalgal pigment phycoerythrin (PE) is of commercial interest as natural colorant in food and cosmetics, as well as fluoroprobes for laboratory analysis. Several methods for extraction and quantification of PE are available but they comprise typically various extraction buffers, repetitive freeze-thaw cycles and liquid nitrogen, making extraction procedures more complicated. A simple method for extraction of PE from cryptophytes is described using standard laboratory materials and equipment. The cryptophyte cells on the filters were disrupted at -80 °C and added phosphate buffer for extraction at 4 °C followed by absorbance measurement. The cryptophyte Rhodomonas salina was used as a model organism. •Simple method for extraction and quantification of phycoerythrin from cryptophytes.•Minimal usage of equipment and chemicals, and low labor costs.•Applicable for industrial and biological purposes.

Efficacy and safety of a combination of azithromycin and chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in two multi-country randomised clinical trials in African adults.

PubMed

Sagara, Issaka; Oduro, Abraham R; Mulenga, Modest; Dieng, Yemou; Ogutu, Bernhards; Tiono, Alfred B; Mugyenyi, Peter; Sie, Ali; Wasunna, Monique; Kain, Kevin C; Djimdé, Abdoulaye A; Sarkar, Shirsendu; Chandra, Richa; Robbins, Jeffery; Dunne, Michael W

2014-11-25

Given increasing rates of resistance to existing therapy, new options for treatment and prophylaxis of malaria are needed. Two randomised, comparative, non-inferiority studies were conducted in Africa, one double-blinded and one open-label. Adults with fever, a positive peripheral blood smear, and a positive rapid diagnostic test for Plasmodium falciparum were randomised in both studies to either azithromycin (AZ) 1,000 mg plus chloroquine (CQ) 600-mg base (AZCQ 1,000 mg) once daily for three days or mefloquine hydrochloride (MQ) 1,250 mg (split dose). In the first study, an additional regimen of AZ 500 mg plus CQ 600-mg base (AZCQ 500 mg) once daily for three days was included. All study participants were hospitalised until three consecutive daily blood smears were negative for asexual P. falciparum parasitaemia. Study participants were evaluated weekly for 42 days, with Day 28 polymerase chain reaction (PCR)-corrected parasitological clearance rate as primary endpoint. A total of 467 subjects were randomised in the two studies. At 28 days' follow-up, PCR-corrected parasitological clearance rates in the per protocol population in the first study were 101/103 (98%) with AZCQ 1,000 mg compared with 102/103 (99%) with MQ (95% confidence interval [CI]: -5.2, 3.3). The AZCQ 500-mg regimen was stopped during an interim study review (six [86%] clearance of seven evaluable; two lost to follow-up). In the second study, clearance rates were similar: AZCQ 1,000 mg 107/107 (100%) vs MQ 111/112 (99%; 95% CI: -1.8, 3.6). Among the participating countries, in vitro CQ resistance based on pfcrt mutation frequency in the baseline isolates across both studies ranged from 20.8% (Zambia) to 96.1% (Uganda). Serious adverse events (AEs; all causality) were observed more frequently with MQ compared with AZCQ (four vs one, respectively), though discontinuations for AEs were similar (four vs three, respectively). Common AEs in the AZ-containing arms included pruritus, vomiting, dizziness, and headache. Among adults with symptomatic uncomplicated falciparum malaria in Africa, the combination of AZ 1,000 mg and CQ 600-mg base once daily for three days resulted in Day 28 PCR-corrected parasitological clearance rates of ≥98% and was non-inferior to treatment with MQ. AZCQ was well tolerated. ClinicalTrials.gov identifiers NCT00082576 and NCT00367653.

Inhibition of autophagy stimulate molecular iodine-induced apoptosis in hormone independent breast tumors

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

Singh, Preeti; Godbole, Madan, E-mail: madangodbole@yahoo.co.in; Rao, Geeta

2011-11-11

Highlights: Black-Right-Pointing-Pointer Molecular iodine (I{sub 2}) causes non-apoptotic cell death in MDA-MB231 breast tumor cells. Black-Right-Pointing-Pointer Autophagy is activated as a survival mechanism in response to I{sub 2} in MDA-MB231. Black-Right-Pointing-Pointer Autophagy inhibition sensitizes tumor cells to I{sub 2}-induced apoptotic cell death. Black-Right-Pointing-Pointer Autophagy inhibitor potentiates apoptosis and tumor regressive effects of I{sub 2} in mice. -- Abstract: Estrogen receptor negative (ER{sup -ve}) and p53 mutant breast tumors are highly aggressive and have fewer treatment options. Previously, we showed that molecular Iodine (I{sub 2}) induces apoptosis in hormone responsive MCF-7 breast cancer cells, and non-apoptotic cell death in ER{sup -ve}-p53more » mutant MDA-MB231 cells (Shrivastava, 2006). Here we show that I{sub 2} (3 {mu}M) treatment enhanced the features of autophagy in MDA-MB231 cells. Since autophagy is a cell survival response to most anti-cancer therapies, we used both in vitro and in vivo systems to determine whether ER{sup -ve} mammary tumors could be sensitized to I{sub 2}-induced apoptosis by inhibiting autophagy. Autophagy inhibition with chloroquine (CQ) and inhibitors for PI3K (3MA, LY294002) and H+/ATPase (baflomycin) resulted in enhanced cell death in I{sub 2} treated MDA-MB231 cells. Further, CQ (20 {mu}M) in combination with I{sub 2}, showed apoptotic features such as increased sub-G1 fraction ({approx}5-fold), expression of cleaved caspase-9 and -3 compared to I{sub 2} treatment alone. Flowcytometry of I{sub 2} and CQ co-treated cells revealed increase in mitochondrial membrane permeability (p < 0.01) and translocation of cathepsin D activity to cytosol relative to I{sub 2} treatment. For in vivo studies ICRC mice were transplanted subcutaneously with MMTV-induced mammary tumors. A significant reduction in tumor volumes, as measured by MRI, was found in I{sub 2} and CQ co-treated mice relative to I{sub 2} or vehicle treated mice. These data indicate that inhibition of autophagy renders ER{sup -ve} breast tumor cells more sensitive to I{sub 2} induced apoptosis. Thus, I{sub 2} together with autophagy inhibitor could have a potential tumorostatic role in ER{sup -ve} aggressive breast tumors that may be evaluated in future studies.« less

Mathematics of quantitative kinetic PCR and the application of standard curves.

PubMed

Rutledge, R G; Côté, C

2003-08-15

Fluorescent monitoring of DNA amplification is the basis of real-time PCR, from which target DNA concentration can be determined from the fractional cycle at which a threshold amount of amplicon DNA is produced. Absolute quantification can be achieved using a standard curve constructed by amplifying known amounts of target DNA. In this study, the mathematics of quantitative PCR are examined in detail, from which several fundamental aspects of the threshold method and the application of standard curves are illustrated. The construction of five replicate standard curves for two pairs of nested primers was used to examine the reproducibility and degree of quantitative variation using SYBER Green I fluorescence. Based upon this analysis the application of a single, well- constructed standard curve could provide an estimated precision of +/-6-21%, depending on the number of cycles required to reach threshold. A simplified method for absolute quantification is also proposed, in which quantitative scale is determined by DNA mass at threshold.

Picoliter Well Array Chip-Based Digital Recombinase Polymerase Amplification for Absolute Quantification of Nucleic Acids.

PubMed

Li, Zhao; Liu, Yong; Wei, Qingquan; Liu, Yuanjie; Liu, Wenwen; Zhang, Xuelian; Yu, Yude

2016-01-01

Absolute, precise quantification methods expand the scope of nucleic acids research and have many practical applications. Digital polymerase chain reaction (dPCR) is a powerful method for nucleic acid detection and absolute quantification. However, it requires thermal cycling and accurate temperature control, which are difficult in resource-limited conditions. Accordingly, isothermal methods, such as recombinase polymerase amplification (RPA), are more attractive. We developed a picoliter well array (PWA) chip with 27,000 consistently sized picoliter reactions (314 pL) for isothermal DNA quantification using digital RPA (dRPA) at 39°C. Sample loading using a scraping liquid blade was simple, fast, and required small reagent volumes (i.e., <20 μL). Passivating the chip surface using a methoxy-PEG-silane agent effectively eliminated cross-contamination during dRPA. Our creative optical design enabled wide-field fluorescence imaging in situ and both end-point and real-time analyses of picoliter wells in a 6-cm(2) area. It was not necessary to use scan shooting and stitch serial small images together. Using this method, we quantified serial dilutions of a Listeria monocytogenes gDNA stock solution from 9 × 10(-1) to 4 × 10(-3) copies per well with an average error of less than 11% (N = 15). Overall dRPA-on-chip processing required less than 30 min, which was a 4-fold decrease compared to dPCR, requiring approximately 2 h. dRPA on the PWA chip provides a simple and highly sensitive method to quantify nucleic acids without thermal cycling or precise micropump/microvalve control. It has applications in fast field analysis and critical clinical diagnostics under resource-limited settings.

Picoliter Well Array Chip-Based Digital Recombinase Polymerase Amplification for Absolute Quantification of Nucleic Acids

PubMed Central

Li, Zhao; Liu, Yong; Wei, Qingquan; Liu, Yuanjie; Liu, Wenwen; Zhang, Xuelian; Yu, Yude

2016-01-01

Absolute, precise quantification methods expand the scope of nucleic acids research and have many practical applications. Digital polymerase chain reaction (dPCR) is a powerful method for nucleic acid detection and absolute quantification. However, it requires thermal cycling and accurate temperature control, which are difficult in resource-limited conditions. Accordingly, isothermal methods, such as recombinase polymerase amplification (RPA), are more attractive. We developed a picoliter well array (PWA) chip with 27,000 consistently sized picoliter reactions (314 pL) for isothermal DNA quantification using digital RPA (dRPA) at 39°C. Sample loading using a scraping liquid blade was simple, fast, and required small reagent volumes (i.e., <20 μL). Passivating the chip surface using a methoxy-PEG-silane agent effectively eliminated cross-contamination during dRPA. Our creative optical design enabled wide-field fluorescence imaging in situ and both end-point and real-time analyses of picoliter wells in a 6-cm2 area. It was not necessary to use scan shooting and stitch serial small images together. Using this method, we quantified serial dilutions of a Listeria monocytogenes gDNA stock solution from 9 × 10-1 to 4 × 10-3 copies per well with an average error of less than 11% (N = 15). Overall dRPA-on-chip processing required less than 30 min, which was a 4-fold decrease compared to dPCR, requiring approximately 2 h. dRPA on the PWA chip provides a simple and highly sensitive method to quantify nucleic acids without thermal cycling or precise micropump/microvalve control. It has applications in fast field analysis and critical clinical diagnostics under resource-limited settings. PMID:27074005

Multivariate Analysis for Quantification of Plutonium(IV) in Nitric Acid Based on Absorption Spectra

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

Lines, Amanda M.; Adami, Susan R.; Sinkov, Sergey I.

Development of more effective, reliable, and fast methods for monitoring process streams is a growing opportunity for analytical applications. Many fields can benefit from on-line monitoring, including the nuclear fuel cycle where improved methods for monitoring radioactive materials will facilitate maintenance of proper safeguards and ensure safe and efficient processing of materials. On-line process monitoring with a focus on optical spectroscopy can provide a fast, non-destructive method for monitoring chemical species. However, identification and quantification of species can be hindered by the complexity of the solutions if bands overlap or show condition-dependent spectral features. Plutonium (IV) is one example ofmore » a species which displays significant spectral variation with changing nitric acid concentration. Single variate analysis (i.e. Beer’s Law) is difficult to apply to the quantification of Pu(IV) unless the nitric acid concentration is known and separate calibration curves have been made for all possible acid strengths. Multivariate, or chemometric, analysis is an approach that allows for the accurate quantification of Pu(IV) without a priori knowledge of nitric acid concentration.« less

75 FR 57309 - Consolidated Tape Association; Notice of Filing and Immediate Effectiveness of the Sixteenth...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-20

... to the Restated Consolidated Quotation Plan September 14, 2010. Pursuant to Section 11A of the... August 27, 2010, the Consolidated Tape Association (``CTA'') Plan and Consolidated Quotation (``CQ... Plan, pursuant to which markets collect and disseminate bid/ask quotation information for listed...

Cultural Intelligence: An Examination of Predictive Relationships in a Study Abroad Population

ERIC Educational Resources Information Center

Banning, Bryan James

2010-01-01

This quantitative study examined the relationships between cultural intelligence (CQ) and four predictor variables: gender, degree level, major, and prior travel abroad, through a post-test only research design. Participants included undergraduate and graduate students enrolled in one of three large, public, research universities in the southeast…

Developing Students' Cultural Intelligence through an Experiential Learning Activity: A Cross-Cultural Consumer Behavior Interview

ERIC Educational Resources Information Center

Kurpis, Lada Helen; Hunter, James

2017-01-01

Business schools can increase their competitiveness by offering students intercultural skills development opportunities integrated into the traditional curricula. This article makes a contribution by proposing an approach to developing students' cultural intelligence that is based on the cultural intelligence (CQ) model, experiential learning…

Concealed Questions. In Search of Answers

ERIC Educational Resources Information Center

Frana, Ilaria

2010-01-01

This dissertation examines the semantic interpretation of various types of DPs in so-called concealed-question (CQ) constructions, as "Bill's phone number" in the sentence "John knows Bill's phone number". The peculiar characteristic of DP-CQs is that they are interpreted as having the meaning of an embedded question. So, for instance, the…

Literature Survey on Decorporation of Radionuclides from the Human Body

DTIC Science & Technology

2002-04-01

66 8. Adverse Health Effects Associated with... effects ........................................... 66 Table 11- Common foods with chelating effects ...Mn Tetracycline Fe, MR, Mn, Mo, Al, Ca Table 11- Common foods with chelating effects Foodstuff Chelate Cq hhPe 1314 99 M. 75’s Eggs 59Fe Soybean 65Zn

Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype.

PubMed

DeBrosse, Suzanne D; Okajima, Kazuki; Zhang, Shulin; Nakouzi, Ghunwa; Schmotzer, Christine L; Lusk-Kopp, Marilyn; Frohnapfel, Mary Beth; Grahame, George; Kerr, Douglas S

2012-11-01

Pyruvate dehydrogenase complex (PDC) deficiency is a relatively common mitochondrial disorder that primarily presents with neurological manifestations and lactic acidemia. We analyzed the clinical outcomes and neurological features of 59 consented symptomatic subjects (27 M, 32 F), who were confirmed to have PDC deficiency with defined mutations in one of the genes of PDC (PDHA1, n = 53; PDHB, n = 4; DLAT, n = 2), including 47 different mutations, of which 22 were novel, and for whom clinical records and/or structured interviews were obtained. 39% of these subjects (23/59) have died. Of these, 91% (21/23) died before age 4 years, 61% (14/23) before 1 year, and 43% (10/23) before 3 months. 56% of males died compared with 25% of females. Causes of death included severe lactic acidosis, respiratory failure, and infection. In subjects surviving past 6 months, a broad range of intellectual outcomes was observed. Of 42 subjects whose intellectual abilities were professionally evaluated, 19% had normal or borderline intellectual ability (CQ/IQ ≥ 70), 10% had mild intellectual disability (ID) (CQ/IQ 55-69), 17% had moderate ID (CQ/IQ 40-54), 24% had severe ID (CQ/IQ 25-39) and 33% had profound ID (CQ/IQ<25). Assessment by parents was comparable. Of 10 subjects who reached age 12 years, 9 had had professional IQ assessments, and only 4 had IQs ≥ 70 (only 2 of these 4 had assessments after age 12 years). The average outcome for females was severe-to-profound ID, whereas that of males was mild-to-moderate ID. Of subjects for whom specific neurological data were available, the majority had hypotonia (89%), and hypertonia or mixed hyper-/hypotonia (49%) were common. Seizures (57%), microcephaly (49%), and structural brain abnormalities including ventriculomegaly (67%) and agenesis, dysgenesis, or hypoplasia of the corpus callosum (55%) were common. Leigh syndrome was found in only 35%. Structural brain abnormalities were more common in females, and Leigh syndrome was more common in males. In a subgroup of 16 ambulatory subjects >3.5 years in whom balance was evaluated, ataxia was found in 13. Peripheral neuropathy was documented in 2 cases but not objectively evaluated in most subjects. Outcomes of this population with genetically confirmed PDC deficiency are heterogeneous and not distinctive. Correlations between specific genotypes and outcomes were not established. Although more females survive, related to the prevalence of X-linked PDHA1 mutations, symptomatic surviving females are generally more severely impaired cognitively and have a different pattern of neurological impairment compared to males. Neonatal or infant onset of symptoms was associated with poor outcomes. Males with PDHA1 mutations and low fibroblast PDC activity were less likely to survive beyond infancy. Recurrence rate in siblings of subjects with PDHA1 mutation was less than 5%. Paradoxically, in this retrospective review, potential factors considered possibly relevant to development, such as in vitro PDC activity, specific mutations, use of ketogenic diets, supplements, or medications, were generally not confirmed to be significantly correlated with objective outcomes of survival or neuro-cognitive function. Therefore, the basis of variability of these outcomes remains largely undetermined. Copyright © 2012 Elsevier Inc. All rights reserved.

Efficient load rating and quantification of life-cycle damage of Indiana bridges due to overweight loads.

DOT National Transportation Integrated Search

2016-02-01

In this study, a computational approach for conducting durability analysis of bridges using detailed finite element models is developed. The underlying approach adopted is based on the hypothesis that the two main factors affecting the life of a brid...

75 FR 67410 - Consolidated Tape Association; Notice of Filing and Immediate Effectiveness of the Seventeenth...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-02

... Amendment to the Restated Consolidated Quotation Plan October 27, 2010. Pursuant to Section 11A of the... October 19, 2010, the Consolidated Tape Association (``CTA'') Plan and Consolidated Quotation (``CQ... markets collect and disseminate bid/ask quotation information for listed securities, is also a ``national...

How Are Kentucky's Children Stacking Up? A County by County Analysis.

ERIC Educational Resources Information Center

Chandler, Betsy

In a county by county analysis, this report assesses the quality of life for Kentucky's children. Researchers developed a child quotient (CQ) based on 18 indicators: per capita income, children in poverty, women receiving inadequate prenatal care, infant deaths, teens giving birth, substandard dwellings, children in foster care, per-pupil…

Development of a Stages of Concern Questionnaire for Preservice Teachers.

ERIC Educational Resources Information Center

O'Sullivan, Kathleen A.; Zielinski, Edward J.

The Stages of Concerns Questionnaire (SoCQ) is an established instrument which has been used primarily with inservice teachers involved in innovations. While it focuses on inservice teachers' concerns about an innovation, the instrument is based on theoretical constructs developed by the work of Frances Fuller and others during the 1960s with…

The Status of Infantry TOW, LAW, and Dragon Training in USAREUR.

DTIC Science & Technology

1977-11-01

TOW duties (guard, CQ runner , etc.); (b) Permanent assignment to other than TOW duties; (c) medical and dental appointments and drug and alcohol abuse...in training areas would be most helpful, and a third said American tanks and ve- hicles could be mocked-up to look like enemy targets and that kites

Would an Influenza Pandemic Qualify as a Major Disaster Under the Stafford Act?

DTIC Science & Technology

2009-12-15

Officials Say Swine Flu Vaccine is Coming, CQ HOMELAND SECURITY, July 9, 2009 (quoting DHS Secretary Janet Napolitano as observing that “the [Stafford...not ready for avian flu outbreak, KANSAS CITY STAR, Dec. 13, 2005, at 1; Sabin Russell, Statewide flu plan ready for public input, SAN FRANCISCO

The Bring Your Own Technology Initiative: An Examination of Teachers' Adoption

ERIC Educational Resources Information Center

Cardoza, Yanet; Tunks, Jeanne

2014-01-01

This case study explored teachers' concerns, use, and actual practices in their adoption of the Bring Your Own Technology (BYOT) initiative. Participants were 12 secondary teachers in a private school setting. The Concerns-Based Adoption Model tools provided data: Stages of Concern Questionnaire (SoCQ), Levels of Use interview, and the Innovation…

75 FR 35627 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-23

... Diego Montgomery Field.... 0/4634 6/9/10 TAKEOFF MINIMUMS AND OBSTACLE DP, AMDT 3. 29-Jul-10 CQ Saipan Francisco C. Ada/ 0/9757 3/16/10 ILS OR LOC/DME RWY 7, AMDT 5A. Saipan Intl. [FR Doc. 2010-14980 Filed 6-22...

Previous International Experience, Cross-Cultural Training, and Expatriates' Cross-Cultural Adjustment: Effects of Cultural Intelligence and Goal Orientation

ERIC Educational Resources Information Center

Koo Moon, Hyoung; Kwon Choi, Byoung; Shik Jung, Jae

2012-01-01

Although various antecedents of expatriates' cross-cultural adjustment have been addressed, previous international experience, predeparture cross-cultural training, and cultural intelligence (CQ) have been most frequently examined. However, there are few attempts that explore the effects of these antecedents simultaneously or consider the possible…

The Impact of Motivational and Metacognitive Cultural Intelligence on the Study Abroad Experience

ERIC Educational Resources Information Center

Racicot, Bernadette M.; Ferry, Diane L.

2016-01-01

The current study used a time-lagged design to examine the effects of Metacognitive and Motivational Cultural Intelligence (CQ) prior to studying abroad on the experiential behavior of students during their study abroad trip and their future interest in work and study abroad opportunities. Using Hayes' conditional process analysis, results…

The effect of coenzyme Q10 in statin myopathy.

PubMed

Zlatohlavek, Lukas; Vrablik, Michal; Grauova, Barbora; Motykova, Eva; Ceska, Richard

2012-01-01

Statins significantly reduce CV morbidity and mortality. Unfortunately, one of the side effects of statins is myopathy, for which statins cannot be administered in sufficient doses or administered at all. The aim of this study was to demonstrate the effect of coenzyme Q10 in patients with statin myopathy. Twenty eight patients aged 60.6±10.7 years were monitored (18 women and 10 men) and treated with different types and doses of statin. Muscle weakness and pain was monitored using a scale of one to ten, on which patients expressed the degree of their inconvenience. Examination of muscle problems was performed prior to administration of CQ10 and after 3 and 6 months of dosing. Statistical analysis was performed using Friedman test, Annova and Students t-test. Pain decreased on average by 53.8% (p<0.0001), muscle weakness by 44.4% (p<0.0001). The CQ10 levels were increased by more than 194% (from 0,903 μg/ml to 2.66 μg/ml; p<0.0001). After a six-month administration of coenzyme Q10, muscle pain and sensitivity statistically significantly decreased.

Adaptations of the Saker-Solomons test: simple, reliable colorimetric field assays for chloroquine and its metabolites in urine.

PubMed

Mount, D L; Nahlen, B L; Patchen, L C; Churchill, F C

1989-01-01

Two field-adapted colorimetric methods for measuring the antimalarial drug chloroquine in urine are described. Both are modifications of the method of Saker and Solomons for screening urine for phencyclidine and other drugs of abuse, using the colour reagent tetrabromophenolphthalein ethyl ester. One method is semiquantitative, detecting the presence of chloroquine (Cq) and its metabolites in urine with a 1 microgram/ml detection limit; it is more sensitive and reliable than the commonly used Dill-Glazko method and is as easy to apply in the field. The second method uses a hand-held, battery-operated filter photometer to quantify Cq and its metabolites with a 2 microgram/ml detection limit and a linear range up to 8 micrograms/ml. The first method was validated in the field using a published quantitative colorimetric method and samples from a malaria study in Nigeria. The second method was validated in the laboratory against high-performance liquid chromatographic results on paired samples from the Nigerian study. Both methods may be used in remote locations where malaria is endemic and no electricity is available.

Computer simulation of a cellular automata model for the immune response in a retrovirus system

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

Pandey, R.B.

1989-02-01

Immune response in a retrovirus system is modeled by a network of three binary cell elements to take into account some of the main functional features of T4 cells, T8 cells, and viruses. Two different intercell interactions are introduced, one of which leads to three fixed points while the other yields bistable fixed points oscillating between a healthy state and a sick state in a mean field treatment. Evolution of these cells is studied for quenched and annealed random interactions on a simple cubic lattice with a nearest neighbor interaction using inhomogenous cellular automata. Populations of T4 cells and viralmore » cells oscillate together with damping (with constant amplitude) for annealed (quenched) interaction on increasing the value of mixing probability B from zero to a characteristic value B/sub ca/ (B/sub cq/). For higher B, the average number of T4 cells increases while that of the viral infected cells decreases monotonically on increasing B, suggesting a phase transition at B/sub ca/ (B/sub cq/).« less

Lysosomal regulation of cholesterol homeostasis in tuberous sclerosis complex is mediated via NPC1 and LDL-R.

PubMed

Filippakis, Harilaos; Alesi, Nicola; Ogorek, Barbara; Nijmeh, Julie; Khabibullin, Damir; Gutierrez, Catherine; Valvezan, Alexander J; Cunningham, James; Priolo, Carmen; Henske, Elizabeth P

2017-06-13

Tuberous sclerosis complex (TSC) is a multisystem disease associated with hyperactive mTORC1. The impact of TSC1/2 deficiency on lysosome-mediated processes is not fully understood. We report here that inhibition of lysosomal function using chloroquine (CQ) upregulates cholesterol homeostasis genes in TSC2-deficient cells. This TSC2-dependent transcriptional signature is associated with increased accumulation and intracellular levels of both total cholesterol and cholesterol esters. Unexpectedly, engaging this CQ-induced cholesterol uptake pathway together with inhibition of de novo cholesterol synthesis allows survival of TSC2-deficient, but not TSC2-expressing cells. The underlying mechanism of TSC2-deficient cell survival is dependent on exogenous cholesterol uptake via LDL-R, and endosomal trafficking mediated by Vps34. Simultaneous inhibition of lysosomal and endosomal trafficking inhibits uptake of esterified cholesterol and cell growth in TSC2-deficient, but not TSC2-expressing cells, highlighting the TSC-dependent lysosome-mediated regulation of cholesterol homeostasis and pointing toward the translational potential of these pathways for the therapy of TSC.

A rapid real-time PCR method to differentiate between mottled skate (Beringraja pulchra) and other skate and ray species.

PubMed

Kim, Mi-Ra; Kwon, Kisung; Jung, Yoo-Kyung; Kang, Tae Sun

2018-07-30

Skates and rays are commercially important fish in South Korea, and among them, Beringraja pulchra has the highest economic value. However, the similar morphological traits among skates and rays are often exploited for seafood fraud. Here, we designed both Beringraja pulchra-specific and skate-universal primer sets, capable of detecting short sequences in the cytochrome oxidase subunit I gene, and developed highly sensitive and reliable quantitative real-time PCR (qPCR) assays to differentiate between Beringraja pulchra and other skate and ray species. AΔCq method based on differences in the amplification efficiency was developed, validated, and then used to confirm the presence of Beringraja pulchra in twenty-six commercial skate products. The averageΔCq value obtained for other skate species (18.94 ± 3.46) was significantly higher than that of Beringraja pulchra (1.18 ± 0.15). For on-site applications, we developed an ultra-fast qPCR assay, allowing for completion of the entire analytical procedure within 30 min. Copyright © 2018 Elsevier Ltd. All rights reserved.

Synthesis, in vitro antimalarial activities and cytotoxicities of amino-artemisinin-ferrocene derivatives.

PubMed

de Lange, Christo; Coertzen, Dina; Smit, Frans J; Wentzel, Johannes F; Wong, Ho Ning; Birkholtz, Lyn-Marie; Haynes, Richard K; N'Da, David D

2017-12-26

Novel derivatives bearing a ferrocene attached via a piperazine linker to C-10 of the artemisinin nucleus were prepared from dihydroartemisinin and screened against chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf) parasites. The overall aim is to imprint oxidant (from the artemisinin) and redox (from the ferrocene) activities. In a preliminary assessment, these compounds were shown to possess activities in the low nM range with the most active being compound 6 with IC 50 values of 2.79 nM against Pf K1 and 3.2 nM against Pf W2. Overall the resistance indices indicate that the compounds have a low potential for cross resistance. Cytotoxicities were determined with Hek293 human embryonic kidney cells and activities against proliferating cells were assessed against A375 human malignant melanoma cells. The selectivity indices of the amino-artemisinin ferrocene derivatives indicate there is overall an appreciably higher selectivity towards the malaria parasite than mammalian cells. Copyright © 2017. Published by Elsevier Ltd.

Optimization of Diamond Nucleic Acid Dye for quantitative PCR.

PubMed

Haines, Alicia M; Tobe, Shanan S; Linacre, Adrian

2016-10-01

Here, we evaluate Diamond Nucleic Acid Dye (DD) for use in quantitative PCR (qPCR) applications. Although DD is a commercially available stain for detection of DNA separated by gel electrophoresis, its use as a detection dye in qPCR has yet to be described. To determine if DD can be used in qPCR, we investigated its inhibitory effects on qPCR at concentrations ranging 0.1-2.5×. Serial dilution of DNA was used to determine the efficiency, sensitivity, and linearity of DD-generated qPCR data in comparison to other commonly used fluorescent dyes such as SYBR Green (SG), EvaGreen (EG), and BRYT Green (BG). DD was found to be comparable with other dyes for qPCR applications, with an R2 value >0.9 and an efficiency of 0.83. Mitochondrial DNA (mtDNA) target signals were successfully produced by DD over a DNA dilution range of ~28 ng- 0.28 pg, demonstrating comparable sensitivity to the other dyes investigated. Cq values obtained using DD were lower than those using EG by almost 7 cycles. We conclude that Diamond Nucleic Acid Dye is a cheaper, less toxic alternative for qPCR applications.

Assessment of pfcrt 72-76 haplotypes eight years after chloroquine withdrawal in Kinshasa, Democratic Republic of Congo.

PubMed

Mvumbi, Dieudonné Makaba; Boreux, Raphael; Sacheli, Rosalie; Lelo, Mvumbi; Lengu, Bobanga; Nani-Tuma, Situakibanza; Melin, Pierrette; Ntumba, Kayembe; Lunganza, Kalala; DeMol, Patrick; Hayette, Marie-Pierre

2013-12-20

In 2001, the World Health Organization (WHO) has recommended the use of artemisinin-based combination therapy (ACT) as the first-line treatment of uncomplicated malaria cases, as monotherapies had become ineffective in many parts of the world. As a result, the Democratic Republic of Congo (DRC) withdrew chloroquine (CQ) from its malaria treatment policy in 2002 and an artesunate (AS)-amodiaquine (AQ) combination became the ACT of choice in DRC in 2005. AQ-resistance (AQR) has been reported in several parts of the world and mutations in codons 72-76 of the Plasmodium falciparum chloroquine-resistance transporter (pfcrt) gene have been strongly correlated with resistance, especially mutations encoding the SVMNT haplotype. This haplotype was first identified in Southeast Asia and South America but was recently reported in two African countries neighbouring DRC. These facts raised two questions: the first about the evolution of CQ resistance (CQR) in DRC and the second about the presence of the SVMNT haplotype, which would compromise the use of AQ as a partner drug for ACT. A total of 213 thick blood films were randomly collected in 2010 from a paediatric clinic in Kinshasa, DRC. Microscopy controls and real-time polymerase chain reaction (RT-PCR) were performed for Plasmodium species identification. Haplotypes of the pfcrt gene were determined by sequencing. The K76T mutation was detected in 145 out of 198 P. falciparum-positive samples (73.2%). In these 145 resistant strains, only the CVIET haplotype was detected. This study is the first to assess the molecular markers of resistance to CQ and AQ after the introduction of ACT in DRC. The results suggest first that CQR is decreasing, as wild-type pfcrt haplotypes were found in only 26.8% of the samples and secondly that the SVMNT haplotype is not yet present in Kinshasa, suggesting that AQ remains valid as a partner drug for ACT in this region.

Chloroquine efficacy for Plasmodium vivax in Myanmar in populations with high genetic diversity and moderate parasite gene flow.

PubMed

Htun, Myo Win; Mon, Nan Cho Nwe; Aye, Khin Myo; Hlaing, Chan Myae; Kyaw, Myat Phone; Handayuni, Irene; Trimarsanto, Hidayat; Bustos, Dorina; Ringwald, Pascal; Price, Ric N; Auburn, Sarah; Thriemer, Kamala

2017-07-10

Plasmodium vivax malaria remains a major public health burden in Myanmar. Resistance to chloroquine (CQ), the first-line treatment for P. vivax, has been reported in the country and has potential to undermine local control efforts. Patients over 6 years of age with uncomplicated P. vivax mono-infection were enrolled into clinical efficacy studies in Myawaddy in 2014 and Kawthoung in 2012. Study participants received a standard dose of CQ (25 mg/kg over 3 days) followed by weekly review until day 28. Pvmdr1 copy number (CN) and microsatellite diversity were assessed on samples from the patients enrolled in the clinical study and additional cross-sectional surveys undertaken in Myawaddy and Shwegyin in 2012. A total of 85 patients were enrolled in the CQ clinical studies, 25 in Myawaddy and 60 in Kawthoung. One patient in Myawaddy (1.2%) had an early treatment failure and two patients (2.3%) in Kawthoung presented with late treatment failures on day 28. The day 28 efficacy was 92.0% (95% CI 71.6-97.9) in Myawaddy and 98.3% (95% CI 88.7-99.8) in Kawthoung. By day 2, 92.2% (23/25) in Myawaddy and 85.0% (51/60) in Kawthoung were aparasitaemic. Genotyping and pvmdr1 CN assessment was undertaken on 43, 52 and 46 clinical isolates from Myawaddy, Kawthoung and Shwegyin respectively. Pvmdr1 amplification was observed in 3.2% (1/31) of isolates in Myawaddy, 0% (0/49) in Kawthoung and 2.5% (1/40) in Shwegyin. Diversity was high in all sites (H E 0.855-0.876), with low inter-population differentiation (F ST 0.016-0.026, P < 0.05). Treatment failures after chloroquine were observed following chloroquine monotherapy, with pvmdr1 amplification present in both Myawaddy and Shwegyin. The results emphasize the importance of ongoing P. vivax drug resistance surveillance in Myanmar, particularly given the potential connectivity between parasite population at different sites.

Concentration-Discharge Behavior of Contaminants in a Stream Impacted by Acid Mine Drainage

NASA Astrophysics Data System (ADS)

Shaw, M. E.; Klein, M.; Herndon, E.

2017-12-01

Acid mine drainage (AMD) has severely degraded streams throughout the Appalachian coal region of the United States. AMD occurs when pyrite contained in coal is exposed to water and air during mining activities and oxidized to release high concentrations of sulfate, metals, and acidity into water bodies. Little is known about the concentration-discharge (CQ) relationships of solutes in AMD-impacted streams due to the complicated nature of acid mine drainage systems. For example, streams may receive inputs from multiple sources that include runoff, constructed treatment systems, and abandoned mines that bypass these systems to continue to contaminate the streams. It is important to understand the CQ relationships of contaminants in AMD-impacted streams in order to elucidate contaminant sources and to predict effects on aquatic ecosystems. Here, we study the CQ behaviors of acid and metals in a contaminated watershed in northeastern Ohio where limestone channels have been installed to remediate water draining from a mine pool into the stream. Stream chemistry was measured in samples collected once per day or once per hour during storm events, and stream flow was measured continuously at the watershed outlet. Increases in stream velocity during storm events resulted in an increase in pH (from 3 to 6) that subsequently decreased back to 3 as flow decreased. Additionally, Fe and Mn concentrations in the stream were high during baseflow (7 and 15 mg/L, respectively) and decreased with increasing discharge during storm events. These results indicate that the treatment system is only effective at neutralizing stream acidity and removing metals when water flow through the limestone channel is continuous. We infer that the acidic and metal-rich baseflow derives from upwelling of contaminated groundwater or subsurface flow from a mine pool. Ongoing studies aim to isolate the source of this baseflow contamination and evaluate the geochemical transformations that occur as it flows into the stream.

Promoter hypermethylation of the RECK gene is associated with its low expression and poor survival of esophageal squamous cell carcinoma

PubMed Central

Zhu, Jing; Ling, Yang; Xu, Yun; Lu, Mingzhu; Liu, Yongping; Zhang, Changsong

2017-01-01

The present study aimed to investigate the association between the methylation status of the reversion-inducing cysteine-rich protein with kazal motifs (RECK) gene and its mRNA expression levels in patients with esophageal squamous cell carcinoma (ESCC). The methylation status of RECK was analyzed by methylation-specific polymerase chain reaction (PCR), and RECK mRNA expression levels were analyzed by quantitative PCR, in 310 paired ESCC tissues. The mean RECK methylation index (MI) was 0.65 in ESCCs and 0.49 in non-tumor samples. There was a significant association between RECK methylation and the American Joint Committee on Cancer stage and lymph node metastasis in ESCC (P<0.0001; P=0.001). The mRNA expression level of RECK was lower in ESCC tissues (mean-∆Cq=−4.66) compared with non-tumor tissues (mean-∆Cq=−2.79), and decreased RECK mRNA expression levels were associated with lymph node metastasis in ESCC. In addition, RECK mRNA levels were decreased in ESCC patients with hypermethylation of the RECK gene (∆MI >0.16; mean-∆∆Cq=−2.85) compared with those with hypomethylation of the RECK gene (∆MI ≤0.16; mean-∆∆Ct=−0.83), and there was a significant difference in the mRNA expression levels of RECK between those with N0–1 and N2–3 lymph node metastasis (P<0.0001). A significant correlation was observed between RECK mRNA expression levels, the MI of RECK and poor postoperative survival (P=0.0003; P<0.0001). The results of the present study suggested that promoter hypermethylation may be an important factor for loss of RECK mRNA expression and may be an indicator of poor survival in ESCC. PMID:28454343

Ecological Distribution and CQ11 Genetic Structure of Culex pipiens Complex (Diptera: Culicidae) in Italy.

PubMed

Di Luca, Marco; Toma, Luciano; Boccolini, Daniela; Severini, Francesco; La Rosa, Giuseppe; Minelli, Giada; Bongiorno, Gioia; Montarsi, Fabrizio; Arnoldi, Daniele; Capelli, Gioia; Rizzoli, Annapaola; Romi, Roberto

2016-01-01

Mosquitoes in the Culex pipiens complex are considered to be involved in the transmission of a range of pathogens, including West Nile virus (WNV). Although its taxonomic status is still debated, the complex includes species, both globally distributed or with a more limited distribution, morphologically similar and characterised by different physiological and behavioural traits, which affect their ability as vectors. In many European countries, Cx. pipiens and its sibling species Culex torrentium occur in sympatry, exhibiting similar bionomic and morphological characters, but only Cx. pipiens appears to play a vector role in WNV transmission. This species consists of two biotypes, pipiens and molestus, which can interbreed when in sympatry, and their hybrids can act as WNV-bridge vectors, due to intermediate ecological features. Considering the yearly WNV outbreaks since 2008 and given the morphological difficulties in recognising species and biotypes, our aim was to molecularly identify and characterised Cx. pipiens and Cx. torrentium in Italy, using recently developed molecular assays. Culex torrentium was not detected; as in other European countries, the pipiens and molestus biotypes were widely found in sympatry with hybrids in most environments. The UPGMA cluster analysis applied to CQ11 genotypic frequencies mainly revealed two groups of Cx. pipiens populations that differed in ecological features. The high propensity of the molestus biotype to exist in hypogean environments, where the habitat's physical characteristics hinder and preclude the gene flow, was shown. These results confirmed the CQ11 assay as a reliable diagnostic method, consistent with the ecological and physiological aspects of the populations analysed. Since the assessment of the actual role of three biotypes in the WNV circulation remains a crucial point to be elucidated, this extensive molecular screening of Cx. pipiens populations can provide new insights into the ecology of the species and may give useful indications to plan and implement WNV surveillance activities in Italy.

Ecological Distribution and CQ11 Genetic Structure of Culex pipiens Complex (Diptera: Culicidae) in Italy

PubMed Central

Di Luca, Marco; Toma, Luciano; Boccolini, Daniela; Severini, Francesco; La Rosa, Giuseppe; Minelli, Giada; Bongiorno, Gioia; Montarsi, Fabrizio; Arnoldi, Daniele; Capelli, Gioia; Rizzoli, Annapaola; Romi, Roberto

2016-01-01

Mosquitoes in the Culex pipiens complex are considered to be involved in the transmission of a range of pathogens, including West Nile virus (WNV). Although its taxonomic status is still debated, the complex includes species, both globally distributed or with a more limited distribution, morphologically similar and characterised by different physiological and behavioural traits, which affect their ability as vectors. In many European countries, Cx. pipiens and its sibling species Culex torrentium occur in sympatry, exhibiting similar bionomic and morphological characters, but only Cx. pipiens appears to play a vector role in WNV transmission. This species consists of two biotypes, pipiens and molestus, which can interbreed when in sympatry, and their hybrids can act as WNV-bridge vectors, due to intermediate ecological features. Considering the yearly WNV outbreaks since 2008 and given the morphological difficulties in recognising species and biotypes, our aim was to molecularly identify and characterised Cx. pipiens and Cx. torrentium in Italy, using recently developed molecular assays. Culex torrentium was not detected; as in other European countries, the pipiens and molestus biotypes were widely found in sympatry with hybrids in most environments. The UPGMA cluster analysis applied to CQ11 genotypic frequencies mainly revealed two groups of Cx. pipiens populations that differed in ecological features. The high propensity of the molestus biotype to exist in hypogean environments, where the habitat’s physical characteristics hinder and preclude the gene flow, was shown. These results confirmed the CQ11 assay as a reliable diagnostic method, consistent with the ecological and physiological aspects of the populations analysed. Since the assessment of the actual role of three biotypes in the WNV circulation remains a crucial point to be elucidated, this extensive molecular screening of Cx. pipiens populations can provide new insights into the ecology of the species and may give useful indications to plan and implement WNV surveillance activities in Italy. PMID:26741494

Explanation of climate and human impacts on sediment discharge change in Darwinian hydrology: Derivation of a differential equation

NASA Astrophysics Data System (ADS)

Zhang, Jianjun; Gao, Guangyao; Fu, Bojie; Zhang, Lu

2018-04-01

The assessment for impacts of climate variability and human activities on suspended sediment yield (SSY) change has long been a question of great interest. However, the sediment generation processes are sophisticated with high nonlinearity and great uncertainty, which give rise to extreme complexity for SSY change assessment in Newtonian approach. Consequently, few approaches can be simply but widely applied to decompose impacts of climatic variability and human activities on SSY change. Thus, it is an urgent need to develop advanced methods that are simple and robust. Since that the Newtonian approach is hardly achievable due to limitation of either observations or knowledge of mechanisms, there have been repeated calls to capture the hydrologic system in Darwinian approach for hydrological change prediction or explanation. As streamflow is the carrier of suspended sediment, SSY change are thus documented in changes of sediment concentrated flow and suspended sediment concentration - water discharge (C-Q) relationships. By deduced corollaries, a differential equation of sediment discharge change was derived to explicitly decompose impacts of climate variability and human activities in Darwinian hydrology. Besides, a new form of sediment rating curves was proposed and curved as C-Q relationships and probability distribution of sediment concentrated flow. River sediment flux can be revealed by this representation, which simply elucidates mechanism of SSY generation covering a range of time scales from finer than rainfall-event to long term. By the new sediment rating curves, the differential equation was partly solved using a segmentation algorithm proposed and validated in this paper, and then was submitted to water balance framework expressed by Budyko-type equation. Thus, for catchment management, hydrologists can obtain explicit explanation of how climate variation and human activities propagate through landscape and result in sediment discharge change. The differential equation is simple and robust for widely application in sediment discharge change assessment, as only discrete data of precipitation, potential evaporation and C-Q observed at gauging stations are required.

Airborne-Measured Spatially-Averaged Temperature and Moisture Turbulent Structure Parameters Over a Heterogeneous Surface

NASA Astrophysics Data System (ADS)

Platis, Andreas; Martinez, Daniel; Bange, Jens

2014-05-01

Turbulent structure parameters of temperature and humidity can be derived from scintillometer measurements along horizontal paths of several 100 m to several 10 km. These parameters can be very useful to estimate the vertical turbulent heat fluxes at the surface (applying MOST). However, there are many assumptions required by this method which can be checked using in situ data, e.g. 1) Were CT2 and CQ2 correctly derived from the initial CN2 scintillometer data (structure parameter of density fluctuations or refraction index, respectively)? 2) What is the influence of the surround hetereogeneous surface regarding its footprint and the weighted averaging effect of the scintillometer method 3) Does MOST provide the correct turbulent fluxes from scintillometer data. To check these issues, in situ data from low-level flight measurements are well suited, since research aircraft cover horizontal distances in very short time (Taylor's hypothesis of a frozen turbulence structure can be applyed very likely). From airborne-measured time series the spatial series are calculated and then their structure functions that finally provide the structure parameters. The influence of the heterogeneous surface can be controlled by the definition of certain moving-average window sizes. A very useful instrument for this task are UAVs since they can fly very low and maintain altitude very precisely. However, the data base of such unmanned operations is still quite thin. So in this contribution we want to present turbulence data obtained with the Helipod, a turbulence probe hanging below a manned helicopter. The structure parameters of temperature and moisture, CT2 and CQ2, in the lower convective boundary layer were derived from data measured using the Helipod in 2003. The measurements were carried out during the LITFASS03 campaign over a heterogeneous land surface around the boundary-layer field site of the Lindenberg Meteorological Observatory-Richard-Aßmann-Observatory (MOL) of the German Meteorological Service during May and June. The synoptic situation of the analyzed days are fair weather conditions with temperature at about 30, sometimes with previous rain events. The spatial series of CT2 and CQ2 showed considerable variability along the flight path that was caused by surface heterogeneity. Measurement flights were performed in the morning and during noon, allowing for a temporal evaluation of the structure parameters during the day. CT2 indicates a high variability between forest, agricultural landscape and lakes at a flight level of 100 m above ground. CQ2 showed lower variations between the different types of soils. The decrease of CT2 with height as predicted by free-convection scaling was confirmed for the analyzed flights.

Molecular analysis of markers associated with chloroquine and sulfadoxine/pyrimethamine resistance in Plasmodium falciparum malaria parasites from southeastern Côte-d'Ivoire by the time of Artemisinin-based Combination Therapy adoption in 2005.

PubMed

Ako, Berenger Aristide; Offianan, André Toure; Johansson, Marnie; Penali, Louis Koné; Nguetta, Simon-Pierre Assanvo; Sibley, Carol Hopkin

2012-01-01

Artemisin-based combination therapies became the recommended therapy in Côte-d'Ivoire in 2005, but both chloroquine (CQ) and sulfadoxine/pyrimethamine (SP) have been heavily used for many decades. Despite this long history, little is known about the geographical distribution of drug resistance-conferring genotypes outside the capital city of Abidjan. In this work, we compared the prevalence of drug-resistant genotypes in Bonoua, an urban area, and Samo, a rural agricultural area, in southeastern Côte-d'Ivoire, about 59 km from Abidjan. Samples were collected from symptomatic patients in both sites during the rainy season in 2005. Genomic DNA was isolated and codons associated with resistance to CQ and SP were analyzed: pfcrt codons Cys-72-Ser, Val-73-Val, Met-74-Ile, Arg-75-Glu, Lys-76-Thr; pfdhfr codons Ala-16-Val, Arg-51-Ile, Cys-59-Arg, Ser-108-Arg/Thr, and Ile-164-Leu; pfdhps codons Ser-436-Ala, Ala-437-Gly, Lys-540-Glu, Ala-581-Gly, and Ala-613-Thr/Ser. A limited number of genotypes were found in Bonoua compared with Samo. In both sites, the triple-mutant allele CVIET of pfcrt predominated: 100% in Bonoua and 86.2% in Samo. The wild-type allele, NCSI of pfdhfr, was common - 50% in Bonoua and 38.7% in Samo - but the triple-mutant IRNI and double-mutant NRNI were also frequent (IRNI, 32.6% in Bonoua and 19.4% in Samo; NRNI, 15.2% in Bonoua and 9.7% in Samo). In Samo, a wide range of different genotypes of Pfdhps was observed, with alleles carrying the Gly-437 codon fixed in Bonoua and comprising 73% of the isolates in Samo. Although these two sites are only 8 km apart, they belonged to very different ecological environments. The overall prevalence of alleles of single-nucleotide polymorphisms associated with resistance to CQ and SP in both locations was among the highest of the region by 2005, although the more rural site showed a more diverse set of alleles and mixed infections. Continued surveillance of these markers will be a useful tool for drug policy, as both CQ and SP are still frequently used years after withdrawal, and SP is recommended by the World Health Organization for intermittent preventive therapy for pregnant women and infants. Data analyzed herein are among the first to be generated during the year of artemisin-based combination-therapy introduction in Côte-d'Ivoire and could be of some interest for malaria policy-makers.

Development and evaluation of evidence-based nursing (EBN) filters and related databases*

PubMed Central

Lavin, Mary A.; Krieger, Mary M.; Meyer, Geralyn A.; Spasser, Mark A.; Cvitan, Tome; Reese, Cordie G.; Carlson, Judith H.; Perry, Anne G.; McNary, Patricia

2005-01-01

Objectives: Difficulties encountered in the retrieval of evidence-based nursing (EBN) literature and recognition of terminology, research focus, and design differences between evidence-based medicine and nursing led to the realization that nursing needs its own filter strategies for evidence-based practice. This article describes the development and evaluation of filters that facilitate evidence-based nursing searches. Methods: An inductive, multistep methodology was employed. A sleep search strategy was developed for uniform application to all filters for filter development and evaluation purposes. An EBN matrix was next developed as a framework to illustrate conceptually the placement of nursing-sensitive filters along two axes: horizontally, an adapted nursing process, and vertically, levels of evidence. Nursing diagnosis, patient outcomes, and primary data filters were developed recursively. Through an interface with the PubMed search engine, the EBN matrix filters were inserted into a database that executes filter searches, retrieves citations, and stores and updates retrieved citations sets hourly. For evaluation purposes, the filters were subjected to sensitivity and specificity analyses and retrieval set comparisons. Once the evaluation was complete, hyperlinks providing access to any one or a combination of completed filters to the EBN matrix were created. Subject searches on any topic may be applied to the filters, which interface with PubMed. Results: Sensitivity and specificity for the combined nursing diagnosis and primary data filter were 64% and 99%, respectively; for the patient outcomes filter, the results were 75% and 71%, respectively. Comparisons were made between the EBN matrix filters (nursing diagnosis and primary data) and PubMed's Clinical Queries (diagnosis and sensitivity) filters. Additional comparisons examined publication types and indexing differences. Review articles accounted for the majority of the publication type differences, because “review” was accepted by the CQ but was “NOT'd” by the EBN filter. Indexing comparisons revealed that although the term “nursing diagnosis” is in Medical Subject Headings (MeSH), the nursing diagnoses themselves (e.g., sleep deprivation, disturbed sleep pattern) are not indexed as nursing diagnoses. As a result, abstracts deemed to be appropriate nursing diagnosis by the EBN filter were not accepted by the CQ diagnosis filter. Conclusions: The EBN filter capture of desired articles may be enhanced by further refinement to achieve a greater degree of filter sensitivity. Retrieval set comparisons revealed publication type differences and indexing issues. The EBN matrix filter “NOT'd” out “review,” while the CQ filter did not. Indexing issues were identified that explained the retrieval of articles deemed appropriate by the EBN filter matrix but not included in the CQ retrieval. These results have MeSH definition and indexing implications as well as implications for clinical decision support in nursing practice. PMID:15685282

Validation of a commercially available enzyme-linked immunoabsorbent assay for the quantification of human α-Synuclein in cerebrospinal fluid.

PubMed

Kruse, Niels; Mollenhauer, Brit

2015-11-01

The quantification of α-Synuclein in cerebrospinal fluid (CSF) as a biomarker has gained tremendous interest in the last years. Several commercially available immunoassays are emerging. We here describe the full validation of one commercially available ELISA assay for the quantification of α-Synuclein in human CSF (Covance alpha-Synuclein ELISA kit). The study was conducted within the BIOMARKAPD project in the European initiative Joint Program for Neurodegenerative Diseases (JPND). We investigated the effect of several pre-analytical and analytical confounders: i.e. (1) need for centrifugation of freshly drawn CSF, (2) sample stability, (3) delay of freezing, (4) volume of storage aliquots, (5) freeze/thaw cycles, (6) thawing conditions, (7) dilution linearity, (8) parallelism, (9) spike recovery, and (10) precision. None of these confounders influenced the levels of α-Synuclein in CSF significantly. We found a very high intra-assay precision. The inter-assay precision was lower than expected due to different performances of kit lots used. Overall the validated immunoassay is useful for the quantification of α-Synuclein in human CSF. Copyright © 2015 Elsevier B.V. All rights reserved.

Quantification of DNA using the luminescent oxygen channeling assay.

PubMed

Patel, R; Pollner, R; de Keczer, S; Pease, J; Pirio, M; DeChene, N; Dafforn, A; Rose, S

2000-09-01

Simplified and cost-effective methods for the detection and quantification of nucleic acid targets are still a challenge in molecular diagnostics. Luminescent oxygen channeling assay (LOCI(TM)) latex particles can be conjugated to synthetic oligodeoxynucleotides and hybridized, via linking probes, to different DNA targets. These oligomer-conjugated LOCI particles survive thermocycling in a PCR reaction and allow quantified detection of DNA targets in both real-time and endpoint formats. The endpoint DNA quantification format utilized two sensitizer bead types that are sensitive to separate illumination wavelengths. These two bead types were uniquely annealed to target or control amplicons, and separate illuminations generated time-resolved chemiluminescence, which distinguished the two amplicon types. In the endpoint method, ratios of the two signals allowed determination of the target DNA concentration over a three-log range. The real-time format allowed quantification of the DNA target over a six-log range with a linear relationship between threshold cycle and log of the number of DNA targets. This is the first report of the use of an oligomer-labeled latex particle assay capable of producing DNA quantification and sequence-specific chemiluminescent signals in a homogeneous format. It is also the first report of the generation of two signals from a LOCI assay. The methods described here have been shown to be easily adaptable to new DNA targets because of the generic nature of the oligomer-labeled LOCI particles.

Modeling qRT-PCR dynamics with application to cancer biomarker quantification.

PubMed

Chervoneva, Inna; Freydin, Boris; Hyslop, Terry; Waldman, Scott A

2017-01-01

Quantitative reverse transcription polymerase chain reaction (qRT-PCR) is widely used for molecular diagnostics and evaluating prognosis in cancer. The utility of mRNA expression biomarkers relies heavily on the accuracy and precision of quantification, which is still challenging for low abundance transcripts. The critical step for quantification is accurate estimation of efficiency needed for computing a relative qRT-PCR expression. We propose a new approach to estimating qRT-PCR efficiency based on modeling dynamics of polymerase chain reaction amplification. In contrast, only models for fluorescence intensity as a function of polymerase chain reaction cycle have been used so far for quantification. The dynamics of qRT-PCR efficiency is modeled using an ordinary differential equation model, and the fitted ordinary differential equation model is used to obtain effective polymerase chain reaction efficiency estimates needed for efficiency-adjusted quantification. The proposed new qRT-PCR efficiency estimates were used to quantify GUCY2C (Guanylate Cyclase 2C) mRNA expression in the blood of colorectal cancer patients. Time to recurrence and GUCY2C expression ratios were analyzed in a joint model for survival and longitudinal outcomes. The joint model with GUCY2C quantified using the proposed polymerase chain reaction efficiency estimates provided clinically meaningful results for association between time to recurrence and longitudinal trends in GUCY2C expression.

Advances in life cycle assessment and emergy evaluation with case studies in gold mining and pineapple production

NASA Astrophysics Data System (ADS)

Ingwersen, Wesley W.

Life cycle assessment (LCA) is an internationally standardized framework for assessing the environmental impacts of products that is rapidly evolving to improve understanding and quantification of how complex product systems depend upon and affect the environment. This dissertation contributes to that evolution through the development of new methods for measuring impacts, estimating the uncertainty of impacts, and measuring ranges of environmental performance, with a focus on product systems in non-OECD countries that have not been well characterized. The integration of a measure of total energy use, emergy, is demonstrated in an LCA of gold from the Yanacocha mine in Peru in the second chapter. A model for estimating the accuracy of emergy results is proposed in the following chapter. The fourth chapter presents a template for LCA-based quantification of the range of environmental performance for tropical agricultural products using the example of fresh pineapple production for export in Costa Rica that can be used to create product labels with environmental information. The final chapter synthesizes how each methodological contribution will together improve the science of measuring product environmental performance.

Sugar nucleotide quantification by liquid chromatography tandem mass spectrometry reveals a distinct profile in Plasmodium falciparum sexual stage parasites

PubMed Central

López-Gutiérrez, Borja; Dinglasan, Rhoel R.

2017-01-01

The obligate intracellular lifestyle of Plasmodium falciparum and the difficulties in obtaining sufficient amounts of biological material have hampered the study of specific metabolic pathways in the malaria parasite. Thus, for example, the pools of sugar nucleotides required to fuel glycosylation reactions have never been studied in-depth in well-synchronized asexual parasites or in other stages of its life cycle. These metabolites are of critical importance, especially considering the renewed interest in the presence of N-, O-, and other glycans in key parasite proteins. In this work, we adapted a liquid chromatography tandem mass spectrometry (LC-MS/MS) method based on the use of porous graphitic carbon (PGC) columns and MS-friendly solvents to quantify sugar nucleotides in the malaria parasite. We report the thorough quantification of the pools of these metabolites throughout the intraerythrocytic cycle of P. falciparum. The sensitivity of the method enabled, for the first time, the targeted analysis of these glycosylation precursors in gametocytes, the parasite sexual stages that are transmissible to the mosquito vector. PMID:28104756

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

Zarate, M.A.; Slotnick, J.; Ramos, M.

The development and implementation of a solid waste management program served to build local capacity in San Mateo Ixtatan between 2002 and 2003 as part of a public health action plan. The program was developed and implemented in two phases: (1) the identification and education of a working team from the community; and (2) the completion of a solid waste classification and quantification study. Social capital and the water cycle were two public health approaches utilized to build a sustainable program. The activities accomplished gained support from the community and municipal authorities. A description of the tasks completed and findingsmore » of the solid waste classification and quantification performed by a local working group are presented in this paper.« less

Cultural Intelligence and Leadership Style in the Education Sector

ERIC Educational Resources Information Center

Aldhaheri, Ali

2017-01-01

Purpose: Schools in UAE are multicultural in nature. In this context, cultural intelligence (CQ) is a tool, which can increase an individual's ability to interact with people outside his/her culture. The purpose of this paper is to explore the perceptions of the school leaders regarding the key influences of cultural intelligence on their ability…

The Surveys to the Companies: A Tool for the Improvement of Degrees

ERIC Educational Resources Information Center

Cruells Cadevall, Montserrat; Roca Vallmajor, Antoni; Escaja Sánchez, Núria; Fernández González, Javier; Garrido Ponce, José Antonio; Giménez Farreras, Jaume; Llauradó Tarragó, Montserrat; Rodriguez Raurell, Laura; Marcos, Josep Oriol Bernad; Arias, Carla Escobar; Vinent, Nuria López; Gratovil, Ma Lluisa Sagristà; Aragay, Carme Navarro

2017-01-01

In scientific and technical degrees, the opinion of the final employers on the given subjects is really important. For this reason, the Quality Committee (CQ) of the Faculty of Chemistry of the University of Barcelona prepared a survey for chemical, engineering and pharmaceutical companies asking about the academic training required by the…

50 CFR 679.82 - Rockfish Program use caps and sideboard limits.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 50 Wildlife and Fisheries 9 2010-10-01 2010-10-01 false Rockfish Program use caps and sideboard... ECONOMIC ZONE OFF ALASKA Rockfish Program § 679.82 Rockfish Program use caps and sideboard limits. (a) Use caps—(1) General. Use caps limit the amount of rockfish QS and CQ of primary rockfish species that may...

78 FR 24258 - Self-Regulatory Organizations; NYSE Arca, Inc.; Chicago Board Options Exchange, Incorporated...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-24

... real-time, low latency data feed that includes CBSX ``BBO data'' and last sale data.\\4\\ CBOE reports CBSX BBO data under the Consolidated Quotation Plan (``CQ Plan'') and CBSX last sale data under the... reports CBSX BBO data and CBSX last sale data under the Nasdaq Unlisted Trading Privileges Plan (``Nasdaq...

The Impact of IQ+EQ+CQ Integration on Student Productivity in Web Design and Development

ERIC Educational Resources Information Center

Zhao, Jensen J.; Zhao, Sherry Y.

2010-01-01

As the entry-level information technology jobs could be easily outsourced offshore, the demand for U.S. employees who are innovative and productive in information technology (IT) project design, development, and management is growing among U.S. companies. This controlled experiment presents how a model of integrating students' intelligence…

76 FR 78810 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-20

... region in which the affected airport is located; 3. The National Flight Procedures Office, 6500 South... Policies and Procedures (44 FR 11034; February 26, 1979); and (3) does not warrant preparation of a... This NOTAM, published in TL 12-01, is hereby rescinded in its entirety. 12-Jan-12......... CQ Rota...

75 FR 34795 - Consolidated Tape Association; Order Approving the Fifteenth Substantive Amendment to the Second...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-18

... Plan (``Amendments'') would amend the Plans to provide that the Participants pay the Network B Administrator a fixed annual fee in exchange for its performance of Network B administrator functions under the... CTA Plan and Section IX (``Financial Matters'') of the CQ Plan each provide that a network's Operating...

78 FR 44984 - Consolidated Tape Association; Notice of Filing and Immediate Effectiveness of the Nineteenth...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-25

... Network A quotation information under the CQ Plan.) Market data users have told the Participants that they... by market data recipients, the Network A Administrator has discovered improper use of the employee... which currently receive both last sale and quotation information. Network B has a small number of data...

A TaqMan-PCR protocol for quantification and differentiation of the phytopathogenic Clavibacter michiganensis subspecies.

PubMed

Bach, H-J; Jessen, I; Schloter, M; Munch, J C

2003-01-01

Real-time TaqMan-PCR assays were developed for detection, differentiation and absolute quantification of the pathogenic subspecies of Clavibacter michiganensis (Cm) in one single PCR run. The designed primer pair, targeting intergenic sequences of the rRNA operon (ITS) common in all subspecies, was suitable for the amplification of the expected 223-nt DNA fragments of all subspecies. Closely related bacteria were completely discriminated, except of Rathayibacter iranicus, from which weak PCR product bands appeared on agarose gel after 35 PCR cycles. Sufficient specificity of PCR detection was reached by introduction of the additional subspecies specific probes used in TaqMan-PCR. Only Cm species were detected and there was clear differentiation among the subspecies C. michiganensis sepedonicus (Cms), C. michiganensis michiganensis (Cmm), C. michiganensis nebraskensis (Cmn), C. michiganensis insidiosus (Cmi) and C. michiganensis tessellarius (Cmt). The TaqMan assays were optimized to enable a simultaneous quantification of each subspecies. Validity is shown by comparison with cell counts.

Loop-Mediated Isothermal Amplification (LAMP) for Rapid Detection and Quantification of Dehalococcoides Biomarker Genes in Commercial Reductive Dechlorinating Cultures KB-1 and SDC-9

PubMed Central

Kanitkar, Yogendra H.; Stedtfeld, Robert D.; Steffan, Robert J.; Hashsham, Syed A.

2016-01-01

Real-time quantitative PCR (qPCR) protocols specific to the reductive dehalogenase (RDase) genes vcrA, bvcA, and tceA are commonly used to quantify Dehalococcoides spp. in groundwater from chlorinated solvent-contaminated sites. In this study, loop-mediated isothermal amplification (LAMP) was developed as an alternative approach for the quantification of these genes. LAMP does not require a real-time thermal cycler (i.e., amplification is isothermal), allowing the method to be performed using less-expensive and potentially field-deployable detection devices. Six LAMP primers were designed for each of three RDase genes (vcrA, bvcA, and tceA) using Primer Explorer V4. The LAMP assays were compared to conventional qPCR approaches using plasmid standards, two commercially available bioaugmentation cultures, KB-1 and SDC-9 (both contain Dehalococcoides species). DNA was extracted over a growth cycle from KB-1 and SDC-9 cultures amended with trichloroethene and vinyl chloride, respectively. All three genes were quantified for KB-1, whereas only vcrA was quantified for SDC-9. A comparison of LAMP and qPCR using standard plasmids indicated that quantification results were similar over a large range of gene concentrations. In addition, the quantitative increase in gene concentrations over one growth cycle of KB-1 and SDC-9 using LAMP was comparable to that of qPCR. The developed LAMP assays for vcrA and tceA genes were validated by comparing quantification on the Gene-Z handheld platform and a real-time thermal cycler using DNA isolated from eight groundwater samples obtained from an SDC-9-bioaugmented site (Tulsa, OK). These assays will be particularly useful at sites subject to bioaugmentation with these two commonly used Dehalococcoides species-containing cultures. PMID:26746711

Stoichiometry and estimates of nutrient standing stocks of larval salamanders in Appalachian headwater streams

Treesearch

Joseph R. Milanovich; John C. Maerz; Amy D. Rosemond

2015-01-01

1.Because of their longevity and skeletal phosphorus demand, vertebrates can have distinct influences on the uptake, storage and recycling of nutrients in ecosystems. Quantification of body stoichiometry, combined with estimates of abundance or biomass, can provide insights into the effect of vertebrates on nutrient cycling. 2.We measured the nutrient content and...

Evaluating the remote sensing and inventory-based estimation of biomass in the western Carpathians

Treesearch

Magdalena Main-Knorn; Gretchen G. Moisen; Sean P. Healey; William S. Keeton; Elizabeth A. Freeman; Patrick Hostert

2011-01-01

Understanding the potential of forest ecosystems as global carbon sinks requires a thorough knowledge of forest carbon dynamics, including both sequestration and fluxes among multiple pools. The accurate quantification of biomass is important to better understand forest productivity and carbon cycling dynamics. Stand-based inventories (SBIs) are widely used for...

Emergy Quantification of Educational Attainment in the U.S. and the Emergy Signature of the Nation from 1900 to 2007

EPA Science Inventory

The information held in the education and experience of a people is a resource that requires time to develop and a cycle of copying and replacement (i.e., the education system) to maintain. Knowledge itself grows with the expanding research component of universities; however, we ...

An Investigation of the Relationship between Iranian EFL Learners' Cultural Intelligence and Their Performance on the IELTS Listening Modules

ERIC Educational Resources Information Center

Rafie, Arezoo; Khosravi, Robab; Nasiri, Mahdi

2016-01-01

This study aimed to investigate the relationship between Iranian EFL Learners' Cultural intelligence (CQ) and their performance on the IELTS Listening Module. Sixty advanced EFL students majoring in English translation at University of Zanjan were matched for the study through the Oxford Quick Placement Test. Cultural Intelligence Scale developed…

47 CFR 80.326 - Notification of resumption of normal working.

Code of Federal Regulations, 2010 CFR

2010-10-01

... handing in the message; (vi) The name and call sign of the mobile station which was in distress; (vii) The...) The name and call sign of the mobile station which was in distress; (vii) The words SEELONCE FEENEE OR... radiotelegraphy, this message consists of: (i) The distress signal SOS; (ii) The call “to all stations” (CQ), sent...

78 FR 21648 - Consolidated Tape Association; Notice of Filing and Immediate Effectiveness of the Seventeenth...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-11

... subscribers pay for Network B last sale information under the CTA Plan and for Network B quotation information under the CQ Plan into one monthly fee of $24.00 per device for both last sale information and quotation... both Plans was in 1995. The CTA Plan, pursuant to which markets collect and disseminate last sale price...

Molecular interaction of selected phytochemicals under the charged environment of Plasmodium falciparum chloroquine resistance transporter (PfCRT) model.

PubMed

Patel, Saumya K; Khedkar, Vijay M; Jha, Prakash C; Jasrai, Yogesh T; Pandya, Himanshu A; George, Linz-Buoy; Highland, Hyacinth N; Skelton, Adam A

2016-01-01

Phytochemicals of Catharanthus roseus Linn. and Tylophora indica have been known for their inhibition of malarial parasite, Plasmodium falciparum in cell culture. Resistance to chloroquine (CQ), a widely used antimalarial drug, is due to the CQ resistance transporter (CRT) system. The present study deals with computational modeling of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein and development of charged environment to mimic a condition of resistance. The model of PfCRT was developed using Protein homology/analogy engine (PHYRE ver 0.2) and was validated based on the results obtained using PSI-PRED. Subsequently, molecular interactions of selected phytochemicals extracted from C. roseus Linn. and T. indica were studied using multiple-iterated genetic algorithm-based docking protocol in order to investigate the translocation of these legends across the PfCRT protein. Further, molecular dynamics studies exhibiting interaction energy estimates of these compounds within the active site of the protein showed that compounds are more selective toward PfCRT. Clusters of conformations with the free energy of binding were estimated which clearly demonstrated the potential channel and by this means the translocation across the PfCRT is anticipated.

A chemotype that inhibits three unrelated pathogenic targets: the botulinum neurotoxin serotype A light chain, P. falciparum malaria, and the Ebola filovirus.

PubMed

Opsenica, Igor; Burnett, James C; Gussio, Rick; Opsenica, Dejan; Todorović, Nina; Lanteri, Charlotte A; Sciotti, Richard J; Gettayacamin, Montip; Basilico, Nicoletta; Taramelli, Donatella; Nuss, Jonathan E; Wanner, Laura; Panchal, Rekha G; Solaja, Bogdan A; Bavari, Sina

2011-03-10

A 1,7-bis(alkylamino)diazachrysene-based small molecule was previously identified as an inhibitor of the botulinum neurotoxin serotype A light chain metalloprotease. Subsequently, a variety of derivatives of this chemotype were synthesized to develop structure-activity relationships, and all are inhibitors of the BoNT/A LC. Three-dimensional analyses indicated that half of the originally discovered 1,7-DAAC structure superimposed well with 4-amino-7-chloroquinoline-based antimalarial agents. This observation led to the discovery that several of the 1,7-DAAC derivatives are potent in vitro inhibitors of Plasmodium falciparum and, in general, are more efficacious against CQ-resistant strains than against CQ-susceptible strains. In addition, by inhibiting β-hematin formation, the most efficacious 1,7-DAAC-based antimalarials employ a mechanism of action analogous to that of 4,7-ACQ-based antimalarials and are well tolerated by normal cells. One candidate was also effective when administered orally in a rodent-based malaria model. Finally, the 1,7-DAAC-based derivatives were examined for Ebola filovirus inhibition in an assay employing Vero76 cells, and three provided promising antiviral activities and acceptably low toxicities.

A chemotype that inhibits three unrelated pathogenic targets: the botulinum neurotoxin serotype A light chain, P. falciparum malaria, and the Ebola filovirus

PubMed Central

Opsenica, Igor; Burnett, James C.; Gussio, Rick; Opsenica, Dejan; Todorović, Nina; Lanteri, Charlotte A.; Sciotti, Richard J.; Gettayacamin, Montip; Basilico, Nicoletta; Taramelli, Donatella; Nuss, Jonathan E.; Wanner, Laura; Panchal, Rekha G.; Šolaja, Bogdan A.; Bavari, Sina

2011-01-01

A 1,7-bis(alkylamino)diazachrysene-based small molecule was previously identified as an inhibitor of the botulinum neurotoxin serotype A light chain metalloprotease. Subsequently, a variety of derivatives of this chemotype were synthesized to develop structure-activity relationships, and all are inhibitors of the BoNT/A LC. Three-dimensional analyses indicated that half of the originally discovered 1,7-DAAC structure superimposed well with 4-amino-7-chloroquinoline-based antimalarial agents. This observation led to the discovery that several of the 1,7-DAAC derivatives are potent in vitro inhibitors of Plasmodium falciparum, and in general, are more efficacious against CQ-resistant strains than against CQ-susceptible strains. In addition, by inhibiting β-hematin formation, the most efficacious 1,7-DAAC-based antimalarials employ a mechanism of action analogous to that of 4,7-ACQ-based antimalarials, and are well tolerated by normal cells. One candidate was also effective when administered orally in a rodent-based malaria model. Finally, the 1,7-DAAC-based derivatives were examined for Ebola filovirus inhibition in an assay employing Vero76 cells, and three provided promising antiviral activities and acceptably low toxicities. PMID:21265542

The river as a chemostat: fresh perspectives on dissolved organic matter flowing down the river continuum

USGS Publications Warehouse

Creed, Irena F.; McKnight, Diane M.; Pellerin, Brian; Green, Mark B.; Bergamaschi, Brian; Aiken, George R.; Burns, Douglas A.; Findlay, Stuart E G; Shanley, James B.; Striegl, Robert G.; Aulenbach, Brent T.; Clow, David W.; Laudon, Hjalmar; McGlynn, Brian L.; McGuire, Kevin J.; Smith, Richard A.; Stackpoole, Sarah M.

2015-01-01

A better understanding is needed of how hydrological and biogeochemical processes control dissolved organic carbon (DOC) concentrations and dissolved organic matter (DOM) composition from headwaters downstream to large rivers. We examined a large DOM dataset from the National Water Information System of the US Geological Survey, which represents approximately 100 000 measurements of DOC concentration and DOM composition at many sites along rivers across the United States. Application of quantile regression revealed a tendency towards downstream spatial and temporal homogenization of DOC concentrations and a shift from dominance of aromatic DOM in headwaters to more aliphatic DOM downstream. The DOC concentration–discharge (C-Q) relationships at each site revealed a downstream tendency towards a slope of zero. We propose that despite complexities in river networks that have driven many revisions to the River Continuum Concept, rivers show a tendency towards chemostasis (C-Q slope of zero) because of a downstream shift from a dominance of hydrologic drivers that connect terrestrial DOM sources to streams in the headwaters towards a dominance of instream and near-stream biogeochemical processes that result in preferential losses of aromatic DOM and preferential gains of aliphatic DOM.

4-Aminoquinoline derivatives: Synthesis, in vitro and in vivo antiplasmodial activity against chloroquine-resistant parasites.

PubMed

Singh, Shailja; Agarwal, Drishti; Sharma, Kumkum; Sharma, Manish; Nielsen, Morten A; Alifrangis, Michael; Singh, Ashok K; Gupta, Rinkoo D; Awasthi, Satish K

2016-10-21

Synthetic quinoline derivatives continue to be considered as candidates for new drug discovery if they act against CQ-resistant strains of malaria even after the widespread emergence of resistance to CQ. In this study, we explored the activities of two series of new 4-aminoquinoline derivatives and found them to be effective against Plasmodium falciparum under in vitro conditions. Further, we selected four most active derivatives 1m, 1o, 2c and 2j and evaluated their antimalarial potential against Plasmodium berghei in vivo. These 4-aminoquinolines cured BALB/c mice infected with P. berghei. The ED50 values were calculated to be 2.062, 2.231, 1.431, 1.623 and 1.18 mg/kg of body weight for each of the compounds 1m, 1o, 2c, 2j and amodiaquine, respectively. Total doses of 500 mg/kg of body weight were well received. The study suggests that these new 4-aminoquinolines should be used for structure activity relationship to find lead molecules for treating multidrug-resistant Plasmodium falciparum and Plasmodium vivax. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

To Rabi Hamiltonian through their Time Dependent Terms can be Reckons as Fractals

NASA Astrophysics Data System (ADS)

Rosary-Oyong, Se, Glory

2016-03-01

For light-matters interactions, ever replies by theLate HE. Mr. Prof M. Barmawi through Bose-Einstein condensates matter-waves ever retrieves [Boyce & DiPrima, 2015] instead of Richard Courant cq HE. Mr. Prof. Sudjoko Danusubroto's LKTM, Lustrum VI ITB, March 2, 1984. Follows ``Modified kernel to Quantum systems thorough Laplace inverse transformation'' whereas ``karyon'' in prokaryotes/eukaryotes meant as well as `kernel' , have been sought for `growth curve' & `potential of proton to other protons' the time dependent terms cos (ωt)exp[-iωot] whose integration y = sin ωt + c proves to be fractals h. 3 guided by Rabi Hamiltonian from Isidor Isaac Rabi,1944. Accompanying ``the Theory of Scale Relativity'' from Laurent Nottale/LUTH, the proofs of considerances whereas `time also are fractals', from Norways for Infra OMAN soughts a benchmark portfolio from Kjell Storvik, 2004: ``Socially Responsible Investment Strategies for the Norwegian Petroleum Fund'' whereas the Rabi frequency ? = 2 ɛ.deg/h can be relatively in comparisons expressed of capacitive [E.d/h]. Acknowledgment to HE. Mr. AUGUST PARENGKUAN if accepts 1995-2005 Invoicing & Fulfillments to ``KOMPAS'' cq the Prodi of Physics ITB.

The brain of the horse: weight and cephalization quotients.

PubMed

Cozzi, Bruno; Povinelli, Michele; Ballarin, Cristina; Granato, Alberto

2014-01-01

The horse is a common domestic animal whose anatomy has been studied since the XVI century. However, a modern neuroanatomy of this species does not exist and most of the data utilized in textbooks and reviews derive from single specimens or relatively old literature. Here, we report information on the brain of Equus caballus obtained by sampling 131 horses, including brain weight (as a whole and subdivided into its constituents), encephalization quotient (EQ), and cerebellar quotient (CQ), and comparisons with what is known about other relevant species. The mean weight of the fresh brains in our experimental series was 598.63 g (SEM ± 7.65), with a mean body weight of 514.12 kg (SEM ± 15.42). The EQ was 0.78 and the CQ was 0.841. The data we obtained indicate that the horse possesses a large, convoluted brain, with a weight similar to that of other hoofed species of like mass. However, the shape of the brain, the noteworthy folding of the neocortex, and the peculiar longitudinal distribution of the gyri suggest an evolutionary specificity at least partially separate from that of the Cetartiodactyla (even-toed mammals and cetaceans) with whom Perissodactyla (odd-toed mammals) are often grouped.

Universal behavior of the interoccurrence times between losses in financial markets: Independence of the time resolution

NASA Astrophysics Data System (ADS)

Ludescher, Josef; Bunde, Armin

2014-12-01

We consider representative financial records (stocks and indices) on time scales between one minute and one day, as well as historical monthly data sets, and show that the distribution PQ(r ) of the interoccurrence times r between losses below a negative threshold -Q , for fixed mean interoccurrence times RQ in multiples of the corresponding time resolutions, can be described on all time scales by the same q exponentials, PQ(r ) ∝1 /{[1+(q -1 ) β r ] 1 /(q -1 )} . We propose that the asset- and time-scale-independent analytic form of PQ(r ) can be regarded as an additional stylized fact of the financial markets and represents a nontrivial test for market models. We analyze the distribution PQ(r ) as well as the autocorrelation CQ(s ) of the interoccurrence times for three market models: (i) multiplicative random cascades, (ii) multifractal random walks, and (iii) the generalized autoregressive conditional heteroskedasticity [GARCH(1,1)] model. We find that only one of the considered models, the multifractal random walk model, approximately reproduces the q -exponential form of PQ(r ) and the power-law decay of CQ(s ) .

Protein turnover measurement using selected reaction monitoring-mass spectrometry (SRM-MS)

PubMed Central

Holman, Stephen W.; Hammond, Dean E.; Simpson, Deborah M.; Waters, John; Hurst, Jane L.

2016-01-01

Protein turnover represents an important mechanism in the functioning of cells, with deregulated synthesis and degradation of proteins implicated in many diseased states. Therefore, proteomics strategies to measure turnover rates with high confidence are of vital importance to understanding many biological processes. In this study, the more widely used approach of non-targeted precursor ion signal intensity (MS1) quantification is compared with selected reaction monitoring (SRM), a data acquisition strategy that records data for specific peptides, to determine if improved quantitative data would be obtained using a targeted quantification approach. Using mouse liver as a model system, turnover measurement of four tricarboxylic acid cycle proteins was performed using both MS1 and SRM quantification strategies. SRM outperformed MS1 in terms of sensitivity and selectivity of measurement, allowing more confident determination of protein turnover rates. SRM data are acquired using cheaper and more widely available tandem quadrupole mass spectrometers, making the approach accessible to a larger number of researchers than MS1 quantification, which is best performed on high mass resolution instruments. SRM acquisition is ideally suited to focused studies where the turnover of tens of proteins is measured, making it applicable in determining the dynamics of proteins complexes and complete metabolic pathways. This article is part of the themed issue ‘Quantitative mass spectrometry’. PMID:27644981

Probabilistic Material Strength Degradation Model for Inconel 718 Components Subjected to High Temperature, High-Cycle and Low-Cycle Mechanical Fatigue, Creep and Thermal Fatigue Effects

NASA Technical Reports Server (NTRS)

Bast, Callie C.; Boyce, Lola

1995-01-01

The development of methodology for a probabilistic material strength degradation is described. The probabilistic model, in the form of a postulated randomized multifactor equation, provides for quantification of uncertainty in the lifetime material strength of aerospace propulsion system components subjected to a number of diverse random effects. This model is embodied in the computer program entitled PROMISS, which can include up to eighteen different effects. Presently, the model includes five effects that typically reduce lifetime strength: high temperature, high-cycle mechanical fatigue, low-cycle mechanical fatigue, creep and thermal fatigue. Results, in the form of cumulative distribution functions, illustrated the sensitivity of lifetime strength to any current value of an effect. In addition, verification studies comparing predictions of high-cycle mechanical fatigue and high temperature effects with experiments are presented. Results from this limited verification study strongly supported that material degradation can be represented by randomized multifactor interaction models.

[Quantitative PCR in the diagnosis of Leishmania].

PubMed

Mortarino, M; Franceschi, A; Mancianti, F; Bazzocchi, C; Genchi, C; Bandi, C

2004-06-01

Polymerase chain reaction (PCR) is a sensitive and rapid method for the diagnosis of canine Leishmania infection and can be performed on a variety of biological samples, including peripheral blood, lymph node, bone marrow and skin. Standard PCR requires electrophoretic analysis of the amplification products and is usually not suitable for quantification of the template DNA (unless competitor-based or other methods are developed), being of reduced usefulness when accurate monitoring of target DNA is required. Quantitative real-time PCR allows the continuous monitoring of the accumulation of PCR products during the amplification reaction. This allows the identification of the cycle of near-logarithmic PCR product generation (threshold cycle) and, by inference, the relative quantification of the template DNA present at the start of the reaction. Since the amplification product are monitored in "real-time" as they form cycle-by-cycle, no post-amplification handling is required. The absolute quantification is performed according either to an internal standard co-amplified with the sample DNA, or to an external standard curve obtained by parallel amplification of serial known concentrations of a reference DNA sequence. From the quantification of the template DNA, an estimation of the relative load of parasites in the different samples can be obtained. The advantages compared to standard and semi-quantitative PCR techniques are reduction of the assay's time and contamination risks, and improved sensitivity. As for standard PCR, the minimal components of the quantitative PCR reaction mixture are the DNA target of the amplification, an oligonucleotide primer pair flanking the target sequence, a suitable DNA polymerase, deoxynucleotides, buffer and salts. Different technologies have been set up for the monitoring of amplification products, generally based on the use of fluorescent probes. For instance, SYBR Green technology is a non-specific detection system based on a fluorescent dsDNA intercalator and it is applicable to all potential targets. TaqMan technology is more specific since performs the direct assessment of the amount of amplified DNA using a fluorescent probe specific for the target sequence flanked by the primer pair. This probe is an oligonucleotide labelled with a reporter dye (fluorescent) and a quencher (which absorbs the fluorescent signal generated by the reporter). The thermic protocol of amplification allows the binding of the fluorescent probe to the target sequence before the binding of the primers and the starting of the polymerization by Taq polymerase. During polymerization, 5'-3' exonuclease activity of Taq polymerase digests the probe and in this way the reporter dye is released from the probe and a fluorescent signal is detected. The intensity of the signal accumulates at the end of each cycle and is related to the amount of the amplification product. In recent years, quantitative PCR methods based either on SYBR Green or TaqMan technology have been set up for the quantification of Leishmania in mouse liver, mouse skin and human peripheral blood, targeting either single-copy chromosomal or multi-copy minicircle sequences with high sensitivity and reproducibility. In particular, real-time PCR seems to be a reliable, rapid and noninvasive method for the diagnosis and follow up of visceral leishmaniasis in humans. At present, the application of real-time PCR for research and clinical diagnosis of Leishmania infection in dogs is still foreseable. As for standard PCR, the high sensitivity of real-time PCR could allow the use of blood sampling that is less invasive and easily performed for monitoring the status of the dogs. The development of a real-time PCR assay for Leishmania infantum infection in dogs could support the standard and optimized serological and PCR methods currenly in use for the diagnosis and follow-up of canine leishmaniasis, and perhaps prediction of recurrences associated with tissue loads of residual pathogens after treatment. At this regard, a TaqMan Real Time PCR method developed for the quantification of Leishmania infantum minicircle DNA in peripheral blood of naturally infected dogs sampled before and at different time points after the beginning of a standard antileishmanial therapy will be illustrated.

Comparing aboveground biomass predictions for an uneven-aged pine-dominated stand using local, regional, and national models

Treesearch

D.C. Bragg; K.M. McElligott

2013-01-01

Sequestration by Arkansas forests removes carbon dioxide from the atmosphere, storing this carbon in biomass that fills a number of critical ecological and socioeconomic functions. We need a better understanding of the contribution of forests to the carbon cycle, including the accurate quantification of tree biomass. Models have long been developed to predict...

Overview of recent aero-optics flight tests

NASA Technical Reports Server (NTRS)

Otten, L. J., III

1980-01-01

A chronological overview of aero-optics test flights is presented highlighting the objectives and conclusions from the tests. Flight tests performed in coordination with the PRESS reentry observation missions and the ALL Cycle 2 laser propagation and tracking demonstrations are described addressing the identification and quantification of distortion phenomena. Finally, current aero-optics flight investigations of an atmospheric turbulence probe are briefly discussed.

TaqMan probe real-time polymerase chain reaction assay for the quantification of canine DNA in chicken nugget.

PubMed

Rahman, Md Mahfujur; Hamid, Sharifah Bee Abd; Basirun, Wan Jefrey; Bhassu, Subha; Rashid, Nur Raifana Abdul; Mustafa, Shuhaimi; Mohd Desa, Mohd Nasir; Ali, Md Eaqub

2016-01-01

This paper describes a short-amplicon-based TaqMan probe quantitative real-time PCR (qPCR) assay for the quantitative detection of canine meat in chicken nuggets, which are very popular across the world, including Malaysia. The assay targeted a 100-bp fragment of canine cytb gene using a canine-specific primer and TaqMan probe. Specificity against 10 different animals and plants species demonstrated threshold cycles (Ct) of 16.13 ± 0.12 to 16.25 ± 0.23 for canine DNA and negative results for the others in a 40-cycle reaction. The assay was tested for the quantification of up to 0.01% canine meat in deliberately spiked chicken nuggets with 99.7% PCR efficiency and 0.995 correlation coefficient. The analysis of the actual and qPCR predicted values showed a high recovery rate (from 87% ± 28% to 112% ± 19%) with a linear regression close to unity (R(2) = 0.999). Finally, samples of three halal-branded commercial chicken nuggets collected from different Malaysian outlets were screened for canine meat, but no contamination was demonstrated.

Gravitational quasi-normal modes of static R 2 Anti-de Sitter black holes

NASA Astrophysics Data System (ADS)

Ma, Hong; Li, Jin

2017-06-01

Not Available Project supported by the National Natural Science Foundation of China (Grant Nos. 11205254, 11178018, 11375279, and 11605015), the Fundamental Research Funds for the Central Universities, China (Grant Nos. 106112016CDJXY300002 and CDJRC10300003), the Chinese State Scholarship Fund, FAPESP (Grant No. 2012/08934-0), and the Natural Science Foundation Project of CQ CSTC (Grant No. 2011BB0052).

Development of a Behaviorally Anchored Rating Scale for Leadership

DTIC Science & Technology

2018-01-01

Research Product 2018-06 Development of a Behaviorally Anchored Rating Scale for Leadership Tatiana H. Toumbeva Krista L...anchored Rating Scale for Leadership 5a. CONTRACT NUMBER W5J9CQ-11-D-0004 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 62278 6...observer- based behavioral measure to help instructors more reliably and accurately evaluate the development of leadership attributes and competencies

Assessing the Development of Cross-Cultural Competence in Soldiers

DTIC Science & Technology

2010-11-01

five stages of CQ development based on models from developmental psychology including Piaget’s Model of Cognitive Development ( Piaget , 1985) and...and competence development , the Stage Model of Cognitive Skill Acquisition (Ross et al., 2005), and the Bennett Developmental Model of... developmental stages of proficiency and expertise (see the Stage Model of Cognitive Development ). At this level, cross-cultural competence is highly refined and

Robustifying the Kalman Filter.

DTIC Science & Technology

1987-11-01

School Code 55 6c ADDRESN Cq> State and ZiP( odk ,) 7b ADDRE SS(City State and Z/IPCode) Monterey, CA 93943-5000 8a NAME J); ;. ND S"ONSOR’Nu Bt, O FiCE... collected are the estimation error 6n - On for n=25, 50, 75, 100 and the estimate of variance Cn, n=25, 50, 75, 100. The number of independent

Optimal Repairman Allocation Models

DTIC Science & Technology

1976-03-01

state X under policy ir. Then lim {k1’ lC0 (^)I) e.(X,k) - 0 k*0 *’-’ (3.1.1) Proof; The result is proven by induction on |CQ(X...following theorem. Theorem 3.1 D. Under the conditions of theorem 3.1 A, define g1[ 1) (X) - g^U), then lim k- lC0 W l-mle (XHkl00^ Ig*11 (X

Assessing Postural Asymmetry with a Podoscope in Infants with Central Coordination Disturbance

ERIC Educational Resources Information Center

Pyzio-Kowalik, Magdalena; Wojtowicz, Dorota; Skrzek, Anna

2013-01-01

The aim of this study was to digitally evaluate the incidence and severity of postural asymmetry in infants with Central Coordination Disturbance (CCD) by using a computer-aided podoscope (PodoBaby) from CQ Elektronik System. A sample of 120 infants aged from 3 months (plus or minus 1 week) to 6 months (plus or minus 1 week) took part in the…

Dual-Modality Prostate Imaging with PET and Transrectal Ultrasound

DTIC Science & Technology

2011-09-01

8!J8!JV+[9V?’*;!Ŝ!?8!,C"’’!𔄂!’A9(!VB"!78!n8! Cq"CBB’[[;!h,(Ve2Be!CJ!&*C,(V(’!V"’BCAV*A2BC>V;! AC>&V*2,CB!CJ!J"e!"’ŖAV(’"!&’(!VB"!2B) UUU ! AV&*C>V

Cure width potential for MOD resin composite molar restorations.

PubMed

Palin, William M; Senyilmaz, Dilek P; Marquis, Peter M; Shortall, Adrian C

2008-08-01

To investigate the capability of modern light-curing units exhibiting differences in emission spectra and light source exit window dimensions, for "one-shot" full-width curing of extensive (molar MOD) resin composite restorations. Specimens of Tetric (TT), Tetric Ceram HB (TC), Tetric Evoceram (TE) and Tetric Ceram Bleach (TB) resin composites containing varying ratios of Lucirin (TPO) and/or camphorquinone (CQ) photoinitiators were packed into a bar-shaped mould (12 mm length x 2 mm width x 2 mm thickness). Each product was irradiated using a halogen (Optilux 401; QTH), a conventional LED (LEDemetron; LED) and two so-called "third generation" oval-footprint LED light-curing units (LCUs) of the same model. The latter featured bimodal emission spectra (blue and ultraviolet diodes) with either high (unmodified output) and approximately 50% (modified output) blue light intensity (UltraLume-5; ULs, ULm, respectively). Vickers hardness number was obtained across the lateral extent of the bar at 1mm increments from the centre point on both upper and lower surfaces of the specimens. Significant linear relationships (R(2)=0.71-0.98) for each distance from the central position of all LCUs were identified between measured light intensity and corresponding upper and lower surface hardness values for each product (P<0.05). No significant differences (P>0.05) were recorded in total upper surface hardness of TC or TE cured with LED (68.7+/-3.2 and 70.5+/-2.5) or ULm (56.8+/-2.0 and 57.7+/-2.0). However, upper surface hardness of TT (CQ only) cured with ULm was significantly decreased (P<0.05) compared with other LCUs. When the ratio of hardness at the edge to central positions of the bar-shaped specimens for either surface was calculated, no significant difference (P>0.05) was identified for TB (containing TPO and decreased CQ) cured with either ULs or ULm (P>0.05) and was significantly increased (P<0.05) when cured with ULs compared with LED and QTH. Variability in light intensity across the curing-tip face, spectral output of dental light-curing units and differences in product photoinitiator chemistry all influence curing efficiency significantly across the width of extensive resin composite geometries.

Where chloroquine still works: the genetic make-up and susceptibility of Plasmodium vivax to chloroquine plus primaquine in Bhutan.

PubMed

Wangchuk, Sonam; Drukpa, Tobgyel; Penjor, Kinley; Peldon, Tashi; Dorjey, Yeshey; Dorji, Kunzang; Chhetri, Vishal; Trimarsanto, Hidayat; To, Sheren; Murphy, Amanda; von Seidlein, Lorenz; Price, Ric N; Thriemer, Kamala; Auburn, Sarah

2016-05-12

Bhutan has made substantial progress in reducing malaria incidence. The national guidelines recommend chloroquine (CQ) and primaquine (PQ) for radical cure of uncomplicated Plasmodium vivax, but the local efficacy has not been assessed. The impact of cases imported from India on the genetic make-up of the local vivax populations is currently unknown. Patients over 4 years of age with uncomplicated P. vivax mono-infection were enrolled into a clinical efficacy study and molecular survey. Study participants received a standard dose of CQ (25 mg/kg over 3 days) followed by weekly review until day 28. On day 28 a 14-day regimen of PQ (0.25 mg/kg/day) was commenced under direct observation. After day 42, patients were followed up monthly for a year. The primary and secondary endpoints were risk of treatment failure at day 28 and at 1 year. Parasite genotyping was undertaken at nine tandem repeat markers, and standard population genetic metrics were applied to examine population diversity and structure in infections thought to be acquired inside or outside of Bhutan. A total of 24 patients were enrolled in the clinical study between April 2013 and October 2015. Eight patients (33.3 %) were lost to follow-up in the first 6 months and another eight patients lost between 6 and 12 months. No (0/24) treatment failures occurred by day 28 and no (0/8) parasitaemia was detected following PQ treatment. Some 95.8 % (23/24) of patients were aparasitaemic by day 2. There were no haemolytic or serious events. Genotyping was undertaken on parasites from 12 autochthonous cases and 16 suspected imported cases. Diversity was high (H E 0.87 and 0.90) in both populations. There was no notable differentiation between the autochthonous and imported populations. CQ and PQ remains effective for radical cure of P. vivax in Bhutan. The genetic analyses indicate that imported infections are sustaining the local vivax population, with concomitant risk of introducing drug-resistant strains.

Supervised Machine Learning Algorithms Can Classify Open-Text Feedback of Doctor Performance With Human-Level Accuracy

PubMed Central

2017-01-01

Background Machine learning techniques may be an effective and efficient way to classify open-text reports on doctor’s activity for the purposes of quality assurance, safety, and continuing professional development. Objective The objective of the study was to evaluate the accuracy of machine learning algorithms trained to classify open-text reports of doctor performance and to assess the potential for classifications to identify significant differences in doctors’ professional performance in the United Kingdom. Methods We used 1636 open-text comments (34,283 words) relating to the performance of 548 doctors collected from a survey of clinicians’ colleagues using the General Medical Council Colleague Questionnaire (GMC-CQ). We coded 77.75% (1272/1636) of the comments into 5 global themes (innovation, interpersonal skills, popularity, professionalism, and respect) using a qualitative framework. We trained 8 machine learning algorithms to classify comments and assessed their performance using several training samples. We evaluated doctor performance using the GMC-CQ and compared scores between doctors with different classifications using t tests. Results Individual algorithm performance was high (range F score=.68 to .83). Interrater agreement between the algorithms and the human coder was highest for codes relating to “popular” (recall=.97), “innovator” (recall=.98), and “respected” (recall=.87) codes and was lower for the “interpersonal” (recall=.80) and “professional” (recall=.82) codes. A 10-fold cross-validation demonstrated similar performance in each analysis. When combined together into an ensemble of multiple algorithms, mean human-computer interrater agreement was .88. Comments that were classified as “respected,” “professional,” and “interpersonal” related to higher doctor scores on the GMC-CQ compared with comments that were not classified (P<.05). Scores did not vary between doctors who were rated as popular or innovative and those who were not rated at all (P>.05). Conclusions Machine learning algorithms can classify open-text feedback of doctor performance into multiple themes derived by human raters with high performance. Colleague open-text comments that signal respect, professionalism, and being interpersonal may be key indicators of doctor’s performance. PMID:28298265

Supervised Machine Learning Algorithms Can Classify Open-Text Feedback of Doctor Performance With Human-Level Accuracy.

PubMed

Gibbons, Chris; Richards, Suzanne; Valderas, Jose Maria; Campbell, John

2017-03-15

Machine learning techniques may be an effective and efficient way to classify open-text reports on doctor's activity for the purposes of quality assurance, safety, and continuing professional development. The objective of the study was to evaluate the accuracy of machine learning algorithms trained to classify open-text reports of doctor performance and to assess the potential for classifications to identify significant differences in doctors' professional performance in the United Kingdom. We used 1636 open-text comments (34,283 words) relating to the performance of 548 doctors collected from a survey of clinicians' colleagues using the General Medical Council Colleague Questionnaire (GMC-CQ). We coded 77.75% (1272/1636) of the comments into 5 global themes (innovation, interpersonal skills, popularity, professionalism, and respect) using a qualitative framework. We trained 8 machine learning algorithms to classify comments and assessed their performance using several training samples. We evaluated doctor performance using the GMC-CQ and compared scores between doctors with different classifications using t tests. Individual algorithm performance was high (range F score=.68 to .83). Interrater agreement between the algorithms and the human coder was highest for codes relating to "popular" (recall=.97), "innovator" (recall=.98), and "respected" (recall=.87) codes and was lower for the "interpersonal" (recall=.80) and "professional" (recall=.82) codes. A 10-fold cross-validation demonstrated similar performance in each analysis. When combined together into an ensemble of multiple algorithms, mean human-computer interrater agreement was .88. Comments that were classified as "respected," "professional," and "interpersonal" related to higher doctor scores on the GMC-CQ compared with comments that were not classified (P<.05). Scores did not vary between doctors who were rated as popular or innovative and those who were not rated at all (P>.05). Machine learning algorithms can classify open-text feedback of doctor performance into multiple themes derived by human raters with high performance. Colleague open-text comments that signal respect, professionalism, and being interpersonal may be key indicators of doctor's performance. ©Chris Gibbons, Suzanne Richards, Jose Maria Valderas, John Campbell. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 15.03.2017.

Quantification of concentrated Chinese medicine granules by quantitative polymerase chain reaction.

PubMed

Lo, Yat-Tung; Shaw, Pang-Chui

2017-10-25

Determination of the amount of constituent in a multi-herb product is important for quality control. In concentrated Chinese medicine granules (CCMG), no dregs are left after dissolution of the CCMG. This study is the first to examine the feasibility of using quantitative polymerase chain reaction (qPCR) to find the amount of CCMG in solution form. DNA was extracted from Hirudo and Zaocys CCMG mixed at different ratios and amplified in qPCR using species-specific primers. The threshold cycle (C T ) obtained was compared with the respective standard curves. Results showed that reproducible quantification results could be obtained (1) for 5-50mg CCMG using a modified DNA extraction protocol, (2) amongst DNA extracted from the same batch of CCMG and (3) amongst different batches of CCMG from the same company. This study demonstrated the constitute amount of CCMG in a mixture could be determined using qPCR. This work has extended the application of DNA techniques for the quantification of herbal products and this approach may be developed for quality assurance in the CCMG industry. Copyright © 2017 Elsevier B.V. All rights reserved.

Simple and Inexpensive Quantification of Ammonia in Whole Blood

PubMed Central

Ayyub, Omar B.; Behrens, Adam M.; Heligman, Brian T.; Natoli, Mary E.; Ayoub, Joseph J.; Cunningham, Gary; Summar, Marshall; Kofinas, Peter

2015-01-01

Quantification of ammonia in whole blood has applications in the diagnosis and management of many hepatic diseases, including cirrhosis and rare urea cycle disorders, amounting to more than 5 million patients in the United States. Current techniques for ammonia measurement suffer from limited range, poor resolution, false positives or large, complex sensor set-ups. Here we demonstrate a technique utilizing inexpensive reagents and simple methods for quantifying ammonia in 100 μl of whole blood. The sensor comprises a modified form of the indophenol reaction, which resists sources of destructive interference in blood, in conjunction with a cation-exchange membrane. The presented sensing scheme is selective against other amine containing molecules such as amino acids and has a shelf life of at least 50 days. Additionally, the resulting system has high sensitivity and allows for the accurate reliable quantification of ammonia in whole human blood samples at a minimum range of 25 to 500 μM, which is clinically for rare hyperammonemic disorders and liver disease. Furthermore, concentrations of 50 and 100 μM ammonia could be reliably discerned with p=0.0001. PMID:25936660

The NEWS Water Cycle Climatology

NASA Astrophysics Data System (ADS)

Rodell, M.; Beaudoing, H. K.; L'Ecuyer, T.; Olson, W. S.

2012-12-01

NASA's Energy and Water Cycle Study (NEWS) program fosters collaborative research towards improved quantification and prediction of water and energy cycle consequences of climate change. In order to measure change, it is first necessary to describe current conditions. The goal of the first phase of the NEWS Water and Energy Cycle Climatology project was to develop "state of the global water cycle" and "state of the global energy cycle" assessments based on data from modern ground and space based observing systems and data integrating models. The project was a multi-institutional collaboration with more than 20 active contributors. This presentation will describe the results of the water cycle component of the first phase of the project, which include seasonal (monthly) climatologies of water fluxes over land, ocean, and atmosphere at continental and ocean basin scales. The requirement of closure of the water budget (i.e., mass conservation) at various scales was exploited to constrain the flux estimates via an optimization approach that will also be described. Further, error assessments were included with the input datasets, and we examine these in relation to inferred uncertainty in the optimized flux estimates in order to gauge our current ability to close the water budget within an expected uncertainty range.

The NEWS Water Cycle Climatology

NASA Technical Reports Server (NTRS)

Rodell, Matthew; Beaudoing, Hiroko Kato; L'Ecuyer, Tristan; William, Olson

2012-01-01

NASA's Energy and Water Cycle Study (NEWS) program fosters collaborative research towards improved quantification and prediction of water and energy cycle consequences of climate change. In order to measure change, it is first necessary to describe current conditions. The goal of the first phase of the NEWS Water and Energy Cycle Climatology project was to develop "state of the global water cycle" and "state of the global energy cycle" assessments based on data from modern ground and space based observing systems and data integrating models. The project was a multi-institutional collaboration with more than 20 active contributors. This presentation will describe the results of the water cycle component of the first phase of the project, which include seasonal (monthly) climatologies of water fluxes over land, ocean, and atmosphere at continental and ocean basin scales. The requirement of closure of the water budget (i.e., mass conservation) at various scales was exploited to constrain the flux estimates via an optimization approach that will also be described. Further, error assessments were included with the input datasets, and we examine these in relation to inferred uncertainty in the optimized flux estimates in order to gauge our current ability to close the water budget within an expected uncertainty range.

Transport of Gas and Solutes in Permeable Estuarine Sediments

DTIC Science & Technology

2012-09-30

produce his Ph.D. dissertation based on this reserach . The acoustic method for detecting and measuring small gas bubbles in marine sands. This...the detection and quantification of small free gas volumes in sandy coastal sediments. After introducing and explaining the instrument, the paper ...influence the sediment erosion threshold, biogeochemical zonations, living space for organisms and thereby the role of the sediments in the cycles of

Distinct oxidative stabilities of char versus soot black carbon: Implications for quantification and environmental recalcitrance

NASA Astrophysics Data System (ADS)

Elmquist, Marie; Cornelissen, Gerard; Kukulska, Zofia; Gustafsson, Örjan

2006-06-01

Sequestration in sediments of black carbon (BC) from vegetation fires and fuel combustion may constitute a significant sink of otherwise rapidly cycling carbon from the atmosphere-biosphere cycle. It also has the potential to provide a historical record of atmospheric BC loadings. Previous treatments of BC as one homogeneous entity are being replaced with the growing awareness of a BC combustion continuum, a range spanning from slightly charred biomass to soot and graphite. Here the relative recalcitrance of different BC forms is evaluated, and implications for both BC quantification and environmental stability are considered. The stabilities of four BC reference materials against thermal oxidation in air were quite distinct with T50%BC values (i.e., the temperature where 50% BC remained in the residue) of 444°C (diesel soot-BC), 388°C (n-hexane soot-BC), 338°C (wood char-BC), and 266°C (grass char-BC). The implications for BC quantification have been illustrated for a thermal oxidation (the CTO-375) method commonly applied to study BC in sediments. This technique measured BC:TOC ratios of 78.3 ± 1.3% for the diesel soot-BC and 45.3 ± 6.1% for n-hexane soot-BC, whereas no CTO375-BC was detected for the two analyzed char-BC materials. The greater lability of char-BC compared to soot-BC likely reflects higher accessibility to internal microporosity in char-BC, facilitating internal O2 transfer. Decreasing the temperature cutoff below 375°C to also include char-BC is not possible as thermograms of nonpyrogenic reference materials indicated that such material would then be artifactually quantified as BC. The presence of mineral oxides in the sediment matrix may lead to a catalytically mediated lowering of the activation energy for soot-BC oxidation but not for char-BC or nonpyrogenic organic material. Several recent studies combine to challenge the proposition of complete recalcitrance of BC. Particularly, the thermal lability of char-BC from grassland fires deserves further attention in order to improve the understanding of BC in the global carbon cycle.

Novel approach to quantitative polymerase chain reaction using real-time detection: application to the detection of gene amplification in breast cancer.

PubMed

Bièche, I; Olivi, M; Champème, M H; Vidaud, D; Lidereau, R; Vidaud, M

1998-11-23

Gene amplification is a common event in the progression of human cancers, and amplified oncogenes have been shown to have diagnostic, prognostic and therapeutic relevance. A kinetic quantitative polymerase-chain-reaction (PCR) method, based on fluorescent TaqMan methodology and a new instrument (ABI Prism 7700 Sequence Detection System) capable of measuring fluorescence in real-time, was used to quantify gene amplification in tumor DNA. Reactions are characterized by the point during cycling when PCR amplification is still in the exponential phase, rather than the amount of PCR product accumulated after a fixed number of cycles. None of the reaction components is limited during the exponential phase, meaning that values are highly reproducible in reactions starting with the same copy number. This greatly improves the precision of DNA quantification. Moreover, real-time PCR does not require post-PCR sample handling, thereby preventing potential PCR-product carry-over contamination; it possesses a wide dynamic range of quantification and results in much faster and higher sample throughput. The real-time PCR method, was used to develop and validate a simple and rapid assay for the detection and quantification of the 3 most frequently amplified genes (myc, ccndl and erbB2) in breast tumors. Extra copies of myc, ccndl and erbB2 were observed in 10, 23 and 15%, respectively, of 108 breast-tumor DNA; the largest observed numbers of gene copies were 4.6, 18.6 and 15.1, respectively. These results correlated well with those of Southern blotting. The use of this new semi-automated technique will make molecular analysis of human cancers simpler and more reliable, and should find broad applications in clinical and research settings.

The analysis and utilization of cycling training data.

PubMed

Jobson, Simon A; Passfield, Louis; Atkinson, Greg; Barton, Gabor; Scarf, Philip

2009-01-01

Most mathematical models of athletic training require the quantification of training intensity and quantity or 'dose'. We aim to summarize both the methods available for such quantification, particularly in relation to cycle sport, and the mathematical techniques that may be used to model the relationship between training and performance. Endurance athletes have used training volume (kilometres per week and/or hours per week) as an index of training dose with some success. However, such methods usually fail to accommodate the potentially important influence of training intensity. The scientific literature has provided some support for alternative methods such as the session rating of perceived exertion, which provides a subjective quantification of the intensity of exercise; and the heart rate-derived training impulse (TRIMP) method, which quantifies the training stimulus as a composite of external loading and physiological response, multiplying the training load (stress) by the training intensity (strain). Other methods described in the scientific literature include 'ordinal categorization' and a heart rate-based excess post-exercise oxygen consumption method. In cycle sport, mobile cycle ergometers (e.g. SRM and PowerTap) are now widely available. These devices allow the continuous measurement of the cyclists' work rate (power output) when riding their own bicycles during training and competition. However, the inherent variability in power output when cycling poses several challenges in attempting to evaluate the exact nature of a session. Such variability means that average power output is incommensurate with the cyclist's physiological strain. A useful alternative may be the use of an exponentially weighted averaging process to represent the data as a 'normalized power'. Several research groups have applied systems theory to analyse the responses to physical training. Impulse-response models aim to relate training loads to performance, taking into account the dynamic and temporal characteristics of training and, therefore, the effects of load sequences over time. Despite the successes of this approach it has some significant limitations, e.g. an excessive number of performance tests to determine model parameters. Non-linear artificial neural networks may provide a more accurate description of the complex non-linear biological adaptation process. However, such models may also be constrained by the large number of datasets required to 'train' the model. A number of alternative mathematical approaches such as the Performance-Potential-Metamodel (PerPot), mixed linear modelling, cluster analysis and chaos theory display conceptual richness. However, much further research is required before such approaches can be considered as viable alternatives to traditional impulse-response models. Some of these methods may not provide useful information about the relationship between training and performance. However, they may help describe the complex physiological training response phenomenon.

Construction Foundation Report, Grand River, Bowman-Haley Project, North Dakota. Volume 1. Text, Drawings, Photos.

DTIC Science & Technology

1985-05-01

tamping rollers. Final compaction was by rubber -t ired rollers. Compaction was to 95% of maximum density. Time between placing the 6" layers and...taree ue go dscribe*he:. 0 IoldNYeRAEL Boreast ol bsnc of eater readngs in the Iiraphic Log ’G I CAYI CQ 5A esL.- ADS@ * nbr ; i cneeeiItt be oetrued O

New Inosine and Guanosine Analogs as Inhibitors of Parasitic Infections.

DTIC Science & Technology

1985-11-30

infections. Although chloroquine (CQ) is generally considered to be one of the most fascinating, useful and versatile drugs developed during the modern...ribonucleosides are of particular interest since these nucleosides may be looked upon as aza- analogues of formycin B. The parent s-triazolo[3,4-f]-as...hexopyranosyl)adenine indicate slightly altered glycon. This type of nucleoside analogues could mimic either as ribonucleo- sides or as 2

MIFT: GIFT Combinatorial Geometry Input to VCS Code

DTIC Science & Technology

1977-03-01

r-w w-^ H ^ß0318is CQ BRL °RCUMr REPORT NO. 1967 —-S: ... MIFT: GIFT COMBINATORIAL GEOMETRY INPUT TO VCS CODE Albert E...TITLE (and Subtitle) MIFT: GIFT Combinatorial Geometry Input to VCS Code S. TYPE OF REPORT & PERIOD COVERED FINAL 6. PERFORMING ORG. REPORT NUMBER...Vehicle Code System (VCS) called MORSE was modified to accept the GIFT combinatorial geometry package. GIFT , as opposed to the geometry package

Instilling a Culture of Accountability at the Department of Homeland Security (DHS): Leveraging the Government Performance and Results Modernization Act (GPRA-MA) of 2010

DTIC Science & Technology

2013-09-01

Estrella et al., Learning from Change: Issues and Experiences in Participatory Monitoring and Evaluation (Ottawa, ON, CAN: IDRC Books, 2000); John Denton...afford:60 59 Estrella et al., Learning from Change: Issues and Experiences in...Administrator’s Companion: A Practical Guide. CQ Press, 2010. Estrella , Marisol, with Jutta Blauert, Dindo Campilan, John Gaventa, Julian Gonsalves

Examining the Support of Modern Athletic Reform Proposals Developed by the Coalition on Intercollegiate Athletics in Response to Higher Education Athletic Reform: A Case Study

ERIC Educational Resources Information Center

Zimmerman, Wade W.; Wickersham, Leah E.

2012-01-01

This study was conducted to determine the success for the diffusion of the Coalition on Intercollegiate Athletics (COIA) white paper Framing the Future: Reforming Intercollegiate Athletics. The Stages of Concern Questionnaire (SoCQ) and personal interviews were utilized to collect data and purposeful sampling was used to identify one NCAA Division…