Bakouh, Naziha; Bellanca, Sebastiano; Nyboer, Britta; Moliner Cubel, Sonia; Karim, Zoubida; Sanchez, Cecilia P; Stein, Wilfred D; Planelles, Gabrielle; Lanzer, Michael
2017-09-29
The chloroquine resistance transporter of the human malaria parasite Plasmodium falciparum , PfCRT, is an important determinant of resistance to several quinoline and quinoline-like antimalarial drugs. PfCRT also plays an essential role in the physiology of the parasite during development inside erythrocytes. However, the function of this transporter besides its role in drug resistance is still unclear. Using electrophysiological and flux experiments conducted on PfCRT-expressing Xenopus laevis oocytes, we show here that both wild-type PfCRT and a PfCRT variant associated with chloroquine resistance transport both ferrous and ferric iron, albeit with different kinetics. In particular, we found that the ability to transport ferrous iron is reduced by the specific polymorphisms acquired by the PfCRT variant as a result of chloroquine selection. We further show that iron and chloroquine transport via PfCRT is electrogenic. If these findings in the Xenopus model extend to P. falciparum in vivo , our data suggest that PfCRT might play a role in iron homeostasis, which is essential for the parasite's development in erythrocytes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Callaghan, Paul S.; Siriwardana, Amila; Hassett, Matthew R.; Roepe, Paul D.
2016-01-01
Background Recent work has perfected yeast-based methods for measuring drug transport by the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT). Methods 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 transpo...
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.
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.
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Chim W Chan
Full Text Available Nearly one million deaths are attributed to malaria every year. Recent reports of multi-drug treatment failure of falciparum malaria underscore the need to understand the molecular basis of drug resistance. Multiple mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt are involved in chloroquine resistance, but the evolution of complex haplotypes is not yet well understood. Using over 4,500 archival human serum specimens collected from 19 Pacific populations between 1959 and 1979, the period including and just prior to the appearance of chloroquine treatment failure in the Pacific, we PCR-amplified and sequenced a portion of the pfcrt exon 2 from 771 P. falciparum-infected individuals to explore the spatial and temporal variation in falciparum malaria prevalence and the evolution of chloroquine resistance. In the Pacific, the prevalence of P. falciparum varied considerably across ecological zones. On the island of New Guinea, the decreases in prevalence of P. falciparum in coastal, high-transmission areas over time were contrasted by the increase in prevalence during the same period in the highlands, where transmission was intermittent. We found 78 unique pfcrt haplotypes consisting of 34 amino acid substitutions and 28 synonymous mutations. More importantly, two pfcrt mutations (N75D and K76T implicated in chloroquine resistance were present in parasites from New Hebrides (now Vanuatu eight years before the first report of treatment failure. Our results also revealed unexpectedly high levels of genetic diversity in pfcrt exon 2 prior to the historical chloroquine resistance selective sweep, particularly in areas where disease burden was relatively low. In the Pacific, parasite genetic isolation, as well as host acquired immune status and genetic resistance to malaria, were important contributors to the evolution of chloroquine resistance in P. falciparum.
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.
Large-scale survey for novel genotypes of Plasmodium falciparum chloroquine-resistance gene pfcrt
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Takahashi Nobuyuki
2012-03-01
Full Text Available Abstract Background In Plasmodium falciparum, resistance to chloroquine (CQ is conferred by a K to T mutation at amino acid position 76 (K76T in the P. falciparum CQ transporter (PfCRT. To date, at least 15 pfcrt genotypes, which are represented by combinations of five amino acids at positions 72-76, have been described in field isolates from various endemic regions. To identify novel mutant pfcrt genotypes and to reveal the genetic relatedness of pfcrt genotypes, a large-scale survey over a wide geographic area was performed. Methods Sequences for exon 2 in pfcrt, including known polymorphic sites at amino acid positions 72, 74, 75 and 76, were obtained from 256 P. falciparum isolates collected from eight endemic countries in Asia (Bangladesh, Cambodia, Lao P.D.R., the Philippines and Thailand, Melanesia (Papua New Guinea and Vanuatu and Africa (Ghana. A haplotype network was constructed based on six microsatellite markers located -29 kb to 24 kb from pfcrt in order to examine the genetic relatedness among mutant pfcrt genotypes. Results In addition to wild type (CVMNK at positions 72-76, four mutant pfcrt were identified; CVIET, CVIDT, SVMNT and CVMNT (mutated amino acids underlined. Haplotype network revealed that there were only three mutant pfcrt lineages, originating in Indochina, Philippines and Melanesia. Importantly, the Indochina lineage contained two mutant pfcrt genotypes, CVIET (n = 95 and CVIDT (n = 14, indicating that CVIDT shares a common origin with CVIET. Similarly, one major haplotype in the Melanesian lineage contained two pfcrt genotypes; SVMNT (n = 71 and CVMNT (n = 3. In Africa, all mutant pfcrt genotypes were the CVIET of the Indochina lineage, probably resulting from the intercontinental migration of CQ resistance from Southeast Asia. Conclusions The number of CQ-mutant lineages observed in this study was identical to that found in previous studies. This supports the hypothesis that the emergence of novel CQ resistance
Bamaga, Omar A A; Mahdy, Mohammed A K; Lim, Yvonne A L
2015-09-01
Malaria is still a major public health problem in Yemen. More than 95% of the malaria cases are due to Plasmodium falciparum. Recently in Yemen, the antimalarial treatment policy was changed from chloroquine (CQ) to artemisinin combination therapy (ACTs). However, CQ is still available and prescribed in the Yemeni market. The persistence of CQ resistance will be prolonged if the shift to ACT and the simultaneous withdrawal of CQ are not rigorously implemented. The aim of the current survey is to detect chloroquine-resistant mutations in P. falciparum chloroquine-resistance transporter (pfcrt) and P. falciparum multi-drug resistance-1 (pfmdr1) genes. These data will be important for future monitoring and assessment of antimalarial drug policy in Yemen. Blood specimens were collected from 735 individuals from different districts of the Hadhramout province, Yemen by house-to-house visit. Mutation-specific nested polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP) methods were used to investigate the mutations in the pfmdr1(codons 86 and 1246) and pfcrt (codons 76, 271, 326, 356 and 371) genes. The overall prevalence of pfcrt mutations at codons 76, 271, 326 and 371 were 50.4%, 58.7%, 54.3% and 44.9%, respectively. All isolates had wild-type pfcrt 356 allele. The majority of pfmdr1 86 alleles (83.3%) and all pfmdr1 1246 alleles were wild type. There was no association between pfcrt mutations and symptomatology, gender and age groups. In conclusion, point mutations in codons 76, 271, 326 and 371 of pfcrt of P. falciparum are high suggesting a sustained high CQ resistance even after 4 years of shifting to ACTs. These findings warrant complete withdrawal of CQ use from the Yemeni market for P. falciparum and careful usage of CQ for treating Plasmodium vivax. Copyright © 2015 Elsevier B.V. All rights reserved.
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Dittrich, Sabine; Alifrangis, Michael; Stohrer, Jörg M
2005-01-01
the SVMNT haplotype. METHOD: Eighty-eight samples from an area with reported in vivo Chloroquine and in vitro Amodiaquine-resistance were screened for the K76T mutation and their Pfcrt-haplotype (c72-76) using a new SSOP-ELISA. RESULTS: Hundred percent of the analysed samples showed the K76T mutation which......OBJECTIVE: The Pfcrt-gene encodes a transmembrane protein located in the Plasmodium falciparum digestive vacuole. Chloroquine resistant (CQR) strains of African and Southeast Asian origin carry the Pfcrt-haplotype (c72-76) CVIET, whereas most South American and Papua New Guinean CQR stains carry...... is highly associated with in vivo drug failure. This very high rate of a CQR-marker is alarming in an area were CQ is still used as first line drug. The distribution of the three main Pfcrt-haplotypes was as follows: 68% CVIET, 31% SVMNT, 0% CVMNT. CONCLUSIONS: These data show, for the first time, the South...
Prevalence of the molecular marker of chloroquine resistance ( pfcrt ...
African Journals Online (AJOL)
In line with the World Health Organization (WHO) guideline on chloroquine (CQ) resistance, CQ was withdrawn as the first-line antimalarial drug in Nigeria in 2005 as a result of ... We monitored the resistance pattern 5 years after withdrawal of CQ, using the pfcrt K76T mutation as a molecular marker for CQ resistance.
Zishiri, Vincent K; Hunter, Roger; Smith, Peter J; Taylor, Dale; Summers, Robert; Kirk, Kiaran; Martin, Rowena E; Egan, Timothy J
2011-05-01
A series of 12 new dibemethin (N-benzyl-N-methyl-1-phenylmethanamine) derivatives bearing an N-aminomethyl group attached to the one phenyl ring and an H, Cl, OCH3 or N(CH3)2 group on the other have been synthesized. These compounds all showed strong chloroquine chemosensitizing activity, comparable to verapamil, when present at 1 μM in an in vitro culture of the chloroquine-resistant W2 strain of the human malaria parasite, Plasmodium falciparum. Their N-formylated derivatives also exhibited resistance-reversing activity, but only at substantially higher IC10 concentrations. A number of the dibemethin derivatives were shown to inhibit chloroquine transport via the parasite's 'chloroquine resistance transporter' (PfCRT) in a Xenopus laevis oocyte expression system. The reduced resistance-reversing activity of the formylated compounds relative to their free amine counterparts can probably be ascribed to two factors: decreased accumulation of the formylated dibemethins within the parasite's internal digestive vacuole (believed to be the site of action of chloroquine), and a reduced ability to inhibit PfCRT. The resistance-reversing activity of the compounds described here demonstrates that the amino group need not be attached to the two aromatic rings via a three or four carbon chain as has been suggested by previous QSAR studies. These compounds may be useful as potential side chains for attaching to a 4,7-dichloroquinoline group in order to generate new resistance-reversing chloroquine analogues with inherent antimalarial activity. Copyright © 2011 Elsevier Masson SAS. All rights reserved.
DEFF Research Database (Denmark)
Zhang, Jenny J; Senaratne, Tharanga N; Daniels, Rachel
2011-01-01
Abstract. Widespread antimalarial resistance has been a barrier to malaria elimination efforts in Sri Lanka. Analysis of genetic markers in historic parasites may uncover trends in the spread of resistance. We examined the frequency of Plasmodium falciparum chloroquine transporter (pfcrt; codons 72......-76) haplotypes in Sri Lanka in 1996-1998 and 2004-2006 using a high-resolution melting assay. Among 59 samples from 1996 to 1998, we detected the SVMNT (86%), CVMNK (10%), and CVIET (2%) haplotypes, with a positive trend in SVMNT and a negative trend in CVMNK frequency (P = 0.004) over time. Among 24 samples...
Griffing, Sean; Syphard, Luke; Sridaran, Sankar; McCollum, Andrea M.; Mixson-Hayden, Tonya; Vinayak, Sumiti; Villegas, Leopoldo; Barnwell, John W.; Escalante, Ananias A.; Udhayakumar, Venkatachalam
2010-01-01
Molecular tools are valuable for determining evolutionary history and the prevalence of drug-resistant malaria parasites. These tools have helped to predict decreased sensitivity to antimalarials and fixation of multidrug resistance genotypes in some regions. In order to assess how historical drug policies impacted Plasmodium falciparum in Venezuela, we examined molecular changes in genes associated with drug resistance. We examined pfmdr1 and pfcrt in samples from Sifontes, Venezuela, and integrated our findings with earlier work describing dhfr and dhps in these samples. We characterized pfmdr1 genotypes and copy number variation, pfcrt genotypes, and proximal microsatellites in 93 samples originating from surveillance from 2003 to 2004. Multicopy pfmdr1 was found in 12% of the samples. Two pfmdr1 alleles, Y184F/N1042D/D1246Y (37%) and Y184F/S1034C/N1042D/D1246Y (63%), were found. These alleles share ancestry, and no evidence of strong selective pressure on mutations was found. pfcrt chloroquine resistance alleles are fixed with two alleles: StctVMNT (91%) and SagtVMNT (9%). These alleles are associated with strong selection. There was also an association between pfcrt, pfmdr1, dhfr, and dhps genotypes/haplotypes. Duplication of pfmdr1 suggests a potential shift in mefloquine sensitivity in this region, which warrants further study. A bottleneck occurred in P. falciparum in Sifontes, Venezuela, and multidrug resistance genotypes are present. This population could be targeted for malaria elimination programs to prevent the possible spread of multidrug-resistant parasites. PMID:20145087
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
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.
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Sharma Yagya D
2007-03-01
Full Text Available Abstract Background Polymorphism in the pfcrt gene underlies Plasmodium falciparum chloroquine resistance (CQR, as sensitive strains consistently carry lysine (K, while CQR strains carry threonine (T at the codon 76. Previous studies have shown that microsatellite (MS haplotype variation can be used to study the evolution of CQR polymorphism and to characterize intra- and inter-population dispersal of CQR in Papua New Guinea (PNG. Methods Here, following identification of new polymorphic MS in introns 2 and 3 within the pfcrt gene (msint2 and msint3, respectively, locus-by-locus and haplotype heterozygosity (H analyses were performed to determine the distribution of this intronic polymorphism among pfcrt chloroquine-sensitive and CQR alleles. Results For MS flanking the pfcrt CQR allele, H ranged from 0.07 (B5M77, -18 kb to 0.094 (9B12, +2 kb suggesting that CQ selection pressure was responsible for strong homogenisation of this gene locus. In a survey of 206 pfcrt-SVMNT allele-containing field samples from malaria-endemic regions of PNG, H for msint2 was 0.201. This observation suggests that pfcrt msint2 exhibits a higher level of diversity than what is expected from the analyses of pfcrt flanking MS. Further analyses showed that one of the three haplotypes present in the early 1980's samples has become the predominant haplotype (frequency = 0.901 in CQR parasite populations collected after 1995 from three PNG sites, when CQR had spread throughout malaria-endemic regions of PNG. Apparent localized diversification of pfcrt haplotypes at each site was also observed among samples collected after 1995, where minor CQR-associated haplotypes were found to be unique to each site. Conclusion In this study, a higher level of diversity at MS loci within the pfcrt gene was observed when compared with the level of diversity at pfcrt flanking MS. While pfcrt (K76T and its immediate flanking region indicate homogenisation in PNG CQR parasite populations
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A Raeisi
2008-04-01
Full Text Available Background: This study investigated the association between pfcrt, T76 allele and chloroquine resistance in patients with falciparum malaria. Molecular assays for point mutations on drugs resistance-related genes are applied tools for monitoring emerging resistance and surveillance malaria control strategies in endemic areas. The mutant genotype at codon 76 of Plasmodium falciparum chloroquine resistance transporter gene (pfcrt has been proposed as a molecular marker for the faster detection of chloroquine resistance in field. Methods: In 64 samples from patients with uncomplicated falciparum malaria from Sarbaz district in southeast of Iran, the clinical response to chloroquine and the prevalence of K76T mutations in pfcrt gene were investigated by in vivo and nested-PCR followed restriction enzyme digestion methods. Results: The occurrence of the K76T mutation was very high (60 of 64, i.e. 93.75% among these filed isolates. Only 4 of 64 isolates harbored wild type K76 codon and no case was a mixed of K76 and 76T codons. All of the 22 (100% chloroquine-resistant and 16.7% of sensitive isolates were found to harbor the 76T mutation and none was found to contain the wild type (K76 allele. Conclusions: The frequency of chloroquine resistance associated point mutation K76T, in pfcrt gene in this region suggest that detection of this mutation can be applied for predicting chloroquine resistance in epidemiologic settings with sufficiently high sensitivity to make it an attractive alternative to time and labor-consuming in vivo trials.
Ndiaye, Magatte; Faye, Babacar; Tine, Roger; Ndiaye, Jean Louis; Lo, Aminata; Abiola, Annie; Dieng, Yemou; Ndiaye, Daouda; Hallett, Rachel; Alifrangis, Michael; Gaye, Oumar
2012-10-01
As a result of widespread antimalarial drug resistance, all African countries with endemic malaria have, in recent years, changed their malaria treatment policy. In Senegal, the health authorities changed from chloroquine (CQ) to a combination of sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) in 2003. Since 2006, the artemisinin combination therapies (ACTs) artemether-lumefantrine (AL) and artesunate plus amodiaquine (AS/AQ) were adopted for uncomplicated malaria treatment. After several years of CQ withdrawal, the current study wished to determine the level of CQ resistance at the molecular level in selected sites in Senegal, because the scientific community is interested in using CQ again. Finger prick blood samples were collected from Plasmodium falciparum-positive children below the age of 10 years (N = 474) during cross-sectional surveys conducted in two study sites in Senegal with different malaria transmission levels. One site is in central Senegal, and the other site is in the southern part of the country. All samples were analyzed for single nucleotide polymorphisms (SNPs) in the P. falciparum CQ resistance transporter gene (Pfcrt; codons 72-76) using polymerase chain reaction (PCR) sequence-specific oligonucleotide probe (SSOP) enzyme-linked immunosorbent assay (ELISA) and real-time PCR methods. In total, the 72- to 76-codon region of Pfcrt was amplified in 449 blood samples (94.7%; 285 and 164 samples from the central and southern sites of Senegal, respectively). In both study areas, the prevalence of the Pfcrt wild-type single CVMNK haplotype was very high; in central Senegal, the prevalence was 70.5% in 2009 and 74.8% in 2010, and in southern Senegal, the prevalence was 65.4% in 2010 and 71.0% in 2011. Comparing data with older studies in Senegal, a sharp decline in the mutant type Pfcrt prevalence is evident: from 65%, 64%, and 59.5% in samples collected from various sites in 2000, 2001, and 2004 to approximately 30% in our study. A similar
The Role of ABC Proteins in Drug Resistant Breast Cancer Cells
2008-04-01
called the Plasmodium falciparum Chloroquine Transporter (PfCRT). While PfCRT is known to be the main molecular determinant of chloroquine resistance...proteins (such as human P-glycoprotein) and labeled PfCRT with a photoaffinity drug analogue . A manuscript is currently in preparation detailing my results...directly responsible for drug response, the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT) (Fidock et al 2000). While not a member of
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Adamou Salissou
2014-01-01
Full Text Available Chloroquine (CQ resistance is widespread in Africa, but few data are available for Niger. Pfcrt haplotypes (aa 56–118 and ex vivo responses to CQ and amodiaquine were characterized for 26 isolates collected in South Niger from children under 15 years of age suffering from uncomplicated falciparum malaria, six years after the introduction of artemisinin-based combinations and the withdrawal of CQ. The wild-type Pfcrt haplotype CVMNK was found in 22 of the 26 isolates, with CVIET sequences observed in only three of the samples. We also describe for the first time a new CVINT haplotype. The ex vivo responses were better for CVMNK than for CVIET parasites. Pfcrt sequence data were compared with those obtained for 26 additional parasitized blood samples collected in Gabon, from an area of CQ resistance used as a control. Our findings suggest that there has been a significant decline in CQ-resistant genotypes since the previous estimates for Niger were obtained. No such decline in molecular resistance to CQ was observed in the subset of samples collected in similar conditions from Gabon. These results have important implications for public health and support the policy implemented in Niger since 2005, which aims to increase the efficacy and availability of antimalarial drugs whilst controlling the spread of resistance.
Al-Mekhlafi, Abdulsalam M; Mahdy, Mohammed A K; Al-Mekhlafi, Hesham M; Azazy, Ahmed A; Fong, Mun Yik
2011-05-27
Malaria remains a significant health problem in Yemen with Plasmodium falciparum being the predominant species which is responsible for 90% of the malaria cases. Despite serious concerns regarding increasing drug resistance, chloroquine is still used for the prevention and treatment of malaria in Yemen. This study was carried out to determine the prevalence of choloroquine resistance (CQR) of P. falciparum isolated from Yemen based on the pfcrt T76 mutation. A cross-sectional study was carried out among 511 participants from four governorates in Yemen. Blood samples were screened using microscopic and species-specific nested PCR based on the 18S rRNA gene to detect and identify Plasmodium species. Blood samples positive for P. falciparum were used for detecting the pfcrt T76 mutation using nested-PCR. The prevalence of pfcrt T76 mutation was 81.5% (66 of 81 isolates). Coastal areas/foothills had higher prevalence of pfcrt T76 mutation compared to highland areas (90.5% vs 71.8%) (p = 0.031). The pfcrt T76 mutation had a significant association with parasitaemia (p = 0.045). Univariate analysis shows a significant association of pfcrt T76 mutation with people aged > 10 years (OR = 9, 95% CI = 2.3 - 36.2, p = 0.001), low household income (OR = 5, 95% CI = 1.3 - 19.5, p = 0.027), no insecticide spray (OR = 3.7, 95% CI = 1.16 - 11.86, p = 0.025) and not sleeping under insecticide treated nets (ITNs) (OR = 4.8, 95% CI = 1.38 - 16.78, p = 0.01). Logistic regression model confirmed age > 10 years and low household income as predictors of pfcrt T76 mutation in Yemen P. falciparum isolates. The high prevalence of pfcrt T76 mutation in Yemen could be a predictive marker for the prevalence of P. falciparum CQR. This finding shows the necessity for an in-vivo therapeutic efficacy test for CQ. P. falciparum CQR should be addressed in the national strategy to control malaria.
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Valérie Andriantsoanirina
2010-10-01
Full Text Available Molecular studies have demonstrated that mutations in the Plasmodium falciparum chloroquine resistance transporter gene (Pfcrt play a major role in chloroquine resistance, while mutations in P. falciparum multidrug resistance gene (Pfmdr-1 act as modulator. In Madagascar, the high rate of chloroquine treatment failure (44% appears disconnected from the overall level of in vitro CQ susceptibility (prevalence of CQ-resistant parasites 60% of isolates, but did not explore their association with P. falciparum chloroquine resistance. To document the association of Pfmdr-1 alleles with chloroquine resistance in Madagascar, 249 P. falciparum samples collected from patients enrolled in a chloroquine in vivo efficacy study were genotyped in Pfcrt/Pfmdr-1 genes as well as the estimation of the Pfmdr-1 copy number. Except 2 isolates, all samples displayed a wild-type Pfcrt allele without Pfmdr-1 amplification. Chloroquine treatment failures were significantly associated with Pfmdr-1 86Y mutant codon (OR = 4.6. The cumulative incidence of recurrence of patients carrying the Pfmdr-1 86Y mutation at day 0 (21 days was shorter than patients carrying Pfmdr-1 86N wild type codon (28 days. In an independent set of 90 selected isolates, in vitro susceptibility to chloroquine was not associated with Pfmdr-1 polymorphisms. Analysis of two microsatellites flanking Pfmdr-1 allele showed that mutations occurred on multiple genetic backgrounds. In Madagascar, Pfmdr-1 polymorphism is associated with late chloroquine clinical failures and unrelated with in vitro susceptibility or Pfcrt genotype. These results highlight the limits of the current in vitro tests routinely used to monitor CQ drug resistance in this unique context. Gaining insight about the mechanisms that regulate polymorphism in Pfmdr1 remains important, particularly regarding the evolution and spread of Pfmdr-1 alleles in P. falciparum populations under changing drug pressure which may have important
Plasmodium falciparum isolates from Angola show the StctVMNT haplotype in the pfcrt gene
2010-01-01
Background Effective treatment remains a mainstay of malaria control, but it is unfortunately strongly compromised by drug resistance, particularly in Plasmodium falciparum, the most important human malaria parasite. Although P. falciparum chemoresistance is well recognized all over the world, limited data are available on the distribution and prevalence of pfcrt and pfmdr1 haplotypes that mediate resistance to commonly used drugs and that show distinct geographic differences. Methods Plasmodium falciparum-infected blood samples collected in 2007 at four municipalities of Luanda, Angola, were genotyped using PCR and direct DNA sequencing. Single nucleotide polymorphisms in the P. falciparum pfcrt and pfmdr1 genes were assessed and haplotype prevalences were determined. Results and Discussion The most prevalent pfcrt haplotype was StctVMNT (representing amino acids at codons 72-76). This result was unexpected, since the StctVMNT haplotype has previously been seen mainly in parasites from South America and India. The CVIET, CVMNT and CVINT drug-resistance haplotypes were also found, and one previously undescribed haplotype (CVMDT) was detected. Regarding pfmdr1, the most prevalent haplotype was YEYSNVD (representing amino acids at codons 86, 130, 184, 1034, 1042, 1109 and 1246). Wild haplotypes for pfcrt and pfmdr1 were uncommon; 3% of field isolates harbored wild type pfcrt (CVMNK), whereas 21% had wild type pfmdr1 (NEYSNVD). The observed predominance of the StctVMNT haplotype in Angola could be a result of frequent travel between Brazil and Angola citizens in the context of selective pressure of heavy CQ use. Conclusions The high prevalence of the pfcrt SVMNT haplotype and the pfmdr1 86Y mutation confirm high-level chloroquine resistance and might suggest reduced efficacy of amodiaquine in Angola. Further studies must be encouraged to examine the in vitro sensitivity of pfcrt SVMNT parasites to artesunate and amodiaquine for better conclusive data. PMID:20565881
DEFF Research Database (Denmark)
Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia
2014-01-01
Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated...... with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized...
DEFF Research Database (Denmark)
Ndiaye, Magatte; Faye, Babacar; Tine, Roger
2012-01-01
Abstract. As a result of widespread antimalarial drug resistance, all African countries with endemic malaria have, in recent years, changed their malaria treatment policy. In Senegal, the health authorities changed from chloroquine (CQ) to a combination of sulfadoxine-pyrimethamine (SP) plus...... at the molecular level in selected sites in Senegal, because the scientific community is interested in using CQ again. Finger prick blood samples were collected from Plasmodium falciparum-positive children below the age of 10 years (N = 474) during cross-sectional surveys conducted in two study sites in Senegal...... with different malaria transmission levels. One site is in central Senegal, and the other site is in the southern part of the country. All samples were analyzed for single nucleotide polymorphisms (SNPs) in the P. falciparum CQ resistance transporter gene (Pfcrt; codons 72-76) using polymerase chain reaction...
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Satish K. Dhingra
2017-05-01
Full Text Available 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.
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Alifrangis, Michael; Dalgaard, Michael B; Lusingu, John P
2006-01-01
Two main haplotypes, CVIET and SVMNT, of the Plasmodium falciparum chloroquine-resistance transporter gene (Pfcrt) are linked to 4-aminoquinoline resistance. The CVIET haplotype has been reported in most malaria-endemic regions, whereas the SVMNT haplotype has only been found outside Africa. We...... investigated Pfcrt haplotype frequencies in Korogwe District, Tanzania, in 2003 and 2004. The SVMNT haplotype was not detected in 2003 but was found in 19% of infected individuals in 2004. Amodiaquine use has increased in the region. The introduction and high prevalence of the SVMNT haplotype may reflect...... this and may raise concern regarding the use of amodiaquine in artemisinin-based combination therapies in Africa....
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
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Alifrangis, Michael; Enosse, Sonia; Pearce, Richard
2005-01-01
Single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum dihydrofolate reductase (dhfr), and dihydropteroate synthetase (dhps), and chloroquine resistance transporter (Pfcrt) genes are used as molecular markers of P. falciparum resistance to sulfadoxine/pyrimethamine and chloroquine....... However, to be a practical tool in the surveillance of drug resistance, simpler methods for high-throughput haplotyping are warranted. Here we describe a quick and simple technique that detects dhfr, dhps, and Pfcrt SNPs using polymerase chain reaction (PCR)- and enzyme-linked immunosorbent assay (ELISA...
No seasonal accumulation of resistant P. falciparum when high-dose chloroquine is used
DEFF Research Database (Denmark)
Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia
2009-01-01
increase of pfcrt 76T if the high doses of CQ commonly used are effective. METHODS AND FINDINGS: P. falciparum parasite density, age, sex, the proportion of chloroquine resistance associated haplotypes pfcrt 76T and P. falciparum multidrug resistance gene 1 86Y were assessed in 988 samples collected from...... to become the dominant P.falciparum type in Guinea-Bissau. This is most likely due to the efficacy of high-dose chloroquine as used in Guinea-Bissau, combined with a loss of fitness associated with pfcrt 76T.......BACKGROUND: Potentially chloroquine resistant P. falciparum, identified by the 76T haplotype in the chloroquine resistance transporter (pfcrt 76T), are highly prevalent throughout Africa. In Guinea-Bissau, normal and double dose chloroquine have respective efficacies of 34% and 78% against P...
PFCRT and DHFR-TS Sequences for Monitoring Drug Resistance in ...
African Journals Online (AJOL)
Erah
from falciparum malaria isolates collected in Adzopé City, Côte d'Ivoire in 2007. Methods: Blood ... performed using specific primers of pfcrt and dhfr-ts. During the study .... The following mixture was prepared to a final volume of 50 ..... following the withdrawal of these anti- malarials as ... Malaria vaccines in Africa. Acta Trop.
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Warhurst David C
2003-09-01
Full Text Available Abstract Background Chloroquine accumulates in the acidic digestive vacuole of the intraerythrocytic malaria parasite, and prevents the detoxication of haematin released during haemoglobin digestion. Changes in protein PfCRT in the digestive vacuole membrane of growing intra-erythrocytic stages of Plasmodium falciparum are crucial for resistance. Expressed in yeast, PfCRT resembles an anion channel. Depressed anion channel function could increase intralysosomal pH to reduce entry of basic drug, or enhanced function could reduce drug interaction with target haematin. The most important resistance-associated change is from positively-charged lysine-76 to neutral threonine which could facilitate drug efflux through a putative channel. It has been proposed that the resistance-reversing effect of verapamil is due to hydrophobic binding to the mutated PfCRT protein, and replacement of the lost positive charge, which repels the access of 4-aminoquinoline cations, thus partially restoring sensitivity. Desethylamodiaquine, the active metabolite of amodiaquine, which has significant activity in chloroquine-resistance, may also act similarly on its own. Methods Changes in physicochemical parameters in different CQ-resistant PfCRT sequences are analysed, and correlations with drug activity on lines transfected with different alleles of the pfcrt gene are examined. Results and conclusions The results support the idea that PfCRT is a channel which, in resistant parasites, can allow efflux of chloroquine from the digestive vacuole. Activity of the chloroquine/verapamil combination and of desethylamodiaquine both correlate with the mean hydrophobicity of PfCRT residues 72-76. This may partly explain clinical-resistance to amodiaquine found in the first chloroquine-resistant malaria cases from South America and enables tentative prediction of amodiaquine's clinical activity against novel haplotypes of PfCRT.
Duah, Nancy O; Matrevi, Sena A; de Souza, Dziedzom K; Binnah, Daniel D; Tamakloe, Mary M; Opoku, Vera S; Onwona, Christiana O; Narh, Charles A; Quashie, Neils B; Abuaku, Benjamin; Duplessis, Christopher; Kronmann, Karl C; Koram, Kwadwo A
2013-10-30
With the introduction of artemisinin-based combination therapy (ACT) in 2005, monitoring of anti-malarial drug efficacy, which includes the use of molecular tools to detect known genetic markers of parasite resistance, is important for first-hand information on the changes in parasite susceptibility to drugs in Ghana. This study investigated the Plasmodium falciparum multidrug resistance gene (pfmdr1) copy number, mutations and the chloroquine resistance transporter gene (pfcrt) mutations in Ghanaian isolates collected in seven years to detect the trends in prevalence of mutations. Archived filter paper blood blots collected from children aged below five years with uncomplicated malaria in 2003-2010 at sentinel sites were used. Using quantitative real-time polymerase chain reaction (qRT-PCR), 756 samples were assessed for pfmdr1 gene copy number. PCR and restriction fragment length polymorphism (RFLP) were used to detect alleles of pfmdr1 86 in 1,102 samples, pfmdr1 184, 1034, 1042 and 1246 in 832 samples and pfcrt 76 in 1,063 samples. Merozoite surface protein 2 (msp2) genotyping was done to select monoclonal infections for copy number analysis. The percentage of isolates with increased pfmdr1 copy number were 4, 27, 9, and 18% for 2003-04, 2005-06, 2007-08 and 2010, respectively. Significant increasing trends for prevalence of pfmdr1 N86 (×(2) = 96.31, p resistance has been reported. The decreasing trend in the prevalence of chloroquine resistance markers after change of treatment policy presents the possibility for future introduction of chloroquine as prophylaxis for malaria risk groups such as children and pregnant women in Ghana.
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Fredrick L Eyase
Full Text Available Single Nucleotide Polymorphisms (SNPs in the Pfmdr1, and Pfcrt, genes of Plasmodium falciparum may confer resistance to a number of anti-malaria drugs. Pfmdr1 86Y and haplotypes at Pfcrt 72-76 have been linked to chloroquine (CQ as well as amodiaquine (AQ resistance. mefloquine (MQ and lumefantrine (LU sensitivities are linked to Pfmdr1 86Y. Additionally, Pfcrt K76 allele carrying parasites have shown tolerance to LU. We investigated the association between Pfmdr1 86/Pfcrt 72-76 and P. falciparum resistance to CQ, AQ, MQ and LU using field samples collected during 2008-2011 from malaria endemic sites in western Kenya. Genomic DNA from these samples was genotyped to examine SNPs and haplotypes in Pfmdr1 and Pfcrt respectively. Additionally, immediate ex vivo and in vitro drug sensitivity profiles were assessed using the malaria SYBR Green I fluorescence-based assay. We observed a rapid but steady percent increase in wild-type parasites with regard to both Pfmdr1 and Pfcrt between 2008 and 2011 (p<0.0001. Equally, a significant reciprocate decrease in AQ and CQ median IC50 values occurred (p<0.0001 during the same period. Thus, the data in this study point to a significantly rapid change in parasite response to AQ and CQ in the study period. This may be due to releasing of drug pressure on the parasite from reduced use of AQ in the face of increased Artemisinin (ART Combination Therapy (ACT administration following the intervention of the Global Fund in 2008. LU has been shown to select for 76K genotypes, thus the observed increase in 76K genotypes coupled with significant cross resistance between LU and MQ, may herald emergence of tolerance against both drugs in future.
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Chance Michael L
2011-08-01
Full Text Available Abstract Background This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for Plasmodium falciparum resistance against CQ and sulphadoxine/pyrimethamine (SP. Methods Between 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for P. falciparum chloroquine resistance transporter gene (pfcrt-76 polymorphisms, mutation pfcrt-S163R and the antifolate resistance-associated mutations dihydrofolate reductase (dhfr-C59R and dihydropteroate synthase (dhps-K540E. Direct DNA sequencing of the pfcrt gene from three representative field samples was carried out after DNA amplification of the 13 exons of the pfcrt gene. Results Treatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant pfcrt T76 was 98% in 112 amplified pre-treatment samples. The presence of pfcrt T76 was poorly predictive of in vivo CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9. The prevalence of dhfr Arg-59 mutation in 99 amplified samples was 5%, while the dhps Glu-540 was not detected in any of 119 amplified samples. Sequencing the pfcrt gene confirmed that Yemeni CQ resistant P. falciparum carry the old world (Asian and African CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371. Conclusion This is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR P. falciparum
Mubjer, Reem A; Adeel, Ahmed A; Chance, Michael L; Hassan, Amir A
2011-08-21
This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ) against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for Plasmodium falciparum resistance against CQ and sulphadoxine/pyrimethamine (SP). Between 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for P. falciparum chloroquine resistance transporter gene (pfcrt)-76 polymorphisms, mutation pfcrt-S163R and the antifolate resistance-associated mutations dihydrofolate reductase (dhfr)-C59R and dihydropteroate synthase (dhps)-K540E. Direct DNA sequencing of the pfcrt gene from three representative field samples was carried out after DNA amplification of the 13 exons of the pfcrt gene. Treatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant pfcrt T76 was 98% in 112 amplified pre-treatment samples. The presence of pfcrt T76 was poorly predictive of in vivo CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9). The prevalence of dhfr Arg-59 mutation in 99 amplified samples was 5%, while the dhps Glu-540 was not detected in any of 119 amplified samples. Sequencing the pfcrt gene confirmed that Yemeni CQ resistant P. falciparum carry the old world (Asian and African) CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371. This is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR P. falciparum parasites from Yemen. Mutant pfcrtT76 is highly prevalent but it
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
Fançony, Cláudia; Gamboa, Dina; Sebastião, Yuri; Hallett, Rachel; Sutherland, Colin; Sousa-Figueiredo, José Carlos
2012-01-01
Artemisinin-based combination therapy for malaria has become widely available across Africa. Populations of Plasmodium falciparum that were previously dominated by chloroquine (CQ)-resistant genotypes are now under different drug selection pressures. P. malariae, P. ovale curtisi, and P. ovale wallikeri are sympatric with P. falciparum across the continent and are frequently present as coinfections. The prevalence of human Plasmodium species was determined by PCR using DNA from blood spots collected during a cross-sectional survey in northern Angola. P. falciparum was genotyped at resistance-associated loci in pfcrt and pfmdr1 by real-time PCR or by direct sequencing of amplicons. Of the 3,316 samples collected, 541 (16.3%) contained Plasmodium species infections; 477 (88.2%) of these were P. falciparum alone, 6.5% were P. falciparum and P. malariae together, and 1.1% were P. vivax alone. The majority of the remainder (3.7%) harbored P. ovale curtisi or P. ovale wallikeri alone or in combination with other species. Of 430 P. falciparum isolates genotyped for pfcrt, 61.6% carried the wild-type allele CVMNK at codons 72 to 76, either alone or in combination with the resistant allele CVIET. No other pfcrt allele was found. Wild-type alleles dominated at codons 86, 184, 1034, 1042, and 1246 of the pfmdr1 locus among the sequenced isolates. In contrast to previous studies, P. falciparum in the study area comprises an approximately equal mix of genotypes associated with CQ sensitivity and with CQ resistance, suggesting either lower drug pressure due to poor access to treatment in rural areas or a rapid impact of the policy change away from the use of standard monotherapies. PMID:22850519
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Chimere Obiora Agomo
Full Text Available The use of antimalarial drugs for prevention and treatment is a major strategy in the prevention of malaria in pregnancy. Although sulphadoxine-pyrimethamine (SP is currently recommended for intermittent preventive treatment of malaria during pregnancy in Nigeria, previously used drugs for prophylaxis such as chloroquine (CQ and pyrimethamine are accessible as they are purchased over the counter. This study describes the markers of absence or presence of resistance to quinoline (Pfcrt and Pfmdr 1 and type 1 antifolate antimalarial medicines (Pfdhfr.Plasmodium falciparum-positive dried blood spots from pregnant women attending antenatal clinics for the first time during current pregnancy were investigated for the presence of mutations at codons 72-76 of Plasmodium falciparum chloroquine resistance transporter (Pfcrt gene by real time polymerase chain reaction (PCR using haplotype-specific probes. PCR followed by sequence analysis was used to identify mutations at codons 86, 184, 1034, 1042 and 1246 of P. falciparum multi-drug resistance-1 (Pfmdr1 gene; and codons 16, 50, 51, 59, 108, 140 and 164 of Pfdhfr gene.Two haplotypes of Pfcrt (n = 54 were observed: CVMNK 13(24.2% and CVIET 41 (75.9% of the samples. The SVMNT haplotype was absent in this population. The Pfmdr1 (n = 28 haplotypes were NYSND 15(53.6%, YYSND 5(17.9%, NFSND 6(21.4% and YFSND 2(7.1%. The Pfdhfr (n = 15 were ACNCSVI 4(26.7%, and ACICNSVI 1(6.7% and ACIRNVI 10 (66.7%. The rate of occurrence of Pfcrt 76T, Pfdhfr108N, Pfmdr186Y and 184F were 75.9%, 73.3%, 25% and 28.1% respectively. The Pfmdr1 86Y was associated with low parasitaemia (median = 71 parasites/μl, P = 0.024 while Pfcrt 76T was associated with young maternal age (mean 24.1 ± 4.5 years; P = 0.006. The median parasitaemia were similar (P>0.05 in wild and mutant strains of Pfcrt 76, Pfmdr1 184 and Pfdhfr 108. There was no association between gravidity or gestational age of the women and presence of mutations in the Pfcrt
On the mechanism of chloroquine resistance in Plasmodium falciparum.
Chinappi, Mauro
2010-11-19
Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.
On the mechanism of chloroquine resistance in Plasmodium falciparum.
Chinappi, Mauro; Via, Allegra; Marcatili, Paolo; Tramontano, Anna
2010-01-01
Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.
On the Mechanism of Chloroquine Resistance in Plasmodium falciparum
Marcatili, Paolo; Tramontano, Anna
2010-01-01
Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data. PMID:21124966
DEFF Research Database (Denmark)
Ursing, Johan; Schmidt, Berit Aydin; Lebbad, Marianne
2007-01-01
Chloroquine resistant malaria was first reported in Guinea-Bissau in 1990 but chloroquine remains the most commonly used antimalarial in the country. Since 1990, we have conducted nearly annual standardized WHO in vitro micro-tests to assess chloroquine resistance. We have identified pfcrt 76T...... and other genetic polymorphisms in samples from 1992, 1993, 1995, 2004 and 2005. We have also monitored drug prescriptions for febrile illnesses. The mean proportion of in vitro tests indicating chloroquine resistance was 33% (range 14-54%) with the exception of an outlying value year 2000. The proportion...... of chloroquine resistant P. falciparum detected by in vitro testing did not increase over time. Pfcrt 76T was associated with chloroquine resistance but pfmdr1 86Y was not. The mean pfcrt 76T prevalence varied between 13% and 38%. The prevalence of SNPs at Pfcrt positions 76, 271, 326 and pfmdr1 position 86 did...
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Warhurst David C
2010-03-01
Full Text Available Abstract Background Parasite resistance to the anti-malarial drug chloroquine is common in eastern Sudan. Dynamic within-host changes in the relative abundance of both sensitive and resistant Plasmodium falciparum parasites were examined in a cohort of chloroquine-treated patients presenting with uncomplicated falciparum malaria, using a novel allele-specific quantitative approach. Methods Treatment outcomes were determined for 93 patients of all ages in a per protocol cohort using a modified 14-day WHO protocol. Parasite DNA samples at days 0, 1, 2, 3, 7 and 14 following treatment were analysed using real-time quantitative PCR methods that distinguished resistant and sensitive genotypes at amino acids 72 - 76 of the pfcrt locus. Results Chloroquine treatment was not efficacious, and of 93 assessable patients, only 10 individuals (10.7%; 95% C.I. 4.34 - 17.2% enjoyed an adequate clinical and parasitological response. Resistant parasites with the haplotype CVIET at codons 72-76 of the pfcrt locus were dominant in the starting population. Chloroquine sensitive parasites with the haplotype CVMNK were detected in 19 individuals prior to treatment (20.43%; 95% C.I. 5.14 - 18.5%. In these patients, CQ treatment rapidly selected CVIET parasites, and this haplotype overwhelmingly dominated the parasite population in each individual by day 2 after treatment. Conclusions Such rapid intra-host selection of particular genotypes after the introduction of drug will cause frequent misidentification of parasite genotypes present in the starting population. This will have a potentially serious confounding effect on clinical trials which employ PCR-corrected estimates of treatment failure, as resistant parasites below the detection threshold in the pre-treatment sample can be erroneously classified as "new" infections during follow-up, over-estimating drug efficacy.
Henriques, Gisela; Hallett, Rachel L; Beshir, Khalid B; Gadalla, Nahla B; Johnson, Rachel E; Burrow, Rebekah; van Schalkwyk, Donelly A; Sawa, Patrick; Omar, Sabah A; Clark, Taane G; Bousema, Teun; Sutherland, Colin J
2014-12-15
The efficacy of artemisinin-based combination therapy (ACT) for Plasmodium falciparum malaria may be threatened by parasites with reduced responsiveness to artemisinins. Among 298 ACT-treated children from Mbita, Kenya, submicroscopic persistence of P. falciparum on day 3 posttreatment was associated with subsequent microscopically detected parasitemia at days 28 or 42. DNA sequences of resistance-associated parasite loci pfcrt, pfmdr1, pfubp1, and pfap2mu were determined in the Mbita cohort before treatment, on days 2 and 3 after initiation of treatment, and on the day of treatment failure. Parasites surviving ACT on day 2 or day 3 posttreatment were significantly more likely than the baseline population to carry the wild-type haplotypes of pfcrt (CVMNK at codons 72-76; P < .001) and pfmdr1 (NFD at codons 86, 184, 1246; P < .001). In contrast, variant alleles of the novel candidate resistance genes pfap2mu (S160N/T; P = .006) and pfubp-1 (E1528D; P < .001) were significantly more prevalent posttreatment. No genetic similarities were found to artemisinin-tolerant parasites recently described in Cambodia. Among treated children in western Kenya, certain P. falciparum genotypes defined at pfcrt, pfmdr1, pfap2mu, and pfubp1 more often survive ACT at the submicroscopic level, and contribute to onward transmission and subsequent patent recrudescence. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
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Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia
2007-01-01
Chloroquine is the most commonly used antimalarial in Guinea-Bissau and high doses are routinely prescribed. Blood from 497 patients treated with different doses of chloroquine or amodiaquine were genotyped. Pfcrt and pfmdr1 polymorphisms were identified. Pfmsp2 analysis identified recrudescent...... infections. The pfcrt 72-76 haplotypes were CVIET and CVMNK. The pfcrt 76T prevalence was 23% at day 0 and 96%, 83% and 100% at recrudescence following treatment with 25 mg/kg and 50 mg/kg of chloroquine and 15 mg/kg of amodiaquine respectively. When treating pfcrt 76T carrying P. falciparum the efficacy...... of 50 mg/kg and 25 mg/kg of chloroquine was 78% and 34% respectively (P = 0.007). The genetic basis of chloroquine resistance is probably the same in Guinea-Bissau as in the rest of Africa. The low pfcrt 76T prevalence suggests that resistance to normal dose chloroquine does not confer a major advantage...
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 (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
DEFF Research Database (Denmark)
Khalil, I F; Alifrangis, M; Tarimo, D S
2005-01-01
The resistance of Plasmodium falciparum to chloroquine (CQ) is probably mediated by point mutations in two genes: pfcrt and pfmdr1. The aim of the present study was to investigate, in patients treated with CQ, the association between host factors, such as immunity and initial level of parasitaemia......, and the ability to clear P. falciparum parasites carrying the key chloroquine-resistance (CQR) mutations, pfcrt 76T and pfmdr1 86Y. Identical CQ-efficacy trials were performed in 51 young children (aged ..., such as level of parasitaemia when treated and age, are also important. The 76T and 86Y alleles could still be used as predictive markers for CQR, in non-immune individuals and low-transmission areas....
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.
DEFF Research Database (Denmark)
Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia
2011-01-01
In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele,......, was routinely used. The present study compared the efficacy and tolerability of a double standard dose of chloroquine with the efficacy and tolerability of artemether-lumefantrine.......In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele...
Gbotosho, Grace O.; Folarin, Onikepe A.; Bustamante, Carolina; Pereira da Silva, Luis Hildebrando; Mesquita, Elieth; Sowunmi, Akintunde; Zalis, Mariano G.; Oduola, Ayoade M. J.; Happi, Christian T.
2012-01-01
The effect of antimalarial drug selection on pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from two distinct geographical locations was determined in 70 and 18 P. falciparum isolates from Nigeria and Brazil, respectively, using nested polymerase chain reaction and direct DNA sequencing approaches. All isolates from Brazil and 72% from Nigeria harbored the mutant SVMNT and CVIET pfcrt haplotype, respectively. The pfcrt CVMNT haplotype was also observed in (7%) of the Nigerian samples. One hundred percent (100%) and 54% of the parasites from Brazil and Nigeria, respectively, harbored wild-type pfmdr1Asn86. We provide first evidence of emergence of the CVMNT haplotype in West Africa. The high prevalence of pfcrt CVIET and SVMNT haplotypes in Nigeria and Brazil, respectively, is indicative of different selective pressure by chloroquine and amodiaquine. Continuous monitoring of pfcrt SVMNT haplotype is required in endemic areas of Africa, where artesunate-amodiaquine combination is used for treatment of acute uncomplicated malaria. PMID:22302850
Genetics of chloroquine-resistant malaria: a haplotypic view
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Gauri Awasthi
2013-12-01
Full Text Available The development and rapid spread of chloroquine resistance (CQR in Plasmodium falciparum have triggered the identification of several genetic target(s in the P. falciparum genome. In particular, mutations in the Pfcrt gene, specifically, K76T and mutations in three other amino acids in the region adjoining K76 (residues 72, 74, 75 and 76, are considered to be highly related to CQR. These various mutations form several different haplotypes and Pfcrt gene polymorphisms and the global distribution of the different CQR- Pfcrt haplotypes in endemic and non-endemic regions of P. falciparum malaria have been the subject of extensive study. Despite the fact that the Pfcrt gene is considered to be the primary CQR gene in P. falciparum , several studies have suggested that this may not be the case. Furthermore, there is a poor correlation between the evolutionary implications of the Pfcrt haplotypes and the inferred migration of CQR P. falciparum based on CQR epidemiological surveillance data. The present paper aims to clarify the existing knowledge on the genetic basis of the different CQR- Pfcrt haplotypes that are prevalent in worldwide populations based on the published literature and to analyse the data to generate hypotheses on the genetics and evolution of CQR malaria.
Fontecha, Gustavo A; Sanchez, Ana L; Mendoza, Meisy; Banegas, Engels; Mejía-Torres, Rosa E
2014-07-01
Countries could use the monitoring of drug resistance in malaria parasites as an effective early warning system to develop the timely response mechanisms that are required to avert the further spread of malaria. Drug resistance surveillance is essential in areas where no drug resistance has been reported, especially if neighbouring countries have previously reported resistance. Here, we present the results of a four-year surveillance program based on the sequencing of the pfcrt gene of Plasmodium falciparum populations from endemic areas of Honduras. All isolates were susceptible to chloroquine, as revealed by the pfcrt "CVMNK" genotype in codons 72-76.
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Addimas Tajebe
2015-03-01
Conclusions: The study showed high prevalence level and fixation of Pfcrt, 76T mutation after chloroquine withdrawal. The prevalence of Pfmdr1 copy number variant suggested that the presence of modulating factor for emergence of Plasmodium falciparum strains with higher copy numbers. However, the prevalence level was not statistically significant.
Jovel, Irina T; Mejía, Rosa E; Banegas, Engels; Piedade, Rita; Alger, Jackeline; Fontecha, Gustavo; Ferreira, Pedro E; Veiga, Maria I; Enamorado, Irma G; Bjorkman, Anders; Ursing, Johan
2011-12-19
In Honduras, chloroquine and primaquine are recommended and still appear to be effective for treatment of Plasmodium falciparum and Plasmodium vivax malaria. The aim of this study was to determine the proportion of resistance associated genetic polymorphisms in P. falciparum and P. vivax collected in Honduras. Blood samples were collected from patients seeking medical attention at the Hospital Escuela in Tegucigalpa from 2004 to 2006 as well as three regional hospitals, two health centres and one regional laboratory during 2009. Single nucleotide polymorphisms in P. falciparum chloroquine resistance transporter (pfcrt), multidrug resistance 1 (pfmdr1), dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes and in P. vivax multidrug resistance 1 (pvmdr1) and dihydrofolate reductase (pvdhfr) genes were detected using PCR based methods. Thirty seven P. falciparum and 64 P. vivax samples were collected. All P. falciparum infections acquired in Honduras carried pfcrt, pfmdr1, pfdhps and pfdhfr alleles associated with chloroquine, amodiaquine and sulphadoxine-pyrimethamine sensitivity only. One patient with parasites acquired on a Pacific Island had pfcrt 76 T and pfmdr1 86Y alleles. That patient and a patient infected in West Africa had pfdhfr 51I, 59 R and 108 N alleles. Pvmdr1 976 F was found in 7/37 and two copies of pvmdr1 were found in 1/37 samples. Pvdhfr 57 L + 58 R was observed in 2/57 samples. The results indicate that P. falciparum from Honduras remain sensitive to chloroquine and sulphadoxine-pyrimethamine. This suggests that chloroquine and sulphadoxine-pyrimethamine should be efficacious for treatment of uncomplicated P. falciparum malaria, supporting current national treatment guidelines. However, genetic polymorphisms associated with chloroquine and sulphadoxine-pyrimethamine tolerance were detected in local P. vivax and imported P. falciparum infections. Continuous monitoring of the prevalence of drug resistant/tolerant P
Molecular epidemiology of drug-resistant Plasmodium falciparum in Benguela province, Angola.
Foumane Ngane, Vincent; Allico Djaman, Joseph; Culeux, Cécile; Piette, Nathalie; Carnevale, Pierre; Besnard, Patrick; Fortes, Filomeno; Basco, Leonardo K; Tahar, Rachida
2015-03-14
The malaria situation has been worsening in Angola, partly due to armed conflict until the recent past and drug-resistant Plasmodium falciparum. Malaria transmission is heterogeneous within the country, and data on drug-resistant malaria in different parts of the country are incomplete. The aim of the present study was to evaluate resistance to 4-aminoquinolines and antifolate drugs in P. falciparum isolates collected in Benguela province, central Angola, using molecular markers. Fingerprick capillary blood was collected from asymptomatic children aged less than 15 years old during a household survey in and around Balombo town in 2010-2011. Samples were screened for P. falciparum by nested PCR. Molecular markers (P. falciparum dihydrofolate reductase [pfdhfr], P. falciparum dihydropteroate synthase [pfdhps], P. falciparum chloroquine resistance transporter [pfcrt], and P. falciparum multidrug-resistance gene 1 [pfmdr1]) were sequenced to determine the key codons associated with drug resistance. A total of 60 blood samples were positive for P. falciparum. Most isolates with successful PCR amplification had mutant pfdhfr alleles, with either double mutant AICNI (69%) or triple mutant AIRNI (21%) haplotypes. A16V, S108T, and I164L substitutions were not found. Many of the isolates were carriers of either SGKAA (60%) or AGKAA (27%) pfdhps haplotype. K540E substitution was absent. There were only two pfcrt haplotypes: wild-type CVMNK (11%) and mutant CVIET (89%). Wild-type pfmdr1 NYSND haplotype was found in 19% of the isolates, whereas single mutant pfmdr1 YYSND and NFSND haplotypes occurred in 48% and 11%, respectively. Double mutant pfmdr1 haplotypes (YFSND and YYSNY) occurred rarely. The results suggest that the high prevalence of mutant pfcrt CVIET haplotype is in agreement with low clinical efficacy of chloroquine observed in earlier studies and that the double pfdhfr mutant AICNI and single pfdhps mutant SGKAA are currently the predominant haplotypes associated
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Gustavo A Fontecha
2014-07-01
Full Text Available Countries could use the monitoring of drug resistance in malaria parasites as an effective early warning system to develop the timely response mechanisms that are required to avert the further spread of malaria. Drug resistance surveillance is essential in areas where no drug resistance has been reported, especially if neighbouring countries have previously reported resistance. Here, we present the results of a four-year surveillance program based on the sequencing of the pfcrt gene of Plasmodium falciparum populations from endemic areas of Honduras. All isolates were susceptible to chloroquine, as revealed by the pfcrt “CVMNK” genotype in codons 72-76.
DEFF Research Database (Denmark)
Alifrangis, Michael; Lusingu, John P; Mmbando, Bruno
2009-01-01
.001). In contrast, the chloroquine-sensitive P. falciparum chloroquine resistance transporter (Pfcrt) CVMNK haplotype increased from 6% to 30% (P use of SP for intermittent presumptive treatment of pregnant women......In January 2007, Tanzania replaced sulfadoxine-pyrimethamine (SP) with artemether-lumefantrine for treatment of uncomplicated malaria. This study examined the impact of widespread SP use on molecular markers of Plasmodium falciparum drug resistance in blood samples from persons living in two...
Arróspide, Nancy; Hijar-Guerra, Gisely; de Mora, Doménica; Diaz-Cortéz, César Eduardo; Veloz-Perez, Raúl; Gutierrez, Sonia; Cabezas-Sánchez, César
2014-04-01
The frequency of mutations in pfCRT and DHFR/DHPS genes of Plasmodium falciparum associated with resistance to chloroquine and sulfadoxine-pyrimethamine was evaluated in 83 strains from the districts of Esmeralda and Machala, located on the borders of Ecuador-Peru and Ecuador-Colombia in 2002. Polymerase chain reaction (PCR), conventional and its variants, was used. Mutations in the pfCRT gene were found in more than 90% of the samples from Esmeralda and Machala. For the DHFR gene, 90% of the strains were mutant samples from Esmeralda, 3 were double mutations and 1 was a triple mutation. In Machala, 25% were simple mutant forms and 75% mixed mutant forms (wild forms/mutant). In conclusion, resistance to chloroquine has been fixed in strains carrying K76T pfCRT mutation, whereas genetic imprinting for resistance to pyrimethamine is evolving, particularly in the district of Esmeralda.
A molecular map of CQR in Mali
Djimde, Abdoulaye A.; Barger, Breanna; Kone, Aminatou; Beavogui, Abdoul H.; Tekete, Mamadou; Fofana, Bakary; Dara, Antoine; Maiga, Hamma; Dembele, Demba; Toure, Sekou; Dama, Souleymane; Ouologuem, Dinkorma; Sangare, Cheick Papa Oumar; Dolo, Amagana; Sogoba, Nofomo; Nimaga, Karamoko; Kone, Yacouba; Doumbo, Ogobara K.
2009-01-01
Plasmodium falciparum CQR transporter point mutation (PfCRT76T) is known to be the key determinant of CQR. Molecular detection of PfCRT76T in field samples may be used for the surveillance of CQR in the malaria endemic countries. The genotype-resistance index (GRI) which is obtained as the ratio of the prevalence of PfCRT 76T to the incidence of CQR in a clinical trial was proposed as a simple andpractical molecular-based addition to the tools currently available for monitoring CQR in the field. In order to validate the GRI model across populations, time, and resistance patterns, we compiled data from the literature and generated new data from a dozen of sites across Mali. We found a mean PfCRT76T mutation prevalence of 84.5% (range 60.9%–95.1%) across all sites. CQR rates predicted from the GRI model was extrapolated onto a map of Mali to show the patterns of resistance throughout the participating regions. We present a comprehensive map of CQR in Mali, which strongly supports recent changes in drug policy away from chloroquine. PMID:20041947
Nkrumah, Louis J; Riegelhaupt, Paul M; Moura, Pedro; Johnson, David J; Patel, Jigar; Hayton, Karen; Ferdig, Michael T; Wellems, Thomas E; Akabas, Myles H; Fidock, David A
2009-06-01
Quinine (QN) continues to be an important treatment option for severe malaria, however resistance to this drug has emerged in field isolates of the etiologic agent Plasmodium falciparum. Quantitative trait loci investigations of QN resistance have mapped three loci of this complex trait. Two coincide with pfcrt and pfmdr1, involved in resistance to chloroquine (CQ) and other quinoline-based antimalarials. A third locus on chromosome 13 contains the sodium-proton exchanger (pfnhe) gene. Previous studies have associated pfnhe polymorphisms with reduced QN sensitivity in culture-adapted field isolates. Here, we provide direct evidence supporting the hypothesis that pfnhe contributes to QN resistance. Using allelic exchange, we reduced pfnhe expression by introducing a truncated 3' untranslated region (UTR) from pfcrt into the endogenous pfnhe 3'UTR. Transfections were performed with 1BB5 and 3BA6 (both CQ- and QN-resistant) as well as GC03 (CQ- and QN-sensitive), all progenies of the HB3xDd2 genetic cross. RNA and protein analyses of the ensuing recombinant clones demonstrated a approximately 50% decrease in pfnhe expression levels. A statistically significant 30% decrease in QN IC(50) values was associated with these decreased expression levels in 1BB5 and 3BA6 but not in GC03. CQ, mefloquine and lumefantrine IC(50) values were unaltered. Cytosolic pH values were similar in all parental lines and recombinant clones. Our observations support a role for pfnhe in QN resistance in a strain-dependent manner, which might be contingent on pre-existing resistance to CQ and/or QN. These data bolster observations that QN resistance is a complex trait requiring the contribution of multiple transporter proteins.
DEFF Research Database (Denmark)
Jelinek, Tomas; Peyerl-Hoffmann, Gabriele; Mühlberger, Nikolai
2002-01-01
and chloroquine. The screening results were used to map the prevalence of mutations and, thus, levels of potential drug resistance in endemic areas world-wide. RESULTS: 337 isolates have been tested so far. Prevalence of mutations that are associated with resistance to chloroquine on the pfcrt and pfmdr genes...
Saksena, Rushika; Matlani, Monika; Singh, Vineeta; Kumar, Amit; Anveshi, Anupam; Kumar, Dilip; Gaind, Rajni
2017-01-01
Concurrent dengue and mixed malaria infections in a single patient present with overlapping clinical manifestations which pose a diagnostic challenge and management dilemma in areas of common endemicities. We report a case of a young male who tested positive for both Plasmodium vivax and Plasmodium falciparum along with dengue infection. He showed signs of early treatment failure to artemisinin combination therapy (artesunate with sulfadoxine+pyrimethamine). Molecular analysis for the drug resistance genes viz: chloroquine resistance ( pfcrt ), multidrug resistance ( pfmdr-1 ), sulfadoxine ( pfdhps ), pyrimethamine ( pfdhfr ), and artemisinin resistance ( keltch 13 ) was performed. A rise in parasitemia from treatment. Mutations in pfcrt , pfmdr-1 , pfdhfr , and pfdhps genes were detected as a possible cause of treatment failure. Increased severity, overlapping symptoms, and suspected resistance to treatment warrants a multidimensional diagnostic approach and diligent therapeutic monitoring.
Alam, Mohammad Shafiul; Ley, Benedikt; Nima, Maisha Khair; Johora, Fatema Tuj; Hossain, Mohammad Enayet; Thriemer, Kamala; Auburn, Sarah; Marfurt, Jutta; Price, Ric N; Khan, Wasif A
2017-08-15
Artemisinin resistance is present in the Greater Mekong region and poses a significant threat for current anti-malarial treatment guidelines in Bangladesh. The aim of this molecular study was to assess the current status of drug resistance in the Chittagong Hill Tracts of Bangladesh near the Myanmar border. Samples were obtained from patients enrolled into a Clinical Trial (NCT02389374) conducted in Alikadam, Bandarban between August 2014 and January 2015. Plasmodium falciparum infections were confirmed by PCR and all P. falciparum positive isolates genotyped for the pfcrt K76T and pfmdr1 N86Y markers. The propeller region of the kelch 13 (k13) gene was sequenced from isolates from patients with delayed parasite clearance. In total, 130 P. falciparum isolates were available for analysis. The pfcrt mutation K76T, associated with chloroquine resistance was found in 81.5% (106/130) of cases and the pfmdr1 mutation N86Y in 13.9% (18/130) cases. No single nucleotide polymorphisms were observed in the k13 propeller region. This study provides molecular evidence for the ongoing presence of chloroquine resistant P. falciparum in Bangladesh, but no evidence of mutations in the k13 propeller domain associated with artemisinin resistance. Monitoring for artemisinin susceptibility in Bangladesh is needed to ensure early detection and containment emerging anti-malarial resistance.
2012-01-01
Background Confirmation of artemisinin-delayed parasite clearance in Plasmodium falciparum along the Thai-Myanmar border has inspired a global response to contain and monitor drug resistance to avert the disastrous consequences of a potential spread to Africa. However, resistance data from Myanmar are sparse, particularly from high-risk areas where limited health services and decades of displacement create conditions for resistance to spread. Subclinical infections may represent an important reservoir for resistance genes that confer a fitness disadvantage relative to wild-type alleles. This study estimates the prevalence of resistance genotypes in three previously unstudied remote populations in Myanmar and tests the a priori hypothesis that resistance gene prevalence would be higher among isolates collected from subclinical infections than isolates collected from febrile clinical patients. A systematic review of resistance studies is provided for context. Methods Community health workers in Karen and Kachin States and an area spanning the Indo-Myanmar border collected dried blood spots from 988 febrile clinical patients and 4,591 villagers with subclinical infection participating in routine prevalence surveys. Samples positive for P. falciparum 18 s ribosomal RNA by real-time PCR were genotyped for P. falciparum multidrug resistance protein (pfmdr1) copy number and the pfcrt K76T polymorphism using multiplex real-time PCR. Results Pfmdr1 copy number increase and the pfcrt K76 polymorphism were determined for 173 and 269 isolates, respectively. Mean pfmdr1 copy number was 1.2 (range: 0.7 to 3.7). Pfmdr1 copy number increase was present in 17.5%, 9.6% and 11.1% of isolates from Karen and Kachin States and the Indo-Myanmar border, respectively. Pfmdr1 amplification was more prevalent in subclinical isolates (20.3%) than clinical isolates (6.4%, odds ratio 3.7, 95% confidence interval 1.1 - 12.5). Pfcrt K76T prevalence ranged from 90-100%. Conclusions Community
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Cheryl C Y Loh
Full Text Available Chloroquine was a cheap, extremely effective drug against Plasmodium falciparum until resistance arose. One approach to reversing resistance is the inhibition of chloroquine efflux from its site of action, the parasite digestive vacuole. Chloroquine accumulation studies have traditionally relied on radiolabelled chloroquine, which poses several challenges. There is a need for development of a safe and biologically relevant substitute. We report here a commercially-available green fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a proxy for chloroquine accumulation. This compound localized to the digestive vacuole of the parasite as observed under confocal microscopy, and inhibited growth of chloroquine-sensitive strain 3D7 more extensively than in the resistant strains 7G8 and K1. Microplate reader measurements indicated suppression of LynxTag-CQGREEN efflux after pretreatment of parasites with known reversal agents. Microsomes carrying either sensitive- or resistant-type PfCRT were assayed for uptake; resistant-type PfCRT exhibited increased accumulation of LynxTag-CQGREEN, which was suppressed by pretreatment with known chemosensitizers. Eight laboratory strains and twelve clinical isolates were sequenced for PfCRT and Pgh1 haplotypes previously reported to contribute to drug resistance, and pfmdr1 copy number and chloroquine IC50s were determined. These data were compared with LynxTag-CQGREEN uptake/fluorescence by multiple linear regression to identify genetic correlates of uptake. Uptake of the compound correlated with the logIC50 of chloroquine and, more weakly, a mutation in Pgh1, F1226Y.
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Löscher Thomas
2006-07-01
Full Text Available Abstract Background In Ethiopia, malaria is caused by both Plasmodium falciparum and Plasmodium vivax. Drug resistance of P. falciparum to sulfadoxine-pyrimethamine (SP and chloroquine (CQ is frequent and intense in some areas. Methods In 100 patients with uncomplicated malaria from Dilla, southern Ethiopia, P. falciparum dhfr and dhps mutations as well as P. vivax dhfr polymorphisms associated with resistance to SP and P. falciparum pfcrt and pfmdr1 mutations conferring CQ resistance were assessed. Results P. falciparum and P. vivax were observed in 69% and 31% of the patients, respectively. Pfdhfr triple mutations and pfdhfr/pfdhps quintuple mutations occurred in 87% and 86% of P. falciparum isolates, respectively. Pfcrt T76 was seen in all and pfmdr1 Y86 in 81% of P. falciparum. The P. vivax dhfr core mutations N117 and R58 were present in 94% and 74%, respectively. Conclusion These data point to an extraordinarily high frequency of drug-resistance mutations in both P. falciparum and P. vivax in southern Ethiopia, and strongly support that both SP and CQ are inadequate drugs for this region.
High-Dose Chloroquine for Treatment of Chloroquine-Resistant Plasmodium falciparum Malaria
DEFF Research Database (Denmark)
Ursing, Johan; Rombo, Lars; Bergqvist, Yngve
2016-01-01
BACKGROUND: Due to development of multidrug-resistant Plasmodium falciparum new antimalarial therapies are needed. In Guinea-Bissau, routinely used triple standard-dose chloroquine remained effective for decades despite the existence of "chloroquine-resistant" P. falciparum. This study aimed...... to determine the in vivo efficacy of higher chloroquine concentrations against P. falciparum with resistance-conferring genotypes. METHODS: Standard or double-dose chloroquine was given to 892 children aged ...-up. The P. falciparum resistance-conferring genotype (pfcrt 76T) and day 7 chloroquine concentrations were determined. Data were divided into age groups (chloroquine is prescribed according to body weight. RESULTS: Adequate clinical...
Prevalence of the molecular marker of chloroquine resistance (pfcrt ...
African Journals Online (AJOL)
Background. In line with the World Health Organization (WHO) guideline on chloroquine (CQ) resistance, CQ was withdrawn as the ... prevention, loss of working hours, etc.1 ... at position 76 being the last in the long process leading to CQ.
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Huang Fang
2012-08-01
Full Text Available Abstract Background The aim of this study was to evaluate the clinical outcome after seven-day artesunate monotherapy for uncomplicated Plasmodium falciparum malaria in Yingjiang County along the China-Myanmar border and investigate genetic polymorphisms in the P. falciparum chloroquine-resistance transporter (pfcrt, multidrug resistance 1 (pfmdr1, dihydrofolate reductase (pfdhfr, dihydropteroate synthase (pfdhps and ATPase (pfatp6 genes. Methods Patients ≥ one year of age with fever (axillary temperature ≥37.5°C or history of fever and P. falciparum mono-infection were included. Patients received anti-malarial treatment with artesunate (total dose of 16 mg/kg over seven days by directly observed therapy. After a 28-day follow-up, treatment efficacy and effectiveness were assessed based on clinical and parasitological outcomes. Treatment failure was defined as recrudescence of the original parasite and distinguished with new infection confirmed by PCR. Analysis of gene mutation and amplification were performed by nested polymerase chain reaction. Results Sixty-five patients were enrolled; 10 withdrew from the study, and six were lost to follow-up. All but two patients demonstrated adequate clinical and parasitological response; 12 had detectable parasitaemia on day 3. These two patients were confirmed to be new infection by PCR. The efficacy of artesunate was 95.9%. The pfcrt mutation in codon 76 was found in all isolates (100%, and mutations in codons 71 and 72 were found in 4.8% of parasite isolates. No mutation of pfmdr1 (codons 86 or 1246 was found. Among all samples, 5.1% were wild type for pfdhfr, whereas the other samples had mutations in four codons (51, 59, 108 and 164, and mutations in pfdhps (codons 436, 437, 540 and 581 were found in all isolates. No samples had mutations in pfatp6 codons 623 or 769, but two new mutations (N683K and R756K were found in 4.6% and 9.2% of parasite isolates, respectively. Conclusion Plasmodium
The role of half-transporters in multidrug resistance
DEFF Research Database (Denmark)
Bates, S E; Robey, R; Miyake, K
2001-01-01
in the role of drug transporters in clinical drug resistance. These newly identified transporters include additional members of the MRP family, ABC2, and a new half-transporter, MXR/BCRP/ABCP1. This half-transporter confers high levels of resistance to mitoxantrone, anthracyclines, and the camptothecins SN-38...
Prevalence and distribution of malaria, Pfcrt , Pfmdr 1 Genes in ...
African Journals Online (AJOL)
This study aimed at evaluating the distribution of malaria, Plasmodium falciparum resistant chloroquine transporter (Pfrct), and Plasmodium falciparum multidrug resistant (Pfmdr 1) mutant genes amongst residents of Benin metropolis, was carried out during the period between October 2008 and April 2010. Seven hundred ...
DEFF Research Database (Denmark)
Mehlotra, Rajeev K; Mattera, Gabriel; Bockarie, Moses J
2008-01-01
. However, both Pfcrt and Pfmdr1 MS haplotypes showed similar levels of low diversity in South American parasite populations. Median-joining network analyses showed that the Pfcrt MS haplotypes correlated well with geography and CQR Pfcrt alleles, whereas there was no distinct Pfmdr1 MS haplotype...
DEFF Research Database (Denmark)
Ndiaye, Magatte; Sow, Doudou; Nag, Sidsel
2017-01-01
of drug resistance. Therefore, surveillance of drug resistance in the malaria parasites is essential. The objective of this pilot study was to test the feasibility of routinely sampled malaria rapid diagnostic tests (RDTs) at a national scale to assess the temporal changes in the molecular profiles...... of antimalarial drug resistance markers of Plasmodium falciparum parasites. Overall, 9,549 positive malaria RDTs were collected from 14 health facilities across the country. A limited random set of RDTs were analyzed regarding Pfcrt gene polymorphisms at codon 72-76. Overall, a high but varied prevalence (> 50...
Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number.
Price, Ric N; Uhlemann, Anne-Catrin; Brockman, Alan; McGready, Rose; Ashley, Elizabeth; Phaipun, Lucy; Patel, Rina; Laing, Kenneth; Looareesuwan, Sornchai; White, Nicholas J; Nosten, François; Krishna, Sanjeev
The borders of Thailand harbour the world's most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known. The relation between polymorphisms in the P falciparum multidrug resistant gene 1 (pfmdr1) and the in-vitro and in-vivo responses to mefloquine were assessed in 618 samples from patients with falciparum malaria studied prospectively over 12 years. pfmdr1 copy number was assessed by a robust real-time PCR assay. Single nucleotide polymorphisms of pfmdr1, P falciparum chloroquine resistance transporter gene (pfcrt) and P falciparum Ca2+ ATPase gene (pfATP6) were assessed by PCR-restriction fragment length polymorphism. Increased copy number of pfmdr1 was the most important determinant of in-vitro and in-vivo resistance to mefloquine, and also to reduced artesunate sensitivity in vitro. In a Cox regression model with control for known confounders, increased pfmdr1 copy number was associated with an attributable hazard ratio (AHR) for treatment failure of 6.3 (95% CI 2.9-13.8, p<0.001) after mefloquine monotherapy and 5.4 (2.0-14.6, p=0.001) after artesunate-mefloquine therapy. Single nucleotide polymorphisms in pfmdr1 were associated with increased mefloquine susceptibility in vitro, but not in vivo. Amplification in pfmdr1 is the main cause of resistance to mefloquine in falciparum malaria. Multidrug resistant P falciparum malaria is common in southeast Asia, but difficult to identify and treat. Genes that encode parasite transport proteins maybe involved in export of drugs and so cause resistance. In this study we show that increase in copy number of pfmdr1, a gene encoding a parasite transport protein, is the best overall predictor of treatment failure with
Structural Biology Meets Drug Resistance: An Overview on Multidrug Resistance Transporters
DEFF Research Database (Denmark)
Shaheen, Aqsa; Iqbal, Mazhar; Mirza, Osman
2017-01-01
. Research on the underlying causes of multidrug resistance in cancerous cells and later on in infectious bacteria revealed the involvement of integral membrane transporters, capable of recognizing a broad range of structurally different molecules as substrates and exporting them from the cell using cellular...... superfamilies, viz., ATP-binding cassette superfamily, major facilitator superfamily and resistance nodulation division superfamily are presented. Further, the future role of structural biology in improving our understanding of drug-transporter interactions and in designing novel inhibitors against MDR pump...... century, mankind has become aware and confronted with the emergence of antibiotic-resistant pathogens. In parallel to the failure of antibiotic therapy against infectious pathogens, there had been continuous reports of cancerous cells not responding to chemotherapy with increase in the duration of therapy...
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Akter Jasmin
2012-11-01
Full Text Available Abstract Background In the past many regions of Bangladesh were hyperendemic for malaria. Malaria control in the 1960s to 1970s eliminated malaria from the plains but in the Chittagong Hill Tracts remained a difficult to control reservoir. The Chittagong Hill Tracts have areas with between 1 and 10% annual malaria rates, predominately 90-95% Plasmodium falciparum. In Southeast Asia, multiplicity of infection for hypo-endemic regions has been approximately 1.5. Few studies on the genetic diversity of P. falciparum have been performed in Bangladesh. Anderson et al. performed a study in Khagrachari, northern Chittagong Hill Tracts in 2002 on 203 patients and found that parasites had a multiplicity of infection of 1.3 by MSP-1, MSP-2 and GLURP genotyping. A total of 94% of the isolates had the K76T Pfcrt chloroquine resistant genotype, and 70% showed the N86Y Pfmdr1 genotype. Antifolate drug resistant genotypes were high with 99% and 73% of parasites having two or more mutations at the dhfr or dhps loci. Methods Nested and real-time polymerase chain reaction (PCR methods were used to genotype P. falciparum using antigenic polymorphic markers and to study anti-malarial drug resistance markers in malaria endemic areas of Bangladesh. Results The analysis of polymorphic and drug resistant genotype on 33 paired recrudescent infections after drug treatment in the period 2004 to 2008 in the Chittagong Hill Tracts, which is just prior to countrywide provision of artemisinin combination therapy. Overall the multiplicity of infection for MSP-1 was 2.7 with a slightly smaller parasite diversity post-treatment. The 13 monoclonal infections by both GLURP and MSP-1 were evenly divided between pre- and post-treatment. The MSP-1 MAD block was most frequent in 66 of the samples. The prevalence of the K76T PfCRT chloroquine resistant allele was approximately 82% of the samples, while the resistant Pfmdr1 N86Y was present in 33% of the samples. Interestingly, the post
Statistical analysis of anomalous transport in resistive interchange turbulence
International Nuclear Information System (INIS)
Sugama, Hideo; Wakatani, Masahiro.
1992-01-01
A new anomalous transport model for resistive interchange turbulence is derived from statistical analysis applying two-scale direct-interaction approximation to resistive magnetohydrodynamic equations with a gravity term. Our model is similar to the K-ε model for eddy viscosity of turbulent shear flows in that anomalous transport coefficients are expressed in terms of by the turbulent kinetic energy K and its dissipation rate ε while K and ε are determined by transport equations. This anomalous transport model can describe some nonlocal effects such as those from boundary conditions which cannot be treated by conventional models based on the transport coefficients represented by locally determined plasma parameters. (author)
Public transport as a reservoir of methicillin-resistant staphylococci.
Stepanović, S; Cirković, I; Djukić, S; Vuković, D; Svabić-Vlahović, M
2008-10-01
The aim of this study was to explore the occurrence of methicillin-resistant staphylococci in a large urban public transport system. Samples were taken from hand rails, which passengers hold onto when they are standing. In total, 1400 swabs taken from 55 vehicles (trolleybuses, trams and buses) were examined. As many as 30.1% samples were positive for the presence of methicillin-resistant coagulase-negative staphylococci (MRCoNS), but none for methicillin-resistant Staphylococcus aureus (MRSA). MRCoNS were isolated from all 55 vehicles. Nearly 50% of MRCoNS isolates displayed resistance not only to beta-lactams, but at least to two or more other classes of antimicrobials as well. This study demonstrated widespread occurrence of MRCoNS on hand rails in public transport vehicles. MRSA was not detected. The recovery of methicillin-resistant staphylococci from public transport system implies a potential risk for transmission of these bacteria in an out-hospital environment.
2012-01-01
Background Drug resistance in the malaria parasite Plasmodium falciparum severely compromises the treatment and control of malaria. A knowledge of the critical mutations conferring resistance to particular drugs is important in understanding modes of drug action and mechanisms of resistances. They are required to design better therapies and limit drug resistance. A mutation in the gene (pfcrt) encoding a membrane transporter has been identified as a principal determinant of chloroquine resistance in P. falciparum, but we lack a full account of higher level chloroquine resistance. Furthermore, the determinants of resistance in the other major human malaria parasite, P. vivax, are not known. To address these questions, we investigated the genetic basis of chloroquine resistance in an isogenic lineage of rodent malaria parasite P. chabaudi in which high level resistance to chloroquine has been progressively selected under laboratory conditions. Results Loci containing the critical genes were mapped by Linkage Group Selection, using a genetic cross between the high-level chloroquine-resistant mutant and a genetically distinct sensitive strain. A novel high-resolution quantitative whole-genome re-sequencing approach was used to reveal three regions of selection on chr11, chr03 and chr02 that appear progressively at increasing drug doses on three chromosomes. Whole-genome sequencing of the chloroquine-resistant parent identified just four point mutations in different genes on these chromosomes. Three mutations are located at the foci of the selection valleys and are therefore predicted to confer different levels of chloroquine resistance. The critical mutation conferring the first level of chloroquine resistance is found in aat1, a putative aminoacid transporter. Conclusions Quantitative trait loci conferring selectable phenotypes, such as drug resistance, can be mapped directly using progressive genome-wide linkage group selection. Quantitative genome-wide short
DEFF Research Database (Denmark)
Nag, Sidsel; Dalgaard, Marlene Danner; Kofoed, Poul-Erik
2017-01-01
Genetic polymorphisms in P. falciparum can be used to indicate the parasite's susceptibility to antimalarial drugs as well as its geographical origin. Both of these factors are key to monitoring development and spread of antimalarial drug resistance. In this study, we combine multiplex PCR, custom...... designed dual indexing and Miseq sequencing for high throughput SNP-profiling of 457 malaria infections from Guinea-Bissau, at the cost of 10 USD per sample. By amplifying and sequencing 15 genetic fragments, we cover 20 resistance-conferring SNPs occurring in pfcrt, pfmdr1, pfdhfr, pfdhps, as well...
Studies on /sup 32/P transport and yellow rust resistance in barley
Energy Technology Data Exchange (ETDEWEB)
Schubert, J. (Akademie der Landwirtschaftswissenschaften der DDR, Aschersleben. Inst. fuer Phytopathologie)
1982-01-01
Several cultivars of barley (Hordeum vulgare L.) differing in their resistance to yellow rust were used to study the influence of the infection with Puccinia striiformis West. (strain 24) on /sup 32/P transport in intact plants and isolated leaves. Close correlations exist between transport processes and resistance. For example, resistant plants seem to have a more intensive matter transport than susceptible ones. The importance of the rate of transport to the effectiveness of hypothetic inducers of resistance reactions and defence substances is discussed.
Gold mining areas in Suriname: reservoirs of malaria resistance?
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Adhin MR
2014-05-01
Full Text Available Malti R Adhin,1 Mergiory Labadie-Bracho,2 Stephen Vreden31Faculty of Medical Sciences, Department of Biochemistry, Anton de Kom Universiteit van Suriname, 2Prof Dr Paul C Flu Institute for Biomedical Sciences, 3Academic Hospital Paramaribo, Paramaribo, SurinameBackground: At present, malaria cases in Suriname occur predominantly in migrants and people living and/or working in areas with gold mining operations. A molecular survey was performed in Plasmodium falciparum isolates originating from persons from gold mining areas to assess the extent and role of mining areas as reservoirs of malaria resistance in Suriname.Methods: The status of 14 putative resistance-associated single nucleotide polymorphisms in the pfdhfr, pfcrt, pfmdr1, and pfATP6 genes was assessed for 28 samples from gold miners diagnosed with P. falciparum malaria using polymerase chain reaction amplification and restriction fragment length polymorphism analysis, and the results were compared with earlier data from nonmining villagers.Results: Isolates from miners showed a high degree of homogeneity, with a fixed pfdhfr Ile51/Asn108, pfmdr1 Phe184/Asp1042/Tyr1246, and pfcrt Thr76 mutant genotype, while an exclusively wild-type genotype was observed for pfmdr1 Asn86 and pfdhfr Ala16, Cys59, and Ile164, and for the pfATP6 positions Leu263/Ala623/Ser769. Small variations were observed for pfmdr1 S1034C. No statistically significant difference could be detected in allele frequencies between mining and nonmining villagers.Conclusion: Despite the increased risk of malaria infection in individuals working/living in gold mining areas, we did not detect an increase in mutation frequency at the 14 analyzed single nucleotide polymorphisms. Therefore, mining areas in Suriname cannot yet be considered as reservoirs for malaria resistance.Keywords: Plasmodium falciparum, gold mining, mutation frequency, Suriname
Genetic diversity of Plasmodium falciparum and distribution of drug resistance haplotypes in Yemen.
Al-Hamidhi, Salama; Mahdy, Mohammed A K; Al-Hashami, Zainab; Al-Farsi, Hissa; Al-mekhlafi, Abdulsalam M; Idris, Mohamed A; Beja-Pereira, Albano; Babiker, Hamza A
2013-07-15
Despite evident success of malaria control in many sites in the Arabian Peninsula, malaria remains endemic in a few spots, in Yemen and south-west of Saudi Arabia. In addition to local transmission, imported malaria sustains an extra source of parasites that can challenge the strengths of local control strategies. This study examined the genetic diversity of Plasmodium falciparum in Yemen and mutations of drug resistant genes, to elucidate parasite structure and distribution of drug resistance genotypes in the region. Five polymorphic loci (MSP-2, Pfg377 and three microsatellites on chromosome 8) not involved in anti-malarial drug resistance, and four drug resistant genes (pfcrt, pfmdr1, dhfr and dhps) were genotyped in 108 P. falciparum isolates collected in three sites in Yemen: Dhamar, Hodeidah and Taiz. High diversity was seen in non-drug genes, pfg377 (He = 0.66), msp-2 (He = 0.80) and three microsatellites on chr 8, 7.7 kb (He = 0.88), 4.3 kb (He = 0.77) and 0.8 kb (He = 0.71). There was a high level of mixed-genotype infections (57%), with an average 1.8 genotypes per patient. No linkage disequilibrium was seen between drug resistant genes and the non-drug markers (p Yemen is indicative of a large parasite reservoir, which represents a challenge to control efforts. The presence of two distinct pfcrt genotype, CVIET and SVMNT, suggests that chloroquine resistance can possibly be related to a migratory path from Africa and Asia. The absence of the triple mutant dhfr genotype (IRN) and dhps mutations supports the use of artesunate + sulphadoxine-pyrimethamine as first-line therapy. However, the prevalent pfmdr1 genotype NFSND [21%] has previously been associated with tolerance/resistance response to artemisinin combination therapy (ACT). Regular surveys are, therefore, important to monitor spread of pfmdr1 and dhfr mutations and response to ACT.
Insight into Two ABC Transporter Families Involved in Lantibiotic Resistance
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Rebecca Clemens
2018-01-01
Full Text Available Antimicrobial peptides, which contain (methyl-lanthionine-rings are called lantibiotics. They are produced by several Gram-positive bacteria and are mainly active against these bacteria. Although these are highly potent antimicrobials, some human pathogenic bacteria express specific ABC transporters that confer resistance and counteract their antimicrobial activity. Two distinct ABC transporter families are known to be involved in this process. These are the Cpr- and Bce-type ABC transporter families, named after their involvement in cationic peptide resistance in Clostridium difficile, and bacitracin efflux in Bacillus subtilis, respectively. Both resistance systems differentiate to each other in terms of the proteins involved. Here, we summarize the current knowledge and describe the divergence as well as the common features present in both the systems to confer lantibiotic resistance.
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Sabyasachi Das
2017-12-01
Full Text Available Chloroquine (CQ is highly effective against P. vivax, due to the rapid spread of CQ resistance in P. falciparum parasites; it is no longer the drug of choice against P. falciparum. This study elucidates the scenario of chloroquine efficacy at times that coincided with a new drug policy and especially assessed the chloroquine resistant molecular markers after withdrawal of chloroquine in Kolkata and Purulia, two malaria endemic zones of West Bengal, India. In vitro CQ susceptibility was tested in 781 patients with P. falciparum mono infections between 2008 and 2013, of which 338 patients had received CQ in 2008–2009. Genotyping of the pfcrt and the pfmdr1 gene was carried out in all isolates. Early treatment failure was detected in 114 patients {43 (31·39% from Kolkata and 71 (35·32% from Purulia} while recrudescence was identified in 13 (9.49% and 17 (8.46% patients from Kolkata and Purulia respectively. In vivo chloroquine resistance was strongly associated with CVMNT-YYSNY (p < 0.01 and SVMNT-YYSNY (p < 0.05 allele in Kolkata. In Purulia chloroquine resistance was associated with CVMNK-YYSNY (P < 0.005, SVMNT-YYSNY (P < 0.01 allele. The proportion of in vitro chloroquine resistance increased in subsequent years to 87.23% and 93·10% in 2013, in Kolkata and Purulia, respectively. Isolates with SVMNT-YFSND, SVMNT-YFSNY, CVIET-YFSND and CVIET-YYSNY haplotypes increased gradually (p < 0.05 from 2010 to 2013, leading to a rise in IC50 (p < 0.05 of chloroquine. An increase in in vitro chloroquine resistance and candidate gene mutations even after five years of chloroquine withdrawal against P. falciparum calls for synchronized research surveillance and proper containment strategies. Keywords: Plasmodium falciparum, ChloroQuine resistance in India, pfcrt polymorphism, pfmdr1 mutation, In vitro chloroquine resistance
Resistive drift wave turbulence and transport
International Nuclear Information System (INIS)
Wakatani, M.
1986-01-01
Our efforts for studying the properties of resistive drift wave turbulence by using model mode-coupling equations are shown. It may be related to the edge turbulence and the associated anomalous transport in tokamaks or in stellarator/heliotron. (author)
Mouse ATP-Binding Cassette (ABC) Transporters Conferring Multi-Drug Resistance
Shuaizhang, L I; Zhang, Wen; Yin, Xuejiao; Xing, Shilai; Xie, Qunhui; Cao, Zhengyu; Zhao, Bin
2015-04-28
The ABC (ATP-binding cassette) transporter is one of the largest and most ancient protein families with members functioning from protozoa to human. The resistance of cancer and tumor cells to anticancer drugs is due to the over-expression of some ABC transporters, which may finally lead to chemotherapy failure. The mouse ABC transporters are classified into seven subfamilies by phylogenetic analysis. The mouse ABC transporter gene, alias, chromosomal location and function have been determined. Within the ABC super-family, the MDR transporters (Abcb1, Abcc1, Abcg2) in mouse models have been proved to be valuable to investigate the biochemistry and physiological functions. This review concentrates on the multidrug resistance of mouse ABC transporters in cancer and tumor cells.
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Monica Shah
Full Text Available Despite the clear public health benefit of insecticide-treated bednets (ITNs, the impact of malaria transmission-reduction by vector control on the spread of drug resistance is not well understood. In the present study, the effect of sustained transmission reduction by ITNs on the prevalence of Plasmodium falciparum gene mutations associated with resistance to the antimalarial drugs sulfadoxine-pyrimethamine (SP and chloroquine (CQ in children under the age of five years was investigated during an ITN trial in Asembo area, western Kenya. During the ITN trial, the national first line antimalarial treatment changed from CQ to SP. Smear-positive samples collected from cross sectional surveys prior to ITN introduction (baseline, n = 250 and five years post-ITN intervention (year 5 survey, n = 242 were genotyped for single nucleotide polymorphisms (SNPs at dhfr-51, 59, 108, 164 and dhps-437, 540 (SP resistance, and pfcrt-76 and pfmdr1-86 (CQ resistance. The association between the drug resistance mutations and epidemiological variables was evaluated. There were significant increases in the prevalence of SP dhps mutations and the dhfr/dhps quintuple mutant, and a significant reduction in the proportion of mixed infections detected at dhfr-51, 59 and dhps-437, 540 SNPs from baseline to the year 5 survey. There was no change in the high prevalence of pfcrt-76 and pfmdr1-86 mutations. Multivariable regression analysis further showed that current antifolate use and year of survey were significantly associated with more SP drug resistance mutations. These results suggest that increased antifolate drug use due to drug policy change likely led to the high prevalence of SP mutations 5 years post-ITN intervention and reduced transmission had no apparent effect on the existing high prevalence of CQ mutations. There is no evidence from the current study that sustained transmission reduction by ITNs reduces the prevalence of genes associated with malaria
Efflux drug transporters at the forefront of antimicrobial resistance.
Rahman, Tahmina; Yarnall, Benjamin; Doyle, Declan A
2017-10-01
Bacterial antibiotic resistance is rapidly becoming a major world health consideration. To combat antibiotics, microorganisms employ their pre-existing defence mechanisms that existed long before man's discovery of antibiotics. Bacteria utilise levels of protection that range from gene upregulation, mutations, adaptive resistance, and production of resistant phenotypes (persisters) to communal behaviour, as in swarming and the ultimate defence of a biofilm. A major part of all of these responses involves the use of antibiotic efflux transporters. At the single cell level, it is becoming apparent that the use of efflux pumps is the first line of defence against an antibiotic, as these pumps decrease the intracellular level of antibiotic while the cell activates the various other levels of protection. This frontline of defence involves a coordinated network of efflux transporters. In the future, inhibition of this efflux transporter network, as a target for novel antibiotic therapy, will require the isolation and then biochemical/biophysical characterisation of each pump against all known and new antibiotics. This depth of knowledge is required so that we can fully understand and tackle the mechanisms of developing antimicrobial resistance.
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.
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Choi Cheol-Hee
2005-10-01
Full Text Available Abstract One of the major problems related with anticancer chemotherapy is resistance against anticancer drugs. The ATP-binding cassette (ABC transporters are a family of transporter proteins that are responsible for drug resistance and a low bioavailability of drugs by pumping a variety of drugs out cells at the expense of ATP hydrolysis. One strategy for reversal of the resistance of tumor cells expressing ABC transporters is combined use of anticancer drugs with chemosensitizers. In this review, the physiological functions and structures of ABC transporters, and the development of chemosensitizers are described focusing on well-known proteins including P-glycoprotein, multidrug resistance associated protein, and breast cancer resistance protein.
Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance
International Nuclear Information System (INIS)
Hembruff, Stacey L; Laberge, Monique L; Villeneuve, David J; Guo, Baoqing; Veitch, Zachary; Cecchetto, Melanie; Parissenti, Amadeo M
2008-01-01
Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7 DOX-2 ), epirubicin (MCF-7 EPI ), paclitaxel (MCF-7 TAX-2 ), or docetaxel (MCF-7 TXT ). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of
Application of column tests and electrical resistivity methods for leachate transport monitoring
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Wychowaniak Dorota
2015-09-01
Full Text Available Development of the human civilization leads to the pollution of environment. One of the contamination which are a real threat to soil and groundwater are leachates from landfills. In this paper the solute transport through soil was considered. For this purpose, the laboratory column tests of chlorides tracer and leachates transport on two soil samples have been carried out. Furthermore, the electrical resistivity method was applied as auxiliary tool to follow the movements of solute through the soil column what allowed to compare between the results obtained with column test method and electrical resistivity measurements. Breakthrough curves obtained by conductivity and resistivity methods represents similar trends which leads to the conclusion about the suitability of electrical resistivity methods for contamination transport monitoring in soil-water systems.
Prevalence of antifolate resistance mutations in Plasmodium falciparum isolates in Afghanistan
2013-01-01
Background Artesunate plus sulphadoxine-pyrimethamine (AS+SP) is now first-line treatment for Plasmodium falciparum infection in several south Asian countries, including Afghanistan. Molecular studies provide a sensitive means to investigate the current state of drug susceptibility to the SP component, and can also provide information on the likely efficacy of other potential forms of artemisinin-combination therapy. Methods During the years 2007 to 2010, 120 blood spots from patients with P. falciparum malaria were obtained in four provinces of Afghanistan. PCR-based methods were used to detect drug-resistance mutations in dhfr, dhps, pfcrt and pfmdr1, as well as to determine copy number of pfmdr1. Results The majority (95.5%) of infections had a double mutation in the dhfr gene (C59R, S108N); no mutations at dhfr positions 16, 51 or 164 were seen. Most isolates were wild type across the dhps gene, but five isolates from the provinces of Kunar and Nangarhar in eastern Afghanistan had the triple mutation A437G / K540E / A581G; all five cases were successfully treated with three receiving AS+SP and two receiving dihydroartemisinin-piperaquine. All isolates showed the pfcrt SVNMT chloroquine resistance haplotype. Five of 79 isolates had the pfmdr1 N86Y mutation, while 52 had pfmdr1 Y184F; positions 1034, 1042 and 1246 were wild type in all isolates. The pfmdr1 gene was not amplified in any sample. Conclusions This study indicates that shortly after the adoption of AS+SP as first-line treatment in Afghanistan, most parasites had a double mutation haplotype in dhfr, and a small number of isolates from eastern Afghanistan harboured a triple mutation haplotype in dhps. The impact of these mutations on the efficacy of AS+SP remains to be assessed in significant numbers of patients, but these results are clearly concerning since they suggest a higher degree of SP resistance than previously detected. Further focused molecular and clinical studies in this region are urgently
Accident-resistant container: safety for warhead transport. Executive summary
International Nuclear Information System (INIS)
Berry, R.E.
1975-11-01
Development testing of model and full-scale hardware to the abnormal environments created during a cargo aircraft crash has demonstrated that the accident-resistant container (ARC) can protect an enclosed warhead from these abnormal environments. This protection reduces the probability of initiation of the warhead HE. Transfer of the plutonium limit to the ARC may permit transporting increased numbers of warheads on a single transport vehicle. Testing of one warhead configuration has been completed. Production can be initiated for transporting that system in the ARC. Other systems need test evaluation and certification before being transported in the ARC
Warhurst, David C; Craig, John C; Raheem, K Saki
2016-01-01
Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p-aminopyridine (pAP) basic aromatic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol substituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logResistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications.
Statistical theory of resistive drift-wave turbulence and transport
International Nuclear Information System (INIS)
Hu, G.; Krommes, J.A.; Bowman, J.C.
1997-01-01
Resistive drift-wave turbulence in a slab geometry is studied by statistical closure methods and direct numerical simulations. The two-field Hasegawa endash Wakatani (HW) fluid model, which evolves the electrostatic potential and plasma density self-consistently, is a paradigm for understanding the generic nonlinear behavior of multiple-field plasma turbulence. A gyrokinetic derivation of the HW model is sketched. The recently developed Realizable Markovian Closure (RMC) is applied to the HW model; spectral properties, nonlinear energy transfers, and turbulent transport calculations are discussed. The closure results are also compared to direct numerical simulation results; excellent agreement is found. The transport scaling with the adiabaticity parameter, which measures the strength of the parallel electron resistivity, is analytically derived and understood through weak- and strong-turbulence analyses. No evidence is found to support previous suggestions that coherent structures cause a large depression of saturated transport from its quasilinear value in the hydrodynamic regime of the HW model. Instead, the depression of transport is well explained by the spectral balance equation of the (second-order) statistical closure when account is taken of incoherent noise. copyright 1997 American Institute of Physics
Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter.
Neyfakh, A A; Borsch, C M; Kaatz, G W
1993-01-01
The gene of the Staphylococcus aureus fluoroquinolone efflux transporter protein NorA confers resistance to a number of structurally dissimilar drugs, not just to fluoroquinolones, when it is expressed in Bacillus subtilis. NorA provides B. subtilis with resistance to the same drugs and to a similar extent as the B. subtilis multidrug transporter protein Bmr does. NorA and Bmr share 44% sequence similarity. Both the NorA- and Bmr-conferred resistances can be completely reversed by reserpine.
A Study of Transport Airplane Crash-Resistant Fuel Systems
National Research Council Canada - National Science Library
Robertson, S
2002-01-01
...), of transport airplane crash-resistant fuel system (CRFS). The report covers the historical studies related to aircraft crash fires and fuel containment concepts undertaken by the FAA, NASA, and the U.S...
Sidhu, Amar Bir Singh; Sun, Qingan; Nkrumah, Louis J; Dunne, Michael W; Sacchettini, James C; Fidock, David A
2007-01-26
Azithromycin (AZ), a broad-spectrum antibacterial macrolide that inhibits protein synthesis, also manifests reasonable efficacy as an antimalarial. Its mode of action against malarial parasites, however, has remained undefined. Our in vitro investigations with the human malarial parasite Plasmodium falciparum document a remarkable increase in AZ potency when exposure is prolonged from one to two generations of intraerythrocytic growth, with AZ producing 50% inhibition of parasite growth at concentrations in the mid to low nanomolar range. In our culture-adapted lines, AZ displayed no synergy with chloroquine (CQ), amodiaquine, or artesunate. AZ activity was also unaffected by mutations in the pfcrt (P. falciparum chloroquine resistance transporter) or pfmdr1 (P. falciparum multidrug resistance-1) drug resistance loci, as determined using transgenic lines. We have selected mutant, AZ-resistant 7G8 and Dd2 parasite lines. In the AZ-resistant 7G8 line, the bacterial-like apicoplast large subunit ribosomal RNA harbored a U438C mutation in domain I. Both AZ-resistant lines revealed a G76V mutation in a conserved region of the apicoplast-encoded P. falciparum ribosomal protein L4 (PfRpl4). This protein is predicted to associate with the nuclear genome-encoded P. falciparum ribosomal protein L22 (PfRpl22) and the large subunit rRNA to form the 50 S ribosome polypeptide exit tunnel that can be occupied by AZ. The PfRpl22 sequence remained unchanged. Molecular modeling of mutant PfRpl4 with AZ suggests an altered orientation of the L75 side chain that could preclude AZ binding. These data imply that AZ acts on the apicoplast bacterial-like translation machinery and identify Pfrpl4 as a potential marker of resistance.
Reteng, Patrick; Vrisca, Visia; Sukarno, Inka; Djarkoni, Ilham Habib; Kalangi, Jane Angela; Jacobs, George Eduardo; Runtuwene, Lucky Ronald; Eshita, Yuki; Maeda, Ryuichiro; Suzuki, Yutaka; Mongan, Arthur Elia; Warouw, Sarah Maria; Yamagishi, Junya; Tuda, Josef
2017-01-01
Background Malaria still poses one of the major threats to human health. Development of effective antimalarial drugs has decreased this threat; however, the emergence of drug-resistant Plasmodium falciparum, a cause of Malaria, is disconcerting. The antimalarial drug chloroquine has been effectively used, but resistant parasites have spread worldwide. Interestingly, the withdrawal of the drug reportedly leads to an increased population of susceptible parasites in some cases. We examined the p...
A novel ABCG-like transporter of Trypanosoma cruzi is involved in natural resistance to benznidazole
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Bianca Zingales
2015-05-01
Full Text Available Benznidazole (BZ is one of the two drugs used for Chagas disease treatment. Nevertheless therapeutic failures of BZ have been reported, which were mostly attributed to variable drug susceptibility among Trypanosoma cruzi strains. ATP-binding cassette (ABC transporters are involved in a variety of translocation processes and some members have been implicated in drug resistance. Here we report the characterisation of the first T. cruzi ABCG transporter gene, named TcABCG1, which is over-expressed in parasite strains naturally resistant to BZ. Comparison of TcABCG1 gene sequence of two TcI BZ-resistant strains with CL Brener BZ-susceptible strain showed several single nucleotide polymorphisms, which determined 11 amino acid changes. CL Brener transfected with TcI transporter genes showed 40-47% increased resistance to BZ, whereas no statistical significant increment in drug resistance was observed when CL Brener was transfected with the homologous gene. Only in the parasites transfected with TcI genes there was 2-2.6-fold increased abundance of TcABCG1 transporter protein. The analysis in wild type strains also suggests that the level of TcABCG1 transporter is related to BZ natural resistance. The characteristics of untranslated regions of TcABCG1 genes of BZ-susceptible and resistant strains were investigated by computational tools.
Magnetic property effect on transport processes in resistance spot welding
Energy Technology Data Exchange (ETDEWEB)
Wei, P S [Department of Mechanical and Electro-Mechanical Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan 80424 (China); Wu, T H, E-mail: pswei@mail.nsysu.edu.tw, E-mail: wux0064@gmail.com [Department of Mechanical Engineering, Yung Ta Institute of Technology and Commerce, Pintong, Taiwan 909 (China)
2011-08-17
This study investigates the effects of the Curie temperature and magnetic permeability on transport variables, solute distribution and nugget shapes during resistance spot welding. The Curie temperature is the temperature below which a metal or alloy is ferromagnetic with a high magnetic permeability, and above which it is paramagnetic with a small magnetic permeability. The model proposed here accounts for electromagnetic force, heat generation and contact resistance at the faying surface and electrode-workpiece interfaces and bulk resistance in workpieces. Contact resistance includes constriction and film resistances, which are functions of hardness, temperature, electrode force and surface condition. The computed results show that transport variables and nugget shapes can be consistently interpreted from the delay of response time and jump of electric current density as a result of finite magnetic diffusion, rather than through the examination of the variations of dynamic electrical resistance with time. The molten nugget on the faying surface is initiated earlier with increasing magnetic permeability and Curie temperature. A high Curie temperature enhances convection and solute mixing, and readily melts through the workpiece surface near the electrode edge. Any means to reduce the Curie temperature or magnetic permeability, such as adjusting the solute content, can be a good way to control weld quality. This study can also be applied to interpret the contact problems encountered in various electronics and packaging technologies, and so on.
Central serotonin and dopamine transporters in overeating, obesity and insulin resistance
Koopman, K.E.M.
2014-01-01
The objectives of this thesis were to study cerebral serotonin transporters (SERT) in the diencephalon and striatal dopamine transporters (DAT) in humans in different metabolic conditions (i.e. lean, obese and insulin resistant state) in relation to feeding behavior and to investigate the early
UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes.
Lim, Michelle Yi-Xiu; LaMonte, Gregory; Lee, Marcus C S; Reimer, Christin; Tan, Bee Huat; Corey, Victoria; Tjahjadi, Bianca F; Chua, Adeline; Nachon, Marie; Wintjens, René; Gedeck, Peter; Malleret, Benoit; Renia, Laurent; Bonamy, Ghislain M C; Ho, Paul Chi-Lui; Yeung, Bryan K S; Chow, Eric D; Lim, Liting; Fidock, David A; Diagana, Thierry T; Winzeler, Elizabeth A; Bifani, Pablo
2016-09-19
A molecular understanding of drug resistance mechanisms enables surveillance of the effectiveness of new antimicrobial therapies during development and deployment in the field. We used conventional drug resistance selection as well as a regime of limiting dilution at early stages of drug treatment to probe two antimalarial imidazolopiperazines, KAF156 and GNF179. The latter approach permits the isolation of low-fitness mutants that might otherwise be out-competed during selection. Whole-genome sequencing of 24 independently derived resistant Plasmodium falciparum clones revealed four parasites with mutations in the known cyclic amine resistance locus (pfcarl) and a further 20 with mutations in two previously unreported P. falciparum drug resistance genes, an acetyl-CoA transporter (pfact) and a UDP-galactose transporter (pfugt). Mutations were validated both in vitro by CRISPR editing in P. falciparum and in vivo by evolution of resistant Plasmodium berghei mutants. Both PfACT and PfUGT were localized to the endoplasmic reticulum by fluorescence microscopy. As mutations in pfact and pfugt conveyed resistance against additional unrelated chemical scaffolds, these genes are probably involved in broad mechanisms of antimalarial drug resistance.
Dermauw, Wannes; Van Leeuwen, Thomas
2014-02-01
About a 100 years ago, the Drosophila white mutant marked the birth of Drosophila genetics. The white gene turned out to encode the first well studied ABC transporter in arthropods. The ABC gene family is now recognized as one of the largest transporter families in all kingdoms of life. The majority of ABC proteins function as primary-active transporters that bind and hydrolyze ATP while transporting a large diversity of substrates across lipid membranes. Although extremely well studied in vertebrates for their role in drug resistance, less is known about the role of this family in the transport of endogenous and exogenous substances in arthropods. The ABC families of five insect species, a crustacean and a chelicerate have been annotated in some detail. We conducted a thorough phylogenetic analysis of the seven arthropod and human ABC protein subfamilies, to infer orthologous relationships that might suggest conserved function. Most orthologous relationships were found in the ABCB half transporter, ABCD, ABCE and ABCF subfamilies, but specific expansions within species and lineages are frequently observed and discussed. We next surveyed the role of ABC transporters in the transport of xenobiotics/plant allelochemicals and their involvement in insecticide resistance. The involvement of ABC transporters in xenobiotic resistance in arthropods is historically not well documented, but an increasing number of studies using unbiased differential gene expression analysis now points to their importance. We give an overview of methods that can be used to link ABC transporters to resistance. ABC proteins have also recently been implicated in the mode of action and resistance to Bt toxins in Lepidoptera. Given the enormous interest in Bt toxicology in transgenic crops, such findings will provide an impetus to further reveal the role of ABC transporters in arthropods. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
Thita, Thunyapit; Jadsri, Pimrat; Thamkhantho, Jarupatr; Ruang-Areerate, Toon; Suwandittakul, Nantana; Sitthichot, Naruemon; Mahotorn, Kittiya; Tan-Ariya, Peerapan; Mungthin, Mathirut
2018-05-15
In Thailand, artemisinin-based combination therapy (ACT) has been used to treat uncomplicated falciparum malaria since 1995. Unfortunately, artemisinin resistance has been reported from Thailand and other Southeast Asian countries since 2003. Malarone ® , a combination of atovaquone-proguanil (ATQ-PG), has been used to cease artemisinin pressure in some areas along Thai-Cambodia border, as part of an artemisinin resistance containment project since 2009. This study aimed to determine genotypes and phenotypes of Plasmodium falciparum isolates collected from the Thai-Cambodia border after the artemisinin resistance containment project compared with those collected before. One hundred and nine of P. falciparum isolates collected from Thai-Cambodia border from Chanthaburi and Trat provinces during 1988-2016 were used in this study. Of these, 58 isolates were collected after the containment. These parasite isolates were characterized for in vitro antimalarial sensitivities including chloroquine (CQ), quinine (QN), mefloquine (MQ), piperaquine (PPQ), artesunate (AS), dihydroartemisinin (DHA), ATQ and PG and genetic markers for drug resistance including the Kelch13 (k13), Plasmodium falciparum chloroquine resistance transporter (pfcrt), P. falciparum multidrug resistance 1 (pfmdr1) and cytochrome b (cytb) genes. Mean CQ, QN, MQ, PPQ and AS IC 50 s of the parasite isolates collected from 2009 to 2016 exhibited significantly higher than those of parasites collected before 2009. Approximately 57% exhibited in vitro MQ resistance. Approximately 94% of the isolates collected from 2009 to 2016 contained the pfmdr1 184F allele. Mutations of the k13 gene were detected in approximately 90% of the parasites collected from 2009 to 2016 which were significantly higher than the parasite isolates collected before. No ATQ-resistant genotype and phenotype of P. falciparum were found among the isolates collected after the containment project. Although the containment project had been
Functional resistance of enamel and the phenomenon of transtegumental fluid transport
Directory of Open Access Journals (Sweden)
Okushko V.R. Okushko R.V. Ursan R.V.
2011-03-01
Full Text Available Current data related to transport of fluid through the covering tissue formations (skin, nail plate, dental enamel, gum valley are being analyzed. A supposition is made of transtegumental fluid transport (TFT as a general biological regularity which is specifically manifested in tissues of different functional purposes. Depending on the peculiarity of the organ, the tooth performs the TFT providing functional resistance of the enamel, whose level is clinically detected in the «test of enamel resistance» (TER used in modern research. The article draws attention to the reasonability of an in-depth study of the tooth physiology, where the central element is TFT. This phenomenon is of interest both from fundamental and highly practical standpoints. Identification of seasonal periods in the functional resistance decline makes it possible to get a distinct effect by means of concentrating prevention efforts on this. The TER sample, as well as other transtegumental fluid transport patterns, is to find place in the system of personalized predictive approach to caries diseases
Influence of multidrug resistance and drug transport proteins on chemotherapy drug metabolism.
Joyce, Helena; McCann, Andrew; Clynes, Martin; Larkin, Annemarie
2015-05-01
Chemotherapy involving the use of anticancer drugs remains an important strategy in the overall management of patients with metastatic cancer. Acquisition of multidrug resistance remains a major impediment to successful chemotherapy. Drug transporters in cell membranes and intracellular drug metabolizing enzymes contribute to the resistance phenotype and determine the pharmacokinetics of anticancer drugs in the body. ATP-binding cassette (ABC) transporters mediate the transport of endogenous metabolites and xenobiotics including cytotoxic drugs out of cells. Solute carrier (SLC) transporters mediate the influx of cytotoxic drugs into cells. This review focuses on the substrate interaction of these transporters, on their biology and what role they play together with drug metabolizing enzymes in eliminating therapeutic drugs from cells. The majority of anticancer drugs are substrates for the ABC transporter and SLC transporter families. Together, these proteins have the ability to control the influx and the efflux of structurally unrelated chemotherapeutic drugs, thereby modulating the intracellular drug concentration. These interactions have important clinical implications for chemotherapy because ultimately they determine therapeutic efficacy, disease progression/relapse and the success or failure of patient treatment.
DEFF Research Database (Denmark)
Sandra, Christensen; Jensen, Niels Frank; Stoeckel, Johanne Danmark
2013-01-01
, respectively. Studies are ongoing to assess glutamate uptake in parental and resistant CRC cells and the effect of inhibition/knockdown of SLC1A1 and -3 on SN38- and Oxp resistance. In conclusion, SN38-and Oxp-resistance in CRC cells is associated with SLC1A1 and -3 dysregulation. As these transporters have...
Slower phloem transport in gymnosperm trees can be attributed to higher sieve element resistance.
Liesche, Johannes; Windt, Carel; Bohr, Tomas; Schulz, Alexander; Jensen, Kaare H
2015-04-01
In trees, carbohydrates produced in photosynthesizing leaves are transported to roots and other sink organs over distances of up to 100 m inside a specialized transport tissue, the phloem. Angiosperm and gymnosperm trees have a fundamentally different phloem anatomy with respect to cell size, shape and connectivity. Whether these differences have an effect on the physiology of carbohydrate transport, however, is not clear. A meta-analysis of the experimental data on phloem transport speed in trees yielded average speeds of 56 cm h(-1) for angiosperm trees and 22 cm h(-1) for gymnosperm trees. Similar values resulted from theoretical modeling using a simple transport resistance model. Analysis of the model parameters clearly identified sieve element (SE) anatomy as the main factor for the significantly slower carbohydrate transport speed inside the phloem in gymnosperm compared with angiosperm trees. In order to investigate the influence of SE anatomy on the hydraulic resistance, anatomical data on SEs and sieve pores were collected by transmission electron microscopy analysis and from the literature for 18 tree species. Calculations showed that the hydraulic resistance is significantly higher in the gymnosperm than in angiosperm trees. The higher resistance is only partially offset by the considerably longer SEs of gymnosperms. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Directory of Open Access Journals (Sweden)
Akala HM
2014-11-01
Full Text Available Hoseah M Akala, Angela O Achieng, Fredrick L Eyase, Dennis W Juma, Luiser Ingasia, Agnes C Cheruiyot, Charles Okello, Duke Omariba, Eunice A Owiti, Catherine Muriuki, Redemptah Yeda, Ben Andagalu, Jacob D Johnson, Edwin Kamau Global Emerging Infections Surveillance Program, United States Army Medical Research Unit-Kenya, Kenya Medical Research Institute, Walter Reed Project, Kisumu and Nairobi, Kenya Background: The renewed malaria eradication efforts require an understanding of the seasonal patterns of frequency of polymorphic variants in order to focus limited funds productively. Although cross-sectional studies in holoendemic areas spanning a single year could be useful in describing parasite genotype status at a given point, such information is inadequate in describing temporal trends in genotype polymorphisms. For Plasmodium falciparum isolates from Kisumu District Hospital, Plasmodium falciparum chloroquine-resistance transporter gene (Pfcrt-K76T and P. falciparum multidrug resistance gene 1 (PfMDR1-N86Y, were analyzed for polymorphisms and parasitemia changes in the 53 months from March 2008 to August 2012. Observations were compared with prevailing climatic factors, including humidity, rainfall, and temperature. Methods: Parasitemia (the percentage of infected red blood cells per total red blood cells was established by microscopy for P. falciparum malaria-positive samples. P. falciparum DNA was extracted from whole blood using a Qiagen DNA Blood Mini Kit. Single nucleotide polymorphism identification at positions Pfcrt-K76T and PfMDR1-N86Y was performed using real-time polymerase chain reaction and/or sequencing. Data on climatic variables were obtained from http://www.tutiempo.net/en/. Results: A total of 895 field isolates from 2008 (n=169, 2009 (n=161, 2010 (n=216, 2011 (n=223, and 2012 (n=126 showed large variations in monthly frequency of PfMDR1-N86Y and Pfcrt-K76T as the mutant genotypes decreased from 68.4%±15% and 38.1%±13% to
Putman, M; van Veen, HW; Degener, JE; Konings, WN
2001-01-01
The active efflux of toxic compounds by (multi)drug transporters is one of the mechanisms that bacteria have developed to resist cytotoxic drugs. The authors describe the role of the lactococcal secondary multidrug transporter LmrP in the resistance to a broad range of clinically important
Kuriakose, Jerrin
2014-01-01
Multidrug resistance (MDR) is the condition where cancer cells or microorganisms cease to respond to multiple drugs. MDR conferred by efflux transporters, that deprive the bioavailability of drugs at their site of action, are a threat to cancer and malarial chemotherapy. Specifically, the mammalian ABC transporter Pglycoprotein (P-gp) has undermined many drugs in treatment of cancer and other disease states. Mutations in the parasitic transporter Plasmodium falciparum chloroquine resistance t...
DEFF Research Database (Denmark)
Lotz, Mikkel Rønne; Boll, Mads; Østerberg, Frederik Westergaard
2016-01-01
-configurations depends on the dimensionality of the current transport (i.e., one- or two-dimensional). At low grain density or low grain boundary resistivity, two-dimensional transport is observed. In contrast, at moderate grain density and high grain resistivity, one-dimensional transport is seen. Ultimately...
Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake
DEFF Research Database (Denmark)
Richter, Erik; Hansen, B F; Hansen, S A
1988-01-01
in the presence of glucose and insulin. The data indicate that exposure to a moderately increased glucose concentration (12 mM) leads to rapidly developing resistance of skeletal-muscle glucose transport and uptake to maximal insulin stimulation. The effect of glucose is enhanced by simultaneous insulin exposure......, whereas exposure for 5 h to insulin itself does not cause measurable resistance to maximal insulin stimulation.......The ability of glucose and insulin to modify insulin-stimulated glucose transport and uptake was investigated in perfused skeletal muscle. Here we report that perfusion of isolated rat hindlimbs for 5 h with 12 mM-glucose and 20,000 microunits of insulin/ml leads to marked, rapidly developing...
Inoue, Juliana; Lopes, Dinora; do Rosário, Virgílio; Machado, Marta; Hristov, Angélica D; Lima, Giselle Fmc; Costa-Nascimento, Maria J; Segurado, Aluísio C; Di Santi, Silvia M
2014-09-19
Anti-malarial resistance in Plasmodium falciparum remains an obstacle for malaria control. Resistance-associated genes were analysed in Brazilian samples over four decades to evaluate the impact of different treatment regimens on the parasite genetic profile. Samples were collected on filter paper from patients infected in the Amazon region from 1984 to 2011. DNA was extracted with Chelex® 100 and monoinfection confirmed by PCR. SNPs in the pfcrt, pfmdr1, pfdhfr and pfdhps genes were assessed by PCR-RFLP. The pfmdr1 copy number was estimated using real time quantitative PCR with SYBR® Green. Parasite response was assessed ex vivo with seven concentrations of each anti-malarial. Patients were treated according to Brazilian guidelines: quinine plus tetracycline or mefloquine in period 1 and ACT in period 2. All 96 samples presented the pfcrt 76T mutant throughout the assessed periods. In addition, all isolates showed ex vivo chloroquine resistance. The pfmdr1 86Y was detected in 1.5% of samples in period 1, and in 25% in period 2. All samples presented the pfmdr1 1246Y. The analysis of pfmdr1 copy number showed amplification in 37.3% in period 1 and in 42% in period 2. Mutations in pfdhfr were shown as follows: 51I in all samples in period 1 and in 81.2% in period 2; 59R in 6.4% in period 2. The pfdhfr 108N and the pfdhps 437G were seen in all samples along time; the pfdhps 540E in 93.7% in period 1 and in 75% in period 2. The 76T mutation associated to chloroquine resistance is still present in the parasite population, although this anti-malarial was withdrawn from the chemotherapy of P. falciparum in Brazil in the mid-1980s. All isolates assayed ex vivo for chloroquine showed resistant phenotype and 76T. No association was observed between pfmdr1 mutations and resistance to quinine, mefloquine and artemisinin derivatives. Additionally, the pfdhfr 108N mutation was detected in all samples throughout the evaluated periods, demonstrating fixation of the mutant
Hot electron transport modelling in fast ignition relevant targets with non-Spitzer resistivity
Energy Technology Data Exchange (ETDEWEB)
Chapman, D A; Hoarty, D J; Swatton, D J R [Plasma Physics Department, AWE, Aldermaston, Reading, Berkshire, RG7 4PR (United Kingdom); Hughes, S J, E-mail: david.chapman@awe.co.u [Computational Physics Group, AWE, Aldermaston, Reading, Berkshire, RG7 4PR (United Kingdom)
2010-08-01
The simple Lee-More model for electrical resistivity is implemented in the hybrid fast electron transport code THOR. The model is shown to reproduce experimental data across a wide range of temperatures using a small number of parameters. The effect of this model on the heating of simple Al targets by a short-pulse laser is studied and compared to the predictions of the classical Spitzer-Haerm resistivity. The model is then used in simulations of hot electron transport experiments using buried layer targets.
International Nuclear Information System (INIS)
Hwang, Ki Ha
2000-02-01
Before the actual construction of radioactive waste repository, analysis of radionuclide transport is required to predict the radiological effect on public and environment. Many models have been developed to predict the realistic radionuclide transport through the repository. In this study, Network Resistance Model (NRM) that is similar to electrical circuit network is adopted to simulate the radionuclide transport. NRM assume the media of repository as the resistance of the radionuclide transport and describes the transport phenomena of radionuclide by connecting the resistance as network. NRM is easy to apply to describe complex system and take less calculation time compared to the other model. The object of this study is to develop the fast, simple and efficient calculation method to simulate the radionuclide with the newly adopted concept using network resistance. New system configuration specially focused on rock edge region is introduced by dividing the rock matrix. By dividing the rock edge from the main rock matrix region, the rock edge region is more carefully analyzed and compared. Rock edge region can accelerate radionuclide transport due to the reducing effect on the total resistivity of rock matrix. Therefore, increased radioactive dose is expected when we apply NRM methodology in the performance assessment of the repository. Result of the performance assessment can be more conservative and reliable. NRM can be applied to other system configuration and for more complex pathways. NRM is simple to us e and easy to modify than any other modeling method
Lubelski, Jacek; Konings, Wil N.; Driessen, Arnold J. M.
Membrane proteins responsible for the active efflux of structurally and functionally unrelated drugs were first characterized in higher eukalyotes. To date, a vast number of transporters contributing to multidrug resistance (MDR transporters) have been reported for a large variety of organisms.
DEFF Research Database (Denmark)
Mohammed, Asia; Ndaro, Arnold; Kalinga, Akili
2013-01-01
Plasmodium falciparum resistance to anti-malarial drugs remains a major obstacle to the control of malaria. In 2001 Tanzania replaced chloroquine (CQ) with sulphadoxine-pyrimethamine (SP) as first-line drug, which in turn was replaced by artemisinin combination therapy in 2006. SP has however......, continued to be used in intermittent preventive treatment of malaria in pregnancy (IPTp) despite reports of high levels of resistance to SP due to the lack of alternatives to SP for IPTp. Recent reports have indicated recovery of CQ-susceptibility in Malawi, Kenya, Mozambique, and Tanzania based...
International Nuclear Information System (INIS)
Němcová-Fürstová, Vlasta; Kopperová, Dana; Balušíková, Kamila; Ehrlichová, Marie; Brynychová, Veronika; Václavíková, Radka; Daniel, Petr; Souček, Pavel; Kovář, Jan
2016-01-01
Development of taxane resistance has become clinically very important issue. The molecular mechanisms underlying the resistance are still unclear. To address this issue, we established paclitaxel-resistant sublines of the SK-BR-3 and MCF-7 breast cancer cell lines that are capable of long-term proliferation in 100 nM and 300 nM paclitaxel, respectively. Application of these concentrations leads to cell death in the original counterpart cells. Both sublines are cross-resistant to doxorubicin, indicating the presence of the MDR phenotype. Interestingly, resistance in both paclitaxel-resistant sublines is circumvented by the second-generation taxane SB-T-1216. Moreover, we demonstrated that it was not possible to establish sublines of SK-BR-3 and MCF-7 cells resistant to this taxane. It means that at least the tested breast cancer cells are unable to develop resistance to some taxanes. Employing mRNA expression profiling of all known human ABC transporters and subsequent Western blot analysis of the expression of selected transporters, we demonstrated that only the ABCB1/PgP and ABCC3/MRP3 proteins were up-regulated in both paclitaxel-resistant sublines. We found up-regulation of ABCG2/BCRP and ABCC4 proteins only in paclitaxel-resistant SK-BR-3 cells. In paclitaxel-resistant MCF-7 cells, ABCB4/MDR3 and ABCC2/MRP2 proteins were up-regulated. Silencing of ABCB1 expression using specific siRNA increased significantly, but did not completely restore full sensitivity to both paclitaxel and doxorubicin. Thus we showed a key, but not exclusive, role for ABCB1 in mechanisms of paclitaxel resistance. It suggests the involvement of multiple mechanisms in paclitaxel resistance in tested breast cancer cells. - Highlights: • Expression of all ABC transporters in paclitaxel-resistant sublines of SK-BR-3 and MCF-7 cells was analyzed. • SK-BR-3 and MCF-7 cells are unable to develop resistance to some taxanes. • Some taxanes are able to overcome developed resistance to
Energy Technology Data Exchange (ETDEWEB)
Němcová-Fürstová, Vlasta, E-mail: vlasta.furstova@lf3.cuni.cz [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Kopperová, Dana; Balušíková, Kamila [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Ehrlichová, Marie; Brynychová, Veronika; Václavíková, Radka [Toxicogenomics Unit, National Institute of Public Health, Prague (Czech Republic); Daniel, Petr [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Souček, Pavel [Toxicogenomics Unit, National Institute of Public Health, Prague (Czech Republic); Kovář, Jan [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic)
2016-11-01
Development of taxane resistance has become clinically very important issue. The molecular mechanisms underlying the resistance are still unclear. To address this issue, we established paclitaxel-resistant sublines of the SK-BR-3 and MCF-7 breast cancer cell lines that are capable of long-term proliferation in 100 nM and 300 nM paclitaxel, respectively. Application of these concentrations leads to cell death in the original counterpart cells. Both sublines are cross-resistant to doxorubicin, indicating the presence of the MDR phenotype. Interestingly, resistance in both paclitaxel-resistant sublines is circumvented by the second-generation taxane SB-T-1216. Moreover, we demonstrated that it was not possible to establish sublines of SK-BR-3 and MCF-7 cells resistant to this taxane. It means that at least the tested breast cancer cells are unable to develop resistance to some taxanes. Employing mRNA expression profiling of all known human ABC transporters and subsequent Western blot analysis of the expression of selected transporters, we demonstrated that only the ABCB1/PgP and ABCC3/MRP3 proteins were up-regulated in both paclitaxel-resistant sublines. We found up-regulation of ABCG2/BCRP and ABCC4 proteins only in paclitaxel-resistant SK-BR-3 cells. In paclitaxel-resistant MCF-7 cells, ABCB4/MDR3 and ABCC2/MRP2 proteins were up-regulated. Silencing of ABCB1 expression using specific siRNA increased significantly, but did not completely restore full sensitivity to both paclitaxel and doxorubicin. Thus we showed a key, but not exclusive, role for ABCB1 in mechanisms of paclitaxel resistance. It suggests the involvement of multiple mechanisms in paclitaxel resistance in tested breast cancer cells. - Highlights: • Expression of all ABC transporters in paclitaxel-resistant sublines of SK-BR-3 and MCF-7 cells was analyzed. • SK-BR-3 and MCF-7 cells are unable to develop resistance to some taxanes. • Some taxanes are able to overcome developed resistance to
Are lipid rafts involved in ABC transporter-mediated drug resistance of tumor cells?
Kok, Jan Willem; Klappe, Karin; Hummel, Ina; Kroesen, Bart-Jan; Sietsma, Hannie; Meszaros, Peter
2008-01-01
Since their discovery, lipid rafts have been implicated in several cellular functions, including protein transport in polarized cells and signal transduction. Also in multidrug resistance lipid rafts may be important with regard to the localization of ATP-binding cassette (ABC) transporters in these
Antimicrobials are used in production agriculture to treat disease and promote animal growth, but the presence of antibiotics in the environment raises concern about widespread antibiotic resistance. This study documents the occurrence and transport of tylosin, tetracycline, enterococci resistant to...
Directory of Open Access Journals (Sweden)
Marta Schielmann
2017-11-01
Full Text Available Oligopeptides incorporating N3-(4-methoxyfumaroyl-L-2,3-diaminopropanoic acid (FMDP, an inhibitor of glucosamine-6-phosphate synthase, exhibited growth inhibitory activity against Candida albicans, with minimal inhibitory concentration values in the 0.05–50 μg mL-1 range. Uptake by the peptide permeases was found to be the main factor limiting an anticandidal activity of these compounds. Di- and tripeptide containing FMDP (F2 and F3 were transported by Ptr2p/Ptr22p peptide transporters (PTR and FMDP-containing hexa-, hepta-, and undecapeptide (F6, F7, and F11 were taken up by the oligopeptide transporters (OPT oligopeptide permeases, preferably by Opt2p/Opt3p. A phenotypic, apparent resistance of C. albicans to FMDP-oligopeptides transported by OPT permeases was triggered by the environmental factors, whereas resistance to those taken up by the PTR system had a genetic basis. Anticandidal activity of longer FMDP-oligopeptides was strongly diminished in minimal media containing easily assimilated ammonium sulfate or L-glutamine as the nitrogen source, both known to downregulate expression of the OPT genes. All FMDP-oligopeptides tested were more active at lower pH and this effect was slightly more remarkable for peptides F6, F7, and F11, compared to F2 and F3. Formation of isolated colonies was observed inside the growth inhibitory zones induced by F2 and F3 but not inside those induced by F6, F7, and F11. The vast majority (98% of those colonies did not originate from truly resistant cells. The true resistance of 2% of isolates was due to the impaired transport of di- and to a lower extent, tripeptides. The resistant cells did not exhibit a lower expression of PTR2, PTR22, or OPT1–3 genes, but mutations in the PTR2 gene resulting in T422H, A320S, D119V, and A320S substitutions in the amino acid sequence of Ptr2p were found.
Rabodoarivelo, Marie Sylvianne; Imperiale, Bélen; andrianiavomikotroka, Rina; Brandao, Angela; Kumar, Parveen; Singh, Sarman; Ferrazoli, Lucilaine; Morcillo, Nora; Rasolofo, Voahangy; Palomino, Juan Carlos; Vandamme, Peter; Martin, Anandi
2015-01-01
Background Detection of drug-resistant tuberculosis is essential for the control of the disease but it is often hampered by the limitation of transport and storage of samples from remote locations to the reference laboratory. We performed a retrospective field study to evaluate the performance of four supports enabling the transport and storage of samples to be used for molecular detection of drug resistance using the GenoType MTBDRplus. Methods Two hundred Mycobacterium tuberculosis strains were selected and spotted on slides, FTA cards, GenoCards, and in ethanol. GenoType MTBDRplus was subsequently performed with the DNA extracted from these supports. Sensitivity and specificity were calculated and compared to the results obtained by drug susceptibility testing. Results For all supports, the overall sensitivity and specificity for detection of resistance to RIF was between 95% and 100%, and for INH between 95% and 98%. Conclusion The four transport and storage supports showed a good sensitivity and specificity for the detection of resistance to RIF and INH in M. tuberculosis strains using the GenoType MTBDRplus. These supports can be maintained at room temperature and could represent an important alternative cost-effective method useful for rapid molecular detection of drug-resistant TB in low-resource settings. PMID:26431352
Liu, Cong; Krishnan, J; Xu, Xiao Yun
2013-03-01
In this paper we systematically investigate the effects of acquired drug resistance at the cellular and tissue scale, with a specific focus on ATP-binding cassette (ABC) transporter-based mechanisms and contrast this with other representative intracellular resistance mechanisms. This is done by developing in silico models wherein the drug resistance mechanism is overlaid on a coarse-grained description of apoptosis; these cellular models are coupled with interstitial drug transport, allowing for a transparent examination of the effect of acquired drug resistances at the tissue level. While ABC transporter-mediated resistance mechanisms counteract drug effect at the cellular level, its tissue-level effect is more complicated, revealing unexpected trends in tissue response as drug stimuli are systematically varied. Qualitatively different behaviour is observed in other drug resistance mechanisms. Overall the paper (i) provides insight into the tissue level functioning of a particular resistance mechanism, (ii) shows that this is very different from other resistance mechanisms of an apparently similar type, and (iii) demonstrates a concrete instance of how the functioning of a negative feedback based cellular adaptive mechanism can have unexpected higher scale effects.
Membrane transporters and drought resistance – a complex issue
Directory of Open Access Journals (Sweden)
Karolina Maria Jarzyniak
2014-12-01
Full Text Available Land plants have evolved complex adaptation strategies to survive changes in water status in the environment. Understanding the molecular nature of such adaptive changes allows the development of rapid innovations to improve crop performance. Plant membrane transport systems play a significant role when adjusting to water scarcity. Here we put proteins participating in transmembrane allocations of various molecules in the context of stomatal, cuticular and root responses, representing a part of the drought resistance strategy. Their role in the transport of signaling molecules, ions or osmolytes is summarized and the challenge of the forthcoming research, resulting from the recent discoveries, is highlighted.
DEFF Research Database (Denmark)
Shaheen, Aqsa; Ismat, Fouzia; Iqbal, Mazhar
2015-01-01
Multidrug resistance mediated by efflux pumps is a well-known phenomenon in infectious bacteria. Although much work has been carried out to characterize multidrug efflux pumps in Gram-negative and Gram-positive bacteria, such information is still lacking for many deadly pathogens. The aim...... of this study was to gain insight into the substrate specificity of previously uncharacterized transporters of Salmonella Typhi to identify their role in the development of multidrug resistance. S. Typhi genes encoding putative members of the major facilitator superfamily were cloned and expressed in the drug......-hypersensitive Escherichia coli strain KAM42, and tested for transport of 25 antibacterial compounds, including representative antibiotics of various classes, antiseptics, dyes and detergents. Of the 15 tested putative transporters, STY0901, STY2458 and STY4874 exhibited a drug-resistance phenotype. Among these, STY4874...
Tsujimoto, Yoshiyuki; Shimizu, Yoshihiro; Otake, Kazuya; Nakamura, Tatsuya; Okada, Ryutaro; Miyazaki, Toshitaka; Watanabe, Kunihiko
2015-01-01
SNQ2 was identified as a caffeine-resistance gene by screening a genomic library of Saccharomyces cerevisiae in a multicopy vector YEp24. SNQ2 encodes an ATP-binding cassette transporter and is highly homologous to PDR5. Multicopy of PDR5 also conferred resistance to caffeine, while its resistance was smaller than that of SNQ2. Residual caffeine contents were analyzed after transiently exposing cells to caffeine. The ratios of caffeine contents were 21.3 ± 8.8% (YEp24-SNQ2) and 81.9 ± 8.7% (YEp24-PDR5) relative to control (YEp24, 100%). In addition, multicopies of SNQ2 or PDR5 conferred resistance to rhodamine 6G (R6G), which was widely used as a substrate for transport assay. R6G was exported by both transporters, and their efflux activities were inhibited by caffeine with half-maximal inhibitory concentrations of 5.3 ± 1.9 (YEp24-SNQ2) and 17.2 ± 9.6 mM (YEp24-PDR5). These results demonstrate that Snq2p is a more functional transporter of caffeine than Pdr5p in yeast cells.
Zaidi, Arsalan Haseeb; Bakkes, Patrick J.; Lubelski, Jacek; Agustiandari, Herfita; Kuipers, Oscar P.; Driessen, Arnold J. M.
2008-01-01
Upon prolonged exposure to cholate and other toxic compounds, Lactococcus lactis develops a multidrug resistance phenotype that has been attributed to an elevated expression of the heterodimeric ABC-type multidrug transporter LmrCD. To investigate the molecular basis of bile acid resistance in L.
Directory of Open Access Journals (Sweden)
Wolfgang Hagmann
2010-09-01
Full Text Available Gemcitabine is widely used as first-line chemotherapeutic drug in the treatment of pancreatic cancer. Our previous experimental chemotherapy studies have shown that treatment of human pancreatic carcinoma cells with 5-fluorouracil (5-FU alters the cellular transporter expression profile and that modulation of the expression of multidrug resistance protein 5 (MRP5; ABCC5 influences the chemoresistance of these tumor cells. Here, we studied the influence of acute and chronic gemcitabine treatment on the expression of relevant uptake and export transporters in pancreatic carcinoma cells by reverse transcription-polymerase chain reaction (RT-PCR, quantitative RT-PCR, and immunoblot analyses. The specific role of MRP5 in cellular gemcitabine sensitivity was studied by cytotoxicity assays using MRP5-overexpressing and MRP5-silenced cells. Exposure to gemcitabine (12 nM for 3 days did not alter the messenger RNA (mRNA expression of MRP1, MRP3, MRP5, and equilibrative nucleoside transporter 1 (ENT1, whereas high dosages of the drug (20 µM for 1 hour elicited up-regulation of these transporters in most cell lines studied. In cells with acquired gemcitabine resistance (up to 160 nM gemcitabine, the mRNA or protein expression of the gemcitabine transporters MRP5 and ENT1 was upregulated in several cell lines. Combined treatment with 5-FU and gemcitabine caused a 5- to 40-fold increase in MRP5 and ENT1 expressions. Cytotoxicity assays using either MRP5-overexpressing (HEK and PANC-1 or MRP5-silenced (PANC1/shMRP5 cells indicated that MRP5 contributes to gemcitabine resistance. Thus, our novel data not only on drug-induced alterations of transporter expression relevant for gemcitabine uptake and export but also on the link between gemcitabine sensitivity and MRP5 expression may lead to improved strategies of future chemotherapy regimens using gemcitabine in pancreatic carcinoma patients.
Zhu, Y. G.
2015-12-01
In addition to material and energy flows, the dynamics and functions of the Earth's critical zone are intensively mediated by biological actions performed by diverse organisms. These biological actions are modulated by the expression of functional genes and their translation into enzymes that catalyze geochemical reactions, such as nutrient turnover and pollutant biodegradation. Although geobiology, as an interdisciplinary research area, is playing and vital role in linking biological and geochemical processes at different temporal and spatial scales, the distribution and transport of functional genes have rarely been investigated from the Earth's critical zone perspectives. To illustrate the framework of studies on the transport and transformation of genetic information in the critical zone, antibiotic resistance is taken as an example. Antibiotic resistance genes are considered as a group of emerging contaminants, and their emergence and spread within the critical zone on one hand are induced by anthropogenic activities, and on other hand are threatening human health worldwide. The transport and transformation of antibiotic resistance genes are controlled by both horizontal gene transfer between bacterial cells and the movement of bacteria harboring antibiotic resistance genes. In this paper, the fate and behavior of antibiotic resistance genes will be discussed in the following aspects: 1) general overview of environmental antibiotic resistance; 2) high through quantification of the resistome in various environmental media; 3) pathways of resistance gene flow within the critical zone; and 4) potential strategies in mitigating antibiotic resistance, particularly from the critical zone perspectives.
Hu, Tao; Liu, Yinshang; Xiao, Hong; Mu, Gang; Yang, Yi-Feng
2017-08-25
The strongly correlated electron fluids in high temperature cuprate superconductors demonstrate an anomalous linear temperature (T) dependent resistivity behavior, which persists to a wide temperature range without exhibiting saturation. As cooling down, those electron fluids lose the resistivity and condense into the superfluid. However, the origin of the linear-T resistivity behavior and its relationship to the strongly correlated superconductivity remain a mystery. Here we report a universal relation [Formula: see text], which bridges the slope of the linear-T-dependent resistivity (dρ/dT) to the London penetration depth λ L at zero temperature among cuprate superconductor Bi 2 Sr 2 CaCu 2 O 8+δ and heavy fermion superconductors CeCoIn 5 , where μ 0 is vacuum permeability, k B is the Boltzmann constant and ħ is the reduced Planck constant. We extend this scaling relation to different systems and found that it holds for other cuprate, pnictide and heavy fermion superconductors as well, regardless of the significant differences in the strength of electronic correlations, transport directions, and doping levels. Our analysis suggests that the scaling relation in strongly correlated superconductors could be described as a hydrodynamic diffusive transport, with the diffusion coefficient (D) approaching the quantum limit D ~ ħ/m*, where m* is the quasi-particle effective mass.
DEFF Research Database (Denmark)
Ranjitkar, Samir; Schousboe, Mette L; Thomsen, Thomas
2011-01-01
ABSTRACT: 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 P. falciparum and Plasmodium vivax CQ and SP resistance to determine...... 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...
Shen, Zhangqi; Luangtongkum, Taradon; Qiang, Zhiyi; Jeon, Byeonghwa; Wang, Liping
2014-01-01
Although bacterial mechanisms involved in the resistance to inorganic arsenic are well understood, the molecular basis for organic arsenic resistance has not been described. Campylobacter jejuni, a major food-borne pathogen causing gastroenteritis in humans, is highly prevalent in poultry and is reportedly resistant to the arsenic compound roxarsone (4-hydroxy-3-nitrobenzenearsonic acid), which has been used as a feed additive in the poultry industry for growth promotion. In this study, we report the identification of a novel membrane transporter (named ArsP) that contributes to organic arsenic resistance in Campylobacter. ArsP is predicted to be a membrane permease containing eight transmembrane helices, distinct from other known arsenic transporters. Analysis of multiple C. jejuni isolates from various animal species revealed that the presence of an intact arsP gene is associated with elevated resistance to roxarsone. In addition, inactivation of arsP in C. jejuni resulted in 4- and 8-fold reductions in the MICs of roxarsone and nitarsone, respectively, compared to that for the wild-type strain. Furthermore, cloning of arsP into a C. jejuni strain lacking a functional arsP gene led to 16- and 64-fold increases in the MICs of roxarsone and nitarsone, respectively. Neither mutation nor overexpression of arsP affected the MICs of inorganic arsenic, including arsenite and arsenate, in Campylobacter. Moreover, acquisition of arsP in NCTC 11168 led to accumulation of less roxarsone than the wild-type strain lacking arsP. Together, these results indicate that ArsP functions as an efflux transporter specific for extrusion of organic arsenic and contributes to the resistance to these compounds in C. jejuni. PMID:24419344
Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod
2012-01-01
In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g....
Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod
2012-09-04
In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane's biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug 5-aza-2'-deoxycytidine (decitabine) significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance.
Directory of Open Access Journals (Sweden)
Archana Vijayakumar
2017-10-01
Full Text Available Lower adipose-ChREBP and de novo lipogenesis (DNL are associated with insulin resistance in humans. Here, we generated adipose-specific ChREBP knockout (AdChREBP KO mice with negligible sucrose-induced DNL in adipose tissue (AT. Chow-fed AdChREBP KO mice are insulin resistant with impaired insulin action in the liver, muscle, and AT and increased AT inflammation. HFD-fed AdChREBP KO mice are also more insulin resistant than controls. Surprisingly, adipocytes lacking ChREBP display a cell-autonomous reduction in insulin-stimulated glucose transport that is mediated by impaired Glut4 translocation and exocytosis, not lower Glut4 levels. AdChREBP KO mice have lower levels of palmitic acid esters of hydroxy stearic acids (PAHSAs in serum, and AT. 9-PAHSA supplementation completely rescues their insulin resistance and AT inflammation. 9-PAHSA also normalizes impaired glucose transport and Glut4 exocytosis in ChREBP KO adipocytes. Thus, loss of adipose-ChREBP is sufficient to cause insulin resistance, potentially by regulating AT glucose transport and flux through specific lipogenic pathways.
DEFF Research Database (Denmark)
Robey, R W; Medina-Pérez, W Y; Nishiyama, K
2001-01-01
We sought to characterize the interactions of flavopiridol with members of the ATP-binding cassette (ABC) transporter family. Cells overexpressing multidrug resistance-1 (MDR-1) and multidrug resistance-associated protein (MRP) did not exhibit appreciable flavopiridol resistance, whereas cell lines...... overexpressing the ABC half-transporter, ABCG2 (MXR/BCRP/ABCP1), were found to be resistant to flavopiridol. Flavopiridol at a concentration of 10 microM was able to prevent MRP-mediated calcein efflux, whereas Pgp-mediated transport of rhodamine 123 was unaffected at flavopiridol concentrations of up to 100...... analysis revealed overexpression of the ABCG2 gene. Western blot confirmed overexpression of ABCG2; neither P-glycoprotein nor MRP overexpression was detected. These results suggest that ABCG2 plays a role in resistance to flavopiridol....
Transport mechanisms in low-resistance ohmic contacts to p-InP formed by rapid thermal annealing
DEFF Research Database (Denmark)
Clausen, Thomas; Leistiko, Otto
1993-01-01
process is related to interdiffusion and compound formation between the metal elements and the InP. The onset of low specific contact resistance is characterized by a change in the dominant transport mechanism; from predominantly a combination of thermionic emission and field emission to purely thermionic......Thermionic emission across a very small effective Schottky barrier (0-0.2 eV) are reported as being the dominant transport process mechanism in very low-resistance ohmic contacts for conventional AuZn(Ni) metallization systems top-InP formed by rapid thermal annealing. The barrier modulation...
Wang, Chao; Cheng, Xiaojing; Lu, Jiabin; Shen, Shuiyun; Yan, Xiaohui; Yin, Jiewei; Wei, Guanghua; Zhang, Junliang
2017-12-07
Remarkable progress has been made in reducing the cathodic Pt loading of PEMFCs; however, a huge performance loss appears at high current densities, indicating the existence of a large oxygen transport resistance associated with the ultralow Pt loading catalyst layer. To reduce the Pt loading without sacrificing cell performance, it is essential to illuminate the oxygen transport mechanism in the catalyst layer. Toward this goal, an experimental approach to measure the oxygen transport resistance in catalyst layers is proposed and realized for the first time in this study. The measuring approach involves a dual-layer catalyst layer design, which consists of a dummy catalyst layer and a practical catalyst layer, followed by changing the thickness of dummy layer to respectively quantify the local and bulk resistances via limiting current measurements combined with linear extrapolation. The experimental results clearly reveal that the local resistance dominates the total resistance in the catalyst layer.
Heni, Martin; Schöpfer, Patricia; Peter, Andreas; Sartorius, Tina; Fritsche, Andreas; Synofzik, Matthis; Häring, Hans-Ulrich; Maetzler, Walter; Hennige, Anita M
2014-08-01
Eating behavior, body weight regulation, peripheral glucose metabolism, and cognitive function depend on adequate insulin action in the brain, and recent studies in humans suggested that impaired insulin action in the brain emerges upon fat intake, obesity, and genetic variants. As insulin enters into the brain in a receptor-mediated fashion, we hypothesized that whole-body insulin sensitivity might affect the transport of insulin into the brain and contribute to the aversive effect of insulin resistance in the central nervous system. In this study, we aimed to determine the ratio of insulin in the cerebrospinal fluid and serum to whole-body insulin sensitivity. Healthy human subjects participated in an oral glucose tolerance test to determine whole-body insulin sensitivity and underwent lumbar puncture. Blood and CSF concentrations of insulin were significantly correlated. The CSF/serum ratio for insulin was significantly associated with whole body insulin sensitivity with reduced insulin transported into the CSF in insulin-resistant subjects. Together, our data suggest that transport of insulin into the CSF relates to peripheral insulin sensitivity and impairs insulin action in the brain. This underlines the need for sensitizing measures in insulin-resistant subjects.
Ali, H.; Yilbas, B. S.
2016-09-01
Phonon cross-plane transport across silicon and diamond thin films pair is considered, and thermal boundary resistance across the films pair interface is examined incorporating the cut-off mismatch and diffusive mismatch models. In the cut-off mismatch model, phonon frequency mismatch for each acoustic branch is incorporated across the interface of the silicon and diamond films pair in line with the dispersion relations of both films. The frequency-dependent and transient solution of the Boltzmann transport equation is presented, and the equilibrium phonon intensity ratios at the silicon and diamond film edges are predicted across the interface for each phonon acoustic branch. Temperature disturbance across the edges of the films pair is incorporated to assess the phonon transport characteristics due to cut-off and diffusive mismatch models across the interface. The effect of heat source size, which is allocated at high-temperature (301 K) edge of the silicon film, on the phonon transport characteristics at the films pair interface is also investigated. It is found that cut-off mismatch model predicts higher values of the thermal boundary resistance across the films pair interface as compared to that of the diffusive mismatch model. The ratio of equilibrium phonon intensity due to the cut-off mismatch over the diffusive mismatch models remains >1 at the silicon edge, while it becomes <1 at the diamond edge for all acoustic branches.
International Nuclear Information System (INIS)
Fuchs, Dominik; Daniel, Volker; Sadeghi, Mahmoud; Opelz, Gerhard; Naujokat, Cord
2010-01-01
Leukemia stem cells are known to exhibit multidrug resistance by expression of ATP-binding cassette (ABC) transporters which constitute transmembrane proteins capable of exporting a wide variety of chemotherapeutic drugs from the cytosol. We show here that human promyeloblastic leukemia KG-1a cells exposed to the histone deacetylase inhibitor phenylbutyrate resemble many characteristics of leukemia stem cells, including expression of functional ABC transporters such as P-glycoprotein, BCRP and MRP8. Consequently, KG-1a cells display resistance to the induction of apoptosis by various chemotherapeutic drugs. Resistance to apoptosis induction by chemotherapeutic drugs can be reversed by cyclosporine A, which effectively inhibits the activity of P-glycoprotein and BCRP, thus demonstrating ABC transporter-mediated drug resistance in KG-1a cells. However, KG-1a are highly sensitive to apoptosis induction by salinomycin, a polyether ionophore antibiotic that has recently been shown to kill human breast cancer stem cell-like cells and to induce apoptosis in human cancer cells displaying multiple mechanisms of drug and apoptosis resistance. Whereas KG-1a cells can be adapted to proliferate in the presence of apoptosis-inducing concentrations of bortezomib and doxorubicin, salinomycin does not permit long-term adaptation of the cells to apoptosis-inducing concentrations. Thus, salinomycin should be regarded as a novel and effective agent for the elimination of leukemia stem cells and other tumor cells exhibiting ABC transporter-mediated multidrug resistance.
Zhang, Jie; Liu, Dan; Zhang, Mengjun; Sun, Yuqi; Zhang, Xiaojun; Guan, Guannan; Zhao, Xiuli; Qiao, Mingxi; Chen, Dawei; Hu, Haiyang
2016-01-01
Polyamidoamine dendrimers, which can deliver drugs and genetic materials to resistant cells, are attracting increased research attention, but their transportation behavior in resistant cells remains unclear. In this paper, we performed a systematic analysis of the cellular uptake, intracellular transportation, and efflux of PAMAM-NH2 dendrimers in multidrug-resistant breast cancer cells (MCF-7/ADR cells) using sensitive breast cancer cells (MCF-7 cells) as the control. We found that the uptake rate of PAMAM-NH2 was much lower and exocytosis of PAMAM-NH2 was much greater in MCF-7/ADR cells than in MCF-7 cells due to the elimination of PAMAM-NH2 from P-glycoprotein and the multidrug resistance-associated protein in MCF-7/ADR cells. Macropinocytosis played a more important role in its uptake in MCF-7/ADR cells than in MCF-7 cells. PAMAM-NH2 aggregated and became more degraded in the lysosomal vesicles of the MCF-7/ADR cells than in those of the MCF-7 cells. The endoplasmic reticulum and Golgi complex were found to participate in the exocytosis rather than endocytosis process of PAMAM-NH2 in both types of cells. Our findings clearly showed the intracellular transportation process of PAMAM-NH2 in MCF-7/ADR cells and provided a guide of using PAMAM-NH2 as a drug and gene vector in resistant cells.
Slower phloem transport in gymnosperm trees can be attributed to higher sieve element resistance
DEFF Research Database (Denmark)
Liesche, Johannes; Windt, Carel; Bohr, Tomas
2015-01-01
resulted from theoretical modeling using a simple transport resistance model. Analysis of the model parameters clearly identified sieve element (SE) anatomy as the main factor for the significantly slower carbohydrate transport speed inside the phloem in gymnosperm compared with angiosperm trees. In order......In trees, carbohydrates produced in photosynthesizing leaves are transported to roots and other sink organs over distances of up to 100 m inside a specialized transport tissue, the phloem. Angiosperm and gymnosperm trees have a fundamentally different phloem anatomy with respect to cell size, shape...... and connectivity. Whether these differences have an effect on the physiology of carbohydrate transport, however, is not clear. A meta-analysis of the experimental data on phloem transport speed in trees yielded average speeds of 56 cm h−1 for angiosperm trees and 22 cm h−1 for gymnosperm trees. Similar values...
Sub-picowatt/kelvin resistive thermometry for probing nanoscale thermal transport.
Zheng, Jianlin; Wingert, Matthew C; Dechaumphai, Edward; Chen, Renkun
2013-11-01
Advanced instrumentation in thermometry holds the key for experimentally probing fundamental heat transfer physics. However, instrumentation with simultaneously high thermometry resolution and low parasitic heat conduction is still not available today. Here we report a resistive thermometry scheme with ~50 μK temperature resolution and ~0.25 pW/K thermal conductance resolution, which is achieved through schemes using both modulated heating and common mode noise rejection. The suspended devices used herein have been specifically designed to possess short thermal time constants and minimal attenuation effects associated with the modulated heating current. Furthermore, we have systematically characterized the parasitic background heat conductance, which is shown to be significantly reduced using the new device design and can be effectively eliminated using a "canceling" scheme. Our results pave the way for probing fundamental nanoscale thermal transport processes using a general scheme based on resistive thermometry.
International Nuclear Information System (INIS)
Liu Weiqing; Hu Linhua; Dai Songyuan; Guo Lei; Jiang Nianquan; Kou Dongxing
2010-01-01
The influence of the series resistance on the electron transport and recombination processes in dye-sensitized solar cells (DSC) has been investigated. The series resistances induced by some parts of DSC, such as the transparent conductive oxide (TCO), the electrolyte layer and the counter electrode, influence the performance of DSC. By combining three frequency-domain techniques, specifically electrochemical impedance spectroscopy (EIS), intensity modulated photocurrent spectroscopy (IMPS) and intensity modulated photovoltage spectroscopy (IMVS), we studied the relationship between the series resistance and the dynamic response of DSC. The results show that the series resistance induced by the TCO or counter electrode predominantly affects the electron transport under short circuit conditions and has no significant influence on the recombination under open circuit conditions. However, the resistance related to the electrolyte layer not only limits the carrier transport but also influences the recombination. Possible reasons for the influence of the series resistance on the electron transport and recombination processes in DSC are also discussed.
P type porous silicon resistivity and carrier transport
International Nuclear Information System (INIS)
Ménard, S.; Fèvre, A.; Billoué, J.; Gautier, G.
2015-01-01
The resistivity of p type porous silicon (PS) is reported on a wide range of PS physical properties. Al/PS/Si/Al structures were used and a rigorous experimental protocol was followed. The PS porosity (P % ) was found to be the major contributor to the PS resistivity (ρ PS ). ρ PS increases exponentially with P % . Values of ρ PS as high as 1 × 10 9 Ω cm at room temperature were obtained once P % exceeds 60%. ρ PS was found to be thermally activated, in particular, when the temperature increases from 30 to 200 °C, a decrease of three decades is observed on ρ PS . Based on these results, it was also possible to deduce the carrier transport mechanisms in PS. For P % lower than 45%, the conduction occurs through band tails and deep levels in the tissue surrounding the crystallites. When P % overpasses 45%, electrons at energy levels close to the Fermi level allow a hopping conduction from crystallite to crystallite to appear. This study confirms the potential of PS as an insulating material for applications such as power electronic devices
Zhang, Xuejun C; Liu, Min; Lu, Guangyuan; Heng, Jie
2018-03-01
Multidrug resistance (MDR) presents a growing challenge to global public health. Drug extrusion transporters play a critical part in MDR; thus, their mechanisms of substrate recognition are being studied in great detail. In this work, we review common structural features of key transporters involved in MDR. Based on our membrane potential-driving hypothesis, we propose a general energy-coupling mechanism for secondary-active antiporters. This putative mechanism provides a common framework for understanding poly-specificity of most-if not all-MDR transporters. © 2017 The Protein Society.
Low resistivity ZnO-GO electron transport layer based CH3NH3PbI3 solar cells
Directory of Open Access Journals (Sweden)
Muhammad Imran Ahmed
2016-06-01
Full Text Available Perovskite based solar cells have demonstrated impressive performances. Controlled environment synthesis and expensive hole transport material impede their potential commercialization. We report ambient air synthesis of hole transport layer free devices using ZnO-GO as electron selective contacts. Solar cells fabricated with hole transport layer free architecture under ambient air conditions with ZnO as electron selective contact achieved an efficiency of 3.02%. We have demonstrated that by incorporating GO in ZnO matrix, low resistivity electron selective contacts, critical to improve the performance, can be achieved. We could achieve max efficiency of 4.52% with our completed devices for ZnO: GO composite. Impedance spectroscopy confirmed the decrease in series resistance and an increase in recombination resistance with inclusion of GO in ZnO matrix. Effect of temperature on completed devices was investigated by recording impedance spectra at 40 and 60 oC, providing indirect evidence of the performance of solar cells at elevated temperatures.
Fine-scale genetic characterization of Plasmodium falciparum
Indian Academy of Sciences (India)
We have initiated such a study and presented herewith the results from the in silico understanding of a seventh chromosomal region of the malarial parasite Plasmodium falciparum encompassing the antigenic var genes (coding pfemp1) and the drug-resistant gene pfcrt located at a specified region of the chromosome 7.
Seasonal variations in antibiotic resistance gene transport in the Almendares River, Havana, Cuba
Directory of Open Access Journals (Sweden)
Charles W Knapp
2012-11-01
Full Text Available Numerous studies have quantified antibiotic resistance genes (ARG in rivers and streams around the world, and significant relationships have been shown that relate different pollutant outputs and increased local ARG levels. However, most studies have not considered ambient flow conditions, which can vary dramatically especially in tropical countries. Here, ARG were quantified in water-column and sediment samples during the dry-and wet-seasons to assess how seasonal and other factors influence ARG transport down the Almendares River (Havana, Cuba. Eight locations were sampled and stream flow estimated during both seasons; qPCR was used to quantify four tetracycline, two erythromycin, and three beta-lactam resistance genes. ARG concentrations were higher in wet-season versus dry-season samples, which combined with higher flows, indicated greater ARG transport downstream during the wet season. Water-column ARG levels were more spatially variable in the dry-season than the wet-season, with the proximity of waste outfalls strongly influencing local ARG levels. Results confirm that dry-season sampling provides a useful picture of the impact of individual waste inputs on local stream ARG levels, whereas, the majority of ARGs in this tropical river were transported downstream during the wet season, possibly due to re-entrainment of ARG from sediments.
Masereeuw, R.; Notenboom, S.; Smeets, P.H.E.; Wouterse, A.C.; Russel, F.G.M.
2003-01-01
Previous studies with mutant transport-deficient rats (TR(-)), in which the multidrug resistance protein 2 (Mrp2) is lacking, have emphasized the importance of this transport protein in the biliary excretion of a wide variety of glutathione conjugates, glucuronides, and other organic anions. Mrp2 is
Keen, Patricia L; Knapp, Charles W; Hall, Kenneth J; Graham, David W
2018-07-01
Environmental transport of contaminants that can influence the development of antibiotic resistance in bacteria is an important concern in the management of ecological and human health risks. Agricultural regions are locales where practices linked to food crop and livestock production can introduce contaminants that could alter the selective pressures for the development of antibiotic resistance in microbiota. This is important in regions where the use of animal manure or municipal biosolids as waste and/or fertilizer could influence selection for antibiotic resistance in pathogenic bacterial species. To investigate the environmental transport of contaminants that could lead to the development of antibiotic resistance in bacteria, a watershed with one of the highest levels of intensity of agricultural activity in Canada was studied; the Sumas River located 60 km east of Vancouver, British Columbia. This two-year assessment monitored four selected tetracycline resistance genes (tet(O), tet(M), tet(Q), tet(W)) and water quality parameters (temperature, specific conductivity, turbidity, suspended solids, nitrate, phosphate and chloride) at eight locations across the watershed. The tetracycline resistance genes (Tc r ) abundances in the Sumas River network ranged between 1.47 × 10 2 and 3.49 × 10 4 copies/mL and ranged between 2.3 and 6.9 copies/mL in a control stream (located far from agricultural activities) for the duration of the study. Further, Tc r abundances that were detected in the wet season months ranged between 1.3 × 10 3 and 2.29 × 10 4 copies/mL compared with dry season months (ranging between 0.6 and 31.2 copies/mL). Highest transport rates between 1.67 × 10 11 and 1.16 × 10 12 copies/s were observed in November 2005 during periods of high rainfall. The study showed that elevated concentrations of antibiotic resistance genes in the order of 10 2 -10 4 copies/mL can move through stream networks in an
International Nuclear Information System (INIS)
Scherff, M; Hoffmann, J; Meyer, B; Danz, Th; Jooss, Ch
2013-01-01
The identification of the cross-plane electric transport mechanisms in different resistance states of metal–oxide sandwich structures is essential for gaining insights into the mechanisms of resistive switching (RS). Here, we present a systematic study of cross-plane electric transport properties of Pr 0.67 Ca 0.33 MnO 3 (PCMO) thin films sandwiched by precious Pt metal electrodes. We observe three different transport regimes: ohmic, nonlinear and RS. The nonlinear regime is associated with colossal magneto-resistance (CMR) and colossal electro-resistance (CER) effects. In contrast to RS, the CMR and CER are volatile resistance effects which persist only during application of strong magnetic or electric fields and they are restricted to low temperatures. At low current densities, the device resistance is dominated by small polaron hopping transport of the PCMO film. At higher electric current densities near the switching threshold, the interface resistance starts to dominate and remarkably also exhibits thermally activated transport properties. Our studies also shed light onto the interplay of colossal resistance effects and RS: at low temperatures, RS can be only induced by reduction of the PCMO resistivity through CMR and CER. This clearly demonstrates the key role of the current density for controlling the amplitude of non-volatile resistive changes. Conversely, the CMR can be used as a probe for the switching induced changes in disorder and correlations. At small switching amplitudes, we observe slight changes in polaron activation energy which can be attributed to changes at the interface. If the switching amplitude exceeds 1000% and more, the CMR effect in the device can be reversibly changed. This indicates persistent changes in electronic or lattice structure of large regions within the PCMO film. (paper)
Negative differential resistance in nanoscale transport in the Coulomb blockade regime
International Nuclear Information System (INIS)
Parida, Prakash; Lakshmi, S; Pati, Swapan K
2009-01-01
Motivated by recent experiments, we have studied the transport behavior of coupled quantum dot systems in the Coulomb blockade regime using the master (rate) equation approach. We explore how electron-electron interactions in a donor-acceptor system, resembling weakly coupled quantum dots with varying charging energy, can modify the system's response to an external bias, taking it from normal Coulomb blockade behavior to negative differential resistance (NDR) in the current-voltage characteristics.
DEFF Research Database (Denmark)
Thomsen, Thomas T; Madsen, Laura B; Hansson, Helle H
2013-01-01
Chloroquine (CQ) use in Mozambique was stopped in 2002 and artemether-lumefantrine (AL) was implemented in 2008. In light of no use of CQ and extensive use of AL, we determined the frequency of molecular markers of Plasmodium falciparum drug resistance/tolerance to CQ and AL in persons living...... in Linga-Linga, an isolated peninsula and in Furvela village, which is located 8 km inland. The P. falciparum chloroquine resistance transporter gene CVMNK wild type increased in frequency from 43.9% in 2009 to 66.4% in 2010 (P = 0.001), and combined P. falciparum multidrug resistance gene 1 N86-184F-D1246...... haplotype increased significantly between years (P = 0.039). The combination of P. falciparum chloroquine resistance transporter gene CVMNK and P. falciparum multidrug resistance gene NFD increased from 24.3% (2009) to 45.3% in (2010, P = 0.017). The rapid changes observed may largely be caused by decreased...
International Nuclear Information System (INIS)
Krebs, Daniel; Bachmann, Tobias; Jonnalagadda, Prasad; Dellmann, Laurent; Raoux, Simone
2014-01-01
Phase-change memory technology has become more mature in recent years. But some fundamental problems linked to the electrical transport properties in the amorphous phase of phase-change materials still need to be solved. The increase of resistance over time, called resistance drift, for example, poses a major challenge for the implementation of multilevel storage, which will eventually be necessary to remain competitive in terms of high storage densities. To link structural properties with electrical transport, a broader knowledge of (i) changes in the density of states (DoS) upon structural relaxation and (ii) the influence of defects on electrical transport is required. In this paper, we present temperature-dependent conductivity and photo-conductivity measurements on the archetype phase change material GeTe. It is shown that trap-limited band transport at high temperatures (above 165 K) and variable range hopping at low temperatures are the predominating transport mechanism. Based on measurements of the temperature dependence of the optical band gap, modulated photo-conductivity and photo-thermal deflection spectroscopy, a DoS model for GeTe was proposed. Using this DoS, the temperature dependence of conductivity and photo-conductivity has been simulated. Our work shows how changes in the DoS (band gap and defect distributions) will affect the electrical transport before and after temperature-accelerated drift. The decrease in conductivity upon annealing can be explained entirely by an increase of the band gap by about 12%. However, low-temperature photo-conductivity measurements revealed that a change in the defect density may also play a role
Gromicho, Marta; Dinis, Joana; Magalhães, Marta; Fernandes, Alexandra R; Tavares, Purificação; Laires, António; Rueff, José; Rodrigues, António Sebastião
2011-10-01
About 20% of patients with chronic myeloid leukemia (CML) do not respond to treatment with imatinib either initially or because of acquired resistance. To study the development of CML drug resistance, an in vitro experimental system comprising cell lines with different resistance levels was established by exposing K562 cells to increasing concentrations of imatinib and dasatinib anticancer agents. The mRNA levels of BCR- ABL1 and of genes involved in drug transport or redistribution (ABCB1, ABCC1, ABCC3, ABCG2, MVP, and SLC22A1) were measured and the ABL1 kinase domain sequenced. Results excluded BCR- ABL1 overexpression and mutations as relevant resistance mechanisms. Most studied transporters were overexpressed in the majority of resistant cell lines. Their expression pattern was dynamic: varying with resistance level and chronic drug exposure. Studied efflux transporters may have an important role at the initial stages of resistance, but after prolonged exposure and for higher doses of drugs other mechanisms might take place.
Vasudevan, Gayatri; Ullman, Buddy; Landfear, Scott M.
2001-01-01
Leishmania parasites lack a purine biosynthetic pathway and depend on surface nucleoside and nucleobase transporters to provide them with host purines. Leishmania donovani possess two closely related genes that encode high affinity adenosine-pyrimidine nucleoside transporters LdNT1.1 and LdNT1.2 and that transport the toxic adenosine analog tubercidin in addition to the natural substrates. In this study, we have characterized a drug-resistant clonal mutant of L. do...
Huls, M.; Brown, C.D.; Windass, A.S.; Sayer, R.; Heuvel, J.J.M.W. van den; Heemskerk, S.; Russel, F.G.M.; Masereeuw, R.
2008-01-01
The Breast Cancer Resistance Protein (BCRP/ABCG2) is a transporter restricting absorption and enhancing excretion of many compounds including anticancer drugs. This transporter is highly expressed in many tissues; however, in human kidney, only the mRNA was found in contrast to the mouse kidney,
African Journals Online (AJOL)
Bla, KB. Vol 9, No 6 (2010) - Articles PFCRT and DHFR-TS Sequences for Monitoring Drug Resistance in Adzopé Area of Côte d'Ivoire After the Withdrawal of Chloroquine and Pyrimethamine Abstract PDF. ISSN: 1596-9827. AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians · for Authors ...
Functional analysis of candidate ABC transporter proteins for sitosterol transport
DEFF Research Database (Denmark)
Albrecht, C; Elliott, J I; Sardini, A
2002-01-01
implicated in lipid movement and expressed in tissues with a role in sterol synthesis and absorption, might also be involved in sitosterol transport. Transport by the multidrug resistance P-glycoprotein (P-gp; Abcb1), the multidrug resistance-associated protein (Mrp1; Abcc1), the breast cancer resistance...
DEFF Research Database (Denmark)
Sørensen, Belinda Halling
Although, cisplatin is one of the most effective broad-spectrum anticancer drugs, prolonged cisplatin treatment often results in development of chemoresistance and subsequent therapeutic failure. Dysregulation of the taurine transporting systems i.e., the taurine transporter (TauT) and volume....... Cisplatin resistance correlates with a reduction in the volume regulated anion current and taurine release mediated by VRACs, as well as an improved cellular accumulation of taurine through TauT. In human ovarian A2780 cancer cells, for instance, cisplatin resistance is associated with an absent swelling......-induced taurine release and inability to volume regulate. The dismissed taurine release was due to an almost absent leucin-rich-repeat containing 8A (LRRC8A) total protein expression. LRRC8A is an important component of VRACs. Cellular taurine contributes to the intracellular pool of organic osmolytes. Moreover...
Velaei, Kobra; Samadi, Nasser; Soltani, Sina; Barazvan, Balal; Soleimani Rad, Jafar
2017-07-01
Shedding light on chemoresistance biology of breast cancer could contribute to enhance the clinical outcome. Intrinsic or acquired resistance to chemotherapy is a major problem in breast cancer treatment. The NFκB pathway by siRNAP65 and JSH-23 as a translocational inhibitor of NFκBP65 in the doxorubicin-resistant MCF-7 (MCF-7/Dox) and MCF-7 cells was blocked. Then, the ABC transporter expression and function were assessed by real-time qRT-PCR and flow cytometry, respectively. Induction of apoptosis was evaluated after inhibition of the NFΚB pathway as well. Our study underlined the upregulation of NFκBP65 and anti-apoptotic Bcl-2 and downregulation of pro-apoptotic Bax in the MCF-7/Dox cells compared with control MCF-7 cells. Here, we showed that interplay between nuclear factor kappa B P65 (NFkBP65) as a transcriptional regulator and ABC transporters in the MCF-7/Dox cancer cells. We found that inhibition of the elevated expression of NFκBP65 in the resistant breast cancer, whether translocational inhibition or silencing by siRNA, decreased the expression and function of MDR1 and MRP1 efflux pumps. Furthermore, the blockade of NFκBP65 promoted apoptosis via modulating Bcl-2 and BAX expression. After inhibition of the NFκBP65 signaling pathway, elevated baseline expression of survival Bcl-2 gene in the resistant breast cells significantly decreased. Suppression of the NFκB pathway has a profound dual impact on promoting the intrinsic apoptotic pathway and reducing ABC transporter function and expression, which are some of the chemoresistance features. It was speculated that the NFκB pathway directly acts on doxorubicin-induced MDR1 and MRP1 expression in MCF-7/Dox cells.
2014-02-01
This report contains the results of a study describing the development of resistance factors for use : with the Kansas Department of Transportation (KDOT) Engineering News Record (ENR) formula for driven : piles. KDOT has verified driven pile resista...
Iwao, Yasuhisa; Yabe, Shizuka; Takano, Tomomi; Higuchi, Wataru; Nishiyama, Akihito; Yamamoto, Tatsuo
2012-01-01
Methicillin-resistant Staphylococcus aureus (MRSA) not only causes disease in hospitals, but also in the community. The characteristics of MRSA transmission in the environment remain uncertain. In this study, MRSA were isolated from public transport in Tokyo and Niigata, Japan. Of 349 trains examined, eight (2.3%) were positive for MRSA. The MRSA isolated belonged to sequence types (STs) 5, 8, 88, and 89, and included community infection-associated ST8 MRSA (with novel type IV staphylococcal cassette chromosome mec) and the ST5 New York/Japan hospital clone. The data indicate that public transport could contribute to the spread of community-acquired MRSA, and awareness of this mode of transmission is necessary. © 2012 The Societies and Blackwell Publishing Asia Pty Ltd.
African Journals Online (AJOL)
abp
2015-06-09
Jun 9, 2015 ... Our study aimed at assessing if parasites resistance profile has been affected by the implementation of the new treatment policies. Before the policy change, several studies have reported a high level of mutants Pfcrt T76 allele up to 65% in the country [10]. This study shows a decrease of this mutation five ...
Sakamoto, K; Margolles, A; van Veen, H W; Konings, W N
2001-09-01
Lactobacillus brevis is a major contaminant of spoiled beer. The organism can grow in beer in spite of the presence of antibacterial hop compounds that give the beer a bitter taste. The hop resistance in L. brevis is, at least in part, dependent on the expression of the horA gene. The deduced amino acid sequence of HorA is 53% identical to that of LmrA, an ATP-binding cassette multidrug transporter in Lactococcus lactis. To study the role of HorA in hop resistance, HorA was functionally expressed in L. lactis as a hexa-histidine-tagged protein using the nisin-controlled gene expression system. HorA expression increased the resistance of L. lactis to hop compounds and cytotoxic drugs. Drug transport studies with L. lactis cells and membrane vesicles and with proteoliposomes containing purified HorA protein identified HorA as a new member of the ABC family of multidrug transporters.
International Nuclear Information System (INIS)
Guzdar, P.N.; Drake, J.F.
1993-01-01
The generation of shear flow by resistive ballooning modes and resistive interchange modes is compared and contrasted using a 3-D fluid code. The resistive ballooning modes give rise to poloidally asymmetric transport and hence drive poloidal rotation due to the Reynold's Stress as well as the anomalous Stringer/Winsor mechanism. On the other hand the resistive interchange mode can drive shear flow only through the Reynold's Stress. The studies show that if the self-consistent sheared flow is suppressed, the resistive ballooning modes give rise to a larger anomalous transport than produced by the resistive interchange modes. Furthermore the shear flow generated by the resistive ballooning modes is larger than that driven by the resistive interchange modes due to the combined effect of the dual mechanisms stated earlier. As a consequence strong suppression of the fluctuations as well as reduction of the transport occurs for resistive ballooning modes. On the other hand, for the resistive interchange modes the level of fluctuation as well as the anomalous transport is not reduced by the self consistent shear flow generated by the Reynold's Stress. This latter result is in agreement with some earlier 3-D simulation of resistive interchange modes
Revalde, Jezrael L; Li, Yan; Hawkins, Bill C; Rosengren, Rhonda J; Paxton, James W
2015-02-01
Curcumin (CUR) is a phytochemical that inhibits the xenobiotic ABC efflux transporters implicated in cancer multidrug resistance (MDR), such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins 1 and 5 (MRP1 and MRP5). The use of CUR in the clinic however, is complicated by its instability and poor pharmacokinetic profile. Monocarbonyl analogs of CUR (MACs) are compounds without CUR's unstable β-diketone moiety and were reported to have improved stability and in vivo disposition. Whether the MACs can be used as MDR reversal agents is less clear, as the absence of a β-diketone may negatively impact transporter inhibition. In this study, we investigated 23 heterocyclic cyclohexanone MACs for inhibitory effects against P-gp, BCRP, MRP1 and MRP5. Using flow cytometry and resistance reversal assays, we found that many of these compounds inhibited the transport activity of the ABC transporters investigated, often with much greater potency than CUR. Overall the analogs were most effective at inhibiting BCRP and we identified three compounds, A12 (2,6-bis((E)-2,5-dimethoxy-benzylidene)cyclohexanone), A13 (2,6-bis((E)-4-hydroxyl-3-methoxybenzylidene)-cyclohexanone) and B11 (3,5-bis((E)-2-fluoro-4,5-dimethoxybenzylidene)-1-methylpiperidin-4-one), as the most promising BCRP inhibitors. These compounds inhibited BCRP activity in a non-cell line, non-substrate-specific manner. Their inhibition occurred by direct transporter interaction rather than modulating protein or cell surface expression. From these results, we concluded that MACs, such as the heterocyclic cyclohexanone analogs in this study, also have potential as MDR reversal agents and may be superior alternatives to the unstable parent compound, CUR. Copyright © 2014 Elsevier Inc. All rights reserved.
Directory of Open Access Journals (Sweden)
Rogers William O
2010-04-01
Full Text Available Abstract Background Chloroquine-resistant Plasmodium falciparum was first described in the Republic of Vanuatu in the early 1980s. In 1991, the Vanuatu Ministry of Health instituted new treatment guidelines for uncomplicated P. falciparum infection consisting of chloroquine/sulphadoxine-pyrimethamine combination therapy. Chloroquine remains the recommended treatment for Plasmodium vivax. Methods In 2005, cross-sectional blood surveys at 45 sites on Malo Island were conducted and 4,060 adults and children screened for malaria. Of those screened, 203 volunteer study subjects without malaria at the time of screening were followed for 13 weeks to observe peak seasonal incidence of infection. Another 54 subjects with malaria were followed over a 28-day period to determine efficacy of anti-malarial therapy; chloroquine alone for P. vivax and chloroquine/sulphadoxine-pyrimethamine for P. falciparum infections. Results The overall prevalence of parasitaemia by mass blood screening was 6%, equally divided between P. falciparum and P. vivax. Twenty percent and 23% of participants with patent P. vivax and P. falciparum parasitaemia, respectively, were febrile at the time of screening. In the incidence study cohort, after 2,303 person-weeks of follow-up, the incidence density of malaria was 1.3 cases per person-year with P. vivax predominating. Among individuals participating in the clinical trial, the 28-day chloroquine P. vivax cure rate was 100%. The 28-day chloroquine/sulphadoxine-pyrimethamine P. falciparum cure rate was 97%. The single treatment failure, confirmed by merozoite surface protein-2 genotyping, was classified as a day 28 late parasitological treatment failure. All P. falciparum isolates carried the Thr-76 pfcrt mutant allele and the double Asn-108 + Arg-59 dhfr mutant alleles. Dhps mutant alleles were not detected in the study sample. Conclusion Peak seasonal malaria prevalence on Malo Island reached hypoendemic levels during the study
Lengacher Sylvain; Nehiri-Sitayeb Touria; Steiner Nadia; Carneiro Lionel; Favrod Céline; Preitner Frédéric; Thorens Bernard; Stehle Jean-Christophe; Dix Laure; Pralong François; Magistretti Pierre J; Pellerin Luc
2013-01-01
The monocarboxylate transporter 1 (MCT1 or SLC16A1) is a carrier of short-chain fatty acids, ketone bodies, and lactate in several tissues. Genetically modified C57BL/6J mice were produced by targeted disruption of the mct1 gene in order to understand the role of this transporter in energy homeostasis. Null mutation was embryonically lethal, but MCT1(+/-) mice developed normally. However, when fed high fat diet (HFD), MCT1(+/-) mice displayed resistance to development of diet-induced obesity ...
Lin, Y. F.; Yannarell, A. C.; Mackie, R. I.; Krapac, I. G.; Chee-Sanford, J. S.; Koike, S.
2008-12-01
The use of antibiotics at concentrated animal feeding operations (CAFOs) for disease prevention, disease treatment, and growth promotion can contribute to the spread of antibiotic compounds, their breakdown products, and antibiotic resistant bacteria and/or the genes that confer resistance. In addition, constitutive use of antibiotics at sub-therapeutic levels can select for antibiotic resistance among the bacteria that inhabit animal intestinal tracts, onsite manure treatment facilities, and any environments receiving significant inputs of manure (e.g. through waste lagoon leakage or fertilizer amendments to farm soils). If the antibiotic resistant organisms persist in these new environments, or if they participate in genetic exchanges with the native microflora, then CAFOs may constitute a significant reservoir for the spread of antibiotic resistance to the environment at large. Our results have demonstrated that leakage from waste treatment lagoons can influence the presence and persistence of tetracycline resistance genes in the shallow aquifer adjacent to swine CAFOs, and molecular phylogeny allowed us to distinguish "native" tetracycline resistance genes in control groundwater wells from manure-associated genes introduced from the lagoon. We have also been able to detect the presence of erythromycin resistance genes in CAFO surface and groundwater even though erythromycin is strictly reserved for use in humans and thus is not utilized at any of these sites. Ongoing research, including modeling of particle transport in groundwater, will help to determine the potential spatial and temporal extent of CAFO-derived antibiotic resistance.
Rijpma, S.R.; Velden, M. van der; Annoura, T.; Matz, J.M.; Kenthirapalan, S.; Kooij, T.W.; Matuschewski, K.; Gemert, G.J.A. van; Vegte-Bolmer, M.G. van de; Siebelink-Stoter, R.; Graumans, W.; Ramesar, J.; Klop, O.; Russel, F.G.; Sauerwein, R.W.; Janse, C.J.; Franke-Fayard, B.M.; Koenderink, J.B.
2016-01-01
Multidrug resistance (MDR) proteins belong to the B subfamily of the ATP Binding Cassette (ABC) transporters, which export a wide range of compounds including pharmaceuticals. In this study, we used reverse genetics to study the role of all seven Plasmodium MDR proteins during the life cycle of
DEFF Research Database (Denmark)
Agergaard, Jakob; Bülow, Jacob; Jensen, Jacob K
2017-01-01
An impaired amino acid sensing is associated with age-related loss of skeletal muscle mass. We tested whether light-load resistance exercise (LL-RE) affects postprandial amino acid transporter (AAT) expression in aging skeletal muscle. Untrained, healthy men (age: +65 years) were subjected to 13 h...
Plausible carrier transport model in organic-inorganic hybrid perovskite resistive memory devices
Park, Nayoung; Kwon, Yongwoo; Choi, Jaeho; Jang, Ho Won; Cha, Pil-Ryung
2018-04-01
We demonstrate thermally assisted hopping (TAH) as an appropriate carrier transport model for CH3NH3PbI3 resistive memories. Organic semiconductors, including organic-inorganic hybrid perovskites, have been previously speculated to follow the space-charge-limited conduction (SCLC) model. However, the SCLC model cannot reproduce the temperature dependence of experimental current-voltage curves. Instead, the TAH model with temperature-dependent trap densities and a constant trap level are demonstrated to well reproduce the experimental results.
Ohya, Hiroki; Shibayama, Yoshihiko; Ogura, Jiro; Narumi, Katsuya; Kobayashi, Masaki; Iseki, Ken
2015-01-01
Regorafenib is a small molecule inhibitor of tyrosine kinases, and has been shown to improve the outcomes of patients with advanced colorectal cancer and advanced gastrointestinal stromal tumors. The transport profiles of regorafenib by various transporters were evaluated. HEK293/organic anion transporting polypeptide 1B1 (OATP1B1) cells exhibited increased drug sensitivity to regorafenib. Regorafenib inhibited the uptake of 3H-estrone sulfate by HEK293/OATP1B1 cells in a dose-dependent manner, but did not affect its elimination by P-glycoproteins. The concentration of regorafenib was significantly lower in LLC-PK1/multidrug resistance protein 2 (MRP2) cells than in LLC-PK1 cells treated with the MRP2 inhibitor, MK571. MK571 abolished the inhibitory effects of regorafenib on intracellular accumulation in LLC-PK1/MRP2 cells. The uptake of regorafenib was significantly higher in HEK293/OATP1B1 cells than in OATP1B1-mock cells. Transport kinetics values were estimated to be Km=15.9 µM and Vmax=1.24 nmol/mg/min. No significant difference was observed in regorafenib concentrations between HEK293/OATP1B3 and OATP1B3-mock cells. These results indicated that regorafenib is a substrate for MRP2 and OATP1B1, and also suggest that the substrate preference of regorafenib may implicate the pharmacokinetic profiles of regorafenib.
Functional evidence of multidrug resistance transporters (MDR in rodent olfactory epithelium.
Directory of Open Access Journals (Sweden)
Adrien Molinas
Full Text Available P-glycoprotein (Pgp and multidrug resistance-associated protein (MRP1 are membrane transporter proteins which function as efflux pumps at cell membranes and are considered to exert a protective function against the entry of xenobiotics. While evidence for Pgp and MRP transporter activity is reported for olfactory tissue, their possible interaction and participation in the olfactory response has not been investigated.Functional activity of putative MDR transporters was assessed by means of the fluorometric calcein acetoxymethyl ester (calcein-AM accumulation assay on acute rat and mouse olfactory tissue slices. Calcein-AM uptake was measured as fluorescence intensity changes in the presence of Pgp or MRP specific inhibitors. Epifluorescence microscopy measured time course analysis in the olfactory epithelium revealed significant inhibitor-dependent calcein uptake in the presence of each of the selected inhibitors. Furthermore, intracellular calcein accumulation in olfactory receptor neurons was also significantly increased in the presence of either one of the Pgp or MRP inhibitors. The presence of Pgp or MRP1 encoding genes in the olfactory mucosa of rat and mouse was confirmed by RT-PCR with appropriate pairs of species-specific primers. Both transporters were expressed in both newborn and adult olfactory mucosa of both species. To assess a possible involvement of MDR transporters in the olfactory response, we examined the electrophysiological response to odorants in the presence of the selected MDR inhibitors by recording electroolfactograms (EOG. In both animal species, MRPs inhibitors induced a marked reduction of the EOG magnitude, while Pgp inhibitors had only a minor or no measurable effect.The findings suggest that both Pgp and MRP transporters are functional in the olfactory mucosa and in olfactory receptor neurons. Pgp and MRPs may be cellular constituents of olfactory receptor neurons and represent potential mechanisms for modulation
Directory of Open Access Journals (Sweden)
Rhiannon N. Hardwick
2016-12-01
Full Text Available Tyrosine and aurora kinases are important effectors in signal transduction pathways that are often involved in aberrant cancer cell growth. Tyrosine (TKI and aurora (AKI kinase inhibitors are anti-cancer agents specifically designed to target such signaling pathways through TKI/AKI binding to the ATP-binding pocket of kinases thereby leading to diminished kinase activity. Some TKIs have been identified as inhibitors of ATP-binding cassette (ABC transporters such as P-glycoprotein and breast cancer resistance protein (BCRP, which are commonly upregulated in malignant cells. TKI/AKIs have been investigated as ABC transporter inhibitors in order to facilitate the accumulation of concomitantly administered chemo-therapeutics within cancer cells. However, ABC transporters are prominently expressed in the liver and other eliminating organs, and their inhibition has been linked to intracellular accumulation of drugs, altered disposition, and toxicity. The potential for TKIs/AKIs to inhibit other important hepatic efflux transporters, particularly multidrug resistance-associated proteins (MRPs, remains unknown. The aim of the current study was to compare the inhibitory potency of 20 selected TKI/AKIs against MRP4 and BCRP through the use of inverted membrane vesicle assays. Relative IC50 values were estimated by determining TKI/AKI inhibition of MRP4-mediated [3H]-dehydroepiandrosterone sulfate uptake and BCRP-mediated [3H]-estrone sulfate uptake. To provide insight to the clinical relevance of TKI/AKI inhibition of ABC efflux transporters, the ratio of the steady-state maximum total plasma concentration (Css to the IC50 for each compound was calculated with Css/IC50 ratio >0.1 deemed potentially clinically relevant. Such analysis identified several potentially clinically relevant inhibitors of MRP4: alisertib, danusertib, erlotinib, lapatinib, neratinib, nilotinib, pazopanib, sorafenib, and tozasertib. The potentially clinically relevant inhibition of
DEFF Research Database (Denmark)
Henriksen, Ulla Birk; Gether, Ulrik; Litman, Thomas
2005-01-01
The ATP binding cassette (ABC) half-transporter ABCG2 (MXR/BCRP/ABCP) is associated with mitoxantrone resistance accompanied by cross-resistance to a broad spectrum of cytotoxic drugs. Here we investigate the functional consequences of mutating a highly conserved lysine in the Walker A motif...
Energy budgets and resistances to energy transport in sparsely vegetated rangeland
Nichols, W.D.
1992-01-01
Partitioning available energy between plants and bare soil in sparsely vegetated rangelands will allow hydrologists and others to gain a greater understanding of water use by native vegetation, especially phreatophytes. Standard methods of conducting energy budget studies result in measurements of latent and sensible heat fluxes above the plant canopy which therefore include the energy fluxes from both the canopy and the soil. One-dimensional theoretical numerical models have been proposed recently for the partitioning of energy in sparse crops. Bowen ratio and other micrometeorological data collected over phreatophytes growing in areas of shallow ground water in central Nevada were used to evaluate the feasibility of using these models, which are based on surface and within-canopy aerodynamic resistances, to determine heat and water vapor transport in sparsely vegetated rangelands. The models appear to provide reasonably good estimates of sensible heat flux from the soil and latent heat flux from the canopy. Estimates of latent heat flux from the soil were less satisfactory. Sensible heat flux from the canopy was not well predicted by the present resistance formulations. Also, estimates of total above-canopy fluxes were not satisfactory when using a single value for above-canopy bulk aerodynamic resistance. ?? 1992.
Low resistivity ZnO-GO electron transport layer based CH{sub 3}NH{sub 3}PbI{sub 3} solar cells
Energy Technology Data Exchange (ETDEWEB)
Ahmed, Muhammad Imran, E-mail: imranrahbar@scme.nust.edu.pk, E-mail: amirhabib@scme.nust.edu.pk; Hussain, Zakir; Mujahid, Mohammad; Khan, Ahmed Nawaz [School of Chemical and Materials Engineering, National University of Sciences and Technology, Islamabad, 44000 (Pakistan); Javaid, Syed Saad [College of Aeronautical Engineering, National University of Sciences and Technology, Islamabad, 44000 (Pakistan); Habib, Amir, E-mail: imranrahbar@scme.nust.edu.pk, E-mail: amirhabib@scme.nust.edu.pk [School of Chemical and Materials Engineering, National University of Sciences and Technology, Islamabad, 44000 (Pakistan); The Department of Physics, College of Sciences, University of Hafar Al Batin, P.O. Box 1803, Hafar Al Batin 31991 Saudi Arabia (Saudi Arabia)
2016-06-15
Perovskite based solar cells have demonstrated impressive performances. Controlled environment synthesis and expensive hole transport material impede their potential commercialization. We report ambient air synthesis of hole transport layer free devices using ZnO-GO as electron selective contacts. Solar cells fabricated with hole transport layer free architecture under ambient air conditions with ZnO as electron selective contact achieved an efficiency of 3.02%. We have demonstrated that by incorporating GO in ZnO matrix, low resistivity electron selective contacts, critical to improve the performance, can be achieved. We could achieve max efficiency of 4.52% with our completed devices for ZnO: GO composite. Impedance spectroscopy confirmed the decrease in series resistance and an increase in recombination resistance with inclusion of GO in ZnO matrix. Effect of temperature on completed devices was investigated by recording impedance spectra at 40 and 60 {sup o}C, providing indirect evidence of the performance of solar cells at elevated temperatures.
A new homolog of FocA transporters identified in cadmium-resistant Euglena gracilis
International Nuclear Information System (INIS)
Delomenie, Claudine; Foti, Emilie; Floch, Enora; Diderot, Vimala; Porquet, Dominique; Dupuy, Corinne; Bonaly, Jacqueline
2007-01-01
To better understand the cellular mechanism of stress resistance to various pollutants (cadmium, pentachlorophenol), we undertook a survey of the Euglena gracilis transcriptome by mRNA differential display and cDNA cloning. We performed a real-time RT-PCR analysis upon four selected genes. One of them significantly changed its expression level in response to stress treatments: B25 gene was overexpressed in Cd-resistant cells whereas it was down-regulated in PCP-adapted cells. By Race assays we obtained for B25 a 1093 bp cDNA. The deduced protein was identified as a bacterial formate/nitrite transporter (FocA) homolog and the gene was named EgFth. From all the data, we concluded that EgFth overexpression was related to chronic exposure to cadmium
Purification of a Multidrug Resistance Transporter for Crystallization Studies
Directory of Open Access Journals (Sweden)
Kamela O. Alegre
2015-03-01
Full Text Available Crystallization of integral membrane proteins is a challenging field and much effort has been invested in optimizing the overexpression and purification steps needed to obtain milligram amounts of pure, stable, monodisperse protein sample for crystallography studies. Our current work involves the structural and functional characterization of the Escherichia coli multidrug resistance transporter MdtM, a member of the major facilitator superfamily (MFS. Here we present a protocol for isolation of MdtM to increase yields of recombinant protein to the milligram quantities necessary for pursuit of structural studies using X-ray crystallography. Purification of MdtM was enhanced by introduction of an elongated His-tag, followed by identification and subsequent removal of chaperonin contamination. For crystallization trials of MdtM, detergent screening using size exclusion chromatography determined that decylmaltoside (DM was the shortest-chain detergent that maintained the protein in a stable, monodispersed state. Crystallization trials of MdtM performed using the hanging-drop diffusion method with commercially available crystallization screens yielded 3D protein crystals under several different conditions. We contend that the purification protocol described here may be employed for production of high-quality protein of other multidrug efflux members of the MFS, a ubiquitous, physiologically and clinically important class of membrane transporters.
Plausible carrier transport model in organic-inorganic hybrid perovskite resistive memory devices
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Nayoung Park
2018-04-01
Full Text Available We demonstrate thermally assisted hopping (TAH as an appropriate carrier transport model for CH3NH3PbI3 resistive memories. Organic semiconductors, including organic-inorganic hybrid perovskites, have been previously speculated to follow the space-charge-limited conduction (SCLC model. However, the SCLC model cannot reproduce the temperature dependence of experimental current-voltage curves. Instead, the TAH model with temperature-dependent trap densities and a constant trap level are demonstrated to well reproduce the experimental results.
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Su Xu
2017-05-01
Full Text Available With the increasing spread of methicillin-resistant Staphylococcus aureus worldwide, fosfomycin has begun to be used more often, either alone or in combination with other antibiotics, for treating methicillin-resistant S. aureus infections, resulting in the emergence of fosfomycin-resistant strains. Fosfomycin resistance is reported to be mediated by fosfomycin-modifying enzymes (FosA, FosB, FosC, and FosX and mutations of the target enzyme MurA or the membrane transporter proteins UhpT and GlpT. Our previous studies indicated that the fos genes might not the major fosfomycin resistance mechanism in S. aureus, whereas mutations of glpT and uhpT seemed to be more related to fosfomycin resistance. However, the precise role of these two genes in S. aureus fosfomycin resistance remains unclear. The aim of the present study was to investigate the role of glpT and uhpT in S. aureus fosfomycin resistance. Homologous recombination was used to knockout the uhpT and glpT genes in S. aureus Newman. Gene complementation was generated by the plasmid pRB473 carrying these two genes. The fosfomycin minimal inhibitory concentration (MIC of the strains was measured by the E-test to observe the influence of gene deletion on antibiotic susceptibility. In addition, growth curves were constructed to determine whether the mutations have a significant influence on bacterial growth. Deletion of uhpT, glpT, and both of them led to increased fosfomycin MIC 0.5 μg/ml to 32 μg/ml, 4 μg/ml, and >1024 μg/ml, respectively. By complementing uhpT and glpT into the deletion mutants, the fosfomycin MIC decreased from 32 to 0.5 μg/ml and from 4 to 0.25 μg/ml, respectively. Moreover, the transporter gene-deleted strains showed no obvious difference in growth curves compared to the parental strain. In summary, our study strongly suggests that mutations of uhpT and glpT lead to fosfomycin resistance in S. aureus, and that uhpT mutation may play a more important role. The high
International Nuclear Information System (INIS)
Kalayda, Ganna V; Wagner, Christina H; Buß, Irina; Reedijk, Jan; Jaehde, Ulrich
2008-01-01
Copper homeostasis proteins ATP7A and ATP7B are assumed to be involved in the intracellular transport of cisplatin. The aim of the present study was to assess the relevance of sub cellular localisation of these transporters for acquired cisplatin resistance in vitro. For this purpose, localisation of ATP7A and ATP7B in A2780 human ovarian carcinoma cells and their cisplatin-resistant variant, A2780cis, was investigated. Sub cellular localisation of ATP7A and ATP7B in sensitive and resistant cells was investigated using confocal fluorescence microscopy after immunohistochemical staining. Co-localisation experiments with a cisplatin analogue modified with a carboxyfluorescein-diacetate residue were performed. Cytotoxicity of the fluorescent cisplatin analogue in A2780 and A2780cis cells was determined using an MTT-based assay. The significance of differences was analysed using Student's t test or Mann-Whitney test as appropriate, p values of < 0.05 were considered significant. In the sensitive cells, both transporters are mainly localised in the trans-Golgi network, whereas they are sequestrated in more peripherally located vesicles in the resistant cells. Altered localisation of ATP7A and ATP7B in A2780cis cells is likely to be a consequence of major abnormalities in intracellular protein trafficking related to a reduced lysosomal compartment in this cell line. Changes in sub cellular localisation of ATP7A and ATP7B may facilitate sequestration of cisplatin in the vesicular structures of A2780cis cells, which may prevent drug binding to genomic DNA and thereby contribute to cisplatin resistance. Our results indicate that alterations in sub cellular localisation of transport proteins may contribute to cisplatin resistance in vitro. Investigation of intracellular protein localisation in primary tumour cell cultures and tumour tissues may help to develop markers of clinically relevant cisplatin resistance. Detection of resistant tumours in patients may in turn
Directory of Open Access Journals (Sweden)
Reedijk Jan
2008-06-01
Full Text Available Abstract Background Copper homeostasis proteins ATP7A and ATP7B are assumed to be involved in the intracellular transport of cisplatin. The aim of the present study was to assess the relevance of sub cellular localisation of these transporters for acquired cisplatin resistance in vitro. For this purpose, localisation of ATP7A and ATP7B in A2780 human ovarian carcinoma cells and their cisplatin-resistant variant, A2780cis, was investigated. Methods Sub cellular localisation of ATP7A and ATP7B in sensitive and resistant cells was investigated using confocal fluorescence microscopy after immunohistochemical staining. Co-localisation experiments with a cisplatin analogue modified with a carboxyfluorescein-diacetate residue were performed. Cytotoxicity of the fluorescent cisplatin analogue in A2780 and A2780cis cells was determined using an MTT-based assay. The significance of differences was analysed using Student's t test or Mann-Whitney test as appropriate, p values of Results In the sensitive cells, both transporters are mainly localised in the trans-Golgi network, whereas they are sequestrated in more peripherally located vesicles in the resistant cells. Altered localisation of ATP7A and ATP7B in A2780cis cells is likely to be a consequence of major abnormalities in intracellular protein trafficking related to a reduced lysosomal compartment in this cell line. Changes in sub cellular localisation of ATP7A and ATP7B may facilitate sequestration of cisplatin in the vesicular structures of A2780cis cells, which may prevent drug binding to genomic DNA and thereby contribute to cisplatin resistance. Conclusion Our results indicate that alterations in sub cellular localisation of transport proteins may contribute to cisplatin resistance in vitro. Investigation of intracellular protein localisation in primary tumour cell cultures and tumour tissues may help to develop markers of clinically relevant cisplatin resistance. Detection of resistant tumours
Dharmapuri, Gangappa; Doneti, Ravinder; Philip, Gundala Harold; Kalle, Arunasree M
2015-07-01
Imatinib mesylate, a tyrosine kinase inhibitor, is very effective in the treatment of chronic myeloid leukemia (CML). However, development of resistance to imatinib therapy is also a very common mechanism observed with long-term administration of the drug. Our previous studies have highlighted the role of cyclooxygenase-2 (COX-2) in regulating the expression of multidrug resistant protein-1 (MDR1), P-gp, in imatinib-resistant K562 cells (IR-K562) via PGE2-cAMP-PKC-NF-κB pathway and inhibition of COX-2 by celecoxib, a COX-2 specific inhibitor, inhibits this pathway and reverses the drug resistance. Studies have identified that not only MDR1 but other ATP-binding cassette transport proteins (ABC transporters) are involved in the development of imatinib resistance. Here, we tried to study the role of COX-2 in the regulation of other ABC transporters such as MRP1, MRP2, MRP3, ABCA2 and ABCG2 that have been already implicated in imatinib resistance development. The results of the study clearly indicated that overexpression of COX-2 lead to upregulation of MRP family proteins in IR-K562 cells and celecoxib down-regulated the ABC transporters through Wnt and MEK signaling pathways. The study signifies that celecoxib in combination with the imatinib can be a good alternate treatment strategy for the reversal of imatinib resistance. Copyright © 2015 Elsevier Ltd. All rights reserved.
International Nuclear Information System (INIS)
Mackinnon, M. J.M; Walliker, D.; Babiker, A.; Ahmed, S.; Abdel-Muhsin, A.; Eltayeb, A.
2007-01-01
We monitored post-treatment Plasmodium falciparum among patients treated with chloroquine (CQ) and pyrimethamine-sulfadoxine (PS) in a village in eastern Sudan. Parasites were examined on day zero (pre-treatment), day 7, day 14 and day 21 (post-treatment) during the transmission season. A further sample was taken two months later (Day 80) at the start of the dry season. Asexual forms and gametocytes were detected by microscopy and reverse transcriptase polymerase chain reaction (RT-PCR) to detect expression of a gametocyte-specific protein pfg377. Gametocyte carriage, as revealed by microscopy, increased significantly following CQ and PS treatment reaching a maximum between days 7 and 14. When measured by RT-PCR, however, there was no significant difference in gametocyte rate between day 0 and day 7 or 14. RT-PCR gametocyte rates dropped dramatically by day 80 post-treatment but were still 33% and 8% in the CQ and PS treated group at this time. Alleles associated with drug resistance of P. falciparum to chloroquine (the chloroquine resistance transporter, pfcrt, and multi-drug resistance, pfmdr-1) and pyrimethamine (dihydrofolate reductase, dhfr) were at high frequency at the beginning of treatment and increased further through time under both drug treatments. Infections with drug-resistant parasites tended to have higher gametocyte prevalence than drug-sensitive infections.
Reidy, P. T.; Walker, D. K.; Dickinson, J. M.; Gundermann, D. M.; Drummond, M. J.; Timmerman, K. L.; Cope, M. B.; Mukherjea, R.; Jennings, K.; Volpi, E.
2014-01-01
Increasing amino acid availability (via infusion or ingestion) at rest or postexercise enhances amino acid transport into human skeletal muscle. It is unknown whether alterations in amino acid availability, from ingesting different dietary proteins, can enhance amino acid transport rates and amino acid transporter (AAT) mRNA expression. We hypothesized that the prolonged hyperaminoacidemia from ingesting a blend of proteins with different digestion rates postexercise would enhance amino acid transport into muscle and AAT expression compared with the ingestion of a rapidly digested protein. In a double-blind, randomized clinical trial, we studied 16 young adults at rest and after acute resistance exercise coupled with postexercise (1 h) ingestion of either a (soy-dairy) protein blend or whey protein. Phenylalanine net balance and transport rate into skeletal muscle were measured using stable isotopic methods in combination with femoral arteriovenous blood sampling and muscle biopsies obtained at rest and 3 and 5 h postexercise. Phenylalanine transport into muscle and mRNA expression of select AATs [system L amino acid transporter 1/solute-linked carrier (SLC) 7A5, CD98/SLC3A2, system A amino acid transporter 2/SLC38A2, proton-assisted amino acid transporter 1/SLC36A1, cationic amino acid transporter 1/SLC7A1] increased to a similar extent in both groups (P protein blend resulted in a prolonged and positive net phenylalanine balance during postexercise recovery compared with whey protein (P protein synthesis increased similarly between groups. We conclude that, while both protein sources enhanced postexercise AAT expression, transport into muscle, and myofibrillar protein synthesis, postexercise ingestion of a protein blend results in a slightly prolonged net amino acid balance across the leg compared with whey protein. PMID:24699854
Stukkens, Yvan; Bultreys, Alain; Grec, Sébastien; Trombik, Tomasz; Vanham, Delphine; Boutry, Marc
2005-09-01
Nicotiana plumbaginifolia NpPDR1, a plasma membrane pleiotropic drug resistance-type ATP-binding cassette transporter formerly named NpABC1, has been suggested to transport the diterpene sclareol, an antifungal compound. However, direct evidence for a role of pleiotropic drug resistance transporters in the plant defense is still lacking. In situ immunolocalization and histochemical analysis using the gusA reporter gene showed that NpPDR1 was constitutively expressed in the whole root, in the leaf glandular trichomes, and in the flower petals. However, NpPDR1 expression was induced in the whole leaf following infection with the fungus Botrytis cinerea, and the bacteria Pseudomonas syringae pv tabaci, Pseudomonas fluorescens, and Pseudomonas marginalis pv marginalis, which do not induce a hypersensitive response in N. plumbaginifolia, whereas a weaker response was observed using P. syringae pv syringae, which does induce a hypersensitive response. Induced NpPDR1 expression was more associated with the jasmonic acid than the salicylic acid signaling pathway. These data suggest that NpPDR1 is involved in both constitutive and jasmonic acid-dependent induced defense. Transgenic plants in which NpPDR1 expression was prevented by RNA interference showed increased sensitivity to sclareol and reduced resistance to B. cinerea. These data show that NpPDR1 is involved in pathogen resistance and thus demonstrate a new role for the ATP-binding cassette transporter family.
Lutz, Jonathan K; van Balen, Joany; Crawford, John Mac; Wilkins, John R; Lee, Jiyoung; Nava-Hoet, Rocio C; Hoet, Armando E
2014-12-01
Little is known about the occurrence and epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in public transportation in the United States. This research sought to determine the background prevalence and phenotypic and genotypic characteristics of MRSA strains circulating on buses from a large, metropolitan transportation agency. Electrostatic wipes were used to collect 237 surface samples from 40 buses randomly selected from July-October 2010. Six samples were collected from each bus immediately postservice and before any cleaning and disinfection. Positive isolates were analyzed for antibiotic resistance, staphylococcal cassette chromosome mec (SCCmec) type, and pulsed-field gel electrophoresis; and potential epidemiologic factors were examined. Of the buses, 68% (27/40) were contaminated with S aureus, and 63% (25/40) were contaminated with MRSA. Seats and seat rails were the surfaces most frequently contaminated, followed by the back door and stanchions. Most (62.9%) of the MRSA isolates were classified as community-associated MRSA clones (SCCmec type IV), and 22.9% were health care-associated MRSA clones (SCCmec type II). Of the MRSA strains, 65% (5/20) were multidrug resistant. MRSA was frequently isolated from commonly touched surfaces in buses serving both hospital and community routes. Phenotypic and genotypic analysis demonstrated that buses may be effective mixing vessels for MRSA strains of both community and health care-associated origin. Copyright © 2014 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
Wehrer, Markus; Lissner, Heidi; Bloem, Esther; French, Helen; Totsche, Kai Uwe
2014-01-01
Non-invasive spatially resolved monitoring techniques may hold the key to observe heterogeneous flow and transport behavior of contaminants in soils. In this study, time-lapse electrical resistivity tomography (ERT) was employed during an infiltration experiment with deicing chemical in a small field lysimeter. Deicing chemicals like potassium formate, which frequently impact soils on airport sites, were infiltrated during snow melt. Chemical composition of seepage water and the electrical response was recorded over the spring period 2010. Time-lapse electrical resistivity tomographs are able to show the infiltration of the melt water loaded with ionic constituents of deicing chemicals and their degradation product hydrogen carbonate. The tomographs indicate early breakthrough behavior in parts of the profile. Groundtruthing with pore fluid conductivity and water content variations shows disagreement between expected and observed bulk conductivity. This was attributed to the different sampling volume of traditional methods and ERT due to a considerable fraction of immobile water in the soil. The results show that ERT can be used as a soil monitoring tool on airport sites if assisted by common soil monitoring techniques.
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Jason P Wendler
Full Text Available Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs.Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set.Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.
International Nuclear Information System (INIS)
Phong, P.T.; Nguyen, L.H.; Manh, D.H.; Phuc, N.X.; Lee, I.-J.
2013-01-01
The temperature dependent resistivity and temperature coefficient of resistance of Ag doped La 0.7−x Ag x Ca 0.3 MnO 3 polycrystalline pellets (x=0, 0.05, 0.10, 0.15, and 0.20) are investigated. Ag substitution enhances the conductivity of this system. The Curie temperature also increases from 260 to 283 K with increasing Ag content. Using phase-coexistence transport model and phase separation model, we calculated the resistivity as a function of temperature and the temperature coefficient of resistivity (TCR) behavior. Comparing the calculated maximum TCR, we found that it is related to activation energy, transition temperature, and disorder in doped manganites. The relationship between the proposed TCR behavior and the transport parameters can suggest conditions improving TCR max of doped manganites for the use of the bolometric infrared detectors
Dual role of LRRC8A-containing transporters on cisplatin resistance in human ovarian cancer cells
DEFF Research Database (Denmark)
Sørensen, Belinda Halling; Dam, Celina Støving; Stürup, Stefan
2016-01-01
Acquired resistance to chemotherapeutic drugs in cancer cells can reflect an ability to limit cellular drug availability, to repair drug induced DNA damage, and to limit initiation/progression of cell death (apoptosis). The leucine-rich-repeat-containing 8A (LRRC8A) protein is an essential...... transporter receptor 1 (CTR1), as well as a concomitant increased expression of copper-transporting P-type ATPases (ATP7A/ATP7B). We also find that cisplatin (Pt) accumulation correlates with LRRC8A protein expression and channel activity, i.e., the cellular Pt content is high when VSOAC is activated...
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Wee Tek Tay
2015-11-01
Full Text Available The use of conventional chemical insecticides and bacterial toxins to control lepidopteran pests of global agriculture has imposed significant selection pressure leading to the rapid evolution of insecticide resistance. Transgenic crops (e.g., cotton expressing the Bt Cry toxins are now used world wide to control these pests, including the highly polyphagous and invasive cotton bollworm Helicoverpa armigera. Since 2004, the Cry2Ab toxin has become widely used for controlling H. armigera, often used in combination with Cry1Ac to delay resistance evolution. Isolation of H. armigera and H. punctigera individuals heterozygous for Cry2Ab resistance in 2002 and 2004, respectively, allowed aspects of Cry2Ab resistance (level, fitness costs, genetic dominance, complementation tests to be characterised in both species. However, the gene identity and genetic changes conferring this resistance were unknown, as was the detailed Cry2Ab mode of action. No cross-resistance to Cry1Ac was observed in mutant lines. Biphasic linkage analysis of a Cry2Ab-resistant H. armigera family followed by exon-primed intron-crossing (EPIC marker mapping and candidate gene sequencing identified three independent resistance-associated INDEL mutations in an ATP-Binding Cassette (ABC transporter gene we named HaABCA2. A deletion mutation was also identified in the H. punctigera homolog from the resistant line. All mutations truncate the ABCA2 protein. Isolation of further Cry2Ab resistance alleles in the same gene from field H. armigera populations indicates unequal resistance allele frequencies and the potential for Bt resistance evolution. Identification of the gene involved in resistance as an ABC transporter of the A subfamily adds to the body of evidence on the crucial role this gene family plays in the mode of action of the Bt Cry toxins. The structural differences between the ABCA2, and that of the C subfamily required for Cry1Ac toxicity, indicate differences in the
49 CFR 236.527 - Roadway element insulation resistance.
2010-10-01
... 49 Transportation 4 2010-10-01 2010-10-01 false Roadway element insulation resistance. 236.527 Section 236.527 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD... element insulation resistance. Insulation resistance between roadway inductor and ground shall be...
Cummings, Jeffrey; Zelcer, Noam; Allen, John D.; Yao, Denggao; Boyd, Gary; Maliepaard, Mark; Friedberg, Thomas H.; Smyth, John F.; Jodrell, Duncan I.
2004-01-01
We have recently shown that drug conjugation catalysed by UDP-glucuronosyltransferases (UGTs) functions as an intrinsic mechanism of resistance to the topoisomerase I inhibitors 7-ethyl-10-hydroxycamptothecin and NU/ICRF 505 in human colon cancer cells and now report on the role of drug transport in
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Yongwoo Kwon
2017-08-01
Full Text Available Methylamine lead iodide (CH3NH3PbI3, which has recently been in the spotlight as a solar cell material, has also recently shown promise for use as an active material in resistive memory cells with ultralow operation voltages, good transparencies, and flexibilities. The material’s defects, which govern its properties, differ vastly depending on the fabrication process. However, the defect chemistry is not yet entirely understood. We have therefore established a macroscopic transport model with defect-related model parameters, such as trap density, trap energy level, and Fermi level, in order to estimate these parameters for fabricated samples based on their electrical data. Our model will serve as an efficient way to analyze the properties of the active material.
Stukkens, Yvan; Bultreys, Alain; Grec, Sébastien; Trombik, Tomasz; Vanham, Delphine; Boutry, Marc
2005-01-01
Nicotiana plumbaginifolia NpPDR1, a plasma membrane pleiotropic drug resistance-type ATP-binding cassette transporter formerly named NpABC1, has been suggested to transport the diterpene sclareol, an antifungal compound. However, direct evidence for a role of pleiotropic drug resistance transporters in the plant defense is still lacking. In situ immunolocalization and histochemical analysis using the gusA reporter gene showed that NpPDR1 was constitutively expressed in the whole root, in the leaf glandular trichomes, and in the flower petals. However, NpPDR1 expression was induced in the whole leaf following infection with the fungus Botrytis cinerea, and the bacteria Pseudomonas syringae pv tabaci, Pseudomonas fluorescens, and Pseudomonas marginalis pv marginalis, which do not induce a hypersensitive response in N. plumbaginifolia, whereas a weaker response was observed using P. syringae pv syringae, which does induce a hypersensitive response. Induced NpPDR1 expression was more associated with the jasmonic acid than the salicylic acid signaling pathway. These data suggest that NpPDR1 is involved in both constitutive and jasmonic acid-dependent induced defense. Transgenic plants in which NpPDR1 expression was prevented by RNA interference showed increased sensitivity to sclareol and reduced resistance to B. cinerea. These data show that NpPDR1 is involved in pathogen resistance and thus demonstrate a new role for the ATP-binding cassette transporter family. PMID:16126865
Accident resistant transport container
Anderson, J.A.; Cole, K.K.
The invention relates to a container for the safe air transport of plutonium having several intermediate wood layers and a load spreader intermediate an inner container and an outer shell for mitigation of shock during a hypothetical accident.
Accident resistant transport container
International Nuclear Information System (INIS)
Andersen, J.A.; Cole, J.K.
1980-01-01
The invention relates to a container for the safe air transport of plutonium having several intermediate wood layers and a load spreader intermediate an inner container and an outer shell for mitigation of shock during a hypothetical accident
Methylammonium-resistant mutants of Nicotiana plumbaginifolia are affected in nitrate transport.
Godon, C; Krapp, A; Leydecker, M T; Daniel-Vedele, F; Caboche, M
1996-02-25
This work reports the isolation and preliminary characterization of Nicotiana plumbaginifolia mutants resistant to methylammonium. Nicotiana plumbaginifolia plants cannot grow on low levels of nitrate in the presence of methylammonium. Methylammonium is not used as a nitrogen source, although it can be efficiently taken up by Nicotiana plumbaginifolia cells and converted into methylglutamine, an analog of glutamine. Glutamine is known to repress the expression of the enzymes that mediate the first two steps in the nitrate assimilatory pathway, nitrate reductase (NR) and nitrite reductase (NiR). Methylammonium has therefore been used, in combination with low concentrations of nitrate, as a selective agent in order to screen for mutants in which the nitrate pathway is de-repressed. Eleven semi-dominant mutants, all belonging to the same complementation group, were identified. The mutant showing the highest resistance to methylammonium was not affected either in the utilization of ammonium, accumulation of methylammonium or in glutamine synthase activity. A series of experiments showed that utilization of nitrite by the wild-type and the mutant was comparable, in the presence or the absence of methylammonium, thus suggesting that the mutation specifically affected nitrate transport or reduction. Although NR mRNA levels were less repressed by methylammonium treatment of the wild-type than the mutant, NR activities of the mutant remained comparable with or without methylammonium, leading to the hypothesis that modified expression of NR is probably not responsible for resistance to methylammonium. Methylammonium inhibited nitrate uptake in the wild-type but had only a limited effect in the mutant. The implications of these results are discussed.
Analysis of the crush environment for lightweight air-transportable accident-resistant containers
International Nuclear Information System (INIS)
McClure, J.D.; Hartman, W.F.
1981-12-01
This report describes the longitudinal dynamic crush environment for a Lightweight Air-Transportable Accident-Resistant Container (LAARC, now called PAT-2) that can be used to transport small quantities of radioactive material. The analysis of the crush environment involves evaluation of the forces imposed upon the LAARC package during the crash of a large, heavily loaded, cargo aircraft. To perform the analysis, a cargo load column was defined which consisted of a longitudinal prism of cargo of cross-sectional area equal to the projected area of the radioactive-material package and length equal to the longitudinal extent of the cargo compartment in a commercial cargo jet aircraft. To bound the problem, two analyses of the cargo load column were performed, a static stability analysis and a dynamic analysis. The results of these analyses can be applied to other packaging designs and suggest that the physical limits or magnitude of the longitudinal crush forces, which are controlled in part by the yield strength of the cargo and the package size, are much smaller than previously estimated
Glyphosate resistance: state of knowledge
Sammons, Robert Douglas; Gaines, Todd A
2014-01-01
Studies of mechanisms of resistance to glyphosate have increased current understanding of herbicide resistance mechanisms. Thus far, single-codon non-synonymous mutations of EPSPS (5-enolypyruvylshikimate-3-phosphate synthase) have been rare and, relative to other herbicide mode of action target-site mutations, unconventionally weak in magnitude for resistance to glyphosate. However, it is possible that weeds will emerge with non-synonymous mutations of two codons of EPSPS to produce an enzyme endowing greater resistance to glyphosate. Today, target-gene duplication is a common glyphosate resistance mechanism and could become a fundamental process for developing any resistance trait. Based on competition and substrate selectivity studies in several species, rapid vacuole sequestration of glyphosate occurs via a transporter mechanism. Conversely, as the chloroplast requires transporters for uptake of important metabolites, transporters associated with the two plastid membranes may separately, or together, successfully block glyphosate delivery. A model based on finite glyphosate dose and limiting time required for chloroplast loading sets the stage for understanding how uniquely different mechanisms can contribute to overall glyphosate resistance. PMID:25180399
Chen, Xu; Wang, Ya-Wen; Gao, Peng
2018-05-09
Spindlin1 (SPIN1), a protein highly expressed in several human cancers, has been correlated with tumorigenesis and development. Alterations of drug metabolizing enzymes and drug transporters are major determinants of chemoresistance in tumor cells. However, whether the metabolizing enzymes and transporters are under the control of SPIN1 in breast cancer chemoresistance has not yet been defined. SPIN1 expression in breast cancer cells and tissues was detected by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Chemosensitivity assays in vitro and in vivo were performed to determine the effect of SPIN1 on Adriamycin resistance. Downstream effectors of SPIN1 were screened by microarray and confirmed by qRT-PCR and Western blot. Luciferase assay and Western blot were used to identify miRNAs regulating SPIN1. We showed that SPIN1 was significantly elevated in drug-resistant breast cancer cell lines and tissues, compared with the chemosensitive ones. SPIN1 enhanced Adriamycin resistance of breast cancer cells in vitro, and downregulation of SPIN1 by miRNA could decrease Adriamycin resistance in vivo. Mechanistically, drug metabolizing enzymes and transporter CYP2C8, UGT2B4, UGT2B17 and ABCB4 were proven to be downstream effectors of SPIN1. Notably, SPIN1 was identified as a direct target of the miR-148/152 family (miR-148a-3p, miR-148b-3p and miR-152-3p). As expected, miR-148a-3p, miR-148b-3p or miR-152-3p could increase Adriamycin sensitivity in breast cancer cells in vitro. Moreover, high expression of SPIN1 or low expression of the miR-148/152 family predicted poorer survival in breast cancer patients. Our results establish that SPIN1, negatively regulated by the miR-148/152 family, enhances Adriamycin resistance in breast cancer via upregulating the expression of drug metabolizing enzymes and drug transporter.
Abramycheva, N Iu; Govorun, V M
2000-01-01
The role of transport activity of Acholeplasma laidlawii plasmatic membrane in the development of resistance to ciprofloxacin was investigated. It was shown that ethidium bromide used as fluoroquinolone analogue in plasmatic membrane efflux pump was accumulated in ciprofloxacin-resistant cells in much less amount. It was estimated that ethidium bromide efflux depended on temperature, glucose and transmembrane electro-chemical proton potential. Inhibitors of efflux systems--reserpine and verapamil enhanced the ethidium bromide accumulation much more intensively in ciprofloxacin resistant cells. The results of investigation allowed to consider the existence of active efflux system for toxic agents in acholeplasma; in the case of ciprofloxacin-resistant strain these systems are inducible.
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Li Xinrui
2012-06-01
Full Text Available Abstract Background Two atherosclerosis-susceptible and -resistant Japanese quail (Coturnix japonica strains obtained by divergent selection are commonly used as models to study atherosclerosis, but no genetic characterization of their phenotypic differences has been reported so far. Our objective was to examine possible differences in the expression of genes involved in cholesterol metabolism and transport in the liver between these two strains and to evaluate the value of this model to analyze the gene system affecting cholesterol metabolism and transport. Methods A factorial study with both strains (atherosclerosis-susceptible versus atherosclerosis-resistant and two diets (control versus cholesterol was carried out. The mRNA concentrations of four genes involved in cholesterol biosynthesis (HMGCR, FDFT1, SQLE and DHCR7 and three genes in cholesterol transport (ABCG5, ABCG8 and APOA1 were assayed using real-time quantitative PCR. Plasma lipids were also assayed. Results Expression of ABCG5 (control diet and ABCG8 (regardless of dietary treatment and expression of HMGCR, FDFT1 and SQLE (regardless of dietary treatment were significantly higher in the atherosclerosis-resistant than in the atherosclerosis-susceptible strain. Plasma triglyceride and LDL levels, and LDL/HDL ratio were significantly higher in the atherosclerosis-susceptible than in the atherosclerosis-resistant strain fed the cholesterol diet. In the atherosclerosis-susceptible strain, ABCG5 expression regressed significantly and positively on plasma LDL level, whereas DHCR7 and SQLE expression regressed significantly and negatively on plasma triglyceride level. Conclusions Our results provide support for the hypothesis that the atherosclerosis-resistant strain metabolizes and excretes cholesterol faster than the atherosclerosis-susceptible strain. We have also demonstrated that these quail strains are a useful model to study cholesterol metabolism and transport in relation with
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Juthamard Surapongchai
2018-04-01
Full Text Available Objectives: The present study investigated the impact of voluntary exercise on insulin-stimulated glucose transport and the protein expression and phosphorylation status of the signaling molecules known to be involved in the glucose transport process in the soleus muscle as well as other cardiometabolic risks in a rat model with insulin resistance syndrome induced by chronic angiotensin II (ANGII infusion.Materials and Methods: Male Sprague-Dawley rats were assigned to sedentary or voluntary wheel running (VWR groups. Following a 6-week period, rats in each group were subdivided and subcutaneously administered either normal saline or ANGII at 100 ng/kg/min for 14 days. Blood pressure, glucose tolerance, insulin-stimulated glucose transport and signaling proteins, including insulin receptor (IR, insulin receptor substrate 1 (IRS-1, Akt, Akt substrate of 160 kDa (AS160, AMPKα, c-Jun NH2-terminal kinase (JNK, p38 MAPK, angiotensin converting enzyme (ACE, ANGII type 1 receptor (AT1R, ACE2, Mas receptor (MasR and oxidative stress marker in the soleus muscle, were evaluated.Results: Exercise protected against the insulin resistance of glucose transport and defective insulin signaling molecules in the soleus muscle; this effect was associated with a significant increase in AMPK Thr172 (43% and decreases in oxidative stress marker (31% and insulin-induced p38 MAPK Thr180/Tyr182 (45% and SAPK/JNK Thr183/Tyr185 (25%, without significant changes in expression of AT1R, AT2R, ACE, ACE2, and MasR when compared to the sedentary rats given ANGII infusion. At the systemic level, VWR significantly decreased body weight, fat weight, and systolic blood pressure as well as improved serum lipid profiles.Conclusion: Voluntary exercise can alleviate insulin resistance of glucose transport and impaired insulin signaling molecules in the soleus muscle and improve whole-body insulin sensitivity in rats chronically administered with ANGII.
DEFF Research Database (Denmark)
Hansen, Henrik; Ottosen, Lisbeth M.; Villumsen, Arne
1999-01-01
Electrodialytic soil remediation is a recently developed method to decontaminate heavy metal polluted soil using ion-exchange membranes. In this method one side of the ion-exchange membrane is in direct contact with the polluted soil. It is of great importance to know if this contact with the soil...... different electrodialytic soil remediation experiments. The experiments showed that after the use in electrodialytic soil remediation, the ion-exchange membranes had transport numbers in the same magnitude as new membranes. The electrical resistance for six membranes did not differ from that of new...
Convective transport resistance in the vitreous humor
Penkova, Anita; Sadhal, Satwindar; Ratanakijsuntorn, Komsan; Moats, Rex; Tang, Yang; Hughes, Patrick; Robinson, Michael; Lee, Susan
2012-11-01
It has been established by MRI visualization experiments that the convection of nanoparticles and large molecules with high rate of water flow in the vitreous humor will experience resistance, depending on the respective permeabilities of the injected solute. A set of experiments conducted with Gd-DTPA (Magnevist, Bayer AG, Leverkusen, Germany) and 30 nm gadolinium-based particles (Gado CELLTrackTM, Biopal, Worcester, MA) as MRI contrast agents showed that the degree of convective transport in this Darcy-type porous medium varies between the two solutes. These experiments consisted of injecting a mixture of the two (a 30 μl solution of 2% Magnevist and 1% nanoparticles) at the middle of the vitreous of an ex vivo whole bovine eye and subjecting the vitreous to water flow rate of 100 μl/min. The water (0.9% saline solution) was injected at the top of the eye, and was allowed to drain through small slits cut at the bottom of the eyeball. After 50 minutes of pumping, MRI images showed that the water flow carried the Gd-DTPA farther than the nanoparticles, even though the two solutes, being mixed, were subjected to the same convective flow conditions. We find that the convected solute lags the water flow, depending on the solute permeability. The usual convection term needs to be adjusted to allow for the filtration effect on the larger particles in the form (1- σ) u . ∇ c with important implications for the modeling of such systems.
Directory of Open Access Journals (Sweden)
Joel Vega-Rodríguez
Full Text Available Malaria is one of the most devastating parasitic diseases worldwide. Plasmodium drug resistance remains a major challenge to malaria control and has led to the re-emergence of the disease. Chloroquine (CQ and artemisinin (ART are thought to exert their anti-malarial activity inducing cytotoxicity in the parasite by blocking heme degradation (for CQ and increasing oxidative stress. Besides the contribution of the CQ resistance transporter (PfCRT and the multidrug resistant gene (pfmdr, CQ resistance has also been associated with increased parasite glutathione (GSH levels. ART resistance was recently shown to be associated with mutations in the K13-propeller protein. To analyze the role of GSH levels in CQ and ART resistance, we generated transgenic Plasmodium berghei parasites either deficient in or overexpressing the gamma-glutamylcysteine synthetase gene (pbggcs encoding the rate-limiting enzyme in GSH biosynthesis. These lines produce either lower (pbggcs-ko or higher (pbggcs-oe levels of GSH than wild type parasites. In addition, GSH levels were determined in P. berghei parasites resistant to CQ and mefloquine (MQ. Increased GSH levels were detected in both, CQ and MQ resistant parasites, when compared to the parental sensitive clone. Sensitivity to CQ and ART remained unaltered in both pgggcs-ko and pbggcs-oe parasites when tested in a 4 days drug suppressive assay. However, recrudescence assays after the parasites have been exposed to a sub-lethal dose of ART showed that parasites with low levels of GSH are more sensitive to ART treatment. These results suggest that GSH levels influence Plasmodium berghei response to ART treatment.
Maintenance of carbohydrate transport in tall trees
DEFF Research Database (Denmark)
Savage, Jessica A.; Beecher, Sierra D.; Clerx, Laura
2017-01-01
Trees present a critical challenge to long-distance transport because as a tree grows in height and the transport pathway increases in length, the hydraulic resistance of the vascular tissue should increase. This has led many to question whether trees can rely on a passive transport mechanism to ...... that reduce transport resistance. As a result, the key to the long-standing mystery of how trees maintain phloem transport as they increase in size lies in the structure of the phloem and its ability to change hydraulic properties with plant height.......Trees present a critical challenge to long-distance transport because as a tree grows in height and the transport pathway increases in length, the hydraulic resistance of the vascular tissue should increase. This has led many to question whether trees can rely on a passive transport mechanism...... in the leaves of a tall tree in situ. Across nine deciduous species, we find that hydraulic resistance in the phloem scales inversely with plant height because of a shift in sieve element structure along the length of individual trees. This scaling relationship seems robust across multiple species despite large...
International Nuclear Information System (INIS)
Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Daniele; Fagret, Daniel; Ghezzi, Catherine; Halimi, Serge; Demongeot, Jacques
2007-01-01
Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using 125 I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p < 0.05; heart, p < 0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p < 0.001; muscle, p < 0.001; heart, p < 0.01) whereas no significant changes were observed in fructose-fed rats. This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. (orig.)
Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Danièle; Halimi, Serge; Demongeot, Jacques; Fagret, Daniel; Ghezzi, Catherine
2007-01-01
Purpose Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state and it has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats with 125I-6-Deoxy-6-Iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Methods Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood were assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Results Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady-state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p<0.01; muscle, p<0.05; heart, p<0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p<0.001; muscle, p<0.001; heart, p<0.01) and whereas no significant changes were observed in fructose-fed rats. Conclusion This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. PMID:17171359
Directory of Open Access Journals (Sweden)
Reeder John C
2010-01-01
Full Text Available Abstract Background Molecular monitoring of parasite resistance has become an important complementary tool in establishing rational anti-malarial drug policies. Community surveys provide a representative sample of the parasite population and can be carried out more rapidly than accrual of samples from clinical cases, but it is not known whether the frequencies of genetic resistance markers in clinical cases differ from those in the overall population, or whether such community surveys can provide good predictions of treatment failure rates. Methods Between 2003 and 2005, in vivo drug efficacy of amodiaquine or chloroquine plus sulphadoxine-pyrimethamine was determined at three sites in Papua New Guinea. The genetic drug resistance profile (i.e., 33 single nucleotide polymorphisms in Plasmodium falciparum crt, mdr1, dhfr, dhps, and ATPase6 was concurrently assessed in 639 community samples collected in the catchment areas of the respective health facilities by using a DNA microarray-based method. Mutant allele and haplotype frequencies were determined and their relationship with treatment failure rates at each site in each year was investigated. Results PCR-corrected in vivo treatment failure rates were between 12% and 28% and varied by site and year with variable longitudinal trends. In the community samples, the frequencies of mutations in pfcrt and pfmdr1 were high and did not show significant changes over time. Mutant allele frequencies in pfdhfr were moderate and those in pfdhps were low. No mutations were detected in pfATPase6. There was much more variation between sites than temporal, within-site, variation in allele and haplotype frequencies. This variation did not correlate well with treatment failure rates. Allele and haplotype frequencies were very similar in clinical and community samples from the same site. Conclusions The relationship between parasite genetics and in vivo treatment failure rate is not straightforward. The
Directory of Open Access Journals (Sweden)
Linda J Gahan
2010-12-01
Full Text Available Transgenic crops producing insecticidal toxins from Bacillus thuringiensis (Bt are commercially successful in reducing pest damage, yet knowledge of resistance mechanisms that threaten their sustainability is incomplete. Insect resistance to the pore-forming Cry1Ac toxin is correlated with the loss of high-affinity, irreversible binding to the mid-gut membrane, but the genetic factors responsible for this change have been elusive. Mutations in a 12-cadherin-domain protein confer some Cry1Ac resistance but do not block this toxin binding in in vitro assays. We sought to identify mutations in other genes that might be responsible for the loss of binding. We employed a map-based cloning approach using a series of backcrosses with 1,060 progeny to identify a resistance gene in the cotton pest Heliothis virescens that segregated independently from the cadherin mutation. We found an inactivating mutation of the ABC transporter ABCC2 that is genetically linked to Cry1Ac resistance and is correlated with loss of Cry1Ac binding to membrane vesicles. ABC proteins are integral membrane proteins with many functions, including export of toxic molecules from the cell, but have not been implicated in the mode of action of Bt toxins before. The reduction in toxin binding due to the inactivating mutation suggests that ABCC2 is involved in membrane integration of the toxin pore. Our findings suggest that ABC proteins may play a key role in the mode of action of Bt toxins and that ABC protein mutations can confer high levels of resistance that could threaten the continued utilization of Bt-expressing crops. However, such mutations may impose a physiological cost on resistant insects, by reducing export of other toxins such as plant secondary compounds from the cell. This weakness could be exploited to manage this mechanism of Bt resistance in the field.
Gahan, Linda J; Pauchet, Yannick; Vogel, Heiko; Heckel, David G
2010-12-16
Transgenic crops producing insecticidal toxins from Bacillus thuringiensis (Bt) are commercially successful in reducing pest damage, yet knowledge of resistance mechanisms that threaten their sustainability is incomplete. Insect resistance to the pore-forming Cry1Ac toxin is correlated with the loss of high-affinity, irreversible binding to the mid-gut membrane, but the genetic factors responsible for this change have been elusive. Mutations in a 12-cadherin-domain protein confer some Cry1Ac resistance but do not block this toxin binding in in vitro assays. We sought to identify mutations in other genes that might be responsible for the loss of binding. We employed a map-based cloning approach using a series of backcrosses with 1,060 progeny to identify a resistance gene in the cotton pest Heliothis virescens that segregated independently from the cadherin mutation. We found an inactivating mutation of the ABC transporter ABCC2 that is genetically linked to Cry1Ac resistance and is correlated with loss of Cry1Ac binding to membrane vesicles. ABC proteins are integral membrane proteins with many functions, including export of toxic molecules from the cell, but have not been implicated in the mode of action of Bt toxins before. The reduction in toxin binding due to the inactivating mutation suggests that ABCC2 is involved in membrane integration of the toxin pore. Our findings suggest that ABC proteins may play a key role in the mode of action of Bt toxins and that ABC protein mutations can confer high levels of resistance that could threaten the continued utilization of Bt-expressing crops. However, such mutations may impose a physiological cost on resistant insects, by reducing export of other toxins such as plant secondary compounds from the cell. This weakness could be exploited to manage this mechanism of Bt resistance in the field.
High prevalence of Plasmodium falciparum pfcrt K76T mutation in ...
African Journals Online (AJOL)
We recommend special attention to be paid to patients with sickle cell disease while .... chloroquine for malaria chemoprophylaxis thus maintaining a selective pressure on these parasites. ... Resistant parasites are important when trying to.
Zhang, Fan; Throm, Stacy L.; Murley, Laura L.; Miller, Laura A.; Zatechka, D. Steven; Guy, R. Kiplin; Kennedy, Rachel; Stewart, Clinton F.
2011-01-01
Breast cancer resistance protein (BCRP; ABCG2), a clinical marker for identifying the side population (SP) cancer stem cell subgroup, affects intestinal absorption, brain penetration, hepatobiliary excretion, and multidrug resistance of many anti-cancer drugs. Nutlin-3a is currently under pre-clinical investigation in a variety of solid tumor and leukemia models as a p53 reactivation agent, and has been recently demonstrated to also have p53 independent actions in cancer cells. In the present study, we first report that nutlin-3a can inhibit the efflux function of BCRP. We observed that although the nutlin-3a IC50 did not differ between BCRP over-expressing and vector control cells, nutlin-3a treatment significantly potentiated the cells to treatment with the BCRP substrate mitoxantrone. Combination index calculations suggested synergism between nutlin-3a and mitoxantrone in cell lines over-expressing BCRP. Upon further investigation, it was confirmed that nutlin-3a increased the intracellular accumulation of BCRP substrates such as mitoxantrone and Hoechst 33342 in cells expressing functional BCRP without altering the expression level or localization of BCRP. Interestingly, nutlin-3b, considered virtually “inactive” in disrupting the MDM2/p53 interaction, reversed Hoechst 33342 efflux with the same potency as nutlin-3a. Intracellular accumulation and bi-directional transport studies using MDCKII cells suggested that nutlin-3a is not a substrate of BCRP. Additionally, an ATPase assay using Sf9 insect cell membranes over-expressing wild-type BCRP indicated that nutlin-3a inhibits BCRP ATPase activity in a dose-dependent fashion. In conclusion, our studies demonstrate that nutlin-3a inhibits BCRP efflux function, which consequently reverses BCRP-related drug resistance. PMID:21459080
Puncture resistance of Type B transport systems
International Nuclear Information System (INIS)
Rack, H.J.; Cheresh, M.C.
1980-01-01
This report describes a recent attempt to develop a test method for use in screening materials and for evaluating the effects of certain parameters, for example section stiffness, on container penetration resistance. In addition, it illustrates the application of this procedure to the selection of a sheet steel for a transuranic waste (TRUPACT) container. The test consists of penetrating a specimen, normally 0.6 m square, with a punch (tup) attached to a falling weight and recording and analyzing the force-time history to determine the energy absorption during the impact event. The test as developed simulates certain aspects of the 10CFR71 drop test in order to provide a means of comparing, for example, the penetrating resistance of various steels, this resistance being defined as the energy required to initiate fracture in the specimen. In summary, this examination suggests that it should be possible to develop a laboratory test to rank and select materials for maximum puncture resistance. Although the initial results appear promising, more effort will be required before this procedure can be routinely applied to examining the various factors which control the puncture resistance of these materials. These results do, nonetheless, show that high-strength, low-alloy steels do offer significant advantages over mild steel for container penetration protection. Indeed, one of these steels, NAX-80, is presently considered as a prime candidate for the TRUPACT container being developed at Sandia National Laboratories
Guo, Zhaojiang; Kang, Shi; Zhu, Xun; Xia, Jixing; Wu, Qingjun; Wang, Shaoli; Xie, Wen; Zhang, Youjun
2015-04-01
Biopesticides or transgenic crops based on Cry toxins from the soil bacterium Bacillus thuringiensis (Bt) effectively control agricultural insect pests. The sustainable use of Bt biopesticides and Bt crops is threatened, however, by the development of Cry resistance in the target pests. The diamondback moth, Plutella xylostella (L.), is the first pest that developed resistance to a Bt biopesticide in the field, and a recent study has shown that the resistance of P. xylostella to Cry1Ac is caused by a mutation in an ATP-binding cassette (ABC) transporter gene (ABCC2). In this study, we report that down-regulation of a novel ABC transporter gene from ABCG subfamily (Pxwhite) is associated with Cry1Ac resistance in P. xylostella. The full-length cDNA sequence of Pxwhite was cloned and analyzed. Spatial-temporal expression detection revealed that Pxwhite was expressed in all tissues and developmental stages, and highest expressed in Malpighian tubule tissue and in egg stage. Sequence variation analysis of Pxwhite indicated the absence of constant non-synonymous mutations between susceptible and resistant strains, whereas midgut transcript analysis showed that Pxwhite was remarkably reduced in all resistant strains and further reduced when larvae of the moderately resistant SZ-R strain were subjected to selection with Cry1Ac toxin. Furthermore, RNA interference (RNAi)-mediated suppression of Pxwhite gene expression significantly reduced larval susceptibility to Cry1Ac toxin, and genetic linkage analysis confirmed that down-regulation of Pxwhite gene is tightly linked to Cry1Ac resistance in P. xylostella. To our knowledge, this is the first report indicating that Pxwhite gene is involved in Cry1Ac resistance in P. xylostella. Copyright © 2015 Elsevier Ltd. All rights reserved.
Sakamoto, Kanta; Margolles, Abelardo; van Veen, Hendrik W.; Konings, Wil N.
2001-01-01
Lactobacillus brevis is a major contaminant of spoiled beer. The organism can grow in beer in spite of the presence of antibacterial hop compounds that give the beer a bitter taste. The hop resistance in L. brevis is, at least in part, dependent on the expression of the horA gene. The deduced amino acid sequence of HorA is 53% identical to that of LmrA, an ATP-binding cassette multidrug transporter in Lactococcus lactis. To study the role of HorA in hop resistance, HorA was functionally expre...
International Nuclear Information System (INIS)
Pedraz-Cuesta, Elena; Christensen, Sandra; Jensen, Anders A.; Jensen, Niels Frank; Bunch, Lennart; Romer, Maria Unni; Brünner, Nils; Stenvang, Jan; Pedersen, Stine Falsig
2015-01-01
Colorectal cancer (CRC) is a leading cause of cancer death globally and new biomarkers and treatments are severely needed. Here, we employed HCT116 and LoVo human CRC cells made resistant to either SN38 or oxaliplatin, to investigate whether altered expression of the high affinity glutamate transporters Solute Carrier (SLC)-1A1 and -1A3 (EAAT3, EAAT1) is associated with the resistant phenotypes. Analyses included real-time quantitative PCR, immunoblotting and immunofluorescence analyses, radioactive tracer flux measurements, and biochemical analyses of cell viability and glutathione content. Results were evaluated using one- and two-way ANOVA and Students two-tailed t-test, as relevant. In SN38-resistant HCT116 and LoVo cells, SLC1A1 expression was down-regulated ~60 % and up-regulated ~4-fold, respectively, at both mRNA and protein level, whereas SLC1A3 protein was undetectable. The changes in SLC1A1 expression were accompanied by parallel changes in DL-Threo-β-Benzyloxyaspartic acid (TBOA)-sensitive, UCPH101-insensitive [ 3 H]-D-Aspartate uptake, consistent with increased activity of SLC1A1 (or other family members), yet not of SLC1A3. DL-TBOA co-treatment concentration-dependently augmented loss of cell viability induced by SN38, while strongly counteracting that induced by oxaliplatin, in both HCT116 and LoVo cells. This reflected neither altered expression of the oxaliplatin transporter Cu 2+ -transporter-1 (CTR1), nor changes in cellular reduced glutathione (GSH), although HCT116 cell resistance per se correlated with increased cellular GSH. DL-TBOA did not significantly alter cellular levels of p21, cleaved PARP-1, or phospho-Retinoblastoma protein, yet altered SLC1A1 subcellular localization, and reduced chemotherapy-induced p53 induction. SLC1A1 expression and glutamate transporter activity are altered in SN38-resistant CRC cells. Importantly, the non-selective glutamate transporter inhibitor DL-TBOA reduces chemotherapy-induced p53 induction and augments
Energy Technology Data Exchange (ETDEWEB)
Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Daniele; Fagret, Daniel; Ghezzi, Catherine [INSERM, E340, 38000 Grenoble, (France); Univ Grenoble, 38000 Grenoble, (France); Halimi, Serge [CHRU Grenoble, Hopital Michallon, Service de Diabetologie, 38000 Grenoble, (France); Demongeot, Jacques [Univ Grenoble, 38000 Grenoble, (France); CNRS, UMR 5525, 38000 Grenoble, (France)
2007-05-15
Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using {sup 125}I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p < 0.05; heart, p < 0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p < 0.001; muscle, p < 0.001; heart, p < 0.01) whereas no significant changes were observed in fructose-fed rats. This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. (orig.)
Directory of Open Access Journals (Sweden)
Victoria ePastor
2014-05-01
Full Text Available Disruption of the high-affinity nitrate transporter NRT2.1 activates the priming defence against Pseudomonas syringae, resulting in enhanced resistance. In this study, it is demonstrated that the high-affinity ammonium transporter AMT1.1 is a negative regulator of Arabidopsis defence responses. The T-DNA knockout mutant amt1.1 displays enhanced resistance against Plectosphaerella cucumerina and reduced susceptibility to P. syringae. The impairment of AMT1.1 induces significant metabolic changes in the absence of challenge, suggesting that amt1.1 retains constitutive defence responses. Interestingly, amt1.1 combats pathogens differently depending on the lifestyle of the pathogen. In addition, N starvation enhances the susceptibility of wild type plants and the mutant amt1.1 to P. syringae whereas it has no effect on P. cucumerina resistance. The metabolic changes of amt1.1 against P. syringae are subtler and are restricted to the phenylpropanoid pathway, which correlates with its reduced susceptibility. By contrast, the amt1.1 mutant responds by activating higher levels of camalexin and callose against P. cucumerina. In addition, amt1.1 shows altered levels of aliphatic and indolic glucosinolates and other Trp-related compounds following infection by the necrotroph. These observations indicate that AMT1.1 may play additional roles that affect N uptake and plant immune responses.
Analytical method for establishing indentation rolling resistance
Gładysiewicz, Lech; Konieczna, Martyna
2018-01-01
Belt conveyors are highly reliable machines able to work in special operating conditions. Harsh environment, long distance of transporting and great mass of transported martials are cause of high energy usage. That is why research in the field of belt conveyor transportation nowadays focuses on reducing the power consumption without lowering their efficiency. In this paper, previous methods for testing rolling resistance are described, and new method designed by authors was presented. New method of testing rolling resistance is quite simple and inexpensive. Moreover it allows to conduct the experimental tests of the impact of different parameters on the value of indentation rolling resistance such as core design, cover thickness, ambient temperature, idler travel frequency, or load value as well. Finally results of tests of relationship between rolling resistance and idler travel frequency and between rolling resistance and idler travel speed was presented.
Electrolyte solution transport in electropolar nanotubes
International Nuclear Information System (INIS)
Zhao Jianbing; Culligan, Patricia J; Chen Xi; Qiao Yu; Zhou Qulan; Li Yibing; Tak, Moonho; Park, Taehyo
2010-01-01
Electrolyte transport in nanochannels plays an important role in a number of emerging areas. Using non-equilibrium molecular dynamics (NEMD) simulations, the fundamental transport behavior of an electrolyte/water solution in a confined model nanoenvironment is systematically investigated by varying the nanochannel dimension, solid phase, electrolyte phase, ion concentration and transport rate. It is found that the shear resistance encountered by the nanofluid strongly depends on these material/system parameters; furthermore, several effects are coupled. The mechanisms of the nanofluidic transport characteristics are explained by considering the unique molecular/ion structure formed inside the nanochannel. The lower shear resistance observed in some of the systems studies could be beneficial for nanoconductors, while the higher shear resistance (or higher effective viscosity) observed in other systems might enhance the performance of energy dissipation devices.
Keniya, Mikhail V; Holmes, Ann R; Niimi, Masakazu; Lamping, Erwin; Gillet, Jean-Pierre; Gottesman, Michael M; Cannon, Richard D
2014-10-06
ABCB5, an ATP-binding cassette (ABC) transporter, is highly expressed in melanoma cells, and may contribute to the extreme resistance of melanomas to chemotherapy by efflux of anti-cancer drugs. Our goal was to determine whether we could functionally express human ABCB5 in the model yeast Saccharomyces cerevisiae, in order to demonstrate an efflux function for ABCB5 in the absence of background pump activity from other human transporters. Heterologous expression would also facilitate drug discovery for this important target. DNAs encoding ABCB5 sequences were cloned into the chromosomal PDR5 locus of a S. cerevisiae strain in which seven endogenous ABC transporters have been deleted. Protein expression in the yeast cells was monitored by immunodetection using both a specific anti-ABCB5 antibody and a cross-reactive anti-ABCB1 antibody. ABCB5 function in recombinant yeast cells was measured by determining whether the cells possessed increased resistance to known pump substrates, compared to the host yeast strain, in assays of yeast growth. Three ABCB5 constructs were made in yeast. One was derived from the ABCB5-β mRNA, which is highly expressed in human tissues but is a truncation of a canonical full-size ABC transporter. Two constructs contained full-length ABCB5 sequences: either a native sequence from cDNA or a synthetic sequence codon-harmonized for S. cerevisiae. Expression of all three constructs in yeast was confirmed by immunodetection. Expression of the codon-harmonized full-length ABCB5 DNA conferred increased resistance, relative to the host yeast strain, to the putative substrates rhodamine 123, daunorubicin, tetramethylrhodamine, FK506, or clorgyline. We conclude that full-length ABCB5 can be functionally expressed in S. cerevisiae and confers drug resistance.
Directory of Open Access Journals (Sweden)
Ting-Ting Song
Full Text Available Multidrug resistance (MDR confers agrochemical compatibility to fungal cells-based mycoinsecticdes but mechanisms involved in MDR remain poorly understood for entomopathogenic fungi, which have been widely applied as biocontrol agents against arthropod pests. Here we characterized the functions of five ATP-binding cassette (ABC transporters, which were classified to the subfamilies ABC-B (Mdr1, ABC-C (Mrp1 and ABC-G (Pdr1, Pdr2 and Pdr5 and selected from 54 full-size ABC proteins of Beauveria bassiana based on their main domain architecture, membrane topology and transcriptional responses to three antifungal inducers. Disruption of each transporter gene resulted in significant reduction in resistance to four to six of eight fungicides or antifungal drugs tested due to their differences in structure and function. Compared with wild-type and complemented (control strains, disruption mutants of all the five transporter genes became significantly less tolerant to the oxidants menadione and H₂O₂ based on 22-41% and 10-31% reductions of their effective concentrations required for the suppression of 50% colony growth at 25°C. Under a standardized spray, the killing actions of ΔPdr5 and ΔMrp1 mutants against Spodoptera litura second-instar larvae were delayed by 59% and 33% respectively. However, no significant virulence change was observed in three other delta mutants. Taken together, the examined five ABC transporters contribute differentially to not only the fungal MDR but antioxidant capability, a phenotype rarely associated with ABC efflux pumps in previous reports; at least some of them are required for the full virulence of B. bassiana, thereby affecting the fungal biocontrol potential. Our results indicate that ABC pump-dependent MDR mechanisms exist in entomopathogenic fungi as do in yeasts and human and plant pathogenic fungi.
Energy Technology Data Exchange (ETDEWEB)
Briat, Arnaud; Slimani, Lotfi; Perret, Pascale; Villemain, Daniele; Fagret, Daniel; Ghezzi, Catherine [INSERM, E0340, Radiopharmaceutiques Biocliniques, Grenoble (France); Univ Grenoble, Grenoble (France); Halimi, Serge [Univ Grenoble, Grenoble (France); Hopital Michallon, Service de Diabetologie, CHRU Grenoble, Grenoble (France); Demongeot, Jacques [Univ Grenoble, Grenoble (France); CNRS, UMR 5525, Grenoble (France)
2007-11-15
Insulin resistance, implying depressed cellular sensitivity to insulin, is a risk factor for type 2 diabetes and cardiovascular disease. This study is the first step towards the development of a technique of insulin resistance measurement in humans with a new tracer of glucose transport, [{sup 123}I]6-deoxy-6-iodo-D-glucose (6DIG). We investigated 6DIG kinetics in anaesthetised control rats and in three models of insulin-resistant rats: fructose fed, Zucker and ZDF. The study of myocardial 6DIG activity was performed under two conditions: first, 6DIG was injected under the baseline condition and then it was injected after a bolus injection of insulin. After each injection, radioactivity was measured over 45 min by external detection via NaI probes, in the heart and blood. A tri-compartment model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the heart. These coefficients were significantly increased with insulin in control rats and did not change significantly in insulin-resistant rats. The ratio of the coefficient obtained under insulin to that obtained under basal conditions gave an index of cardiac insulin resistance for each animal. The mean values of these ratios were significantly lower in insulin-resistant than in control rats: 1.16 {+-} 0.06 vs 2.28 {+-} 0.18 (p < 0.001) for the fructose-fed group, 0.92 {+-} 0.05 vs 1.62 {+-} 0.25 (p < 0.01) for the Zucker group and 1.34 {+-} 0.06 vs 2.01 {+-} 0.26 (p < 0.05) for the ZDF group. These results show that 6DIG could be a useful tracer to image cardiac insulin resistance. (orig.)
Analytical method for establishing indentation rolling resistance
Directory of Open Access Journals (Sweden)
Gładysiewicz Lech
2018-01-01
Full Text Available Belt conveyors are highly reliable machines able to work in special operating conditions. Harsh environment, long distance of transporting and great mass of transported martials are cause of high energy usage. That is why research in the field of belt conveyor transportation nowadays focuses on reducing the power consumption without lowering their efficiency. In this paper, previous methods for testing rolling resistance are described, and new method designed by authors was presented. New method of testing rolling resistance is quite simple and inexpensive. Moreover it allows to conduct the experimental tests of the impact of different parameters on the value of indentation rolling resistance such as core design, cover thickness, ambient temperature, idler travel frequency, or load value as well. Finally results of tests of relationship between rolling resistance and idler travel frequency and between rolling resistance and idler travel speed was presented.
Scheffer, GL; Maliepaard, M; Pijnenborg, ACLM; van Gastelen, MA; Schroeijers, AB; Allen, JD; Ross, DD; van der Valk, P; Dalton, WS; Schellens, JHM; Scheper, RJ; de Jong, MC
2000-01-01
Tumor cells may display a multidrug resistant phenotype by overexpression of ATP-binding cassette transporters such as multidrug resistance (,MDR1) P-glycoprotein, multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP). The presence of BCRP has thus far been reported
DEFF Research Database (Denmark)
Cuesta, Elena Pedraz; Christensen, Sandra; Jensen, Anders A.
2015-01-01
affinity glutamate transporters Solute Carrier (SLC)-1A1 and -1A3 (EAAT3, EAAT1) is associated with the resistant phenotypes. Analyses included real-time quantitative PCR, immunoblotting and immunofluorescence analyses, radioactive tracer flux measurements, and biochemical analyses of cell viability...... was undetectable. The changes in SLC1A1 expression were accompanied by parallel changes in DL-Threo-β-Benzyloxyaspartic acid (TBOA)-sensitive, UCPH101-insensitive [(3)H]-D-Aspartate uptake, consistent with increased activity of SLC1A1 (or other family members), yet not of SLC1A3. DL-TBOA co-treatment concentration...... and glutamate transporter activity are altered in SN38-resistant CRC cells. Importantly, the non-selective glutamate transporter inhibitor DL-TBOA reduces chemotherapy-induced p53 induction and augments CRC cell death induced by SN38, while attenuating that induced by oxaliplatin. These findings may point...
High prevalence of Plasmodium falciparum pfcrt K76T mutation in ...
African Journals Online (AJOL)
This study investigated the prevalence of malaria in SCD patients and mutations associated with CQ resistance. Children diagnosed with sickle cell disease attending both outpatient clinic and those admitted at Bugando Medical Centre in north-western Tanzania were screened for malaria using thick blood smear. A dried ...
Polder, R.B.; Peelen, W.H.A.
2014-01-01
The electrical resistivity of concrete can provide information about its transport properties, which is relevant for durability performance. For example, resistivity is inversely proportional to chloride diffusion, at least within similar concrete compositions. A methodology is proposed for on-site
2015-01-01
Aminopyrazoles are a new class of antimalarial compounds identified in a cellular antiparasitic screen with potent activity against Plasmodium falciparum asexual and sexual stage parasites. To investigate their unknown mechanism of action and thus identify their target, we cultured parasites in the presence of a representative member of the aminopyrazole series, GNF-Pf4492, to select for resistance. Whole genome sequencing of three resistant lines showed that each had acquired independent mutations in a P-type cation-transporter ATPase, PfATP4 (PF3D7_1211900), a protein implicated as the novel Plasmodium spp. target of another, structurally unrelated, class of antimalarials called the spiroindolones and characterized as an important sodium transporter of the cell. Similarly to the spiroindolones, GNF-Pf4492 blocks parasite transmission to mosquitoes and disrupts intracellular sodium homeostasis. Our data demonstrate that PfATP4 plays a critical role in cellular processes, can be inhibited by two distinct antimalarial pharmacophores, and supports the recent observations that PfATP4 is a critical antimalarial target. PMID:25322084
Mohapatra, Pradyumna Kishore; Sarma, Devojit Kumar; Prakash, Anil; Bora, Khukumoni; Ahmed, Md. Atique; Sarma, Bibhas; Goswami, Basanta Kumar; Bhattacharyya, Dibya Ranjan; Mahanta, Jagadish
2014-01-01
North-east India, being a corridor to South-east Asia, is believed to play an important role in transmitting drug resistant Plasmodium falciparum malaria to India and South Asia. North-east India was the first place in India to record the emergence of drug resistance to chloroquine as well as sulphadoxine/pyrimethamine. Presently chloroquine resistance is widespread all over the North-east India and resistance to other anti-malarials is increasing. In this study both in vivo therapeutic efficacy and molecular assays were used to screen the spectrum of drug resistance to chloroquine and sulphadoxine/pyrimethamine in the circulating P. falciparum strains. A total of 220 P. falciparum positives subjects were enrolled in the study for therapeutic assessment of chloroquine and sulphadoxine/pyrimethamine and assessment of point mutations conferring resistances to these drugs were carried out by genotyping the isolates following standard methods. Overall clinical failures in sulphadoxine/pyrimethamine and chloroquine were found 12.6 and 69.5% respectively, while overall treatment failures recorded were 13.7 and 81.5% in the two arms. Nearly all (99.0%) the isolates had mutant pfcrt genotype (76T), while 68% had mutant pfmdr-1 genotype (86Y). Mutation in dhps 437 codon was the most prevalent one while dhfr codon 108 showed 100% mutation. A total of 23 unique haplotypes at the dhps locus and 7 at dhfr locus were found while dhps-dhfr combined loci revealed 49 unique haplotypes. Prevalence of double, triple and quadruple mutations were common while 1 haplotype was found with all five mutated codons (F/AGEGS/T) at dhps locus. Detection of quadruple mutants (51I/59R/108N/164L) in the present study, earlier recorded from Car Nicobar Island, India only, indicates the presence of high levels of resistance to sulphadoxine/pyrimethamine in north-east India. Associations between resistant haplotypes and the clinical outcomes and emerging resistance in sulphadoxine/pyrimethamine in
International Nuclear Information System (INIS)
Briat, Arnaud; Slimani, Lotfi; Perret, Pascale; Villemain, Daniele; Fagret, Daniel; Ghezzi, Catherine; Halimi, Serge; Demongeot, Jacques
2007-01-01
Insulin resistance, implying depressed cellular sensitivity to insulin, is a risk factor for type 2 diabetes and cardiovascular disease. This study is the first step towards the development of a technique of insulin resistance measurement in humans with a new tracer of glucose transport, [ 123 I]6-deoxy-6-iodo-D-glucose (6DIG). We investigated 6DIG kinetics in anaesthetised control rats and in three models of insulin-resistant rats: fructose fed, Zucker and ZDF. The study of myocardial 6DIG activity was performed under two conditions: first, 6DIG was injected under the baseline condition and then it was injected after a bolus injection of insulin. After each injection, radioactivity was measured over 45 min by external detection via NaI probes, in the heart and blood. A tri-compartment model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the heart. These coefficients were significantly increased with insulin in control rats and did not change significantly in insulin-resistant rats. The ratio of the coefficient obtained under insulin to that obtained under basal conditions gave an index of cardiac insulin resistance for each animal. The mean values of these ratios were significantly lower in insulin-resistant than in control rats: 1.16 ± 0.06 vs 2.28 ± 0.18 (p < 0.001) for the fructose-fed group, 0.92 ± 0.05 vs 1.62 ± 0.25 (p < 0.01) for the Zucker group and 1.34 ± 0.06 vs 2.01 ± 0.26 (p < 0.05) for the ZDF group. These results show that 6DIG could be a useful tracer to image cardiac insulin resistance. (orig.)
International Nuclear Information System (INIS)
Katanuma, I.; Kiwamoto, Y.; Adachi, S.; Inutake, M.; Ishii, K.; Yatsu, K.; Sawada, K.; Miyoshi, S.
1987-05-01
Calculations are made for neoclassical resonant-plateau transports in the geometry of the effectively axisymmetrized tandem mirror GAMMA 10 magnetic field, which has minimum B inbord anchors inside the axisymmetric plug/barrier mirror cells. Azimuthal drifts at the local non-axisymmetric regions are included. The radial potential profile is determined by solving selfconsistently the charge neutrality equation. A finite resistance connecting end plate to machine ground provides appropriate boundary conditions on the radial electrostatic potential distribution so that it can be determined uniquely. The calculation is consistent with experimental results of GAMMA 10. (author)
Natural polyphenols: Influence on membrane transporters
Directory of Open Access Journals (Sweden)
Saad Abdulrahman Hussain
2016-03-01
Full Text Available Accumulated evidences have focused on the use of natural polyphenolic compounds as nutraceuticals, since they showed a wide range of bioactivities and exhibited protection against variety of age related disorders. Polyphenols have variable potencies to interact, and hence alter the activities of various transporter proteins, many of them classified as ATP-Binding Cassette transporters, like multidrug resistance protein (MDRP, and p-glycoprotein (P-gp. Some of the efflux transporters are generally linked with anticancer and antiviral drug resistance; in this context, polyphenols may be beneficial in modulating drug resistance by increasing the efficacy of anticancer and antiviral drugs. Additionally, these effects were implicated to explain the influence of dietary polyphenols on drug efficacy as result of food-drug interactions. However, limited data are available about the influence of these components on uptake transporters. Therefore, the objective of this article is to review the potential efficacies of polyphenols in modulating the functional integrity of uptake transporter proteins, including those terminated the effect of neurotransmitters, and their possible influence in neuropharmacology. [J Complement Med Res 2016; 5(1.000: 97-104
Toussaint, Frédéric; Pierman, Baptiste; Bertin, Aurélie; Lévy, Daniel; Boutry, Marc
2017-05-04
Pleiotropic drug resistance (PDR) transporters belong to the ABCG subfamily of ATP-binding cassette (ABC) transporters and are involved in the transport of various molecules across plasma membranes. During evolution, PDR genes appeared independently in fungi and in plants from a duplication of a half-size ABC gene. The enzymatic properties of purified PDR transporters from yeast have been characterized. This is not the case for any plant PDR transporter, or, incidentally, for any purified plant ABC transporter. Yet, plant PDR transporters play important roles in plant physiology such as hormone signaling or resistance to pathogens or herbivores. Here, we describe the expression, purification, enzymatic characterization and 2D analysis by electron microscopy of NpABCG5/NpPDR5 from Nicotiana plumbaginifolia , which has been shown to be involved in the plant defense against herbivores. We constitutively expressed NpABCG5/NpPDR5, provided with a His-tag in a homologous system: suspension cells from Nicotiana tabacum (Bright Yellow 2 line). NpABCG5/NpPDR5 was targeted to the plasma membrane and was solubilized by dodecyl maltoside and purified by Ni-affinity chromatography. The ATP-hydrolyzing specific activity (27 nmol min -1 mg -1 ) was stimulated seven-fold in the presence of 0.1% asolectin. Electron microscopy analysis indicated that NpABCG5/NpPDR5 is monomeric and with dimensions shorter than those of known ABC transporters. Enzymatic data (optimal pH and sensitivity to inhibitors) confirmed that plant and fungal PDR transporters have different properties. These data also show that N. tabacum suspension cells are a convenient host for the purification and biochemical characterization of ABC transporters. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.
Efflux drug transporters at the forefront of antimicrobial resistance
Rahman, Tahmina; Yarnall, Benjamin; Doyle, Declan A.
2017-01-01
Bacterial antibiotic resistance is rapidly becoming a major world health consideration. To combat antibiotics, microorganisms employ their pre-existing defence mechanisms that existed long before man’s discovery of antibiotics. Bacteria utilise levels of protection that range from gene upregulation, mutations, adaptive resistance, and production of resistant phenotypes (persisters) to communal behaviour, as in swarming and the ultimate defence of a biofilm. A major part of all of these respon...
Polymorphism in ABC transporter genes of Dirofilaria immitis
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Thangadurai Mani
2017-08-01
Full Text Available Dirofilaria immitis, a filarial nematode, causes dirofilariasis in dogs, cats and occasionally in humans. Prevention of the disease has been mainly by monthly use of the macrocyclic lactone (ML endectocides during the mosquito transmission season. Recently, ML resistance has been confirmed in D. immitis and therefore, there is a need to find new classes of anthelmintics. One of the mechanisms associated with ML resistance in nematodes has been the possible role of ATP binding cassette (ABC transporters in reducing drug concentrations at receptor sites. ABC transporters, mainly from sub-families B, C and G, may contribute to multidrug resistance (MDR by active efflux of drugs out of the cell. Gene products of ABC transporters may thus serve as the targets for agents that may modulate susceptibility to drugs, by inhibiting drug transport. ABC transporters are believed to be involved in a variety of physiological functions critical to the parasite, such as sterol transport, and therefore may also serve as the target for drugs that can act as anthelmintics on their own. Knowledge of polymorphism in these ABC transporter genes in nematode parasites could provide useful information for the process of drug design. We have identified 15 ABC transporter genes from sub-families A, B, C and G, in D. immitis, by comparative genomic approaches and analyzed them for polymorphism. Whole genome sequencing data from four ML susceptible (SUS and four loss of efficacy (LOE pooled populations were used for single nucleotide polymorphism (SNP genotyping. Out of 231 SNPs identified in those 15 ABC transporter genes, 89 and 75 of them were specific to the SUS or LOE populations, respectively. A few of the SNPs identified may affect gene expression, protein function, substrate specificity or resistance development and may be useful for transporter inhibitor/anthelmintic drug design, or in order to anticipate resistance development. Keywords: Dirofilaria immitis
Lai, I-Lu; Chou, Chih-Chien; Lai, Po-Ting; Fang, Chun-Sheng; Shirley, Lawrence A.; Yan, Ribai; Mo, Xiaokui; Bloomston, Mark; Kulp, Samuel K.; Bekaii-Saab, Tanios; Chen, Ching-Shih
2014-01-01
Gemcitabine resistance remains a significant clinical challenge. Here, we used a novel glucose transporter (Glut) inhibitor, CG-5, as a proof-of-concept compound to investigate the therapeutic utility of targeting the Warburg effect to overcome gemcitabine resistance in pancreatic cancer. The effects of gemcitabine and/or CG-5 on viability, survival, glucose uptake and DNA damage were evaluated in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cell lines. Mechanistic studies were conducted to determine the molecular basis of gemcitabine resistance and the mechanism of CG-5-induced sensitization to gemcitabine. The effects of CG-5 on gemcitabine sensitivity were investigated in a xenograft tumor model of gemcitabine-resistant pancreatic cancer. In contrast to gemcitabine-sensitive pancreatic cancer cells, the resistant Panc-1 and Panc-1GemR cells responded to gemcitabine by increasing the expression of ribonucleotide reductase M2 catalytic subunit (RRM2) through E2F1-mediated transcriptional activation. Acting as a pan-Glut inhibitor, CG-5 abrogated this gemcitabine-induced upregulation of RRM2 through decreased E2F1 expression, thereby enhancing gemcitabine-induced DNA damage and inhibition of cell survival. This CG-5-induced inhibition of E2F1 expression was mediated by the induction of a previously unreported E2F1-targeted microRNA, miR-520f. The addition of oral CG-5 to gemcitabine therapy caused greater suppression of Panc-1GemR xenograft tumor growth in vivo than either drug alone. Glut inhibition may be an effective strategy to enhance gemcitabine activity for the treatment of pancreatic cancer. PMID:24879635
International Nuclear Information System (INIS)
Barone-Rochette, Gilles
2013-01-01
Insulin resistance (IR), characterized by a depressed cellular sensitivity to insulin in insulin-sensitive organs, is a central feature to obesity, the metabolic syndrome, and diabetes mellitus and leads to increase cardiovascular diseases, particularly heart failure. All these events are today serious public health problems. But actually, there is no simple tool to measure insulin resistance. The gold standard technique remains the hyperinsulinemic euglycemic clamp. However, the complexity and length of this technique render it unsuitable for routine clinical use. Many methods or index have been proposed to assess insulin resistance in human, but none have shown enough relevance to be used in clinical use. The U1039 INSERM unit previously has validated a new tracer of glucose transport, radiolabelled with 123 iodine and has developed a fast and simple imaging protocol with a small animal gamma camera, which allows the obtaining of an IR index for each organ, showing more discriminating for the heart. The project of my thesis was the human transfer of this measurement technique, perfectly validated in animal. The first part of this thesis evaluated to tolerance, in vivo kinetics, distribution and dosimetry of novel tracer of glucose transport, the [ 123 I]-6DIG. The safeties of new tracer and measurement technique were adequate. There were no adverse effects with excellent tolerance of the whole protocol. 6DIG eliminating was fast, primarily in the urine and complete within 72 h. The effective whole-body absorbed dose for a complete scan with injection of 92.5 * 2 MBq was between 3 to 4 mSv. The second part of this thesis evaluated in human feasibility and reproducibility of the measurement technique validated in animal. The third part showed techniques used to allow human transfer of this method. The study protocol was applied on 12 subjects (healthy volunteers (n=6) and type 2 diabetic patients (n=6)). With a method adapted to measure in humans, we determined an
International Nuclear Information System (INIS)
Pouard, M.
1984-03-01
In the framework of mechanical tests and to answer the different requests for tests, the T.C.R (Transport Conditionnement et Retraitement) laboratory got test facilities. These installations allow to carry out tests of resistance to shocks, mainly at the safety level of components of nuclear power plants, mockups of transport casks for fuel elements and transport containers for radioactive materials. They include a tower and a catapult. This paper give a decription of the facilities and explain their operation way [fr
ABC transporters in Arthropods: genomic comparison and role in insecticide transport and resistance
Dermauw, W.; Van Leeuwen, T.
2014-01-01
About a 100 years ago, the Drosophila white mutant marked the birth of Drosophila genetics. The white gene turned out to encode the first well studied ABC transporter in arthropods. The ABC gene family is now recognized as one of the largest transporter families in all kingdoms of life. The majority
Interfacial Water-Transport Effects in Proton-Exchange Membranes
Energy Technology Data Exchange (ETDEWEB)
Kienitz, Brian; Yamada, Haruhiko; Nonoyama, Nobuaki; Weber, Adam
2009-11-19
It is well known that the proton-exchange membrane is perhaps the most critical component of a polymer-electrolyte fuel cell. Typical membranes, such as Nafion(R), require hydration to conduct efficiently and are instrumental in cell water management. Recently, evidence has been shown that these membranes might have different interfacial morphology and transport properties than in the bulk. In this paper, experimental data combined with theoretical simulations will be presented that explore the existence and impact of interfacial resistance on water transport for Nafion(R) 21x membranes. A mass-transfer coefficient for the interfacial resistance is calculated from experimental data using different permeation cells. This coefficient is shown to depend exponentially on relative humidity or water activity. The interfacial resistance does not seem to exist for liquid/membrane or membrane/membrane interfaces. The effect of the interfacial resistance is to flatten the water-content profiles within the membrane during operation. Under typical operating conditions, the resistance is on par with the water-transport resistance of the bulk membrane. Thus, the interfacial resistance can be dominant especially in thin, dry membranes and can affect overall fuel-cell performance.
Seydel, J K; Coats, E A; Cordes, H P; Wiese, M
1994-10-01
Some aspects of drug membrane interaction and its influence on drug transport, accumulation, efficacy and resistance have been discussed. The interactions manifest themselves macroscopically in changes in the physical and thermodynamic properties of "pure membranes" or bilayers. As various amounts of foreign molecules enter the membrane, in particular the main gel to liquid crystalline phase transition can be dramatically changed. This may change permeability, cell-fusion, cell resistance and may also lead to changes in conformation of the embedded receptor proteins. Furthermore, specific interactions with lipids may lead to drug accumulation in membranes and thus to much larger concentrations at the active site than present in the surrounding water phase. The lipid environment may also lead to changes in the preferred conformation of drug molecules. These events are directly related to drug efficacy. The determination of essential molecular criteria for the interaction could be used to design new and more selective therapeutics. This excursion in some aspects of drug membrane interaction underlines the importance of lipids and their interaction with drug molecules for our understanding of drug action, but this is not really a new thought but has been formulated in 1884 by THUDICUM: "Phospholipids are the centre, life and chemical soul of all bioplasm whatsoever, that of plants as well as of animals".
Directory of Open Access Journals (Sweden)
Légaré Danielle
2011-10-01
Full Text Available Abstract Background Several mutations were present in the genome of Streptococcus pneumoniae linezolid-resistant strains but the role of several of these mutations had not been experimentally tested. To analyze the role of these mutations, we reconstituted resistance by serial whole genome transformation of a novel resistant isolate into two strains with sensitive background. We sequenced the parent mutant and two independent transformants exhibiting similar minimum inhibitory concentration to linezolid. Results Comparative genomic analyses revealed that transformants acquired G2576T transversions in every gene copy of 23S rRNA and that the number of altered copies correlated with the level of linezolid resistance and cross-resistance to florfenicol and chloramphenicol. One of the transformants also acquired a mutation present in the parent mutant leading to the overexpression of an ABC transporter (spr1021. The acquisition of these mutations conferred a fitness cost however, which was further enhanced by the acquisition of a mutation in a RNA methyltransferase implicated in resistance. Interestingly, the fitness of the transformants could be restored in part by the acquisition of altered copies of the L3 and L16 ribosomal proteins and by mutations leading to the overexpression of the spr1887 ABC transporter that were present in the original linezolid-resistant mutant. Conclusions Our results demonstrate the usefulness of whole genome approaches at detecting major determinants of resistance as well as compensatory mutations that alleviate the fitness cost associated with resistance.
Shukla, Suneet; Wu, Chung-Pu; Nandigama, Krishnamachary; Ambudkar, Suresh V.
2008-01-01
Vitamin K3 (Menadione; 2-methyl-1,4-naphthoquinone) is a structural precursor of vitamins K1 and K2 which are essential for blood clotting. The naturally occurring structural analog of this vitamin, plumbagin (5-hydroxy-menadione), is known to modulate cellular proliferation, apoptosis, carcinogenesis, and radioresistance. We, here, report that both vitamin K3 and plumbagin are substrates of the multidrug resistance-linked ATP binding cassette (ABC) drug transporter, ABCG2. Vitamin K3 and plumbagin specifically inhibited the ABCG2-mediated efflux of mitoxantrone, but did not have any effect on the ABCB1-mediated efflux of rhodamine 123. This inhibition of ABCG2 function was due to their interaction at the substrate-binding site(s). They inhibited the binding of [125I]-Iodoarylazidoprazosin (IAAP), a substrate of ABCG2, to this transporter in a concentration-dependent manner with IC50 values of 7.3 and 22.6 μM, respectively, but had no effect on the binding of this photoaffinity analog to ABCB1. Both compounds stimulated ABCG2-mediated ATP hydrolysis and also inhibited the mitoxantrone-stimulated ATPase activity of this transporter, but did not have any significant effect on the ATPase activity of ABCB1. In a cytotoxicity assay, ABCG2-expressing HEK cells were 2.8- and 2.3-fold resistant to plumbagin and vitamin K3, respectively, compared to the control cells, suggesting that they are substrates of this transporter. Collectively, these data demonstrate for the first time that vitamin K3 is a substrate of the ABCG2 transporter. Thus, ABCG2 may have a role in the regulation of vitamin K3 levels in the body. In addition, vitamin K3 and its structural derivative, plumbagin, could potentially be used to modulate ABCG2 function. PMID:18065489
Altered membrane permeability in multidrug resistant Escherichia ...
African Journals Online (AJOL)
PRECIOUS
2009-11-02
Nov 2, 2009 ... involvement during the transport of β - lactams in multidrug resistant Escherichia coli isolated from extra-intestinal infections. Also, the ... lactam resistance in multidrug resistant E. coli in ESBL and non-ESBL isolates. .... and decreased susceptibility to carbapenems, particularly ertapenem (Perez et al.,.
Nonlocal nature of the resistance in classical ballistic transport
International Nuclear Information System (INIS)
Sukhorukov, E.V.; Levinson, I.B.
1990-01-01
An investigation is made of the resistance of ballistic microstructures formed in the two-dimensional electron gas of a GaAs/AlGaAs heterojunction representing combinations of long channels. It is shown that the nonlocal nature of the resistance (dependence on the measurement method) is unrelated to the quantum nature of the electron behavior, but is solely due to the ballistic nature of microstructures and does not disappear in the classical limit. An analog of the Landauer equation is obtained for the resistance measured by the four-probe method allowing for the geometry of the measuring probes
Directory of Open Access Journals (Sweden)
Susanna J E Veringa
Full Text Available Pediatric high-grade gliomas (pHGG, including diffuse intrinsic pontine gliomas (DIPG, are the leading cause of cancer-related death in children. While it is clear that surgery (if possible, and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.
The varied functions of aluminium-activated malate transporters-much more than aluminium resistance.
Palmer, Antony J; Baker, Alison; Muench, Stephen P
2016-06-15
The ALMT (aluminium-activated malate transporter) family comprises a functionally diverse but structurally similar group of ion channels. They are found ubiquitously in plant species, expressed throughout different tissues, and located in either the plasma membrane or tonoplast. The first family member identified was TaALMT1, discovered in wheat root tips, which was found to be involved in aluminium resistance by means of malate exudation into the soil. However, since this discovery other family members have been shown to have many other functions such as roles in stomatal opening, general anionic homoeostasis, and in economically valuable traits such as fruit flavour. Recent evidence has also shown that ALMT proteins can act as key molecular actors in GABA (γ-aminobutyric acid) signalling, the first evidence that GABA can act as a signal transducer in plants. © 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
Wang, Hsin; Porter, Wallace D.; Böttner, Harald; König, Jan; Chen, Lidong; Bai, Shengqiang; Tritt, Terry M.; Mayolet, Alex; Senawiratne, Jayantha; Smith, Charlene; Harris, Fred; Gilbert, Patricia; Sharp, Jeff W.; Lo, Jason; Kleinke, Holger; Kiss, Laszlo
2013-04-01
Recent research and development of high-temperature thermoelectric materials has demonstrated great potential for converting automobile exhaust heat directly into electricity. Thermoelectrics based on classic bismuth telluride have also started to impact the automotive industry by enhancing air-conditioning efficiency and integrated cabin climate control. In addition to engineering challenges of making reliable and efficient devices to withstand thermal and mechanical cycling, the remaining issues in thermoelectric power generation and refrigeration are mostly materials related. The dimensionless figure of merit, ZT, still needs to be improved from the current value of 1.0 to 1.5 to above 2.0 to be competitive with other alternative technologies. In the meantime, the thermoelectric community could greatly benefit from the development of international test standards, improved test methods, and better characterization tools. Internationally, thermoelectrics have been recognized by many countries as a key component for improving energy efficiency. The International Energy Agency (IEA) group under the Implementing Agreement for Advanced Materials for Transportation (AMT) identified thermoelectric materials as an important area in 2009. This paper is part I of the international round-robin testing of transport properties of bulk thermoelectrics. The main foci in part I are the measurement of two electronic transport properties: Seebeck coefficient and electrical resistivity.
Divide and conquer: processive transport enables multidrug transporters to tackle challenging drugs
Directory of Open Access Journals (Sweden)
Nir Fluman
2014-09-01
Full Text Available Multidrug transporters are membrane proteins that catalyze efflux of antibiotics and other toxic compounds from cells, thereby conferring drug resistance on various organisms. Unlike most solute transporters that transport a single type of compound or similar analogues, multidrug transporters are extremely promiscuous. They transport a broad spectrum of dissimilar drugs and represent a serious obstacle to antimicrobial or anticancer chemotherapy. Many challenging aspects of multidrug transporters, which are unique, have been studied in detail, including their ability to interact with chemically unrelated drugs, and how they utilize energy to drive efflux of compounds that are not only structurally but electrically different. A new and surprising dimension of the promiscuous nature of multidrug transporters has been described recently: they can move long molecules through the membrane in a processive manner.
Directory of Open Access Journals (Sweden)
Stéphanie Coumes-Florens
2011-01-01
Full Text Available Signal transduction systems and ABC transporters often contribute jointly to adaptive bacterial responses to environmental changes. In Bacillus subtilis, three such pairs are involved in responses to antibiotics: BceRSAB, YvcPQRS and YxdJKLM. They are characterized by a histidine kinase belonging to the intramembrane sensing kinase family and by a translocator possessing an unusually large extracytoplasmic loop. It was established here using a phylogenomic approach that systems of this kind are specific but widespread in Firmicutes, where they originated. The present phylogenetic analyses brought to light a highly dynamic evolutionary history involving numerous horizontal gene transfers, duplications and lost events, leading to a great variety of Bce-like repertories in members of this bacterial phylum. Based on these phylogenetic analyses, it was proposed to subdivide the Bce-like modules into six well-defined subfamilies. Functional studies were performed on members of subfamily IV comprising BceRSAB from B. subtilis, the expression of which was found to require the signal transduction system as well as the ABC transporter itself. The present results suggest, for the members of this subfamily, the occurrence of interactions between one component of each partner, the kinase and the corresponding translocator. At functional and/or structural levels, bacitracin dependent expression of bceAB and bacitracin resistance processes require the presence of the BceB translocator loop. Some other members of subfamily IV were also found to participate in bacitracin resistance processes. Taken together our study suggests that this regulatory mechanism might constitute an important common antibiotic resistance mechanism in Firmicutes. [Supplemental material is available online at http://www.genome.org.].
Influence of yellow rust infextion on 32P transport in detached barley leaves
International Nuclear Information System (INIS)
Schubert, J.
1982-01-01
Several barley cultivars (Hordeum vulgare L.) differing in their resistance to yellow rust (Puccinia striiformis West.) were tested for relationships between changes of 32 P transport in detached leaves and resistance to yellow rust disease. Investigation carried out with detached second leaves from plants infected at their first leaf revealed a matter transport in these leaves changed by the infection. Transport was also influenced by inoculation with yellow rust uredospores. In that case rust infection influenced the basipetal transport less strongly in resistent plants than in susceptible ones. Connected with the findings the influence of fungal substances on transport processes is discussed in general. (author)
ABC transporters in fish species: a review
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Marta eFerreira
2014-07-01
Full Text Available ATP-binding cassette (ABC proteins were first recognized for their role in multidrug resistance (MDR in chemotherapeutic treatments, which is a major impediment for the successful treatment of many forms of malignant tumors in humans. These proteins, highly conserved throughout vertebrate species, were later related to cellular detoxification and accounted as responsible for protecting aquatic organisms from xenobiotic insults in the so-called multixenobiotic resistance mechanism (MXR. In recent years, research on these proteins in aquatic species has highlighted their importance in the detoxification mechanisms in fish thus it is of extreme added value to continue these studies. Several transporters have been pointed out as relevant in the ecotoxicological context associated to the transport of xenobiotics, such as P-glycoproteins (Pgps, multidrug-resistance-associated proteins (MRPs 1-5 and breast resistance associated protein (BCRP. In mammals, several nuclear receptors have been identified as mediators of phase I and II metabolizing enzymes and ABC transporters. In aquatic species, knowledge on co-regulation of detoxification mechanism is scarce and needs to be addressed. The interaction of emergent contaminants, with chemosensitizer potential, with ABC transporters in aquatic organisms can compromise detoxification processes and have population effects and should be studied in more detail. This review intends to summarize the recent advances in research on MXR mechanisms in fish species, focusing in 1 regulation and functioning of ABC proteins; 2 cooperation with phase I and II biotransformation enzymes; and 3 ecotoxicological relevance and information on emergent pollutants with ability to modulate ABC transporters expression and activity. Several lines of evidence are clear suggesting the important role of these transporters in detoxification mechanisms and must be further investigated in fish.
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Reeder John C
2008-04-01
Full Text Available Abstract Background In Papua New Guinea (PNG, combination therapy with amodiaquine (AQ or chloroquine (CQ plus sulphadoxine-pyrimethamine (SP was introduced as first-line treatment against uncomplicated malaria in 2000. Methods We assessed in vivo treatment failure rates with AQ+SP in two different areas in PNG and twenty-four molecular drug resistance markers of Plasmodium falciparum were characterized in pre-treatment samples. The aim of the study was to investigate the association between infecting genotype and treatment response in order to identify useful predictors of treatment failure with AQ+SP. Results In 2004, Day-28 treatment failure rates for AQ+SP were 29% in the Karimui and 19% in the South Wosera area, respectively. The strongest independent predictors for treatment failure with AQ+SP were pfmdr1 N86Y (OR = 7.87, p pfdhps A437G (OR = 3.44, p pfcrt K76T, A220S, N326D, and I356L did not help to increase the predictive value, the most likely reason being that these mutations reached almost fixed levels. Though mutations in SP related markers pfdhfr S108N and C59R were not associated with treatment failure, they increased the predictive value of pfdhps A437G. The difference in treatment failure rate in the two sites was reflected in the corresponding genetic profile of the parasite populations, with significant differences seen in the allele frequencies of mutant pfmdr1 N86Y, pfmdr1 Y184F, pfcrt A220S, and pfdhps A437G. Conclusion The study provides evidence for high levels of resistance to the combination regimen of AQ+SP in PNG and indicates which of the many molecular markers analysed are useful for the monitoring of parasite resistance to combinations with AQ+SP.
Dai, Fuhong; Yoo, Won Gi; Lee, Ji-Yun; Lu, Yanyan; Pak, Jhang Ho; Sohn, Woon-Mok; Hong, Sung-Jong
2017-11-21
Multidrug resistance-associated protein 4 (MRP4) is a member of the C subfamily of the ABC family of ATP-binding cassette (ABC) transporters. MRP4 regulates ATP-dependent efflux of various organic anionic substrates and bile acids out of cells. Since Clonorchis sinensis lives in host's bile duct, accumulation of bile juice can be toxic to the worm's tissues and cells. Therefore, C. sinensis needs bile transporters to reduce accumulation of bile acids within its body. We cloned MRP4 (CsMRP4) from C. sinensis and obtained a cDNA encoding an open reading frame of 1469 amino acids. Phylogenetic analysis revealed that CsMRP4 belonged to the MRP/SUR/CFTR subfamily. A tertiary structure of CsMRP4 was generated by homology modeling based on multiple structures of MRP1 and P-glycoprotein. CsMRP4 had two membrane-spanning domains (MSD1 & 2) and two nucleotide-binding domains (NBD1 & 2) as common structural folds. Docking simulation with nine bile acids showed that CsMRP4 transports bile acids through the inner cavity. Moreover, it was found that CsMRP4 mRNA was more abundant in the metacercariae than in the adults. Mouse immune serum, generated against the CsMRP4-NBD1 (24.9 kDa) fragment, localized CsMRP4 mainly in mesenchymal tissues and oral and ventral suckers of the metacercariae and the adults. Our findings shed new light on MRPs and their homologs and provide a platform for further structural and functional investigations on the bile transporters and parasites' survival.
Multidrug resistance in enteric and other gram-negative bacteria.
George, A M
1996-05-15
In Gram-negative bacteria, multidrug resistance is a term that is used to describe mechanisms of resistance by chromosomal genes that are activated by induction or mutation caused by the stress of exposure to antibiotics in natural and clinical environments. Unlike plasmid-borne resistance genes, there is no alteration or degradation of drugs or need for genetic transfer. Exposure to a single drug leads to cross-resistance to many other structurally and functionally unrelated drugs. The only mechanism identified for multidrug resistance in bacteria is drug efflux by membrane transporters, even though many of these transporters remain to be identified. The enteric bacteria exhibit mostly complex multidrug resistance systems which are often regulated by operons or regulons. The purpose of this review is to survey molecular mechanisms of multidrug resistance in enteric and other Gram-negative bacteria, and to speculate on the origins and natural physiological functions of the genes involved.
Comparison of Strategies to Overcome Drug Resistance: Learning from Various Kingdoms
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Hiroshi Ogawara
2018-06-01
Full Text Available Drug resistance, especially antibiotic resistance, is a growing threat to human health. To overcome this problem, it is significant to know precisely the mechanisms of drug resistance and/or self-resistance in various kingdoms, from bacteria through plants to animals, once more. This review compares the molecular mechanisms of the resistance against phycotoxins, toxins from marine and terrestrial animals, plants and fungi, and antibiotics. The results reveal that each kingdom possesses the characteristic features. The main mechanisms in each kingdom are transporters/efflux pumps in phycotoxins, mutation and modification of targets and sequestration in marine and terrestrial animal toxins, ABC transporters and sequestration in plant toxins, transporters in fungal toxins, and various or mixed mechanisms in antibiotics. Antibiotic producers in particular make tremendous efforts for avoiding suicide, and are more flexible and adaptable to the changes of environments. With these features in mind, potential alternative strategies to overcome these resistance problems are discussed. This paper will provide clues for solving the issues of drug resistance.
Desulfurization Sorbents for Transport-Bed Applications
International Nuclear Information System (INIS)
Gupta, Raghubir P.; Turk, Brian S.; Vierheilig, Albert A.
1997-01-01
This project extends the prior work on the development of fluidizable zinc titanate particles using a spray-drying technique to impart high reactivity and attrition resistance. The specific objectives are: (1) To develop highly reactive and attrition-resistant zinc titanate sorbents in 40- to 150-(micro)m particle size range for transport reactor applications; (2) To transfer sorbent production technology to private sector; and (3) To provide technical support to Sierra Pacific Clean Coal Technology Demonstration plant and FETC's Hot-Gas Desulfurization Process Development Unit (PDU), both employing a transport reactor system
International Nuclear Information System (INIS)
Edenstrasser, J.W.
1995-01-01
A multiple time-scale derivative expansion scheme is applied to the dimensionless Fokker--Planck equation and to Maxwell's equations, where the parameter range of a typical fusion plasma was assumed. Within kinetic theory, the four time scales considered are those of Larmor gyration, particle transit, collisions, and classical transport. The corresponding magnetohydrodynamic (MHD) time scales are those of ion Larmor gyration, Alfven, MHD collision, and resistive diffusion. The solution of the zeroth-order equations results in the force-free equilibria and ideal Ohm's law. The solution of the first-order equations leads under the assumption of a weak collisional plasma to the ideal MHD equations. On the MHD-collision time scale, not only the full set of the MHD transport equations is obtained, but also turbulent terms, where the related transport quantities are one order in the expansion parameter larger than those of classical transport. Finally, at the resistive diffusion time scale the known transport equations are arrived at including, however, also turbulent contributions. copyright 1995 American Institute of Physics
DEFF Research Database (Denmark)
Nielsen, D; Eriksen, J; Maare, C
2000-01-01
An Ehrlich ascites tumour cell line (EHR2) was selected in vivo for resistance to mitoxantrone (MITOX). The resistant cell line (EHR2/MITOX) was 6123-, 33-, and 30-fold-resistant to mitoxantrone, daunorubicin, and etoposide, respectively, but retained sensitivity to vincristine. The resistant cel...... to be associated with: 1) a quantitative reduction in topoisomerase IIalpha and beta protein; 2) reduced drug accumulation, probably as a result of increased expression of a novel transport protein with ATPase activity; and 3) increased expression of MRP mRNA....
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Stefanie Klinger
2018-03-01
Full Text Available Background: Beneficial effects of Resveratrol (RSV have been demonstrated, including effects on transporters and channels. However, little is known about how RSV influences intestinal transport. The aim of this study was to further characterize the effects of RSV on intestinal transport and the respective mechanisms. Methods: Porcine jejunum and ileum were incubated with RSV (300 µM, 30 min in Ussing chambers (functional studies and tissue bathes (detection of protein expression, phosphorylation, association with detergent resistant membranes (DRMs. Results: RSV reduced alanine and glucose-induced short circuit currents (ΔIsc and influenced forskolin-induced ΔIsc. The phosphorylation of sodium–glucose-linked transporter 1 (SGLT1, AMP-activated protein kinase (AMPK, protein kinase A substrates (PKA-S and liver kinase B1 (LKB1 increased but a causative relation to the inhibitory effects could not directly be established. The DRM association of SGLT1, peptide transporter 1 (PEPT1 and (phosphorylated Na+/H+-exchanger 3 (NHE3 did not change. Conclusion: RSV influences the intestinal transport of glucose, alanine and chloride and is likely to affect other transport processes. As the effects of protein kinase activation vary between the intestinal localizations, it would appear that increasing cyclic adenosine monophosphate (cAMP levels are part of the mechanism. Nonetheless, the physiological responses depend on cell type-specific structures.
Multiple nucleobase transporters contribute to boscalid sensitivity in Aspergillus nidulans.
Kalampokis, Ioannis F; Kapetanakis, George C; Aliferis, Konstantinos A; Diallinas, George
2018-03-01
The development of fungicide-resistant fungal populations represents a major challenge for the agrochemical and agri-food sectors, which threatens food supply and security. The issue becomes complex for fungi that cause quantitative and qualitative losses due to mycotoxin biosynthesis. Nonetheless, currently, the molecular details underlying fungicide action and fungal resistance mechanisms are partially known. Here, we have investigated whether plasma membrane transporters contribute to specific fungicide uptake in the model fungus Aspergillus nidulans. Independent physiological tests and toxicity screening of selected fungicides provided evidence that the antifungal activity of Succinate Dehydrogenase Inhibitors (SDHIs) is associated with the expression of several nucleobase-related transporters. In particular, it was shown that a strain genetically inactivated in all seven nucleobase-related transporters is resistant to the fungicide boscalid, whereas none of the single null mutants exhibited significant resistance level. By constructing and testing isogenic strains that over-express each one of the seven transporters, we confirmed that five of them, namely, UapC, AzgA, FycB, CntA, and FurA, contribute to boscalid uptake. Additionally, by employing metabolomics we have examined the effect of boscalid on the metabolism of isogenic strains expressing or genetically lacking boscalid-related nucleobase transporters. The results confirmed the involvement of specific nucleobase transporters in fungicide uptake, leading to the discovery of corresponding metabolites-biomarkers. This work is the first report on the involvement of specific transporters in fungicide uptake and toxicity and their impact on fungal metabolism regulation and results might be further exploited towards the deeper understanding of fungal resistance to fungicides. Copyright © 2018 Elsevier Inc. All rights reserved.
Downregulation of taurine uptake in multidrug resistant Ehrlich ascites tumor cells
DEFF Research Database (Denmark)
Poulsen, K A; Litman, Thomas; Eriksen, J
2002-01-01
In daunorubicin resistant Ehrlich ascites tumor cells (DNR), the initial taurine uptake was reduced by 56% as compared to the parental, drug sensitive Ehrlich cells. Kinetic experiments indicated that taurine uptake in Ehrlich cells occurs via both high- and low-affinity transporters. The maximal...... rate constant for the initial taurine uptake was reduced by 45% (high-affinity system) and 49% (low affinity system) in the resistant subline whereas the affinity of the transporters to taurine was unchanged. By immunoblotting we identified 3 TauT protein bands in the 50-70 kDa region. A visible...... reduction in the intensity of the band with the lowest molecular weight was observed in resistant cells. Quantitative RT-PCR indicated a significant reduction in the amount of taurine transporter mRNA in the resistant cells. Drug resistance in DNR Ehrlich cells is associated with overexpression of the mdr1...
Rosário, Carlos M. M.; Thöner, Bo; Schönhals, Alexander; Menzel, Stephan; Wuttig, Matthias; Waser, Rainer; Sobolev, Nikolai A.; Wouters, Dirk J.
2018-05-01
Conductive filaments play a key role in redox-based resistive random access memory (ReRAM) devices based on the valence change mechanism, where the change of the resistance is ascribed to the modulation of the oxygen content in a local region of these conductive filaments. However, a deep understanding of the filaments' composition and structure is still a matter of debate. We approached the problem by comparing the electronic transport, at temperatures from 300 K down to 2 K, in the filaments and in TaOx films exhibiting a substoichiometric oxygen content. The filaments were created in Ta (15 nm)/Ta2O5 (5 nm)/Pt crossbar ReRAM structures. In the TaOx thin films with various oxygen contents, the in-plane transport was studied. There is a close similarity between the electrical properties of the conductive filaments in the ReRAM devices and of the TaOx films with x ˜ 1, evidencing also no dimensionality difference for the electrical transport. More specifically, for both systems there are two different conduction processes: one in the higher temperature range (from 50 K up to ˜300 K), where the conductivity follows a √{ T } dependence, and one at lower temperatures (<50 K), where the conductivity follows the exp(-1 / √{ T } ) dependence. This suggests a strong similarity between the material composition and structure of the filaments and those of the substoichiometric TaOx films. We also discuss the temperature dependence of the conductivity in the framework of possible transport mechanisms, mainly of those normally observed for granular metals.
Shukla, Suneet; Wu, Chung-Pu; Nandigama, Krishnamachary; Ambudkar, Suresh V
2007-12-01
Vitamin K3 (menadione; 2-methyl-1,4-naphthoquinone) is a structural precursor of vitamins K1 and K2, which are essential for blood clotting. The naturally occurring structural analogue of this vitamin, plumbagin (5-hydroxy-menadione), is known to modulate cellular proliferation, apoptosis, carcinogenesis, and radioresistance. We here report that both vitamin K3 and plumbagin are substrates of the multidrug resistance-linked ATP binding cassette drug transporter, ABCG2. Vitamin K3 and plumbagin specifically inhibited the ABCG2-mediated efflux of mitoxantrone but did not have any effect on the ABCB1-mediated efflux of rhodamine 123. This inhibition of ABCG2 function was due to their interaction at the substrate-binding site(s). Vitamin K3 and plumbagin inhibited the binding of [(125)I]iodoarylazidoprazosin, a substrate of ABCG2, to this transporter in a concentration-dependent manner with IC(50) values of 7.3 and 22.6 micromol/L, respectively, but had no effect on the binding of the photoaffinity analogue to ABCB1. Both compounds stimulated ABCG2-mediated ATP hydrolysis and also inhibited the mitoxantrone-stimulated ATPase activity of the ABCG2 transporter, but did not have any significant effect on the ATPase activity of ABCB1. In a cytotoxicity assay, ABCG2-expressing HEK cells were 2.8- and 2.3-fold resistant to plumbagin and vitamin K3, respectively, compared with the control cells, suggesting that they are substrates of this transporter. Collectively, these data show for the first time that vitamin K3 is a substrate of the ABCG2 transporter. Thus, ABCG2 may have a role in the regulation of vitamin K3 levels in the body. In addition, vitamin K3 and its structural derivative, plumbagin, could potentially be used to modulate ABCG2 function.
Influence of yellow rust infection on /sup 32/P transport in detached barley leaves
Energy Technology Data Exchange (ETDEWEB)
Schubert, J. (Akademie der Landwirtschaftswissenschaften der DDR, Aschersleben. Inst. fuer Phytopathologie)
1982-01-01
Several barley cultivars (Hordeum vulgare L.) differing in their resistance to yellow rust (Puccinia striiformis West.) were tested for relationships between changes of /sup 32/P transport in detached leaves and resistance to yellow rust disease. Investigation carried out with detached second leaves from plants infected at their first leaf revealed a matter transport in these leaves changed by the infection. Transport was also influenced by inoculation with yellow rust uredospores. In that case rust infection influenced the basipetal transport less strongly in resistent plants than in susceptible ones. Connected with the findings the influence of fungal substances on transport processes is discussed in general.
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Li-Hung Chen
Full Text Available Major Facilitator Superfamily (MFS transporters play an important role in multidrug resistance in fungi. We report an AaMFS19 gene encoding a MFS transporter required for cellular resistance to oxidative stress and fungicides in the phytopathogenic fungus Alternaria alternata. AaMFS19, containing 12 transmembrane domains, displays activity toward a broad range of substrates. Fungal mutants lacking AaMFS19 display profound hypersensitivities to cumyl hydroperoxide, potassium superoxide, many singlet oxygen-generating compounds (eosin Y, rose Bengal, hematoporphyrin, methylene blue, and cercosporin, and the cell wall biosynthesis inhibitor, Congo red. AaMFS19 mutants also increase sensitivity to copper ions, clotrimazole, fludioxonil, and kocide fungicides, 2-chloro-5-hydroxypyridine (CHP, and 2,3,5-triiodobenzoic acid (TIBA. AaMFS19 mutants induce smaller necrotic lesions on leaves of a susceptible citrus cultivar. All observed phenotypes in the mutant are restored by introducing and expressing a wild-type copy of AaMFS19. The wild-type strain of A. alternata treated with either CHP or TIBA reduces radial growth and formation and germination of conidia, increases hyphal branching, and results in decreased expression of the AaMFS19 gene. The expression of AaMFS19 is regulated by the Yap1 transcription activator, the Hog1 and Fus3 mitogen-activated protein (MAP kinases, the 'two component' histidine kinase, and the Skn7 response regulator. Our results demonstrate that A. alternata confers resistance to different chemicals via a membrane-bound MFS transporter.
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.
International Nuclear Information System (INIS)
Ridenti, Marco A.; Pascholati, Paulo R.
2009-01-01
In this work it is presented a computer based instrumentation system which was developed to perform data acquisition and integrate the control of different devices in an experimental study of electron transport dynamics in an avalanche mode resistive plate chamber detector in the Radiation Technology Center (CTR) at IPEN/CNEN-SP. System control and data acquisition was performed by a computer program called RPCLabOperator written in MatLab environment running on a LeCroy WavePro 7000 digital oscilloscope. (author)
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Fuhong Dai
2017-11-01
Full Text Available Abstract Background Multidrug resistance-associated protein 4 (MRP4 is a member of the C subfamily of the ABC family of ATP-binding cassette (ABC transporters. MRP4 regulates ATP-dependent efflux of various organic anionic substrates and bile acids out of cells. Since Clonorchis sinensis lives in host’s bile duct, accumulation of bile juice can be toxic to the worm’s tissues and cells. Therefore, C. sinensis needs bile transporters to reduce accumulation of bile acids within its body. Results We cloned MRP4 (CsMRP4 from C. sinensis and obtained a cDNA encoding an open reading frame of 1469 amino acids. Phylogenetic analysis revealed that CsMRP4 belonged to the MRP/SUR/CFTR subfamily. A tertiary structure of CsMRP4 was generated by homology modeling based on multiple structures of MRP1 and P-glycoprotein. CsMRP4 had two membrane-spanning domains (MSD1 & 2 and two nucleotide-binding domains (NBD1 & 2 as common structural folds. Docking simulation with nine bile acids showed that CsMRP4 transports bile acids through the inner cavity. Moreover, it was found that CsMRP4 mRNA was more abundant in the metacercariae than in the adults. Mouse immune serum, generated against the CsMRP4-NBD1 (24.9 kDa fragment, localized CsMRP4 mainly in mesenchymal tissues and oral and ventral suckers of the metacercariae and the adults. Conclusions Our findings shed new light on MRPs and their homologs and provide a platform for further structural and functional investigations on the bile transporters and parasites’ survival.
A four-probe thermal transport measurement method for nanostructures
Energy Technology Data Exchange (ETDEWEB)
Kim, Jaehyun; Ou, Eric; Sellan, Daniel P.; Shi, Li, E-mail: lishi@mail.utexas.edu [Department of Mechanical Engineering, The University of Texas at Austin, Austin, Texas 78712 (United States)
2015-04-15
Several experimental techniques reported in recent years have enabled the measurement of thermal transport properties of nanostructures. However, eliminating the contact thermal resistance error from the measurement results has remained a critical challenge. Here, we report a different four-probe measurement method that can separately obtain both the intrinsic thermal conductance and the contact thermal resistance of individual nanostructures. The measurement device consists of four microfabricated, suspended metal lines that act as resistive heaters and thermometers, across which the nanostructure sample is assembled. The method takes advantage of the variation in the heat flow along the suspended nanostructure and across its contacts to the four suspended heater and thermometer lines, and uses sixteen sets of temperature and heat flow measurements to obtain nine of the thermal resistances in the measurement device and the nanostructure sample, including the intrinsic thermal resistance and the two contact thermal resistances to the middle suspended segment of the nanostructure. Two single crystalline Si nanowires with different cross sections are measured in this work to demonstrate the effectiveness of the method. This four-probe thermal transport measurement method can lead to future discoveries of unique size-dependent thermal transport phenomena in nanostructures and low-dimensional materials, in addition to providing reliable experimental data for calibrating theoretical models.
A four-probe thermal transport measurement method for nanostructures
International Nuclear Information System (INIS)
Kim, Jaehyun; Ou, Eric; Sellan, Daniel P.; Shi, Li
2015-01-01
Several experimental techniques reported in recent years have enabled the measurement of thermal transport properties of nanostructures. However, eliminating the contact thermal resistance error from the measurement results has remained a critical challenge. Here, we report a different four-probe measurement method that can separately obtain both the intrinsic thermal conductance and the contact thermal resistance of individual nanostructures. The measurement device consists of four microfabricated, suspended metal lines that act as resistive heaters and thermometers, across which the nanostructure sample is assembled. The method takes advantage of the variation in the heat flow along the suspended nanostructure and across its contacts to the four suspended heater and thermometer lines, and uses sixteen sets of temperature and heat flow measurements to obtain nine of the thermal resistances in the measurement device and the nanostructure sample, including the intrinsic thermal resistance and the two contact thermal resistances to the middle suspended segment of the nanostructure. Two single crystalline Si nanowires with different cross sections are measured in this work to demonstrate the effectiveness of the method. This four-probe thermal transport measurement method can lead to future discoveries of unique size-dependent thermal transport phenomena in nanostructures and low-dimensional materials, in addition to providing reliable experimental data for calibrating theoretical models
Swanson, Ryan D; Binley, Andrew; Keating, Kristina; France, Samantha; Osterman, Gordon; Day-Lewis, Frederick D.; Singha, Kamini
2015-01-01
The advection-dispersion equation (ADE) fails to describe commonly observed non-Fickian solute transport in saturated porous media, necessitating the use of other models such as the dual-domain mass-transfer (DDMT) model. DDMT model parameters are commonly calibrated via curve fitting, providing little insight into the relation between effective parameters and physical properties of the medium. There is a clear need for material characterization techniques that can provide insight into the geometry and connectedness of pore spaces related to transport model parameters. Here, we consider proton nuclear magnetic resonance (NMR), direct-current (DC) resistivity, and complex conductivity (CC) measurements for this purpose, and assess these methods using glass beads as a control and two different samples of the zeolite clinoptilolite, a material that demonstrates non-Fickian transport due to intragranular porosity. We estimate DDMT parameters via calibration of a transport model to column-scale solute tracer tests, and compare NMR, DC resistivity, CC results, which reveal that grain size alone does not control transport properties and measured geophysical parameters; rather, volume and arrangement of the pore space play important roles. NMR cannot provide estimates of more-mobile and less-mobile pore volumes in the absence of tracer tests because these estimates depend critically on the selection of a material-dependent and flow-dependent cutoff time. Increased electrical connectedness from DC resistivity measurements are associated with greater mobile pore space determined from transport model calibration. CC was hypothesized to be related to length scales of mass transfer, but the CC response is unrelated to DDMT.
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Smita Rai
Full Text Available BACKGROUND: In view of the recent upsurge in the phenomenon of therapeutic failure, drug resistance in Leishmania, developed under natural field conditions, has become a great concern yet little understood. Accordingly, the study of determinants of antimony resistance is urgently warranted. Efflux transporters have been reported in Leishmania but their role in clinical resistance is still unknown. The present study was designed to elucidate the mechanism of natural antimony resistance in L. donovani field isolates by analyzing the functionality of efflux pump(s and expression profiles of known genes involved in transport and thiol based redox metabolism. METHODOLOGY/PRINCIPAL FINDINGS: We selected 7 clinical isolates (2 sensitive and 5 resistant in addition to laboratory sensitive reference and SbIII resistant mutant strains for the present study. Functional characterization using flow cytometry identified efflux pumps that transported substrates of both P-gp and MRPA and were inhibited by the calmodulin antagonist trifluoperazine. For the first time, verapamil sensitive efflux pumps for rhodamine 123 were observed in L. donovani that were differentially active in resistant isolates. RT-PCR confirmed the over-expression of MRPA in isolates with high resistance index only. Resistant isolates also exhibited consistent down regulation of AQP1 and elevated intracellular thiol levels which were accompanied with increased expression of ODC and TR genes. Interestingly, γ-GCS is not implicated in clinical resistance in L. donovani isolates. CONCLUSIONS/SIGNIFICANCE: Here we demonstrate for the first time, the role of P-gp type plasma membrane efflux transporter(s in antimony resistance in L. donovani field isolates. Further, decreased levels of AQP1 and elevated thiols levels have emerged as biomarkers for clinical resistance.
[Resistance to target-based therapy and its circumvention].
Nishio, Kazuto
2004-07-01
Intrinsic and acquired resistance to molecular target therapy critically limits the outcome of cancer treatments. Target levels including quantitative and gene alteration should be determinants for the resistance. Downstream of the target molecules, drug metabolism, and drug transport influences the tumor sensitivity to molecular target therapy. The mechanisms of resistance to antibody therapy have not been fully clarified. Correlative clinical studies using these biomarkers of resistance are extremely important for circumvention of clinical resistance to target based therapy.
Resistance to antibiotics in Lacid acid bacteria - strain Lactococcus
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Filipić Brankica
2015-01-01
Full Text Available Lactic acid bacteria (LAB are widely used in the food industry, especially in the production of fermented dairy products and meat. The most studied species among Lis Lactococcus lactis. L. lactis strains are of great importance in the production of fermented dairy products such as yogurt, butter, fresh cheese and some kind of semi-hard cheese. Although L. lactis acquired the „Generally Regarded As Safe“ (GRAS status, many investigations indicated that lactococci may act as reservoirs of antibiotic resistance genes, which could be transferred to other bacterial species in human gastrointestinal tract including pathogens. The genome analysis of L. lactis indicated the presence of at least 40 putative drug transporter genes, and only four multidrug resistance (MDR transporters are functionally characterized: LmrA, LmrP, LmrCD i CmbT. LmrA is the first described MDR transporter in prokaryotes. LmrCD is responsible for resistance to cholate, which is an integral part of human bile and LmrCD is important for intestinal survival of lactococci that are used as probiotics. Secondary multidrug transporter LmrP confers resistance to lincosamides, macrolides, streptogramins and tetracyclines. CmbT protein has an effect on the host cell resistance to lincomycin, sulfadiazine, streptomycin, rifampicin, puromycin and sulfametoxazole. Since the food chain is an important way of transmitting resistance genes in human and animal population, it is of great importance to study the mechanisms of resistance in lactococci and other LAB, intended for the food industry. [Projekat Ministarstva nauke Republike Srbije, br. 173019: Izučavanje gena i molekularnih mehanizama u osnovi probiotičke aktivnosti bakterija mlečne kiseline izolovanih sa područja Zapadnog Balkana
Directory of Open Access Journals (Sweden)
Masayuki Tokita
2016-05-01
Full Text Available Gel becomes an important class of soft materials since it can be seen in a wide variety of the chemical and the biological systems. The unique properties of gel arise from the structure, namely, the three-dimensional polymer network that is swollen by a huge amount of solvent. Despite the small volume fraction of the polymer network, which is usually only a few percent or less, gel shows the typical properties that belong to solids such as the elasticity. Gel is, therefore, regarded as a dilute solid because its elasticity is much smaller than that of typical solids. Because of the diluted structure, small molecules can pass along the open space of the polymer network. In addition to the viscous resistance of gel fluid, however, the substance experiences resistance due to the polymer network of gel during the transport process. It is, therefore, of importance to study the diffusion of the small molecules in gel as well as the flow of gel fluid itself through the polymer network of gel. It may be natural to assume that the effects of the resistance due to the polymer network of gel depends strongly on the network structure. Therefore, detailed study on the transport processes in and through gel may open a new insight into the relationship between the structure and the transport properties of gel. The two typical transport processes in and through gel, that is, the diffusion of small molecules due to the thermal fluctuations and the flow of gel fluid that is caused by the mechanical pressure gradient will be reviewed.
Shah, Abdul Haseeb; Banerjee, Atanu; Rawal, Manpreet Kaur; Saxena, Ajay Kumar; Mondal, Alok Kumar; Prasad, Rajendra
2015-08-01
The ABC transporter Cdr1 protein of Candida albicans, which plays a major role in antifungal resistance, has two transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs). The 12 transmembrane helices of TMDs that are interconnected by extracellular and intracellular loops (ICLs) mainly harbor substrate recognition sites where drugs bind while cytoplasmic NBDs hydrolyze ATP which powers drug efflux. The coupling of ATP hydrolysis to drug transport requires proper communication between NBDs and TMDs typically accomplished by ICLs. This study examines the role of cytoplasmic ICLs of Cdr1p by rationally predicting the critical residues on the basis of their interatomic distances. Among nine pairs that fall within a proximity of trafficking. These results point to a new role for ICL/NBD interacting residues in PDR ABC transporters in protein folding and trafficking. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Zhang, Yun-Kai; Zhang, Guan-Nan; Wang, Yi-Jun; Patel, Bhargav A.; Talele, Tanaji T.; Yang, Dong-Hua; Chen, Zhe-Sheng
2016-05-01
ATP-Binding Cassette transporters are involved in the efflux of xenobiotic compounds and are responsible for decreasing drug accumulation in multidrug resistant (MDR) cells. Discovered by structure-based virtual screening algorithms, bafetinib, a Bcr-Abl/Lyn tyrosine kinase inhibitor, was found to have inhibitory effects on both ABCB1- and ABCG2-mediated MDR in this in-vitro investigation. Bafetinib significantly sensitized ABCB1 and ABCG2 overexpressing MDR cells to their anticancer substrates and increased the intracellular accumulation of anticancer drugs, particularly doxorubicin and [3H]-paclitaxel in ABCB1 overexpressing cells; mitoxantrone and [3H]-mitoxantrone in ABCG2 overexpressing cells, respectively. Bafetinib stimulated ABCB1 ATPase activities while inhibited ABCG2 ATPase activities. There were no significant changes in the expression level or the subcellular distribution of ABCB1 and ABCG2 in the cells exposed to 3 μM of bafetinib. Overall, our study indicated that bafetinib reversed ABCB1- and ABCG2-mediated MDR by blocking the drug efflux function of these transporters. These findings might be useful in developing combination therapy for MDR cancer treatment.
Review of prediction for thermal contact resistance
Institute of Scientific and Technical Information of China (English)
无
2010-01-01
Theoretical prediction research on thermal contact resistance is reviewed in this paper. In general, modeling or simulating the thermal contact resistance involves several aspects, including the descriptions of surface topography, the analysis of micro mechanical deformation, and the thermal models. Some key problems are proposed for accurately predicting the thermal resistance of two solid contact surfaces. We provide a perspective on further promising research, which would be beneficial to understanding mechanisms and engineering applications of the thermal contact resistance in heat transport phenomena.
Time-lapse electrical resistivity anomalies due to contaminant transport around landfills
Directory of Open Access Journals (Sweden)
J. Yang
2007-06-01
Full Text Available The extent of landfill leachate can be delineated by geo-electrical imaging as a response to the varying electrical resistivity in the contaminated area. This research was based on a combination of hydrogeological numerical simulation followed by geophysical forward and inversion modeling performed to evaluate the migration of a contaminant plume from a landfill. As a first step, groundwater flow and contaminant transport was simulated using the finite elements numerical modeling software FEFLOW. The extent of the contaminant plume was acquired through a hydrogeological model depicting the distributions of leachate concentration in the system. Next, based on the empirical relationship between the concentration and electrical conductivity of the leachate in the porous media, the corresponding geo-electrical structure was derived from the hydrogeological model. Finally, forward and inversion computations of geo-electrical anomalies were performed using the finite difference numerical modeling software DCIP2D/DCIP3D. The image obtained by geophysical inversion of the electric data was expected to be consistent with the initial hydrogeological model, as described by the distribution of leachate concentration. Numerical case studies were conducted for various geological conditions, hydraulic parameters and electrode arrays, from which conclusions were drawn regarding the suitability of the methodology to assess simple to more complex geo-electrical models. Thus, optimal mapping and monitoring configurations were determined.
Jin, Xin; Zhang, Hui-xin; Zhang, Yan-fen; Cui, Wen-wen; Bi, Yao; He, Qi-long; Zhou, Sheng-shan
2015-03-01
To study the effect of Jinlida on changes in expression of skeletal muscle lipid transport enzymes in fat-induced insulin resistance ApoE -/- mice. Eight male C57BL/6J mice were selected in the normal group (NF), 40 male ApoE -/- mice were fed for 16 weeks, divided into the model group (HF), the rosiglitazone group ( LGLT), the Jinlida low-dose group (JLDL), the Jinlida medium-dose group (JLDM), the Jinlida high-dose group (JLDH) and then orally given drugs for 8 weeks. The organization free fatty acids, BCA protein concentration determination methods were used to determine the skeletal muscle FFA content. The Real-time fluorescent quantitative reverse transcription PCR ( RT-PCR) and Western blot method were adopted to determine mRNA and protein expressions of mice fatty acids transposition enzyme (FAT/CD36), carnitine palm acyltransferase 1 (CPT1), peroxide proliferators-activated receptor α( PPAR α). Jinlida could decrease fasting blood glucose (FBG), cholesterol (TC), triglyceride (TG), free fatty acid (FFA) and fasting insulin (FIns) and raise insulin sensitive index (ISI) in mice to varying degrees. It could also up-regulate mRNA and protein expressions of CPT1 and PPARα, and down-regulate mRNA and protein levels of FAT/CD36. Jinlida can improve fat-induced insulin resistance ApoE -/- in mice by adjusting the changes in expression of skeletal muscle lipid transport enzymes.
Modeling polyolefin deformation resistance in a growing microparticle
Agarwal, U.S.
2004-01-01
When polyolefins are produced on heterogeneous catalysts, they encapsulate the catalyst fragments and present diffusional resistance to further monomer transport to the catalyst fragments. In addition, the deposited polymer layer brings in viscoelastic resistance, since it must be deformed to make
Laufer, Miriam K; Thesing, Phillip C; Dzinjalamala, Fraction K; Nyirenda, Osward M; Masonga, Rhoda; Laurens, Matthew B; Stokes-Riner, Abbie; Taylor, Terrie E; Plowe, Christopher V
2012-01-01
The predominance of chloroquine-susceptible falciparum malaria in Malawi more than a decade after chloroquine's withdrawal permits contemplation of re-introducing chloroquine for targeted uses. We aimed to compare the ability of different partner drugs to preserve chloroquine efficacy and prevent the re-emergence of resistance. Children with uncomplicated malaria were enrolled at a government health center in Blantyre, Malawi. Participants were randomized to receive chloroquine alone or combined with artesunate, azithromycin or atovaquone-proguanil for all episodes of uncomplicated malaria for one year. The primary outcome was incidence of clinical malaria. Secondary endpoints included treatment efficacy, and incidence of the chloroquine resistance marker pfcrt T76 and of anemia. Of the 640 children enrolled, 628 were included in the intention-to-treat analysis. Malaria incidence (95% confidence interval) was 0.59 (.46-.74), .61 (.49-.76), .63 (.50-.79) and .68 (.54-.86) episodes/person-year for group randomized to receive chloroquine alone or in combination with artesunate, azithromycin or atovaquone-proguanil respectively and the differences were not statistically significant. Treatment efficacy for first episodes was 100% for chloroquine monotherapy and 97.9% for subsequent episodes of malaria. Similar results were seen in each of the chloroquine combination groups. The incidence of pfcrt T76 in pure form was 0%; mixed infections with both K76 and T76 were found in two out of 911 infections. Young children treated with chloroquine-azithromycin had higher hemoglobin concentrations at the study's end than did those in the chloroquine monotherapy group. Sustained chloroquine efficacy with repeated treatment supports the eventual re-introduction of chloroquine combinations for targeted uses such as intermittent preventive treatment. ClinicalTrials.gov NCT00379821.
MRP proteins as potential mediators of heavy metal resistance in zebrafish cells.
Long, Yong; Li, Qing; Wang, Youhui; Cui, Zongbin
2011-04-01
Acquired resistance of mammalian cells to heavy metals is closely relevant to enhanced expression of several multidrug resistance-associated proteins (MRP), but it remains unclear whether MRP proteins confer resistance to heavy metals in zebrafish. In this study, we obtained zebrafish (Danio rerio) fibroblast-like ZF4 cells with resistance to toxic heavy metals after chronic cadmium exposure and selection for 6months. These cadmium-resistant cells (ZF4-Cd) were maintained in 5μM cadmium and displayed cross-resistance to cadmium, mercury, arsenite and arsenate. ZF4-Cd cells remained the resistance to heavy metals after protracted culture in cadmium-free medium. In comparison with ZF4-WT cells, ZF4-Cd cells exhibited accelerated rate of cadmium excretion, enhanced activity of MRP-like transport, elevated expression of abcc2, abcc4 and mt2 genes, and increased content of cellular GSH. Inhibition of MRP-like transport activity, GSH biosynthesis and GST activity significantly attenuated the resistance of ZF4-Cd cells to heavy metals. The results indicate that some of MRP transporters are involved in the efflux of heavy metals conjugated with cellular GSH and thus play crucial roles in heavy metal detoxification of zebrafish cells. Copyright © 2010 Elsevier Inc. All rights reserved.
Directory of Open Access Journals (Sweden)
Seok Kyu eKang
2015-05-01
Full Text Available Ischemia in the immature brain is an important cause of neonatal seizures. Temporal evolution of acquired neonatal seizures and their response to anticonvulsants are of great interest, given the unreliability of the clinical correlates and poor efficacy of first-line anti-seizure drugs. The expression and function of the electroneutral chloride co-transporters KCC2 and NKCC1 influence the anti-seizure efficacy of GABAA-agonists. To investigate ischemia-induced seizure susceptibility and efficacy of the GABAA-agonist phenobarbital (PB, with NKCC1 antagonist bumetanide (BTN as an adjunct treatment, we utilized permanent unilateral carotid-ligation to produce acute ischemic-seizures in postnatal day 7, 10 and 12 CD1 mice. Immediate post-ligation video-electroencephalograms (EEGs quantitatively evaluated baseline and post-treatment seizure burdens. Brains were examined for stroke-injury and western blot analyses to evaluate the expression of KCC2 and NKCC1. Severity of acute ischemic seizures post-ligation was highest at P7. PB was an efficacious anti-seizure agent at P10 and P12, but not at P7. BTN failed as an adjunct, at all ages tested and significantly blunted PB-efficacy at P10. Significant acute post-ischemic downregulation of KCC2 was detected at all ages. At P7, males displayed higher age-dependent seizure susceptibility, associated with a significant developmental lag in their KCC2 expression. This study established a novel neonatal mouse model of PB-resistant seizures that demonstrates age/sex-dependent susceptibility. The age-dependent profile of KCC2 expression and its post-insult downregulation may underlie the PB-resistance reported in this model. Blocking NKCC1 with low-dose BTN following PB treatment failed to improve PB-efficacy.
Conceptual designs of radioactive canister transporters
International Nuclear Information System (INIS)
1978-02-01
This report covers conceptual designs of transporters for the vertical, horizontal, and inclined installation of canisters containing spent-fuel elements, high-level waste, cladding waste, and intermediate-level waste (low-level waste is not discussed). Included in the discussion are cask concepts; transporter vehicle designs; concepts for mechanisms for handling and manipulating casks, canisters, and concrete plugs; transporter and repository operating cycles; shielding calculations; operator radiation dosages; radiation-resistant materials; and criteria for future design efforts
Shukla, Suneet; Wu, Chung-Pu; Nandigama, Krishnamachary; Ambudkar, Suresh V.
2007-01-01
Vitamin K3 (Menadione; 2-methyl-1,4-naphthoquinone) is a structural precursor of vitamins K1 and K2 which are essential for blood clotting. The naturally occurring structural analog of this vitamin, plumbagin (5-hydroxy-menadione), is known to modulate cellular proliferation, apoptosis, carcinogenesis, and radioresistance. We, here, report that both vitamin K3 and plumbagin are substrates of the multidrug resistance-linked ATP binding cassette (ABC) drug transporter, ABCG2. Vitamin K3 and plu...
Canine osteosarcoma cells exhibit resistance to aurora kinase inhibitors.
Cannon, C M; Pozniak, J; Scott, M C; Ito, D; Gorden, B H; Graef, A J; Modiano, J F
2015-03-01
We evaluated the effect of Aurora kinase inhibitors AZD1152 and VX680 on canine osteosarcoma cells. Cytotoxicity was seen in all four cell lines; however, half-maximal inhibitory concentrations were significantly higher than in human leukaemia and canine lymphoma cells. AZD1152 reduced Aurora kinase B phosphorylation, indicating resistance was not because of failure of target recognition. Efflux mediated by ABCB1 and ABCG2 transporters is one known mechanism of resistance against these drugs and verapamil enhanced AZD1152-induced apoptosis; however, these transporters were only expressed by a small percentage of cells in each line and the effects of verapamil were modest, suggesting other mechanisms contribute to resistance. Our results indicate that canine osteosarcoma cells are resistant to Aurora kinase inhibitors and suggest that these compounds are unlikely to be useful as single agents for this disease. Further investigation of these resistance mechanisms and the potential utility of Aurora kinase inhibitors in multi-agent protocols is warranted. © 2013 Blackwell Publishing Ltd.
Is there ballistic transport in metallic nano-objects? Ballistic versus diffusive contributions
International Nuclear Information System (INIS)
Garcia, N; Bai Ming; Lu Yonghua; Munoz, M; Cheng Hao; Levanyuk, A P
2007-01-01
When discussing the resistance of an atomic-or nanometre-size contact we should consider both its ballistic and its diffusive contributions. But there is a contribution of the leads to the resistance of the contact as well. In this context, the geometry and the roughness of the surfaces limiting the system will contribute to the resistance, and these contributions should be added to the ideal ballistic resistance of the nanocontact. We have calculated, for metallic materials, the serial resistance of the leads arising from the roughness, and our calculations show that the ohmic resistance is as important as the ballistic resistance of the constriction. The classical resistance is a lower limit to the quantum resistance of the leads. Many examples of earlier experiments show that the mean free path of the transport electrons is of the order of the size of the contacts or the leads. This is not compatible with the idea of ballistic transport. This result may put in serious difficulties the current, existing interpretation of experimental data in metals where only small serial resistances compared with the ballistic component of the total resistance have been taken into account. The two-dimensional electron gas (2DEG) is also discussed and the serial corrections appear to be smaller than for metals. Experiments with these last systems are proposed that may reveal new interesting aspects in the physics of ballistic and diffusive transport
MRP3, an organic anion transporter able to transport anti-cancer drugs
Kool, Marcel; van der Linden, Marcel; de Haas, Marcel; Scheffer, George L.; de Vree, J. Marleen L.; Smith, Alexander J.; Jansen, Gerrit; Peters, Godefridus J.; Ponne, Nico; Scheper, Rik J.; Elferink, Ronald P. J. Oude; Baas, Frank; Borst, Piet
1999-01-01
The human multidrug-resistance protein (MRP) gene family contains at least six members: MRP1, encoding the multidrug-resistance protein; MRP2 or cMOAT, encoding the canalicular multispecific organic anion transporter; and four homologs, called MRP3, MRP4, MRP5, and MRP6. In this report, we characterize MRP3, the closest homolog of MRP1. Cell lines were retrovirally transduced with MRP3 cDNA, and new monoclonal antibodies specific for MRP3 were generated. We show that MRP3 is an organic anion ...
Trimaran Resistance Artificial Neural Network
2011-01-01
11th International Conference on Fast Sea Transportation FAST 2011, Honolulu, Hawaii, USA, September 2011 Trimaran Resistance Artificial Neural Network Richard...Trimaran Resistance Artificial Neural Network 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e... Artificial Neural Network and is restricted to the center and side-hull configurations tested. The value in the parametric model is that it is able to
Malaria prevalence in Nias District, North Sumatra Province, Indonesia
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Laowo Idaman
2007-08-01
Full Text Available Abstract Background The Nias district of the North Sumatra Province of Indonesia has long been known to be endemic for malaria. Following the economic crisis at the end of 1998 and the subsequent tsunami and earthquake, in December 2004 and March 2005, respectively, the malaria control programme in the area deteriorated. The present study aims to provide baseline data for the establishment of a suitable malaria control programme in the area and to analyse the frequency distribution of drug resistance alleles associated with resistance to chloroquine and sulphadoxine-pyrimethamine. Methods Malariometric and entomology surveys were performed in three subdistricts. Thin and thick blood smears were stained with Giemsa and examined under binocular light microscopy. Blood blots on filter paper were also prepared for isolation of parasite and host DNA to be used for molecular analysis of band 3 (SAO, pfcrt, pfmdr1, dhfr, and dhps. In addition, haemoglobin measurement was performed in the second and third surveys for the subjects less than 10 years old. Results Results of the three surveys revealed an average slide positivity rate of 8.13%, with a relatively higher rate in certain foci. Host genetic analysis, to identify the Band 3 deletion associated with Southeast Asian Ovalocytosis (SAO, revealed an overall frequency of 1.0% among the 1,484 samples examined. One hundred six Plasmodium falciparum isolates from three sub-districts were successfully analysed. Alleles of the dhfr and dhps genes associated with resistance to sulphadoxine-pyrimethamine, dhfr C59R and S108N, and dhps A437G and K540E, were present at frequencies of 52.2%, 82.5%, 1.18% and 1.18%, respectively. The pfmdr1 alleles N86Y and N1042D, putatively associated with mefloquine resistance, were present at 31.4% and 2%, respectively. All but one sample carried the pfcrt 76T allele associated with chloroquine resistance. Entomologic surveys identified three potential anopheline vectors in
Bloem, E.; French, H. K.
2013-12-01
Monitoring contaminant transport at contaminated sites requires optimization of the configuration of a limited number of samplings points combined with heterogeneous flow and preferential flowpaths. Especially monitoring processes in the unsaturated zone is a major challenge due to the limited volume monitored by for example suction cups and their risk to clog in a highly active degradation zone. To make progress on soil contamination assessment and site characterization there is a strong need to integrate field-sale extensively instrumented tools, with non-invasive (geophysical) methods which provide spatially integrated measurements also in the unsaturated zone. Examples of sites that might require monitoring activities in the unsaturated zone are airports with winter frost where large quantities of de-icing chemicals are used each winter; salt and contaminant infiltration along roads; constructed infiltration systems for treatment of sewerage or landfill seepage. Electrical resistivity methods have proved to be useful as an indirect measurement of subsurface properties and processes at the field-scale. The non-uniqueness of the interpretation techniques can be reduced by constraining the inversion through the addition of independent geophysical measurements along the same profile. Or interpretation and understanding of geophysical images can be improved by the combination with classical measurements of soil physical properties, soil suction, contaminant concentration and temperatures. In our experiment, at the research field station at Gardermoen, Oslo airport, we applied a degradable de-icing chemical and an inactive tracer to the snow cover prior to snowmelt. To study the solute transport processes in the unsaturated zone time-lapse cross borehole electrical resistivity tomography (ERT) measurements were conducted at the same time as soil water samples were extracted at multiple depths with suction cups. Measurements of soil temperature, and soil tension were
ATP-binding cassette (ABC) transporters in normal and pathological lung
van der Deen, M; de Vries, EGE; Timens, W; Scheper, RJ; Timmer-Bosscha, H; Postma, DS
2005-01-01
ATP-binding cassette ( ABC) transporters are a family of transmembrane proteins that can transport a wide variety of substrates across biological membranes in an energy-dependent manner. Many ABC transporters such as P-glycoprotein ( P-gp), multidrug resistance-associated protein 1 ( MRP1) and
Hamdoun, Amro M; Griffin, Fred J; Cherr, Gary N
2002-11-13
The toxicity of water-soluble fractions of biodegraded crude oil (BWSF) to embryos and larvae of two marine invertebrates, the white sea urchin (Lytechinus anamesus) and the fat innkeeper (Urechis caupo), was studied. Santa Barbara Channel crude oil was artificially weathered and subjected to biodegradation using a mixed microbe culture obtained from natural oil seep sites. The degradation culture inoculated with seep sediment microbes accumulated 43.7 microg/l water-soluble hydrocarbons. In contrast water-soluble fractions from the non-degraded cultures (NWSF) only accumulated 3.05 microg/l. BWSF proved deleterious to Lytechinus embryo development at low concentrations (EC50 = 0.33 mg/l) but was essentially non-toxic to Urechis embryos/larvae up to 3.0 mg/l. An established mechanism for handling of a wide array of xenobiotics in Urechis embryos is the multixenobiotoic resistance transporter multixenobiotic response (MXR, also known as multidrug resistance, MDR). This mechanism is primarily mediated by ATP-dependent, efflux pumps that extrude a wide array of xenobiotic compounds. In this study, we show that Lytechinus larvae do not appear to express MXR efflux protein nor MXR mediated dye efflux capacity. In contrast, BWSF acts as a competitive inhibitor of MXR transport-mediated dye efflux in Urechis larvae. These results suggest that MXR may be an important mechanism for extrusion of the by-products of crude oil degradation by microbes, and that the level of its expression may determine the susceptibility of organisms to degraded oil hydrocarbons. Copyright 2002 Elsevier Science B.V.
International Nuclear Information System (INIS)
Lin, Chun-Cheng; Tang, Jian-Fu; Su, Hsiu-Hsien; Hong, Cheng-Shong; Huang, Chih-Yu; Chu, Sheng-Yuan
2016-01-01
The multi-step resistive switching (RS) behavior of a unipolar Pt/Li 0.06 Zn 0.94 O/Pt resistive random access memory (RRAM) device is investigated. It is found that the RRAM device exhibits normal, 2-, 3-, and 4-step RESET behaviors under different compliance currents. The transport mechanism within the device is investigated by means of current-voltage curves, in-situ transmission electron microscopy, and electrochemical impedance spectroscopy. It is shown that the ion transport mechanism is dominated by Ohmic behavior under low electric fields and the Poole-Frenkel emission effect (normal RS behavior) or Li + ion diffusion (2-, 3-, and 4-step RESET behaviors) under high electric fields.
Transportation Network Topologies
Alexandrov, Natalia (Editor)
2004-01-01
The existing U.S. hub-and-spoke air transportation system is reaching saturation. Major aspects of the current system, such as capacity, safety, mobility, customer satisfaction, security, communications, and ecological effects, require improvements. The changing dynamics - increased presence of general aviation, unmanned autonomous vehicles, military aircraft in civil airspace as part of homeland defense - contributes to growing complexity of airspace. The system has proven remarkably resistant to change. NASA Langley Research Center and the National Institute of Aerospace conducted a workshop on Transportation Network Topologies on 9-10 December 2003 in Williamsburg, Virginia. The workshop aimed to examine the feasibility of traditional methods for complex system analysis and design as well as potential novel alternatives in application to transportation systems, identify state-of-the-art models and methods, conduct gap analysis, and thus to lay a foundation for establishing a focused research program in complex systems applied to air transportation.
The amended regulations for the safe transport of radioactive materials in Japan
International Nuclear Information System (INIS)
Takemura, Yoshio
1978-01-01
To cope with the inadequacies of the laws and regulations including the Law Concerning Prevention of Radiation Injuries Due to Radioisotopes, Etc., the Amended Regulations for the Safe Transport of Radioactive Materials in Japan has been issued. It is based on the Regulations of IAEA for the Safe Transport of Radioactive Materials and the Technical Standards for the Transport of Radioactive Materials decided by the AEC of Japan. In the amended regulations, emphasis is placed on the safety design of transporting goods. They are classified in Types L, A and B according to shock resistance and fire resistance, and the quantities of radioisotopes allowed to be contained in respective types are specified. The following matters are described: basic ideas concerning the types of transporting goods, test standards for the goods, transport standards for the goods, and nondestructive test apparatuses in transport. (Mori, K.)
Ionic Resistance and Permselectivity Tradeoffs in Anion Exchange Membranes
Geise, Geoffrey M.
2013-10-23
Salinity gradient energy technologies, such as reverse electrodialysis (RED) and capacitive mixing based on Donnan potential (Capmix CDP), could help address the global need for noncarbon-based energy. Anion exchange membranes (AEMs) are a key component in these systems, and improved AEMs are needed in order to optimize and extend salinity gradient energy technologies. We measured ionic resistance and permselectivity properties of quaternary ammonium-functionalized AEMs based on poly(sulfone) and poly(phenylene oxide) polymer backbones and developed structure-property relationships between the transport properties and the water content and fixed charge concentration of the membranes. Ion transport and ion exclusion properties depend on the volume fraction of water in the polymer membrane, and the chemical nature of the polymer itself can influence fine-tuning of the transport properties to obtain membranes with other useful properties, such as chemical and dimensional stability. The ionic resistance of the AEMs considered in this study decreased by more than 3 orders of magnitude (i.e., from 3900 to 1.6 Ω m) and the permselectivity decreased by 6% (i.e., from 0.91 to 0.85) as the volume fraction of water in the polymer was varied by a factor of 3.8 (i.e., from 0.1 to 0.38). Water content was used to rationalize a tradeoff relationship between the permselectivity and ionic resistance of these AEMs whereby polymers with higher water content tend to have lower ionic resistance and lower permselectivity. The correlation of ion transport properties with water volume fraction and fixed charge concentration is discussed with emphasis on the importance of considering water volume fraction when interpreting ion transport data. © 2013 American Chemical Society.
Technological alternatives for plutonium transport
International Nuclear Information System (INIS)
1978-12-01
This paper considers alternative transport modes (air, sea, road, rail) for moving (1) plutonium from a reprocessing plant to a store or a fuel fabrication facility, and (2) MOX fuel from the latter to a reactor. These transport modes and differing forms of plutonium are considered in terms of: their proliferation resistance and safeguards; environmental and safety aspects; and economic aspects. It is tentatively proposed that the transport of plutonium could continue by air or sea where long distances are involved and by road or rail over shorter distances; this would be acceptable from the non-proliferation, environmental impact and economic aspects - there may be advantages in protection if plutonium is transported in the form of mixed oxide
Directory of Open Access Journals (Sweden)
Nancy Arróspide
Full Text Available Se evaluó la frecuencia de mutaciones en los genes pfCRT y DHFR/DHPS del Plasmodium falciparum asociados a la resistencia a cloroquina y sulfadoxina-pirimetamina en 83 cepas provenientes de los distritos Esmeralda y Machala ubicados en las fronteras entre Ecuador-Perú y Ecuador-Colombia durante el año 2002. Se empleó la reacción en cadena de polimerasa (PCR convencional y sus variantes. El gen pfCRT presentó más de 90% de muestras mutantes en Esmeralda y Machala. Para el gen DHFR, el 90% de las cepas fueron muestras mutantes en Esmeralda, tres fueron mutaciones dobles y una triple; en Machala se encontró 25% de formas mutantes simples y 75% de formas mixtas (formas silvestres/mutantes. En conclusión, la resistencia a cloroquina se ha fijado en las cepas portadoras de la mutación K76T pfCRT, mientras que la impronta genética a la resistencia a pirimetamina está en evolución, principalmente en el distrito de Esmeralda
49 CFR 236.552 - Insulation resistance; requirement.
2010-10-01
... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RULES, STANDARDS, AND INSTRUCTIONS GOVERNING THE INSTALLATION... resistance between wiring and ground of continuous inductive automatic cab signal system, automatic train...
Miah, M Fahad; Conseil, Gwenaëlle; Cole, Susan P C
2016-01-22
Multidrug resistance protein 4 (MRP4) is a member of subfamily C of the ATP-binding cassette superfamily of membrane transport proteins. MRP4 mediates the ATP-dependent efflux of many endogenous and exogenous solutes across the plasma membrane, and in polarized cells, it localizes to the apical or basolateral plasma membrane depending on the tissue type. MRP4 is a 170 kDa glycoprotein and here we show that MRP4 is simultaneously N-glycosylated at Asn746 and Asn754. Furthermore, confocal immunofluorescence studies showed that N-glycans do not affect MRP4's apical membrane localization in polarized LLC-PK1 cells or basolateral membrane localization in polarized MDCKI cells. However, vesicular transport assays showed that N-glycans differentially affect MRP4's ability to transport prostaglandin E2, but not estradiol glucuronide. Together these data indicate that N-glycosylation at Asn746 and Asn754 is not essential for plasma membrane localization of MRP4 but cause substrate-selective effects on its transport activity. Copyright © 2015 Elsevier Inc. All rights reserved.
Brewer, Denise
The air transport industry (ATI) is a dynamic, communal, international, and intercultural environment in which the daily operations of airlines, airports, and service providers are dependent on information technology (IT). Many of the IT legacy systems are more than 30 years old, and current regulations and the globally distributed workplace have brought profound changes to the way the ATI community interacts. The purpose of the study was to identify the areas of resistance to change in the ATI community and the corresponding factors in change management requirements that minimize product development delays and lead to a successful and timely shift from legacy to open web-based systems in upgrading ATI operations. The research questions centered on product development team processes as well as the members' perceived need for acceptance of change. A qualitative case study approach rooted in complexity theory was employed using a single case of an intercultural product development team dispersed globally. Qualitative data gathered from questionnaires were organized using Nvivo software, which coded the words and themes. Once coded, themes emerged identifying the areas of resistance within the product development team. Results of follow-up interviews with team members suggests that intercultural relationship building prior to and during project execution; focus on common team goals; and, development of relationships to enhance interpersonal respect, understanding and overall communication help overcome resistance to change. Positive social change in the form of intercultural group effectiveness evidenced in increased team functioning during major project transitions is likely to result when global managers devote time to cultural understanding.
Contribution of chloride channel permease to fluoride resistance in Streptococcus mutans.
Murata, Takatoshi; Hanada, Nobuhiro
2016-06-01
Genes encoding fluoride transporters have been identified in bacterial and archaeal species. The genome sequence of the cariogenic Streptococcus mutans bacteria suggests the presence of a putative fluoride transporter, which is referred to as a chloride channel permease. Two homologues of this gene (GenBank locus tags SMU_1290c and SMU_1289c) reside in tandem in the genome of S. mutans The aim of this study was to determine whether the chloride channel permeases contribute to fluoride resistance. We constructed SMU_1290c- and SMU_1289c-knockout S. mutans UA159 strains. We also constructed a double-knockout strain lacking both genes. SMU_1290c or SMU_1289c was transformed into a fluoride transporter- disrupted Escherichia coli strain. All bacterial strains were cultured under appropriate conditions with or without sodium fluoride, and fluoride resistance was evaluated. All three gene-knockout S. mutans strains showed lower resistance to sodium fluoride than did the wild-type strain. No significant changes in resistance to other sodium halides were recognized between the wild-type and double-knockout strains. Both SMU_1290c and SMU_1289c transformation rescued fluoride transporter-disrupted E. coli cell from fluoride toxicity. We conclude that the chloride channel permeases contribute to fluoride resistance in S. mutans. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Multi-polar resistance switching and memory effect in copper phthalocyanine junctions
International Nuclear Information System (INIS)
Qiao Shi-Zhu; Kang Shi-Shou; Li Qiang; Zhong Hai; Kang Yun; Yu Shu-Yun; Han Guang-Bing; Yan Shi-Shen; Mei Liang-Mo; Qin Yu-Feng
2014-01-01
Copper phthalocyanine junctions, fabricated by magnetron sputtering and evaporating methods, show multi-polar (unipolar and bipolar) resistance switching and the memory effect. The multi-polar resistance switching has not been observed simultaneously in one organic material before. With both electrodes being cobalt, the unipolar resistance switching is universal. The high resistance state is switched to the low resistance state when the bias reaches the set voltage. Generally, the set voltage increases with the thickness of copper phthalocyanine and decreases with increasing dwell time of bias. Moreover, the low resistance state could be switched to the high resistance state by absorbing the phonon energy. The stability of the low resistance state could be tuned by different electrodes. In Au/copper phthalocyanine/Co system, the low resistance state is far more stable, and the bipolar resistance switching is found. Temperature dependence of electrical transport measurements demonstrates that there are no obvious differences in the electrical transport mechanism before and after the resistance switching. They fit quite well with Mott variable range hopping theory. The effect of Al 2 O 3 on the resistance switching is excluded by control experiments. The holes trapping and detrapping in copper phthalocyanine layer are responsible for the resistance switching, and the interfacial effect between electrodes and copper phthalocyanine layer affects the memory effect. (interdisciplinary physics and related areas of science and technology)
Pathogenesis of Insulin Resistance in Skeletal Muscle
Directory of Open Access Journals (Sweden)
Muhammad A. Abdul-Ghani
2010-01-01
Full Text Available Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Recent studies have reported a mitochondrial defect in oxidative phosphorylation in skeletal muscle in variety of insulin resistant states. In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle.
Directory of Open Access Journals (Sweden)
Hallett Rachel
2010-01-01
Full Text Available Abstract Background The efficacy of amodiaquine (AQ, sulphadoxine-pyrimethamine (SP and the combination of SP+AQ in the treatment of Cameroonian children with clinical malaria was investigated. The prevalence of molecular markers for resistance to these drugs was studied to set the baseline for surveillance of their evolution with time. Methods Seven hundred and sixty children aged 6-59 months with uncomplicated falciparum malaria were studied in three ecologically different regions of Cameroon - Mutengene (littoral equatorial forest, Yaoundé (forest-savannah mosaic and Garoua (guinea-savannah. Study children were randomized to receive either AQ, SP or the combination AQ+SP. Clinical outcome was classified according to WHO criteria, as either early treatment failure (ETF, late clinical failure (LCF, late parasitological failure (LPF or adequate clinical and parasitological response (ACPR. The occurrence of mutations in pfcrt, pfmdr1, dhfr and dhps genes was studied by either RFLP or dot blot techniques and the prevalence of these mutations related to parasitological and therapeutic failures. Results After correction for the occurrence of re-infection by PCR, ACPRs on day 28 for AQ, SP and AQ+SP were 71.2%, 70.1% and 80.9%, in Garoua, 79.2%, 62.5%, and 81.9% in Mutengene, and 80.3%, 67.5% and 76.2% in Yaoundé respectively. High levels of Pfcrt 76T (87.11% and Pfmdr1 86Y mutations (73.83% were associated with quinoline resistance in the south compared to the north, 31.67% (76T and 22.08% (86Y. There was a significant variation (p dhps gene was extremely rare (0.3% and occurred only in Mutengene while the pfmdr1 1034K and 1040D mutations were not detected in any of the three sites. Conclusion In this study the prevalence of molecular markers for quinoline and anti-folate resistances showed high levels and differed between the south and north of Cameroon. AQ, SP and AQ+SP treatments were well tolerated but with low levels of efficacy that
Kinetic Theory of Electronic Transport in Random Magnetic Fields
Lucas, Andrew
2018-03-01
We present the theory of quasiparticle transport in perturbatively small inhomogeneous magnetic fields across the ballistic-to-hydrodynamic crossover. In the hydrodynamic limit, the resistivity ρ generically grows proportionally to the rate of momentum-conserving electron-electron collisions at large enough temperatures T . In particular, the resulting flow of electrons provides a simple scenario where viscous effects suppress conductance below the ballistic value. This new mechanism for ρ ∝T2 resistivity in a Fermi liquid may describe low T transport in single-band SrTiO3 .
Energy Technology Data Exchange (ETDEWEB)
Lin, Chun-Cheng [Department of Electrical Engineering, National Cheng Kung University, Tainan 701, Taiwan (China); Department of Mathematic and Physical Sciences, R.O.C. Air Force Academy, Kaohsiung 820, Taiwan (China); Tang, Jian-Fu; Su, Hsiu-Hsien [Department of Electrical Engineering, National Cheng Kung University, Tainan 701, Taiwan (China); Hong, Cheng-Shong; Huang, Chih-Yu [Department of Electronic Engineering, National Kaohsiung Normal University, Kaohsiung 802, Taiwan (China); Chu, Sheng-Yuan, E-mail: chusy@mail.ncku.edu.tw [Department of Electrical Engineering, National Cheng Kung University, Tainan 701, Taiwan (China); Center for Micro/Nano Science and Technology, National Cheng Kung University, Tainan 701, Taiwan (China)
2016-06-28
The multi-step resistive switching (RS) behavior of a unipolar Pt/Li{sub 0.06}Zn{sub 0.94}O/Pt resistive random access memory (RRAM) device is investigated. It is found that the RRAM device exhibits normal, 2-, 3-, and 4-step RESET behaviors under different compliance currents. The transport mechanism within the device is investigated by means of current-voltage curves, in-situ transmission electron microscopy, and electrochemical impedance spectroscopy. It is shown that the ion transport mechanism is dominated by Ohmic behavior under low electric fields and the Poole-Frenkel emission effect (normal RS behavior) or Li{sup +} ion diffusion (2-, 3-, and 4-step RESET behaviors) under high electric fields.
Influence of multidrug resistance on 18F-FCH cellular uptake in a glioblastoma model
International Nuclear Information System (INIS)
Vanpouille, Claire; Jeune, Nathalie le; Clotagatide, Anthony; Dubois, Francis; Kryza, David; Janier, Marc; Perek, Nathalie
2009-01-01
Multidrug resistance, aggressiveness and accelerated choline metabolism are hallmarks of malignancy and have motivated the development of new PET tracers like 18 F-FCH, an analogue of choline. Our aim was to study the relationship of multidrug resistance of cultured glioma cell lines and 18 F-FCH tracer uptake. We used an in vitro multidrug-resistant (MDR) glioma model composed of sensitive parental U87MG and derived resistant cells U87MG-CIS and U87MG-DOX. Aggressiveness, choline metabolism and transport were studied, particularly the expression of choline kinase (CK) and high-affinity choline transporter (CHT1). FCH transport studies were assessed in our glioblastoma model. As expected, the resistant cell lines express P-glycoprotein (Pgp), multidrug resistance-associated protein isoform 1 (MRP1) and elevated glutathione (GSH) content and are also more mobile and more invasive than the sensitive U87MG cells. Our results show an overexpression of CK and CHT1 in the resistant cell lines compared to the sensitive cell lines. We found an increased uptake of FCH (in % of uptake per 200,000 cells) in the resistant cells compared to the sensitive ones (U87MG: 0.89±0.14; U87MG-CIS: 1.27±0.18; U87MG-DOX: 1.33±0.13) in line with accelerated choline metabolism and aggressive phenotype. FCH uptake is not influenced by the two ATP-dependant efflux pumps: Pgp and MRP1. FCH would be an interesting probe for glioma imaging which would not be effluxed from the resistant cells by the classic MDR ABC transporters. Our results clearly show that FCH uptake reflects accelerated choline metabolism and is related to tumour aggressiveness and drug resistance. (orig.)
Directory of Open Access Journals (Sweden)
Peter M Jones
Full Text Available ABC transporters are integral membrane pumps that are responsible for the import or export of a diverse range of molecules across cell membranes. ABC transporters have been implicated in many phenomena of medical importance, including cystic fibrosis and multidrug resistance in humans. The molecular architecture of ABC transporters comprises two transmembrane domains and two ATP-binding cassettes, or nucleotide-binding domains (NBDs, which are highly conserved and contain motifs that are crucial to ATP binding and hydrolysis. Despite the improved clarity of recent structural, biophysical, and biochemical data, the seemingly simple process of ATP binding and hydrolysis remains controversial, with a major unresolved issue being whether the NBD protomers separate during the catalytic cycle. Here chemical cross-linking data is presented for the bacterial ABC multidrug resistance (MDR transporter LmrA. These indicate that in the absence of nucleotide or substrate, the NBDs come into contact to a significant extent, even at 4°C, where ATPase activity is abrogated. The data are clearly not in accord with an inward-closed conformation akin to that observed in a crystal structure of V. cholerae MsbA. Rather, they suggest a head-to-tail configuration 'sandwich' dimer similar to that observed in crystal structures of nucleotide-bound ABC NBDs. We argue the data are more readily reconciled with the notion that the NBDs are in proximity while undergoing intra-domain motions, than with an NBD 'Switch' mechanism in which the NBD monomers separate in between ATP hydrolysis cycles.
Resistance switching at the nanometre scale in amorphous carbon
International Nuclear Information System (INIS)
Sebastian, Abu; Rossel, Christophe; Pozidis, Haralampos; Eleftheriou, Evangelos; Pauza, Andrew; Shelby, Robert M; RodrIguez, Arantxa Fraile
2011-01-01
The electrical transport and resistance switching mechanism in amorphous carbon (a-C) is investigated at the nanoscale. The electrical conduction in a-C thin films is shown to be captured well by a Poole-Frenkel transport model that involves nonisolated traps. Moreover, at high electric fields a field-induced threshold switching phenomenon is observed. The following resistance change is attributed to Joule heating and subsequent localized thermal annealing. We demonstrate that the mechanism is mostly due to clustering of the existing sp 2 sites within the sp 3 matrix. The electrical conduction behaviour, field-induced switching and Joule-heating-induced rearrangement of atomic order resulting in a resistance change are all reminiscent of conventional phase-change memory materials. This suggests the potential of a-C as a similar nonvolatile memory candidate material.
Directory of Open Access Journals (Sweden)
Miriam K Laufer
Full Text Available The predominance of chloroquine-susceptible falciparum malaria in Malawi more than a decade after chloroquine's withdrawal permits contemplation of re-introducing chloroquine for targeted uses. We aimed to compare the ability of different partner drugs to preserve chloroquine efficacy and prevent the re-emergence of resistance.Children with uncomplicated malaria were enrolled at a government health center in Blantyre, Malawi. Participants were randomized to receive chloroquine alone or combined with artesunate, azithromycin or atovaquone-proguanil for all episodes of uncomplicated malaria for one year. The primary outcome was incidence of clinical malaria. Secondary endpoints included treatment efficacy, and incidence of the chloroquine resistance marker pfcrt T76 and of anemia. Of the 640 children enrolled, 628 were included in the intention-to-treat analysis. Malaria incidence (95% confidence interval was 0.59 (.46-.74, .61 (.49-.76, .63 (.50-.79 and .68 (.54-.86 episodes/person-year for group randomized to receive chloroquine alone or in combination with artesunate, azithromycin or atovaquone-proguanil respectively and the differences were not statistically significant. Treatment efficacy for first episodes was 100% for chloroquine monotherapy and 97.9% for subsequent episodes of malaria. Similar results were seen in each of the chloroquine combination groups. The incidence of pfcrt T76 in pure form was 0%; mixed infections with both K76 and T76 were found in two out of 911 infections. Young children treated with chloroquine-azithromycin had higher hemoglobin concentrations at the study's end than did those in the chloroquine monotherapy group.Sustained chloroquine efficacy with repeated treatment supports the eventual re-introduction of chloroquine combinations for targeted uses such as intermittent preventive treatment.ClinicalTrials.gov NCT00379821.
Electron transport in InAs/AlGaSb ballistic rectifiers
International Nuclear Information System (INIS)
Maemoto, Toshihiko; Koyama, Masatoshi; Furukawa, Masashi; Takahashi, Hiroshi; Sasa, Shigehiko; Inoue, Masataka
2006-01-01
Nonlinear transport properties of a ballistic rectifier fabricated from InAs/AlGaSb heterostructures are reported. The operation of the ballistic rectifier is based on the guidance of carriers by a square anti-dot structure. The structure was defined by electron beam lithography and wet chemical etching. The DC characteristics and magneto-transport properties of the ballistic rectifier have been measured at 77 K and 4.2 K. Rectification effects relying on the ballistic transport were observed. From the four-terminal resistance measured at low magnetic fields, we also observed magneto-resistance fluctuations corresponding to the electron trajectories and symmetry-breaking electron scattering, which are influenced by the magnetic field strength
Within plant resistance to water flow in tomato and sweet melons ...
African Journals Online (AJOL)
Efficient water resource management in relation to water use and crop yields is premised on the knowledge of plant resistance to water flow. However, such studies are limited and for most crops, the within plant resistance to water flow remains largely unknown. In this study, within plant resistance to water transport ...
On the theory of gaseous transport to plant canopies
Bache, D. H.
Solutions of the convection-diffusion equations are developed to show the relationship between bulk transport parameters affecting gaseous transfer to plant canopies and local rates of transfer within the canopy. Foliage density is considered to be uniform and the drag coefficient of elements is specified by cd = γu- n with u as the local wind-speed and γ and n constants. Under conditions of high surface resistance, the bulk deposition velocity at the top of the canopy vg( h) approaches a limit defined by v g(h) = v̂gL p(1-ψ v̂gL p/u ∗) , where v̂g is the local deposition rate, Lp the effective foliage area, u ∗ the friction velocity and ψ a structure coefficient. From this, a criterion is proposed for defining the conditions in which the local resistances may be added in parallel. Comparisons with the external model for the bulk transport resistance rp = ra + rb + rc (where r p = 1/v g(h) and ra is a diffusive resistance between the apparent momentum sink and height h) shows that the bulk surface resistance r c = r̂s/L p( r̂s being a local surface resistance due to internal properties of the surface) and r b = overliner̂p-r a, appearing as an excess aerodynamic component; overliner̂p refers to the depth-averaged value of r̂p—the resistance to transfer through the laminar sublayer enveloping individual canopy elements. In conditions of zero surface resistance the bulk transport rate rp, o can be specified by r p,o/r a = E( r̂p/r̂∗) hq with E and q as constants, the term r̂p/r̂∗ referring to the resistances to mass and momentum transfer to canopy elements. A general expression is formulated for the sublayer Stanton number B -1 r bu ∗ at the extremes of high and zero surface resistance. In conditions of low surface resistance, it is shown that the terms rb + rc cannot be conveniently separated into equivalent aerodynamic and surface components as at the limit of high surface resistance. This conclusion is a departure from previous
Horvath, Deanna M; Murphy, Robyn M; Mollica, Janelle P; Hayes, Alan; Goodman, Craig A
2016-11-01
This study investigated the effect of taurine and β-alanine supplementation on muscle function and muscle taurine transporter (TauT) protein expression in mdx mice. Wild-type (WT) and mdx mice (5 months) were supplemented with taurine or β-alanine for 4 weeks, after which in vitro contractile properties, fatigue resistance and force recovery, and the expression of the TauT protein and proteins involved in excitation-contraction (E-C) coupling were examined in fast-twitch muscle. There was no difference in basal TauT protein expression or basal taurine content between mdx than WT muscle. Supplementation with taurine and β-alanine increased and reduced taurine content, respectively, in muscle from WT and mdx mice but had no effect of TauT protein. Taurine supplementation reduced body and muscle mass, and enhanced fatigue resistance and force recovery in mdx muscle. β-Alanine supplementation enhanced fatigue resistance in WT and mdx muscle. There was no difference in the basal expression of key E-C coupling proteins [ryanodine receptor 1 (RyR1), dihydropyridine receptor (DHPR), sarco(endo)plasmic reticulum Ca 2+ -ATPase 1 (SERCA1) or calsequestrin 1 (CSQ1)] between WT and mdx mice, and the expression of these proteins was not altered by taurine or β-alanine supplementation. These findings suggest that TauT protein expression is relatively insensitive to changes in muscle taurine content in WT and mdx mice, and that taurine and β-alanine supplementation may be viable therapeutic strategies to improve fatigue resistance of dystrophic skeletal muscle.
2010-10-01
... 49 Transportation 2 2010-10-01 2010-10-01 false Specification 21PF fire and shock resistant, phenolic-foam insulated, metal overpack. 178.358 Section 178.358 Transportation Other Regulations Relating... Class 7 (Radioactive) Materials § 178.358 Specification 21PF fire and shock resistant, phenolic-foam...
Detection of multidrug-resistant tuberculosis from stored DNA Samples: A multicenter study
Marie Sylvianne Rabodoarivelo; A Brandao; M C Cergole Novella; A G C. Bombonatte; B Imperiale; N Rakotosamimanana; N Morcillo; V Rasolofo; J C Palomino; A Martin
2018-01-01
Background: In low-income countries, rapid detection of tuberculosis (TB) drug resistance is often restricted by the difficulties of transporting and storing sputum samples from remote health centers to the reference laboratories where molecular tests are available. The aim of this study was to evaluate the performance of four transport and storage systems for molecular detection of rifampicin (RIF) and isoniazid (INH) resistance. Methods: This was a multicenter study. Molecular detection of ...
A simple Boltzmann transport equation for ballistic to diffusive transient heat transport
International Nuclear Information System (INIS)
Maassen, Jesse; Lundstrom, Mark
2015-01-01
Developing simplified, but accurate, theoretical approaches to treat heat transport on all length and time scales is needed to further enable scientific insight and technology innovation. Using a simplified form of the Boltzmann transport equation (BTE), originally developed for electron transport, we demonstrate how ballistic phonon effects and finite-velocity propagation are easily and naturally captured. We show how this approach compares well to the phonon BTE, and readily handles a full phonon dispersion and energy-dependent mean-free-path. This study of transient heat transport shows (i) how fundamental temperature jumps at the contacts depend simply on the ballistic thermal resistance, (ii) that phonon transport at early times approach the ballistic limit in samples of any length, and (iii) perceived reductions in heat conduction, when ballistic effects are present, originate from reductions in temperature gradient. Importantly, this framework can be recast exactly as the Cattaneo and hyperbolic heat equations, and we discuss how the key to capturing ballistic heat effects is to use the correct physical boundary conditions
Directory of Open Access Journals (Sweden)
García-Lobo Juan M
2010-04-01
Full Text Available Abstract Background Urease is a virulence factor that plays a role in the resistance of Brucella to low pH conditions, both in vivo and in vitro. Brucella contains two separate urease gene clusters, ure1 and ure2. Although only ure1 codes for an active urease, ure2 is also transcribed, but its contribution to Brucella biology is unknown. Results Re-examination of the ure2 locus showed that the operon includes five genes downstream of ureABCEFGDT that are orthologs to a nikKMLQO cluster encoding an ECF-type transport system for nickel. ureT and nikO mutants were constructed and analyzed for urease activity and acid resistance. A non-polar ureT mutant was unaffected in urease activity at neutral pH but showed a significantly decreased activity at acidic pH. It also showed a decreased survival rate to pH 2 at low concentration of urea when compared to the wild type. The nikO mutant had decreased urease activity and acid resistance at all urea concentrations tested, and this phenotype could be reverted by the addition of nickel to the growth medium. Conclusions Based on these results, we concluded that the operon ure2 codes for an acid-activated urea transporter and a nickel transporter necessary for the maximal activity of the urease whose structural subunits are encoded exclusively by the genes in the ure1 operon.
Overcoming Multidrug Resistance in Cancer Stem Cells
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Karobi Moitra
2015-01-01
Full Text Available The principle mechanism of protection of stem cells is through the expression of ATP-binding cassette (ABC transporters. These transporters serve as the guardians of the stem cell population in the body. Unfortunately these very same ABC efflux pumps afford protection to cancer stem cells in tumors, shielding them from the adverse effects of chemotherapy. A number of strategies to circumvent the function of these transporters in cancer stem cells are currently under investigation. These strategies include the development of competitive and allosteric modulators, nanoparticle mediated delivery of inhibitors, targeted transcriptional regulation of ABC transporters, miRNA mediated inhibition, and targeting of signaling pathways that modulate ABC transporters. The role of ABC transporters in cancer stem cells will be explored in this paper and strategies aimed at overcoming drug resistance caused by these particular transporters will also be discussed.
Energy Technology Data Exchange (ETDEWEB)
Moreau, X.; Saez, G.; Thiery, A. [Equipe ' Biomarqueurs and Bioindicateurs Environnementaux' , UMR-CNRS 6116 IMEP, Universite de Provence, 3 Place Victor Hugo, 13331 Marseille cedex 3 (France); Clot-Faybesse, O.; Guiraudie-Capraz, G. [' Neurobiologie Integrative et Adaptative' -UMR 6149, Universite de Provence, 3 Place Victor Hugo, 13331 Marseille cedex 3 (France); Bienboire-Frosini, C. [' Neurobiologie Integrative et Adaptative' -UMR 6149, Universite de Provence, 3 Place Victor Hugo, 13331 Marseille cedex 3 (France); Pherosynthese, Le Rieu Neuf, 84490 St Saturnin d' Apt (France); Martin, C. [Equipe ' Biomarqueurs and Bioindicateurs Environnementaux' , UMR-CNRS 6116 IMEP, UAPV, 33 rue Louis Pasteur, 84000 Avignon (France); De Jong, L. [Equipe ' Biomarqueurs and Bioindicateurs Environnementaux' , UMR-CNRS 6116 IMEP, Universite de Provence, 3 Place Victor Hugo, 13331 Marseille cedex 3 (France)], E-mail: laetitia.moreau@univ-provence.fr
2008-06-15
A new simple and sensitive method to distinguish chemically polluted from unpolluted situations in freshwater ecosystems is reported. For this purpose, Chironomus gr thumni larvae were collected from a polluted urban river downstream a sewage treatment plant. For the first time, ELISA assay was used to semi-quantify the multixenobiotic resistance transporters (MXR) in these small pertinent bioindicators. The use of samples immediately fixed in the field gives a delay to isolate larvae and allows multi-sampling along a longitudinal transect in a river at a given time. Results exhibit an induction of MXR proteins in larvae from the polluted river and a deinduction in larvae maintained 11 days in unpolluted water. They show new evidences to use midge larvae in biomonitoring environmental programs. They answer to first biomarker calibration steps for the ongoing development of MXR transporters as a detection tool of xenobiotic impacts on bioindicator invertebrates in their freshwater habitats. - Semi-quantification of midge larval MXR transporters by ELISA is a simple and sensitive method to detect chemically polluted situations in running freshwaters.
International Nuclear Information System (INIS)
Moreau, X.; Saez, G.; Thiery, A.; Clot-Faybesse, O.; Guiraudie-Capraz, G.; Bienboire-Frosini, C.; Martin, C.; De Jong, L.
2008-01-01
A new simple and sensitive method to distinguish chemically polluted from unpolluted situations in freshwater ecosystems is reported. For this purpose, Chironomus gr thumni larvae were collected from a polluted urban river downstream a sewage treatment plant. For the first time, ELISA assay was used to semi-quantify the multixenobiotic resistance transporters (MXR) in these small pertinent bioindicators. The use of samples immediately fixed in the field gives a delay to isolate larvae and allows multi-sampling along a longitudinal transect in a river at a given time. Results exhibit an induction of MXR proteins in larvae from the polluted river and a deinduction in larvae maintained 11 days in unpolluted water. They show new evidences to use midge larvae in biomonitoring environmental programs. They answer to first biomarker calibration steps for the ongoing development of MXR transporters as a detection tool of xenobiotic impacts on bioindicator invertebrates in their freshwater habitats. - Semi-quantification of midge larval MXR transporters by ELISA is a simple and sensitive method to detect chemically polluted situations in running freshwaters
Lysosomes as mediators of drug resistance in cancer.
Zhitomirsky, Benny; Assaraf, Yehuda G
2016-01-01
Drug resistance remains a leading cause of chemotherapeutic treatment failure and cancer-related mortality. While some mechanisms of anticancer drug resistance have been well characterized, multiple mechanisms remain elusive. In this respect, passive ion trapping-based lysosomal sequestration of multiple hydrophobic weak-base chemotherapeutic agents was found to reduce the accessibility of these drugs to their target sites, resulting in a markedly reduced cytotoxic effect and drug resistance. Recently we have demonstrated that lysosomal sequestration of hydrophobic weak base drugs triggers TFEB-mediated lysosomal biogenesis resulting in an enlarged lysosomal compartment, capable of enhanced drug sequestration. This study further showed that cancer cells with an increased number of drug-accumulating lysosomes are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. In addition to passive drug sequestration of hydrophobic weak base chemotherapeutics, other mechanisms of lysosome-mediated drug resistance have also been reported; these include active lysosomal drug sequestration mediated by ATP-driven transporters from the ABC superfamily, and a role for lysosomal copper transporters in cancer resistance to platinum-based chemotherapeutics. Furthermore, lysosomal exocytosis was suggested as a mechanism to facilitate the clearance of chemotherapeutics which highly accumulated in lysosomes, thus providing an additional line of resistance, supplementing the organelle entrapment of chemotherapeutics away from their target sites. Along with these mechanisms of lysosome-mediated drug resistance, several approaches were recently developed for the overcoming of drug resistance or exploiting lysosomal drug sequestration, including lysosomal photodestruction and drug-induced lysosomal membrane permeabilization. In this review we explore the current literature addressing the role of lysosomes in mediating cancer drug
Copper-resistant halophilic bacterium isolated from the polluted Maruit Lake, Egypt.
Osman, O; Tanguichi, H; Ikeda, K; Park, P; Tanabe-Hosoi, S; Nagata, S
2010-04-01
To isolate and characterize copper-resistant halophilic bacteria from the polluted Maruit Lake, Egypt and identify the role of plasmids in toxic metal resistance. We isolated strain MA2, showing high copper resistance up to the 1.5 mmol l(-1) concentration; it was also resistant to other metals such as nickel, cobalt and zinc and a group of antibiotics. Partial 16S rRNA analysis revealed that strain MA2 belonged to the genus Halomonas. Copper uptake, measured by atomic absorption spectrophotometery, was higher in the absence of NaCl than in the presence of 0.5-1.0 mol l(-1) NaCl during 5-15 min of incubation. Cell fractionation and electron microscopic observation clarified that most of the copper accumulated in the outer membrane and periplasmic fractions of the cells. Plasmid screening yielded two plasmids: pMA21 (11 kb) and pMA22 (5 kb). Plasmid curing resulted in a strain that lost both the plasmids and was sensitive to cobalt and chromate but not copper, nickel and zinc. This cured strain also showed weak growth in the presence of 0.5-1.0 mol l(-1) NaCl. Partial sequencing of both plasmids led to the identification of different toxic metals transporters but copper transporters were not identified. The highest cell viability was found in the presence of 1.0 mol l(-1) NaCl at different copper concentrations, and copper uptake was optimal in the absence of NaCl. Plasmid pMA21 encoded chromate, cobalt, zinc and cadmium transporters, whereas pMA22 encoded specific zinc and RND (resistance, nodulation, cell division) efflux transporters as well as different kinds of metabolic enzymes. Copper resistance was mainly incorporated in the chromosome. Strain MA2 is a fast and efficient tool for copper bioremediation and the isolated plasmids show significant characteristics of both toxic metal and antibiotic resistance.
Density effects on tokamak edge turbulence and transport with magnetic X-points
International Nuclear Information System (INIS)
Xu, X.Q.; Cohen, R.H.; Nevins, W.M.; Rognlien, T.D.; Ryutov, D.D.; Umansky, M.V.; Pearlstein, L.D.; Bulmer, R.H.; Russell, D.A.; Myra, J.R.; D'Ippolito, D.A.; Greenwald, M.; Snyder, P.B.; Mahdavi, M.A.
2005-01-01
Results are presented from the 3D electromagnetic turbulence code BOUT, the 2D transport code UEDGE, and theoretical analysis of boundary turbulence and transport in a real divertor-plasma geometry and its relationship to the density limit. Key results include: (1) a transition of the boundary turbulence from resistive X-point to resistive-ballooning as a critical plasma density is exceeded; (2) formation of an X-point MARFE in 2D UEDGE transport simulations for increasing outboard radial transport as found by BOUT for increasing density; (3) identification of convective transport by localized plasma 'blobs' in the SOL at high density during neutral fueling, and decorrelation of turbulence between the midplane and the divertor leg due to strong X-point magnetic shear; (4) a new divertor-leg instability driven at high plasma beta by a radial tilt of the divertor plate. (author)
Directory of Open Access Journals (Sweden)
Teixeira Miguel C
2012-07-01
Full Text Available Abstract Background The understanding of the molecular basis of yeast tolerance to ethanol may guide the design of rational strategies to increase process performance in industrial alcoholic fermentations. A set of 21 genes encoding multidrug transporters from the ATP-Binding Cassette (ABC Superfamily and Major Facilitator Superfamily (MFS in S. cerevisiae were scrutinized for a role in ethanol stress resistance. Results A yeast multidrug resistance ABC transporter encoded by the PDR18 gene, proposed to play a role in the incorporation of ergosterol in the yeast plasma membrane, was found to confer resistance to growth inhibitory concentrations of ethanol. PDR18 expression was seen to contribute to decreased 3 H-ethanol intracellular concentrations and decreased plasma membrane permeabilization of yeast cells challenged with inhibitory ethanol concentrations. Given the increased tolerance to ethanol of cells expressing PDR18, the final concentration of ethanol produced during high gravity alcoholic fermentation by yeast cells devoid of PDR18 was lower than the final ethanol concentration produced by the corresponding parental strain. Moreover, an engineered yeast strain in which the PDR18 promoter was replaced in the genome by the stronger PDR5 promoter, leading to increased PDR18 mRNA levels during alcoholic fermentation, was able to attain a 6 % higher ethanol concentration and a 17 % higher ethanol production yield than the parental strain. The improved fermentative performance of yeast cells over-expressing PDR18 was found to correlate with their increased ethanol tolerance and ability to restrain plasma membrane permeabilization induced throughout high gravity fermentation. Conclusions PDR18 gene over-expression increases yeast ethanol tolerance and fermentation performance leading to the production of highly inhibitory concentrations of ethanol. PDR18 overexpression in industrial yeast strains appears to be a promising approach to
Coffee Consumption Attenuates Insulin Resistance and Glucose ...
African Journals Online (AJOL)
olayemitoyin
Alzheimer's disease (CBS 2012), dementia (Health news 2012) and ... the effects of coffee on insulin resistance and glucose tolerance as ..... mortality among patients with type 2 diabetes. ... transporter family: Structure, function and tissue-.
Silver resistance in Gram-negative bacteria: a dissection of endogenous and exogenous mechanisms.
Randall, Christopher P; Gupta, Arya; Jackson, Nicole; Busse, David; O'Neill, Alex J
2015-04-01
To gain a more detailed understanding of endogenous (mutational) and exogenous (horizontally acquired) resistance to silver in Gram-negative pathogens, with an emphasis on clarifying the genetic bases for resistance. A suite of microbiological and molecular genetic techniques was employed to select and characterize endogenous and exogenous silver resistance in several Gram-negative species. In Escherichia coli, endogenous resistance arose after 6 days of exposure to silver, a consequence of two point mutations that were both necessary and sufficient for the phenotype. These mutations, in ompR and cusS, respectively conferred loss of the OmpC/F porins and derepression of the CusCFBA efflux transporter, both phenotypic changes previously linked to reduced intracellular accumulation of silver. Exogenous resistance involved derepression of the SilCFBA efflux transporter as a consequence of mutation in silS, but was additionally contingent on expression of the periplasmic silver-sequestration protein SilE. Silver resistance could be selected at high frequency (>10(-9)) from Enterobacteriaceae lacking OmpC/F porins or harbouring the sil operon and both endogenous and exogenous resistance were associated with modest fitness costs in vitro. Both endogenous and exogenous silver resistance are dependent on the derepressed expression of closely related efflux transporters and are therefore mechanistically similar phenotypes. The ease with which silver resistance can become selected in some bacterial pathogens in vitro suggests that there would be benefit in improved surveillance for silver-resistant isolates in the clinic, along with greater control over use of silver-containing products, in order to best preserve the clinical utility of silver. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.
Mechanisms of drug resistance in cancer cells
International Nuclear Information System (INIS)
Iqbal, M.P.
2003-01-01
Development of drug resist chemotherapy. For the past several years, investigators have been striving hard to unravel mechanisms of drug resistance in cancer cells. Using different experimental models of cancer, some of the major mechanisms of drug resistance identified in mammalian cells include: (a) Altered transport of the drug (decreased influx of the drug; increased efflux of the drug (role of P-glycoprotein; role of polyglutamation; role of multiple drug resistance associated protein)), (b) Increase in total amount of target enzyme/protein (gene amplification), (c) alteration in the target enzyme/protein (low affinity enzyme), (d) Elevation of cellular glutathione, (e) Inhibition of drug-induced apoptosis (mutation in p53 tumor suppressor gene; increased expression of bcl-xl gene). (author)
Benchmarking of electrolyte mass transport in next generation lithium batteries
Directory of Open Access Journals (Sweden)
Jonas Lindberg
2017-12-01
Full Text Available Beyond conductivity and viscosity, little is often known about the mass transport properties of next generation lithium battery electrolytes, thus, making performance estimation uncertain when concentration gradients are present, as conductivity only describes performance in the absence of these gradients. This study experimentally measured the diffusion resistivity, originating from voltage loss due to a concentration gradient, together with the ohmic resistivity, obtained from ionic conductivity measurements, hence, evaluating electrolytes both with and without the presence of concentration gradients. Under galvanostatic conditions, the concentration gradients, of all electrolytes examined, developed quickly and the diffusion resistivity rapidly dominated the ohmic resistivity. The electrolytes investigated consisted of lithium salt in: room temperature ionic liquids (RTIL, RTIL mixed organic carbonates, dimethyl sulfoxide (DMSO, and a conventional Li-ion battery electrolyte. At steady state the RTIL electrolytes displayed a diffusion resistivity ~ 20 times greater than the ohmic resistivity. The DMSO-based electrolyte showed mass transport properties similar to the conventional Li-ion battery electrolyte. In conclusion, the results presented in this study show that the diffusion polarization must be considered in applications where high energy and power density are desired.
Dynamic resistance of a high-T c coated conductor wire in a perpendicular magnetic field at 77 K
Jiang, Zhenan; Toyomoto, Ryuki; Amemiya, Naoyuki; Zhang, Xingyou; Bumby, Chris W.
2017-03-01
Superconducting high-T c coated conductor (CC) wires comprise a ceramic thin film with a large aspect ratio. This geometry can lead to significant dissipative losses when exposed to an alternating magnetic field. Here we report experimental measurements of the ‘dynamic resistance’ of commercially available SuperPower and Fujikura CC wires in an AC perpendicular field. The onset of dynamic resistance occurs at a threshold field amplitude, which is determined by the total DC transport current and the penetration field of the conductor. We show that the field-dependence of the normalised magnetisation loss provides an unambiguous value for this threshold field at zero transport current. From this insight we then obtain an expression for the dynamic resistance in perpendicular field. This approach implies a linear relationship between dynamic resistance and applied field amplitude, and also between threshold field and transport current and this is consistent with our experimental data. The analytical expression obtained yields values that closely agree with measurements obtained across a wide range of frequencies and transport currents, and for multiple CC wires produced by different wire manufacturers and with significantly differing dimensions and critical currents. We further show that at high transport currents, the measured DC resistance includes an additional nonlinear term which is due to flux-flow resistance incurred by the DC transport current. This occurs once the field-dependent critical current of the wire falls below the DC transport current for part of each field cycle. Our results provide an effective and simple approach to calculating the dynamic resistance of a CC wire, at current and field magnitudes consistent with those expected in superconducting machines.
Nuclear materials transport worldwide
International Nuclear Information System (INIS)
Stellpflug, J.
1987-01-01
This Greenpeace report shows: nuclear materials transport is an extremely hazardous business. There is no safe protection against accidents, kidnapping, or sabotage. Any moment of a day, at any place, a nuclear transport accident may bring the world to disaster, releasing plutonium or radioactive fission products to the environment. Such an event is not less probable than the MCA at Chernobyl. The author of the book in hand follows the secret track of radioactive materials around the world, from uranium mines to the nuclear power plants, from reprocessing facilities to the waste repositories. He explores the routes of transport and the risks involved, he gives the names of transport firms and discloses incidents and carelessness, tells about damaged waste drums and plutonium that 'disappeared'. He also tells about worldwide, organised resistance to such nuclear transports, explaining the Greenpeace missions on the open sea, or the 'day X' operation at the Gorleben site, informing the reader about protests and actions for a world freed from the threat of nuclear energy. (orig./HP) [de
International Nuclear Information System (INIS)
Takano, Hiroyuki; Takumi, Shota; Ikema, Satoshi; Mizoue, Nozomi; Hotta, Yuki; Shiozaki, Kazuhiro; Sugiyama, Yasumasa; Furukawa, Tatsuhiko; Komatsu, Masaharu
2014-01-01
Microcystin-LR is a cyclic peptide released by several bloom-forming cyanobacteria. Understanding the mechanism of microcystin-LR toxicity is important, because of the both potencies of its acute cytotoxicity and tumor-promoting activity in hepatocytes of animals and humans. Recently, we have reported that the expression of human hepatocyte uptake transporter OATP1B3 was critical for the selective uptake of microcystin-LR into hepatocytes and for induction of its fatal cytotoxicity. In this study, we demonstrated a novel function of microcystin-LR which induced bipotential changes including anoikis resistance and cytoskeleton reorganization to OATP1B3-transfected HEK293 cells (HEK293-OATP1B3). After exposure to microcystin-LR, HEK293-OATP1B3 cells were divided to the floating cells and remaining adherent cells. After collection and reseeding the floating cells into a fresh flask, cells were confluently proliferated (HEK293-OATP1B3-FL) under the microcystin-LR-free condition. Both the proliferated HEK293-OATP1B3-FL and remaining adherent HEK293-OATP1B3-AD cells changed the character with down- and up-regulation of E-cadherin, respectively. Additionally, these cells acquired resistance to microcystin-LR. These results suggest that microcystin-LR could be associated with not only tumor promotion, but also epithelial–mesenchymal transition-mediated cancer metastasis. Furthermore, microcystin-LR might induce the cytoskeleton reorganization be accompanied epithelial–mesenchymal transition
Mathematical Modeling of Contact Resistance in Silicon Photovoltaic Cells
Black, J. P.
2013-10-22
In screen-printed silicon-crystalline solar cells, the contact resistance of a thin interfacial glass layer between the silicon and the silver electrode plays a limiting role for electron transport. We analyze a simple model for electron transport across this layer, based on the driftdiffusion equations. We utilize the size of the current/Debye length to conduct asymptotic techniques to simplify the model; we solve the model numerically to find that the effective contact resistance may be a monotonic increasing, monotonic decreasing, or nonmonotonic function of the electron flux, depending on the values of the physical parameters. © 2013 Society for Industrial and Applied Mathematics.
The resistance to impact of spent Magnox fuel transport flasks
International Nuclear Information System (INIS)
Anon.
1985-01-01
This book completes the papers of the four-year programme of research and demonstrations embarked upon by the CEGB in 1981, culminating in the spectacular train crash at Old Dalby in July 1984. It explains the CEGB's operations in relation to the transportation of spent Magnox fuel. The public tests described in this book are more effective in improving public understanding and confidence than any amount of explanations could have been, raising the wider question of how best the scientific community can respond to the legitimate concerns of the man and woman in the street about the generating of electricity from nuclear power. The contents are: Taking care; irradiated fuel transport in the UK; programming for flask safety; the use of scale models in impact testing; flask analytical studies; drop test facilities; demonstration drop test; a study of flask transport impact hazards; impact of Magnox irradiated fuel transport flasks into rock and concrete; rail crash demonstration scenarios; horizontal impact testing of quarter scale flasks using masonry targets; horizontal crash testing and analysis of model flatrols; flatrol test; analysis of full scale impact into an abutment; analysis of primary impact forces in the train crash demonstration; horizontal impact tests of quarter scale Magnox flasks and stylised model locomotives; predictive estimates for behaviour in the train crash demonstration; design and organization of the crash; execution of the crash demonstration by British Rail; instrumentation for the train crash demonstration; photography for the crash demonstration; a summary of the CEGB's flask accident impact studies
Drug transporters in breast cancer
DEFF Research Database (Denmark)
Kümler, Iben; Stenvang, Jan; Moreira, José
2015-01-01
Despite the advances that have taken place in the past decade, including the development of novel molecular targeted agents, cytotoxic chemotherapy remains the mainstay of cancer treatment. In breast cancer, anthracyclines and taxanes are the two main chemotherapeutic options used on a routine...... basis. Although effective, their usefulness is limited by the inevitable development of resistance, a lack of response to drug-induced cancer cell death. A large body of research has resulted in the characterization of a plethora of mechanisms involved in resistance; ATP-binding cassette transporter...
Guimerà, Xavier; Dorado, Antonio David; Bonsfills, Anna; Gabriel, Gemma; Gabriel, David; Gamisans, Xavier
2016-10-01
Knowledge of mass transport mechanisms in biofilm-based technologies such as biofilters is essential to improve bioreactors performance by preventing mass transport limitation. External and internal mass transport in biofilms was characterized in heterotrophic biofilms grown on a flat plate bioreactor. Mass transport resistance through the liquid-biofilm interphase and diffusion within biofilms were quantified by in situ measurements using microsensors with a high spatial resolution (mass transport coefficients. The sensitivity of external and internal mass transport resistances to flow conditions within the range of typical fluid velocities over biofilms (Reynolds numbers between 0.5 and 7) was assessed. Estimated external mass transfer coefficients at different liquid phase flow velocities showed discrepancies with studies considering laminar conditions in the diffusive boundary layer near the liquid-biofilm interphase. The correlation of effective diffusivity with flow velocities showed that the heterogeneous structure of biofilms defines the transport mechanisms inside biofilms. Internal mass transport was driven by diffusion through cell clusters and aggregates at Re below 2.8. Conversely, mass transport was driven by advection within pores, voids and water channels at Re above 5.6. Between both flow velocities, mass transport occurred by a combination of advection and diffusion. Effective diffusivities estimated at different biofilm densities showed a linear increase of mass transport resistance due to a porosity decrease up to biofilm densities of 50 g VSS·L(-1). Mass transport was strongly limited at higher biofilm densities. Internal mass transport results were used to propose an empirical correlation to assess the effective diffusivity within biofilms considering the influence of hydrodynamics and biofilm density. Copyright © 2016 Elsevier Ltd. All rights reserved.
Kang, Seok Kyu; Markowitz, Geoffrey J; Kim, Shin Tae; Johnston, Michael V; Kadam, Shilpa D
2015-01-01
Ischemia in the immature brain is an important cause of neonatal seizures. Temporal evolution of acquired neonatal seizures and their response to anticonvulsants are of great interest, given the unreliability of the clinical correlates and poor efficacy of first-line anti-seizure drugs. The expression and function of the electroneutral chloride co-transporters KCC2 and NKCC1 influence the anti-seizure efficacy of GABAA-agonists. To investigate ischemia-induced seizure susceptibility and efficacy of the GABAA-agonist phenobarbital (PB), with NKCC1 antagonist bumetanide (BTN) as an adjunct treatment, we utilized permanent unilateral carotid-ligation to produce acute ischemic-seizures in post-natal day 7, 10, and 12 CD1 mice. Immediate post-ligation video-electroencephalograms (EEGs) quantitatively evaluated baseline and post-treatment seizure burdens. Brains were examined for stroke-injury and western blot analyses to evaluate the expression of KCC2 and NKCC1. Severity of acute ischemic seizures post-ligation was highest at P7. PB was an efficacious anti-seizure agent at P10 and P12, but not at P7. BTN failed as an adjunct, at all ages tested and significantly blunted PB-efficacy at P10. Significant acute post-ischemic downregulation of KCC2 was detected at all ages. At P7, males displayed higher age-dependent seizure susceptibility, associated with a significant developmental lag in their KCC2 expression. This study established a novel neonatal mouse model of PB-resistant seizures that demonstrates age/sex-dependent susceptibility. The age-dependent profile of KCC2 expression and its post-insult downregulation may underlie the PB-resistance reported in this model. Blocking NKCC1 with low-dose BTN following PB treatment failed to improve PB-efficacy.
Multidrug transporters from bacteria to man : similarities in structure and function
van Veen, HW; Konings, WN
Organisms ranging from bacteria to man possess transmembrane transporters which confer resistance to toxic corn pounds. Underlining their biological significance, prokaryotic and eukaryotic multidrug transport proteins are very similar in structure and function. Therefore, a study of the factors
International Nuclear Information System (INIS)
Wanek, Thomas; Traxl, Alexander; Bankstahl, Jens P.; Bankstahl, Marion; Sauberer, Michael; Langer, Oliver; Kuntner, Claudia
2015-01-01
Introduction: Transport of 2-[ 18 F]fluoro-2-deoxy-D-glucose ([ 18 F]FDG) by the multidrug efflux transporters P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) at the blood–brain barrier (BBB) may confound the interpretation of [ 18 F]FDG brain PET data. Aim of this study was to assess the influence of ABCB1 and ABCG2 at the BBB on brain distribution of [ 18 F]FDG in vivo by performing [ 18 F]FDG PET scans in wild-type and transporter knockout mice and by evaluating changes in [ 18 F]FDG brain distribution after transporter inhibition. Methods: Dynamic small-animal PET experiments (60 min) were performed with [ 18 F]FDG in groups of wild-type and transporter knockout mice (Abcb1a/b (−/−) , Abcg2 (−/−) and Abcb1a/b (−/−) Abcg2 (−/−) ) and in wild-type rats without and with i.v. pretreatment with the known ABCB1 inhibitor tariquidar (15 mg/kg, given at 2 h before PET). Blood was sampled from animals from the orbital sinus vein at the end of the PET scans and measured in a gamma counter. Brain uptake of [ 18 F]FDG was expressed as the brain-to-blood radioactivity concentration ratio in the last PET time frame (K b,brain ). Results: K b,brain values of [ 18 F]FDG were not significantly different between different mouse types both without and with tariquidar pretreatment. The blood-to-brain transfer rate constant of [ 18 F]FDG was significantly lower in tariquidar-treated as compared with vehicle-treated rats (0.350 ± 0.025 mL/min/g versus 0.416 ± 0.024 mL/min/g, p = 0.026, paired t-test) but K b,brain values were not significantly different between both rat groups. Conclusion: Our results show that [ 18 F]FDG is not transported by Abcb1 at the mouse and rat BBB in vivo. In addition we found no evidence for Abcg2 transport of [ 18 F]FDG at the mouse BBB. Advances in knowledge and implications for patient care: Our findings imply that functional activity of ABCB1 and ABCG2 at the BBB does not need to be taken into account when
Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan
Jonker, JW; Smit, JW; Brinkhuis, RF; Maliepaard, M; Beijnen, JH; Schellens, JHM; Schinkel, AH
2000-01-01
Background and Methods: Breast cancer resistance protein (BCRP/MXR/ABCP) is a multidrug-resistance protein that is a member of the adenosine triphosphate-binding cassette family of drug transporters. BCRP can render tumor cells resistant to the anticancer drugs topotecan, mitoxantrone, doxorubicin,
Pressure gradient turbulent transport and collisionless reconnection
International Nuclear Information System (INIS)
Connor, J.W.
1993-01-01
The scale invariance technique is employed to discuss pressure gradient driven turbulent transport when an Ohm's law with electron inertia, rather than resistivity, is relevant. An expression for thermal diffusivity which has many features appropriate to L-mode transport in tokamaks, is seen to have greater generality than indicated by their particular calculation. The results of applying the technique to a more appropriate collisionless Ohm's law are discussed. (Author)
nitrosoguanidine-induced cadmium resistant mutants of Aspergillus
Indian Academy of Sciences (India)
Unknown
nitrosoguanidine-induced cadmium resistant mutants of. Aspergillus niger. SAMAR ... gens and UV irradiation to study transportation of cad- mium ion through cell ..... Rowley W S 1993 Yeast bZib proteins mediate pleiotropic drug and metal ...
Remanent resistance changes in metal- PrCaMnO-metal sandwich structures
Energy Technology Data Exchange (ETDEWEB)
Scherff, Malte; Meyer, Bjoern-Uwe; Scholz, Julius; Hoffmann, Joerg; Jooss, Christian [Institute of Materials Physics, University of Goettingen (Germany)
2012-07-01
The non-volatile electric pulse induced resistance change (EPIR) seems to be a rather common feature of oxides sandwiched by electrodes. However, microscopic mechanisms are discussed controversially. We present electrical transport measurements of sputtered Pr{sub 0.7}Ca{sub 0.3}MnO{sub 3} films sandwiched by metallic electrodes with variation of electrode materials, device geometry and PCMO deposition parameters. Cross-plane transport measurements have been performed as function of temperature and magnetic field. Specifically, the transition from dynamic resistance changes due to non-linear transport to remanent switching is analyzed. By analyzing changes of magneto-resistance at low temperatures in different resistance states we aim for separation between interface and film contributions to switching. Comparing switching behavior in symmetric and asymmetric electrode configuration allows for identification of the active, single interface in the switching process and the origin of an observed switching polarity inversion. The influence of excitation field and power on the switching characteristics of different noble metal electrodes is discussed. Samples from macroscopic devices and in situ stimulated sandwich structures were studied in a transmission electron microscope in order to investigate the induced structural, chemical and electronic changes.
Theory-based transport simulations of TFTR L-mode temperature profiles
International Nuclear Information System (INIS)
Bateman, G.
1991-01-01
The temperature profiles from a selection of TFTR L-mode discharges are simulated with the 1-1/2-D BALDUR transport code using a combination of theoretically derived transport models, called the Multi-Mode Model. The present version of the Multi-Mode Model consists of effective thermal diffusivities resulting from trapped electron modes and ion temperature gradient (η i ) modes, which dominate in the core of the plasma, together with resistive ballooning modes, which dominate in the periphery. Within the context of this transport model and the TFTR simulations reported here, the scaling of confinement with heating power comes from the temperature dependence of the η i and trapped electron modes, while the scaling with current comes mostly from resistive ballooning modes. 24 refs., 16 figs., 3 tabs
Recent advances on uric acid transporters
Xu, Liuqing; Shi, Yingfeng; Zhuang, Shougang; Liu, Na
2017-01-01
Uric acid is the product of purine metabolism and its increased levels result in hyperuricemia. A number of epidemiological reports link hyperuricemia with multiple disorders, such as kidney diseases, cardiovascular diseases and diabetes. Recent studies also showed that expression and functional changes of urate transporters are associated with hyperuricemia. Uric acid transporters are divided into two categories: urate reabsorption transporters, including urate anion transporter 1 (URAT1), organic anion transporter 4 (OAT4) and glucose transporter 9 (GLUT9), and urate excretion transporetrs, including OAT1, OAT3, urate transporter (UAT), multidrug resistance protein 4 (MRP4/ABCC4), ABCG-2 and sodium-dependent phosphate transport protein. In the kidney, uric acid transporters decrease the reabsorption of urate and increase its secretion. These transporters’ dysfunction would lead to hyperuricemia. As the function of urate transporters is important to control the level of serum uric acid, studies on the functional role of uric acid transporter may provide a new strategy to treat hyperuricemia associated diseases, such as gout, chronic kidney disease, hyperlipidemia, hypertension, coronary heart disease, diabetes and other disorders. This review article summarizes the physiology of urate reabsorption and excretion transporters and highlights the recent advances on their roles in hyperuricemia and various diseases. PMID:29246027
Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.
Directory of Open Access Journals (Sweden)
Juan D Unciti-Broceta
2015-06-01
Full Text Available African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.
Evaluation of static resistance of deep foundations.
2017-05-01
The focus of this research was to evaluate and improve Florida Department of Transportation (FDOT) FB-Deep software prediction of nominal resistance of H-piles, prestressed concrete piles in limestone, large diameter (> 36) open steel and concrete...
International Nuclear Information System (INIS)
Cha, Dowon; Ahn, Jae Hwan; Kim, Hyung Soon; Kim, Yongchan
2015-01-01
The clamping force should be applied to a proton electrolyte membrane (PEM) fuel cell due to its structural characteristics. The clamping force affects the ohmic and mass transport resistances in the PEM fuel cell. In this study, the effects of the clamping force on the water transport and performance characteristics of a PEM fuel cell are experimentally investigated with variations in the relative humidity and current density. The water transport characteristics were analyzed by calculating the net drag coefficient. The ohmic resistance decreased with the increase in the clamping force due to the reduced contact resistance and more even membrane hydration. However, the mass transport resistance increased with the increase in the clamping force due to the gas diffusion layer compression. The net drag coefficient decreased with the increase in the clamping force due to high water back-diffusion. Additionally, the relationship between the total resistance and the net drag coefficient was investigated. - Highlights: • Effects of clamping force on the performance of a PEM fuel cell are investigated. • Water transport characteristics are analyzed using net drag coefficient. • Ohmic resistance decreased with clamping force, but mass transport resistance increased. • Net drag coefficient decreased with the increase in clamping force. • Total resistance was significantly degraded for a net drag coefficient below 0.2.
Molecular properties of bacterial multidrug transporters
Putman, M; van Veen, HW; Konings, WN
2000-01-01
One of the mechanisms that bacteria utilize to evade the toxic effects of antibiotics is the active extrusion of structurally unrelated drugs from the cell. Both intrinsic and acquired multidrug transporters play an important role in antibiotic resistance of several pathogens, including Neisseria
Isolation of parafluorophenylalanine-resistant mutants from HeLa cell cultures
International Nuclear Information System (INIS)
Yim, L.K.; Stuart, W.D.
1983-01-01
This report describes a method to isolate temperature-conditional phenylalanine transport mutants from the transformed human cell line HeLa. Using ultraviolet light as a mutagenic agent and DL-parafluorophenylalanine (PFPA), a poisonous analogue of L-phenylalanine, as a selective agent, mutagenized cells were selected for survival in the presence of PFPA at a temperature of 39 degrees C. Survivors of the mutagenesis and selection procedures were removed from the culture dishes by trypsin and cloned at a temperature of 35 degrees C. Seven of these lines isolated demonstrated continued resistance to PFPA at 39 degrees C. These lines were tested for uptake of L-phenylalanine at an external concentration of 100 microM and for continued resistance to PFPA at two concentrations. Cells were tested at 35 and at 39 degrees C. The data were compared to those obtained for the parental HeLa cell line under identical conditions. The seven mutant cell lines demonstrated varying resistances to PFPA and varying levels of accumulation of L-phenylalanine when tested at 35 and 39 degrees C. Three mutant lines were additionally tested for L-phenylalanine tRNA charging levels and for transport of L-arginine. The lines had parental cell levels of tRNA charging and L-arginine transport which suggest that the induced genetic defect affects a specific L-phenylalanine transport system
Influence of coal slurry particle composition on pipeline hydraulic transportation behavior
Li-an, Zhao; Ronghuan, Cai; Tieli, Wang
2018-02-01
Acting as a new type of energy transportation mode, the coal pipeline hydraulic transmission can reduce the energy transportation cost and the fly ash pollution of the conventional coal transportation. In this study, the effect of average velocity, particle size and pumping time on particle composition of coal particles during hydraulic conveying was investigated by ring tube test. Meanwhile, the effects of particle composition change on slurry viscosity, transmission resistance and critical sedimentation velocity were studied based on the experimental data. The experimental and theoretical analysis indicate that the alter of slurry particle composition can lead to the change of viscosity, resistance and critical velocity of slurry. Moreover, based on the previous studies, the critical velocity calculation model of coal slurry is proposed.
Surface resistivity measurement of plasma treated polymers
International Nuclear Information System (INIS)
Simon, D.; Pigram, P.J.; Liesegang, J.
2000-01-01
Full text: Resistivity of insulators is an important property of materials used within the integrated circuit and packaging industries. The measurement of electrical resistivity of insulator materials in the surface region in this work is interpreted through observations of surface charge decay. A self-field driven and diffusion charge transport theory is used to model the process and resistivity values obtained computationally. Data for the charge decay of surface charged samples are collected by suspending them inside a coaxial cylinder connected to an electrometer. Samples used have been low density polyethylene LDPE sheet, both pristine and surface treated. Some samples have been treated by air plasma at low vacuum pressures for different periods of time; others have been washed in ethyl acetate and then plasma treated before the resistivity measurement. The sets of resistivity measurements form the various treatments are compared below. X-ray photoelectron spectroscopy (XPS) has also been used to investigate and account for the observed variations in surface resistivity
Directory of Open Access Journals (Sweden)
Aizati N A Daud
Full Text Available A number of transporter proteins are expressed in the placenta, and they facilitate the placental transfer of drugs. The inhibition of P-glycoprotein (P-gp was previously found to be associated with an increase in the risk of congenital anomalies caused by drug substrates of this transporter. We now explore the role of other placental transporter proteins.A population-based case-referent study was performed using cases with congenital anomalies (N = 5,131 from EUROCAT Northern Netherlands, a registry of congenital anomalies. The referent population (N = 31,055 was selected from the pregnancy IADB.nl, a pharmacy prescription database.Ten placental transporters known to have comparable expression levels in the placenta to that of P-gp, were selected in this study. In total, 147 drugs were identified to be substrates, inhibitors or inducers, of these transporters. Fifty-eight of these drugs were used by at least one mother in our cases or referent population, and 28 were used in both. The highest user rate was observed for the substrates of multidrug resistance-associated protein 1, mainly folic acid (6% of cases, 8% of referents, and breast cancer resistance protein, mainly nitrofurantoin (2.3% of cases, 2.9% of referents. In contrast to P-gp, drug interactions involving substrates of these transporters did not have a significant effect on the risk of congenital anomalies.Some of the drugs which are substrates or inhibitors of placental transporters were commonly used during pregnancy. No significant effect of transporter inhibition was found on fetal drug exposure, possibly due to a limited number of exposures.
Lightweight Monorail Transport System
Weir, Harold F.; Wood, Kenneth E.; Strecker, Myron T.
1987-01-01
Report proposes monorail transportation system for zero-gravity environment. System carries materials and parts between locations on space station. Includes tubular rails instead of open channels usually found in overhead conveyor systems. Since resistance to torque of closed tube greater than that of open channel for same amount of material, tubular monorail designed for higher loads or for greater spacing between support points.
Phylogenetic analysis of fungal ABC transporters
Kovalchuk, A.; Driessen, A.J.M.
2010-01-01
Background: The superfamily of ABC proteins is among the largest known in nature. Its members are mainly, but not exclusively, involved in the transport of a broad range of substrates across biological membranes. Many contribute to multidrug resistance in microbial pathogens and cancer cells. The
Nanoscale hotspots due to nonequilibrium thermal transport
International Nuclear Information System (INIS)
Sinha, Sanjiv; Goodson, Kenneth E.
2004-01-01
Recent experimental and modeling efforts have been directed towards the issue of temperature localization and hotspot formation in the vicinity of nanoscale heat generating devices. The nonequilibrium transport conditions which develop around these nanoscale devices results in elevated temperatures near the heat source which can not be predicted by continuum diffusion theory. Efforts to determine the severity of this temperature localization phenomena in silicon devices near and above room temperature are of technological importance to the development of microelectronics and other nanotechnologies. In this work, we have developed a new modeling tool in order to explore the magnitude of the additional thermal resistance which forms around nanoscale hotspots from temperatures of 100-1000K. The models are based on a two fluid approximation in which thermal energy is transferred between ''stationary'' optical phonons and fast propagating acoustic phonon modes. The results of the model have shown excellent agreement with experimental results of localized hotspots in silicon at lower temperatures. The model predicts that the effect of added thermal resistance due to the nonequilibrium phonon distribution is greatest at lower temperatures, but is maintained out to temperatures of 1000K. The resistance predicted by the numerical code can be easily integrated with continuum models in order to predict the temperature distribution around nanoscale heat sources with improved accuracy. Additional research efforts also focused on the measurements of the thermal resistance of silicon thin films at higher temperatures, with a focus on polycrystalline silicon. This work was intended to provide much needed experimental data on the thermal transport properties for micro and nanoscale devices built with this material. Initial experiments have shown that the exposure of polycrystalline silicon to high temperatures may induce recrystallization and radically increase the thermal
Cha, Hi-jea; Müller, Reinke T; Pos, Klaas M
2014-08-01
Multidrug efflux transporters recognize a variety of structurally unrelated compounds for which the molecular basis is poorly understood. For the resistance nodulation and cell division (RND) inner membrane component AcrB of the AcrAB-TolC multidrug efflux system from Escherichia coli, drug binding occurs at the access and deep binding pockets. These two binding areas are separated by an 11-amino-acid-residue-containing switch loop whose conformational flexibility is speculated to be essential for drug binding and transport. A G616N substitution in the switch loop has a distinct and local effect on the orientation of the loop and on the ability to transport larger drugs. Here, we report a distinct phenotypical pattern of drug recognition and transport for the G616N variant, indicating that drug substrates with minimal projection areas of >70 Å(2) are less well transported than other substrates. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
Wang, De-Shen; Patel, Atish; Shukla, Suneet; Zhang, Yun-Kai; Wang, Yi-Jun; Kathawala, Rishil J; Robey, Robert W; Zhang, Li; Yang, Dong-Hua; Talele, Tanaji T; Bates, Susan E; Ambudkar, Suresh V; Xu, Rui-Hua; Chen, Zhe-Sheng
2014-06-30
ABCG2 is a potential biomarker causing multidrug resistance (MDR) in Non-Small Cell Lung Cancer (NSCLC). We conducted this study to investigate whether Icotinib, a small-molecule inhibitor of EGFR tyrosine kinase, could interact with ABCG2 transporter in NSCLC. Our results showed that Icotinib reversed ABCG2-mediated MDR by antagonizing the drug efflux function of ABCG2. Icotinib stimulated the ATPase activity in a concentration-dependent manner and inhibited the photolabeling of ABCG2 with [125I]-Iodoarylazidoprazosin, demonstrating that it interacts at the drug-binding pocket. Homology modeling predicted the binding conformation of Icotinib at Asn629 centroid-based grid of ABCG2. However, Icotinib at reversal concentration did not affect the expression levels of AKT and ABCG2. Furthermore, a combination of Icotinib and topotecan exhibited significant synergistic anticancer activity against NCI-H460/MX20 tumor xenografts. However, the inhibition of transport activity of ABCG2 was insufficient to overcome pemetrexed resistance in NCI-H460/MX20 cells, which was due to the co-upregulated thymidylate synthase (TS) and ABCG2 expression. This is the first report to show that the up-regulation of TS in ABCG2-overexpressing cell line NCI-H460/MX20 may play a role of resistance to pemetrexate. Our findings suggested different possible strategies of overcoming the resistance of topotecan and pemetrexed in the NSCLC patients.
International Nuclear Information System (INIS)
Lipperheide, R.; Wille, U.
2006-01-01
A theory of spin-polarized electron transport in ferromagnet-semiconductor heterostructures, based on a unified semiclassical description of ballistic and diffusive transport in semiconductors, is outlined. The aim is to provide a framework for studying the interplay of spin relaxation and transport mechanism in spintronic devices. Transport inside the (nondegenerate) semiconductor is described in terms of a thermoballistic current, in which electrons move ballistically in the electric field arising from internal and external electrostatic potentials, and are thermalized at randomly distributed equilibration points. Spin relaxation is allowed to take place during the ballistic motion. For arbitrary potential profile and arbitrary values of the momentum and spin relaxation lengths, an integral equation for a spin transport function determining the spin polarization in the semiconductor is derived. For field-driven transport in a homogeneous semiconductor, the integral equation can be converted into a second-order differential equation that generalizes the spin drift-diffusion equation. The spin polarization in ferromagnet-semiconductor structures is obtained by matching the spin-resolved chemical potentials at the interfaces, with allowance for spin-selective interface resistances. Illustrative examples are considered
Resistivity of thiol-modified gold thin films
International Nuclear Information System (INIS)
Correa-Puerta, Jonathan; Del Campo, Valeria; Henríquez, Ricardo; Häberle, Patricio
2014-01-01
In this work, we study the effect of thiol self assembled monolayers on the electrical resistivity of metallic thin films. The analysis is based on the Fuchs–Sondheimer–Lucas theory and on electrical transport measurements. We determined resistivity change due to dodecanethiol adsorption on gold thin films. For this purpose, we controlled the deposition and annealing temperatures of the films to change the surface topography and to diminish the effect of electron grain boundary scattering. Results show that the electrical response to the absorption of thiols strongly depends on the initial topography of the surface. - Highlights: • We study the effect of self assembled monolayers on the resistivity of thin films. • Fuchs–Sondheimer theory reproduces the resistivity increase due to thiol deposition. • We determined resistivity change due to dodecanethiol deposition on gold thin films. • The electrical response strongly depends on the substrate surface topography
Resistivity of thiol-modified gold thin films
Energy Technology Data Exchange (ETDEWEB)
Correa-Puerta, Jonathan [Instituto de Física, Pontificia Universidad Católica de Valparaíso, Av. Universidad 330, Curauma, Valparaíso (Chile); Del Campo, Valeria [Departamento de Física, Universidad Técnica Federico Santa María, Av. España 1680, Valparaiso 2390123 (Chile); Henríquez, Ricardo, E-mail: ricardo.henriquez@usm.cl [Departamento de Física, Universidad Técnica Federico Santa María, Av. España 1680, Valparaiso 2390123 (Chile); Häberle, Patricio [Departamento de Física, Universidad Técnica Federico Santa María, Av. España 1680, Valparaiso 2390123 (Chile)
2014-11-03
In this work, we study the effect of thiol self assembled monolayers on the electrical resistivity of metallic thin films. The analysis is based on the Fuchs–Sondheimer–Lucas theory and on electrical transport measurements. We determined resistivity change due to dodecanethiol adsorption on gold thin films. For this purpose, we controlled the deposition and annealing temperatures of the films to change the surface topography and to diminish the effect of electron grain boundary scattering. Results show that the electrical response to the absorption of thiols strongly depends on the initial topography of the surface. - Highlights: • We study the effect of self assembled monolayers on the resistivity of thin films. • Fuchs–Sondheimer theory reproduces the resistivity increase due to thiol deposition. • We determined resistivity change due to dodecanethiol deposition on gold thin films. • The electrical response strongly depends on the substrate surface topography.
Understanding the resistivity and absolute thermoelectric power of disordered metals and alloys
International Nuclear Information System (INIS)
Gasser, Jean-Georges
2008-01-01
We recall definitions of the electronic transport properties, direct coefficients like electrical and thermal transport conductivities and crossed thermoelectric coefficients like the Seebeck, Peltier and Thomson coefficients. We discuss the links between the different electronic transport coefficients and the experimental problems in measuring these properties in liquid metals. The electronic transport properties are interpreted in terms of the scattering of electrons by 'pseudo-atoms'. The absolute thermoelectric power (ATP), thermopower or Seebeck coefficient is known as the derivative of the electrical resistivity versus energy. The key is to understand the concept of resistivity versus energy. We show that the resistivity follows approximately a 1/E curve. The structure factor modulates this curve and, for a Fermi energy corresponding to noble and divalent metals, induces a positive thermopower when the free electron theory predicts a negative one. A second modulation is introduced by the pseudopotential squared form factor or equivalently by the squared t matrix of the scattering potential. This term sometimes introduces an anti-resonance (divalent metals) which lowers the resistivity, and sometimes a resonance having an important effect on the transition metals. Following the position of the Fermi energy, the thermopower can be positive or negative. For heavy semi-metals, the density of states splits into an s and a p band, themselves different from a free electron E 0.5 curve. The electrons available to be scattered enter the Ziman formula. Thus if the density of states is not a free electron one, a third modulation of the ρ ≅ 1/E curve is needed, which also can change the sign of the thermopower. For alloys, different contributions weighted by the concentrations are needed to explain the concentration dependent resistivity or thermopower. The formalism is the same for amorphous metals. It is possible that this mechanism can be extended to high
Thermodynamic Resistance to Matter Flow at The Interface of a Porous Membrane.
Glavatskiy, K S; Bhatia, Suresh K
2016-04-12
Nanoporous materials are important in industrial separation, but their application is subject to strong interfacial barriers to the entry and transport of fluids. At certain conditions the fluid inside and outside the nanoporous material can be viewed as a two-phase system, with an interface between them, which poses an excess resistance to matter flow. We show that there exist two kinds of phenomena which influence the interfacial resistance: hydrodynamic effects and thermodynamic effects, which are independent of each other. Here, we investigate the role of the thermodynamic effects in carbon nanotubes (CNTs) and slit pores and compare the associated thermodynmic resistance with that due to hydrodynamic effects traditionally modeled by the established Sampson expression. Using CH4 and CO2 as model fluids, we show that the thermodynamic resistance is especially important for moderate to high pressures, at which the fluid within the CNT or slit pore is in the condensed state. Further, we show that at such pressures the thermodynamic resistance becomes comparable with the internal resistance to fluid transport at length scales typical of membranes used in fuel cells, and of importance in membrane-based separation, and nanofluidics in general.
Surface proton transport of fully protonated poly(aspartic acid) thin films on quartz substrates
Nagao, Yuki; Kubo, Takahiro
2014-12-01
Thin film structure and the proton transport property of fully protonated poly(aspartic acid) (P-Asp100) have been investigated. An earlier study assessed partially protonated poly(aspartic acid), highly oriented thin film structure and enhancement of the internal proton transport. In this study of P-Asp100, IR p-polarized multiple-angle incidence resolution (P-MAIR) spectra were measured to investigate the thin film structure. The obtained thin films, with thicknesses of 120-670 nm, had no oriented structure. Relative humidity dependence of the resistance, proton conductivity, and normalized resistance were examined to ascertain the proton transport property of P-Asp100 thin films. The obtained data showed that the proton transport of P-Asp100 thin films might occur on the surface, not inside of the thin film. This phenomenon might be related with the proton transport of the biological system.
Effect of the interface resistance in non-local Hanle measurements
International Nuclear Information System (INIS)
Villamor, Estitxu; Hueso, Luis E.; Casanova, Fèlix
2015-01-01
We use lateral spin valves with varying interface resistance to measure non-local Hanle effect in order to extract the spin-diffusion length of the non-magnetic channel. A general expression that describes spin injection and transport, taking into account the influence of the interface resistance, is used to fit our results. Whereas the fitted spin-diffusion length value is in agreement with the one obtained from standard non-local measurements in the case of a finite interface resistance, in the case of transparent contacts a clear disagreement is observed. The use of a corrected expression, recently proposed to account for the anisotropy of the spin absorption at the ferromagnetic electrodes, still yields a deviation of the fitted spin-diffusion length which increases for shorter channel distances. This deviation shows how sensitive the non-local Hanle fittings are, evidencing the complexity of obtaining spin transport information from such type of measurements
Functional imaging of the multidrug resistance in vivo
International Nuclear Information System (INIS)
Lee, Jae Tae
2001-01-01
Although diverse mechanisms are involved in multidrug resistance for chemotherapeutic drugs, the development of cellular P-glycoprotein(Pgp) and multidrug-resistance associated protein (MRP) are improtant factors in the chemotherapy failure to cancer. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However these methods do not yield information about dynamic function of Pgp and MRP in vivo. Single photon emission tomograpy (SPECT) and positron emission tomograpy (PET) are available for the detection of Pgp and MRP-mediated transport. 99m Tc-sestaMIBI and other 99m Tc-radiopharmaceuticals are substrates for Pgp and MRP, and have been used in clinical studies of tumor imaging, and to visualize blockade of Pgp-mediated transport after modulation of Pgp pump. Colchicine, verapamil and daunorubicin labeled with 11 C have been evaluated for the quantification of Pgp-mediated transport with PET in vivo and reported to be feasible substrates with which to image Pgp function in tumors. Leukotrienes are specific substrates for MRP and N- (11 C]acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively in vivo. Results obtained from recent publications are reviewed to confirm the feasibility of using SPECT and PET to study the functionality of MDR transportes in vivo
Composite Transport Model and Water and Solute Transport across Plant Roots: An Update.
Kim, Yangmin X; Ranathunge, Kosala; Lee, Seulbi; Lee, Yejin; Lee, Deogbae; Sung, Jwakyung
2018-01-01
The present review examines recent experimental findings in root transport phenomena in terms of the composite transport model (CTM). It has been a well-accepted conceptual model to explain the complex water and solute flows across the root that has been related to the composite anatomical structure. There are three parallel pathways involved in the transport of water and solutes in roots - apoplast, symplast, and transcellular paths. The role of aquaporins (AQPs), which facilitate water flows through the transcellular path, and root apoplast is examined in terms of the CTM. The contribution of the plasma membrane bound AQPs for the overall water transport in the whole plant level was varying depending on the plant species, age of roots with varying developmental stages of apoplastic barriers, and driving forces (hydrostatic vs. osmotic). Many studies have demonstrated that the apoplastic barriers, such as Casparian bands in the primary anticlinal walls and suberin lamellae in the secondary cell walls, in the endo- and exodermis are not perfect barriers and unable to completely block the transport of water and some solute transport into the stele. Recent research on water and solute transport of roots with and without exodermis triggered the importance of the extension of conventional CTM adding resistances that arrange in series (epidermis, exodermis, mid-cortex, endodermis, and pericycle). The extension of the model may answer current questions about the applicability of CTM for composite water and solute transport of roots that contain complex anatomical structures with heterogeneous cell layers.
The role of contact resistance in graphene field-effect devices
Giubileo, Filippo; Di Bartolomeo, Antonio
2017-08-01
The extremely high carrier mobility and the unique band structure, make graphene very useful for field-effect transistor applications. According to several works, the primary limitation to graphene based transistor performance is not related to the material quality, but to extrinsic factors that affect the electronic transport properties. One of the most important parasitic element is the contact resistance appearing between graphene and the metal electrodes functioning as the source and the drain. Ohmic contacts to graphene, with low contact resistances, are necessary for injection and extraction of majority charge carriers to prevent transistor parameter fluctuations caused by variations of the contact resistance. The International Technology Roadmap for Semiconductors, toward integration and down-scaling of graphene electronic devices, identifies as a challenge the development of a CMOS compatible process that enables reproducible formation of low contact resistance. However, the contact resistance is still not well understood despite it is a crucial barrier towards further improvements. In this paper, we review the experimental and theoretical activity that in the last decade has been focusing on the reduction of the contact resistance in graphene transistors. We will summarize the specific properties of graphene-metal contacts with particular attention to the nature of metals, impact of fabrication process, Fermi level pinning, interface modifications induced through surface processes, charge transport mechanism, and edge contact formation.
Miyazaki, Haruko; Miyazaki, Yoshitsugu; Geber, Antonia; Parkinson, Tanya; Hitchcock, Christopher; Falconer, Derek J.; Ward, Douglas J.; Marsden, Katherine; Bennett, John E.
1998-01-01
Sequential Candida glabrata isolates were obtained from the mouth of a patient infected with human immunodeficiency virus type 1 who was receiving high doses of fluconazole for oropharyngeal thrush. Fluconazole-susceptible colonies were replaced by resistant colonies that exhibited both increased fluconazole efflux and increased transcripts of a gene which codes for a protein with 72.5% identity to Pdr5p, an ABC multidrug transporter in Saccharomyces cerevisiae. The deduced protein had a molecular mass of 175 kDa and was composed of two homologous halves, each with six putative transmembrane domains and highly conserved sequences of ATP-binding domains. When the earliest and most azole-susceptible isolate of C. glabrata from this patient was exposed to fluconazole, increased transcripts of the PDR5 homolog appeared, linking azole exposure to regulation of this gene. PMID:9661006
IncA/C plasmids conferring high azithromycin resistance in vibrio cholerae.
Wang, Ruibai; Liu, Haican; Zhao, Xiuqin; Li, Jie; Wan, Kanglin
2018-01-01
Azithromycin (AZM) is a clinically important antibiotic against Vibrio cholerae, especially for inhibiting V. cholerae colonisation of the intestine and for the treatment of severe cholera in children and pregnant women. An IncA/C plasmid was isolated from two high minimum inhibitory concentration (MIC) AZM-resistant V. cholerae strains of the two mainly pathogenic serogroups (O1 and O139) isolated in China. In the 172 predicted open reading frames (ORFs), 16 genes were related to antibiotic resistance, of which 5 were well-defined genes associated with macrolide resistance. The five macrolide resistance genes distributed in two clusters, mphR-mrx-mph(K) and mel-mph2, flanked by insertion sequence elements and involving two kinds of resistance mechanism. Deletion of the complete region of the two clusters deceased the AZM MIC from ≥64 µg/mL to ≤0.5 µg/mL. This IncA/C plasmid shows great ability to accumulate antibiotic resistance genes. In addition to 11 resistance genes to other antibiotics, 5 macrolide resistance genes with different function were gathered repeatedly through transposition on one plasmid. This genotype could not be simply explained by antibiotic stress applied on the host from the environment or treatment. These phosphorylases and transmembrane transporters might be involved in the transport and metabolism of other non-antibiotic substances, enabling this kind of plasmid to propagate better in the host. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
Sagova-Mareckova, Marketa; Ulanova, Dana; Sanderova, Petra; Omelka, Marek; Kamenik, Zdenek; Olsovska, Jana; Kopecky, Jan
2015-04-01
Distribution and evolutionary history of resistance genes in environmental actinobacteria provide information on intensity of antibiosis and evolution of specific secondary metabolic pathways at a given site. To this day, actinobacteria producing biologically active compounds were isolated mostly from soil but only a limited range of soil environments were commonly sampled. Consequently, soil remains an unexplored environment in search for novel producers and related evolutionary questions. Ninety actinobacteria strains isolated at contrasting soil sites were characterized phylogenetically by 16S rRNA gene, for presence of erm and ABC transporter resistance genes and antibiotic production. An analogous analysis was performed in silico with 246 and 31 strains from Integrated Microbial Genomes (JGI_IMG) database selected by the presence of ABC transporter genes and erm genes, respectively. In the isolates, distances of erm gene sequences were significantly correlated to phylogenetic distances based on 16S rRNA genes, while ABC transporter gene distances were not. The phylogenetic distance of isolates was significantly correlated to soil pH and organic matter content of isolation sites. In the analysis of JGI_IMG datasets the correlation between phylogeny of resistance genes and the strain phylogeny based on 16S rRNA genes or five housekeeping genes was observed for both the erm genes and ABC transporter genes in both actinobacteria and streptomycetes. However, in the analysis of sequences from genomes where both resistance genes occurred together the correlation was observed for both ABC transporter and erm genes in actinobacteria but in streptomycetes only in the erm gene. The type of erm resistance gene sequences was influenced by linkage to 16S rRNA gene sequences and site characteristics. The phylogeny of ABC transporter gene was correlated to 16S rRNA genes mainly above the genus level. The results support the concept of new specific secondary metabolite
Energy Technology Data Exchange (ETDEWEB)
Kim, Jaekwang; Kim, Daeun; Lee, Ilbok; Son, Hyungbin; Lee, Donghyun; Yoon, Songhun [Chung-Ang University, Seoul (Korea, Republic of); Shim, Hyewon [Korea Institute of Nuclear Nonproliferation and Control, Daejeon (Korea, Republic of); Lee, Jinwoo [POSTECH, Pohang (Korea, Republic of)
2016-02-15
Hexagonally ordered mesoporous carbon materials were prepared and used as electrode materials in an electric double-layer capacitor. Using this electrode, the change of electrolyte resistance within the mesopores was investigated according to the bulk electrolyte concentration. Using three different electrochemical transient experiments-imaginary capacitance analysis, chronoamperometry, and hronopotentiometry-the time constant associated with electrolyte transport was determined, which was then used to obtain the electrolyte resistance within the mesopores. With decreasing electrolyte concentration, the increase in electrolyte resistance was smaller than the increase in the resistivity of the bulk electrolyte, which is indicative of a different environment for ionic transport within the mesopores. On using the confinement effect within the mesopores, the predicted higher concentration within mesopore probably results in lower electrolyte resistance, especially under low bulk concentrations.
Electronic transport in narrow-gap semiconductor nanowires
International Nuclear Information System (INIS)
Bloemers, Christian
2012-01-01
Throughout this work the electronic transport properties of InAs, InN, and GaAs/InAs core/shell nanowires have been analyzed. This includes the analysis of specific resistivity at room temperature and low temperatures as well as the breakdown of resistivity by a contribution of mobility and carrier concentration using gate measurements. While the InN nanowires showed homogeneous transport properties, there was a large statistical spread in the properties of InAs nanowires. Differing crystal structures and the surface conditions are identified to be the main reasons for the statistical spread. Both quantities of influence have been pointed out by comparing the transport parameters before and after a surface treatment (electron irradiation and long time ambient air exposure), and by comparing the transport parameters of wires grown by different growth methods which exhibit different kinds of crystal structure. In particular, the temperature dependence of the conductivity revealed different activation energies in nanowires with differing crystal structures. An explanation has been suggested in terms of stacking fault induced potential barriers. A field-effect measurement setup has been utilized to determine the nanowire mobility and carrier concentration. Even though this method is widely used for nanowires, it is subject to a serious disadvantage concerning the influence of surface and interface states on the measurements. As an alternative method which does not suffer from this drawback, Hall measurements have been successfully performed on InAs nanowires for the first time. These measurements became possible because of the utilization of a new electron beam lithographic procedure with an alignment accuracy in the 5 nm range. Carrier concentration values could be determined and compared to the ones obtained from conventional field-effect measurements. The results of the Hall measurements revealed a methodical overestimation of the carrier concentrations obtained
Electronic transport in narrow-gap semiconductor nanowires
Energy Technology Data Exchange (ETDEWEB)
Bloemers, Christian
2012-10-19
Throughout this work the electronic transport properties of InAs, InN, and GaAs/InAs core/shell nanowires have been analyzed. This includes the analysis of specific resistivity at room temperature and low temperatures as well as the breakdown of resistivity by a contribution of mobility and carrier concentration using gate measurements. While the InN nanowires showed homogeneous transport properties, there was a large statistical spread in the properties of InAs nanowires. Differing crystal structures and the surface conditions are identified to be the main reasons for the statistical spread. Both quantities of influence have been pointed out by comparing the transport parameters before and after a surface treatment (electron irradiation and long time ambient air exposure), and by comparing the transport parameters of wires grown by different growth methods which exhibit different kinds of crystal structure. In particular, the temperature dependence of the conductivity revealed different activation energies in nanowires with differing crystal structures. An explanation has been suggested in terms of stacking fault induced potential barriers. A field-effect measurement setup has been utilized to determine the nanowire mobility and carrier concentration. Even though this method is widely used for nanowires, it is subject to a serious disadvantage concerning the influence of surface and interface states on the measurements. As an alternative method which does not suffer from this drawback, Hall measurements have been successfully performed on InAs nanowires for the first time. These measurements became possible because of the utilization of a new electron beam lithographic procedure with an alignment accuracy in the 5 nm range. Carrier concentration values could be determined and compared to the ones obtained from conventional field-effect measurements. The results of the Hall measurements revealed a methodical overestimation of the carrier concentrations obtained
Metallic electrical transport in inter-graphitic planes of an individual tubular carbon nanocone
Energy Technology Data Exchange (ETDEWEB)
Wang, Q; Gao, R X; Qu, S L [Department of Optics and Electronics Science, Harbin Institute of Technology at Wei Hai, Weihai 264209 (China); Li, J J; Gu, C Z [Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100080 (China)], E-mail: wq19750505@tom.com
2009-04-08
Tubular carbon cones (TCCs) with a herring-bone-like graphitic structure are synthesized on gold wire via the bias-assisted hot filament chemical vapor deposition (HFCVD) method. The electrical transport properties of an individual TCC are studied in the temperature range from 300 to 500 K by using a double probe scanning electron microscopy (DPSEM) in situ electrical measurement system. The high-resistance I-V characteristics of W-TCC-Au back-to-back double junctions show that electrons tunnel through the W-TCC junction, while thermoionic transport through the Au-TCC junction contributes to low-resistance properties. Temperature dependence of the electrical characteristics indicates that inter-graphitic-plane electrical transport in TCC is metallic.
Probing electrical transport in individual carbon nanotubes and junctions
International Nuclear Information System (INIS)
Kim, Tae-Hwan; Wendelken, John F; Li Anping; Du Gaohui; Li Wenzhi
2008-01-01
The electrical transport properties of individual carbon nanotubes (CNTs) and multi-terminal junctions of CNTs are investigated with a quadraprobe scanning tunneling microscope. The CNTs used in this study are made of stacked herringbone-type conical graphite sheets with a cone angle of ∼20 deg. to the tube axis, and the CNT junctions have no catalytic particles in the junction areas. The CNTs have a significantly higher resistivity than conventional CNTs with concentric walls. The straight CNTs display linear current-voltage (I-V) characteristics, indicating diffusive transport rather than ballistic transport. The structural deformation in CNTs with bends substantially increases the resistivity in comparison with that for the straight segments on the same CNTs, and the I-V curve departs slightly from linearity in curved segments. The junction area of the CNT junctions behaves like an ohmic-type scattering center with linear I-V characteristics. In addition, a gating effect has not been observed, in contrast to the case for conventional multi-walled CNT junctions. These unusual transport properties can be attributed to the enhanced inter-layer interaction in the herringbone-type CNTs.
Flavonoids as modulators of metabolic enzymes and drug transporters.
Miron, Anca; Aprotosoaie, Ana Clara; Trifan, Adriana; Xiao, Jianbo
2017-06-01
Flavonoids, natural compounds found in plants and in plant-derived foods and beverages, have been extensively studied with regard to their capacity to modulate metabolic enzymes and drug transporters. In vitro, flavonoids predominantly inhibit the major phase I drug-metabolizing enzyme CYP450 3A4 and the enzymes responsible for the bioactivation of procarcinogens (CYP1 enzymes) and upregulate the enzymes involved in carcinogen detoxification (UDP-glucuronosyltransferases, glutathione S-transferases (GSTs)). Flavonoids have been reported to inhibit ATP-binding cassette (ABC) transporters (multidrug resistance (MDR)-associated proteins, breast cancer-resistance protein) that contribute to the development of MDR. P-glycoprotein, an ABC transporter that limits drug bioavailability and also induces MDR, was differently modulated by flavonoids. Flavonoids and their phase II metabolites (sulfates, glucuronides) inhibit organic anion transporters involved in the tubular uptake of nephrotoxic compounds. In vivo studies have partially confirmed in vitro findings, suggesting that the mechanisms underlying the modulatory effects of flavonoids are complex and difficult to predict in vivo. Data summarized in this review strongly support the view that flavonoids are promising candidates for the enhancement of oral drug bioavailability, chemoprevention, and reversal of MDR. © 2017 New York Academy of Sciences.
Chen, Lin; Cao, Zhao-long; Han, Fang; Gao, Zhan-cheng; He, Quan-ying
2010-02-20
The persistence of sleep disordered breathing (SDB) symptoms after tonsil and/or adenoid (T&A) surgery are common in children with obstructive sleep apnea (OSA). We tested the hypothesis that disturbances of glucose transporters (GLUTs) in intraabdominal adipose tissue caused by chronic intermittent hypoxia (CIH) from the pedo-period could facilitate the appearance of periphery insulin resistance in Sprague-Dawley (SD) rats. We tested the hypothesis that the changes of GLUTs in adipose tissue may be one of the reasons for persistent SDB among clinical OSA children after T&A surgery. Thirty 21-day-old SD rats were randomly divided into a CIH group, a chronic continuous hypoxia (CCH) group, and a normal oxygen group (control group) and exposed for 40 days. The changes of weight, fasting blood glucose and fasting blood insulin levels were measured. Hyperinsulinemic-euglycemic clamp techniques were used to measure insulin resistance in each animal. Real-time quantitative PCR and Western blotting were used to measure GLUT mRNA and proteins in intraabdominal adipose tissue. Additional intraabdomial white adipose tissue (WAT) was also processed into paraffin sections and directly observed for GLUTs1-4 expression. When compared with control group, CIH increased blood fasting insulin levels, (245.07 +/- 53.89) pg/ml vs. (168.63 +/- 38.70) pg/ml, P = 0.038, and decreased the mean glucose infusion rate (GIR), (7.25 +/- 1.29) mg x kg(-1) x min(-1) vs. (13.34 +/- 1.54) mg x kg(-1) x min(-1), P < 0.001. GLUT-4 mRNA and protein expression was significantly reduced after CIH compared with CCH or normal oxygen rats, 0.002 +/- 0.002 vs. 0.039 +/- 0.009, P < 0.001; 0.642 +/- 0.073 vs. 1.000 +/- 0.103, P = 0.035. CIH in young rats could induce insulin resistance via adverse effects on glycometabolism. These findings emphasize the importance of early detection and treatment of insulin insensitivity in obese childhood OSA.
Drug efflux proteins in multidrug resistant bacteria
vanVeen, HW; Konings, WN
Bacteria contain an array of transport proteins in their cytoplasmic membrane. Many of these proteins play an important role in conferring resistance to toxic compounds. The multidrug efflux systems encountered in prokaryotic cells are very similar to those observed in eukaryotic cells. Therefore, a
Energy Technology Data Exchange (ETDEWEB)
Marignac, Y.; Coeytaux, X. [Wise-Paris, 75 (France); Large, J.H. [Nuclear Engineer, Large and Associates, Londres (United Kingdom)
2004-09-15
This report concerns the safety and the protection of plutonium dioxide transported from Cogema La Hague to the mixed oxide fuel plant of Marcoule and Cadarache. The French approach of the transport safety is based on the combining of two essential principles: the first one affirms that the performances of the FS47 container in regard of containment (norms TS-R-1 from IAEA for the accidental conditions) is conceived to resist in any situation even terrorism or sabotage. In fact, the IAEA norm follows a probabilistic study without a voluntary attack such a terrorist one. The second principle rests on the ability to prevent the treat of terrorism acts, because of a secrecy policy on the plutonium transport. It appeared that the Green peace association has succeeded several times to know exactly the hours, the trips of the plutonium transport and this simple thing raises more questions than it solves. (N.C.)
Temperature relaxation and the Kapitza boundary resistance paradox
Brink, Alec Maassen van den; Dekker, H.
1994-01-01
The calculation of the Kapitza boundary resistance between dissimilar harmonic solids has since long (Little [Can. J. Phys. 37, 334 (1959)]) suffered from a paradox: this resistance erroneously tends to a finite value in the limit of identical solids. We resolve this paradox by calculating temperature differences in the final heat-transporting state, rather than with respect to the initial state of local equilibrium. For a one-dimensional model we thus derive an exact, paradox-free formula fo...
Hassan, Karl A; Liu, Qi; Henderson, Peter J F; Paulsen, Ian T
2015-02-10
Multidrug efflux systems are a major cause of resistance to antimicrobials in bacteria, including those pathogenic to humans, animals, and plants. These proteins are ubiquitous in these pathogens, and five families of bacterial multidrug efflux systems have been identified to date. By using transcriptomic and biochemical analyses, we recently identified the novel AceI (Acinetobacter chlorhexidine efflux) protein from Acinetobacter baumannii that conferred resistance to the biocide chlorhexidine, via an active efflux mechanism. Proteins homologous to AceI are encoded in the genomes of many other bacterial species and are particularly prominent within proteobacterial lineages. In this study, we expressed 23 homologs of AceI and examined their resistance and/or transport profiles. MIC analyses demonstrated that, like AceI, many of the homologs conferred resistance to chlorhexidine. Many of the AceI homologs conferred resistance to additional biocides, including benzalkonium, dequalinium, proflavine, and acriflavine. We conducted fluorimetric transport assays using the AceI homolog from Vibrio parahaemolyticus and confirmed that resistance to both proflavine and acriflavine was mediated by an active efflux mechanism. These results show that this group of AceI homologs represent a new family of bacterial multidrug efflux pumps, which we have designated the proteobacterial antimicrobial compound efflux (PACE) family of transport proteins. Bacterial multidrug efflux pumps are an important class of resistance determinants that can be found in every bacterial genome sequenced to date. These transport proteins have important protective functions for the bacterial cell but are a significant problem in the clinical setting, since a single efflux system can mediate resistance to many structurally and mechanistically diverse antibiotics and biocides. In this study, we demonstrate that proteins related to the Acinetobacter baumannii AceI transporter are a new class of multidrug
Genetic architecture of artemisinin-resistant Plasmodium falciparum
Miotto, Olivo; Amato, Roberto; Ashley, Elizabeth A; MacInnis, Bronwyn; Almagro-Garcia, Jacob; Amaratunga, Chanaki; Lim, Pharath; Mead, Daniel; Oyola, Samuel O; Dhorda, Mehul; Imwong, Mallika; Woodrow, Charles; Manske, Magnus; Stalker, Jim; Drury, Eleanor; Campino, Susana; Amenga-Etego, Lucas; Thanh, Thuy-Nhien Nguyen; Tran, Hien Tinh; Ringwald, Pascal; Bethell, Delia; Nosten, Francois; Phyo, Aung Pyae; Pukrittayakamee, Sasithon; Chotivanich, Kesinee; Chuor, Char Meng; Nguon, Chea; Suon, Seila; Sreng, Sokunthea; Newton, Paul N; Mayxay, Mayfong; Khanthavong, Maniphone; Hongvanthong, Bouasy; Htut, Ye; Han, Kay Thwe; Kyaw, Myat Phone; Faiz, Md Abul; Fanello, Caterina I; Onyamboko, Marie; Mokuolu, Olugbenga A; Jacob, Christopher G; Takala-Harrison, Shannon; Plowe, Christopher V; Day, Nicholas P; Dondorp, Arjen M; Spencer, Chris C A; McVean, Gilean; Fairhurst, Rick M; White, Nicholas J; Kwiatkowski, Dominic P
2015-01-01
We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population. PMID:25599401
Evers, R.; Kool, M.; Smith, A. J.; van Deemter, L.; de Haas, M.; Borst, P.
2000-01-01
The human multidrug transporter MDR1 P-glycoprotein and the multidrug resistance proteins MRP1 and MRP2 transport a range of cytotoxic drugs, resulting in multidrug resistance in tumour cells. To overcome this form of drug resistance in patients, several inhibitors (reversal agents) of these
Energy Technology Data Exchange (ETDEWEB)
Esser, Lothar; Shukla, Suneet; Zhou, Fei; Ambudkar, Suresh V.; Xia, Di
2016-07-27
P-glycoprotein (P-gp) is a polyspecific ATP-dependent transporter linked to multidrug resistance in cancers that plays important roles in the pharmacokinetics of a large number of drugs. The drug-resistance phenotype of P-gp can be modulated by the monoclonal antibody UIC2, which specifically recognizes human P-gp in a conformation-dependent manner. Here, the purification, sequence determination and high-resolution structure of the Fab fragment of UIC2 (UIC2/Fab) are reported. Purified UIC2/Fab binds human P-gp with a 1:1 stoichiometry. Crystals of UIC2/Fab are triclinic (space group
Directory of Open Access Journals (Sweden)
Goffeau André
2009-10-01
Full Text Available Abstract Background Pleiotropic Drug Resistant transporters (PDR are members of the ATP-Binding Cassette (ABC subfamily which export antifungals and other xenobiotics in fungi and plants. This subfamily of transmembrane transporters has nine known members in Saccharomyces cerevisiae. We have analyzed the complex evolution of the pleiotropic drug resistance proteins (Pdrp subfamily where gene duplications and deletions occur independently in individual genomes. This study was carried out on 62 Pdrp from nine hemiascomycetous species, seven of which span 6 of the 14 clades of the Saccharomyces complex while the two others species, Debaryomyces hansenii and Yarrowia lipolytica, are further apart from an evolutive point of view. Results Combined phylogenetic and neighborhood analyses enabled us to identify five Pdrp clusters in the Saccharomyces complex. Three of them comprise orthologs of the Pdrp sensu stricto, Pdr5p, Pdr10p, Pdr12p, Pdr15p, Snq2p and YNR070wp. The evolutive pathway of the orthologs of Snq2 and YNR070w is particularly complex due to a tandem gene array in Eremothecium gossypii, Kluyveromyces lactis and Saccharomyces (Lachancea kluyveri. This pathway and different cases of duplications and deletions were clarified by using a neighborhood analysis based on synteny. For the two distant species, Yarrowia lipolytica and Debaryomyces hansenii, no neighborhood evidence is available for these clusters and many homologs of Pdr5 and Pdr15 are phylogenetically assigned to species-based clusters. Two other clusters comprise the orthologs of the sensu lato Pdrp, Aus1p/Pdr11p and YOL075cp respectively. The evolutionary pathway of these clusters is simpler. Nevertheless, orthologs of these genes are missing in some species. Conclusion Numerous duplications were traced among the Hemiascomycetous Pdrp studied. The role of the Whole Genome Duplication (WGD is sorted out and our analyses confirm the common ancestrality of Pdr5p and Pdr15p. A tandem
Seret, Marie-Line; Diffels, Julie F; Goffeau, André; Baret, Philippe V
2009-10-01
Pleiotropic Drug Resistant transporters (PDR) are members of the ATP-Binding Cassette (ABC) subfamily which export antifungals and other xenobiotics in fungi and plants. This subfamily of transmembrane transporters has nine known members in Saccharomyces cerevisiae. We have analyzed the complex evolution of the pleiotropic drug resistance proteins (Pdrp) subfamily where gene duplications and deletions occur independently in individual genomes. This study was carried out on 62 Pdrp from nine hemiascomycetous species, seven of which span 6 of the 14 clades of the Saccharomyces complex while the two others species, Debaryomyces hansenii and Yarrowia lipolytica, are further apart from an evolutive point of view. Combined phylogenetic and neighborhood analyses enabled us to identify five Pdrp clusters in the Saccharomyces complex. Three of them comprise orthologs of the Pdrp sensu stricto, Pdr5p, Pdr10p, Pdr12p, Pdr15p, Snq2p and YNR070wp. The evolutive pathway of the orthologs of Snq2 and YNR070w is particularly complex due to a tandem gene array in Eremothecium gossypii, Kluyveromyces lactis and Saccharomyces (Lachancea) kluyveri. This pathway and different cases of duplications and deletions were clarified by using a neighborhood analysis based on synteny. For the two distant species, Yarrowia lipolytica and Debaryomyces hansenii, no neighborhood evidence is available for these clusters and many homologs of Pdr5 and Pdr15 are phylogenetically assigned to species-based clusters. Two other clusters comprise the orthologs of the sensu lato Pdrp, Aus1p/Pdr11p and YOL075cp respectively. The evolutionary pathway of these clusters is simpler. Nevertheless, orthologs of these genes are missing in some species. Numerous duplications were traced among the Hemiascomycetous Pdrp studied. The role of the Whole Genome Duplication (WGD) is sorted out and our analyses confirm the common ancestrality of Pdr5p and Pdr15p. A tandem gene array is observed in Eremothecium gossypii. One
Tutorial: Determination of thermal boundary resistance by molecular dynamics simulations
Liang, Zhi; Hu, Ming
2018-05-01
Due to the high surface-to-volume ratio of nanostructured components in microelectronics and other advanced devices, the thermal resistance at material interfaces can strongly affect the overall thermal behavior in these devices. Therefore, the thermal boundary resistance, R, must be taken into account in the thermal analysis of nanoscale structures and devices. This article is a tutorial on the determination of R and the analysis of interfacial thermal transport via molecular dynamics (MD) simulations. In addition to reviewing the commonly used equilibrium and non-equilibrium MD models for the determination of R, we also discuss several MD simulation methods which can be used to understand interfacial thermal transport behavior. To illustrate how these MD models work for various interfaces, we will show several examples of MD simulation results on thermal transport across solid-solid, solid-liquid, and solid-gas interfaces. The advantages and drawbacks of a few other MD models such as approach-to-equilibrium MD and first-principles MD are also discussed.
Surface proton transport of fully protonated poly(aspartic acid) thin films on quartz substrates
Energy Technology Data Exchange (ETDEWEB)
Nagao, Yuki, E-mail: ynagao@jaist.ac.jp; Kubo, Takahiro
2014-12-30
Graphical abstract: - Highlights: • Proton transport of fully protonated poly(aspartic acid) thin film was investigated. • The thin film structure differed greatly from the partially protonated one. • Proton transport occurs on the surface, not inside of the thin film. • This result contributes to biological transport systems such as bacteriorhodopsin. - Abstract: Thin film structure and the proton transport property of fully protonated poly(aspartic acid) (P-Asp100) have been investigated. An earlier study assessed partially protonated poly(aspartic acid), highly oriented thin film structure and enhancement of the internal proton transport. In this study of P-Asp100, IR p-polarized multiple-angle incidence resolution (P-MAIR) spectra were measured to investigate the thin film structure. The obtained thin films, with thicknesses of 120–670 nm, had no oriented structure. Relative humidity dependence of the resistance, proton conductivity, and normalized resistance were examined to ascertain the proton transport property of P-Asp100 thin films. The obtained data showed that the proton transport of P-Asp100 thin films might occur on the surface, not inside of the thin film. This phenomenon might be related with the proton transport of the biological system.
Surface proton transport of fully protonated poly(aspartic acid) thin films on quartz substrates
International Nuclear Information System (INIS)
Nagao, Yuki; Kubo, Takahiro
2014-01-01
Graphical abstract: - Highlights: • Proton transport of fully protonated poly(aspartic acid) thin film was investigated. • The thin film structure differed greatly from the partially protonated one. • Proton transport occurs on the surface, not inside of the thin film. • This result contributes to biological transport systems such as bacteriorhodopsin. - Abstract: Thin film structure and the proton transport property of fully protonated poly(aspartic acid) (P-Asp100) have been investigated. An earlier study assessed partially protonated poly(aspartic acid), highly oriented thin film structure and enhancement of the internal proton transport. In this study of P-Asp100, IR p-polarized multiple-angle incidence resolution (P-MAIR) spectra were measured to investigate the thin film structure. The obtained thin films, with thicknesses of 120–670 nm, had no oriented structure. Relative humidity dependence of the resistance, proton conductivity, and normalized resistance were examined to ascertain the proton transport property of P-Asp100 thin films. The obtained data showed that the proton transport of P-Asp100 thin films might occur on the surface, not inside of the thin film. This phenomenon might be related with the proton transport of the biological system
Catchment areas for public transport
DEFF Research Database (Denmark)
Andersen, Jonas Lohmann Elkjær; Landex, Alex
2008-01-01
In the planning of public transport catchment areas of stops are often included to estimate potential number of travellers. There are different approaches to GIS-based catchment area analyses depending on the desired level of detail. The Circular Buffer approach is the fundamental, but also....../from stations. The article also shows how the refinement of the Service Area approach with additional time resistance results in smaller catchment areas when the feeder routes cross stairs. It is concluded that GIS-based catchment area analyses are a multiple decision support tool for planning of public...... transport where the level of detail can be suited to the purpose....
Altered membrane permeability in multidrug resistant Escherichia ...
African Journals Online (AJOL)
The study was conducted with the objective of examining the outer membrane proteins and their involvement during the transport of β - lactams in multidrug resistant Escherichia coli isolated from extra-intestinal infections. Also, the response of gram negative bacterial biomembrane alteration was studied using extended ...
Composite Transport Model and Water and Solute Transport across Plant Roots: An Update
Directory of Open Access Journals (Sweden)
Yangmin X. Kim
2018-02-01
Full Text Available The present review examines recent experimental findings in root transport phenomena in terms of the composite transport model (CTM. It has been a well-accepted conceptual model to explain the complex water and solute flows across the root that has been related to the composite anatomical structure. There are three parallel pathways involved in the transport of water and solutes in roots – apoplast, symplast, and transcellular paths. The role of aquaporins (AQPs, which facilitate water flows through the transcellular path, and root apoplast is examined in terms of the CTM. The contribution of the plasma membrane bound AQPs for the overall water transport in the whole plant level was varying depending on the plant species, age of roots with varying developmental stages of apoplastic barriers, and driving forces (hydrostatic vs. osmotic. Many studies have demonstrated that the apoplastic barriers, such as Casparian bands in the primary anticlinal walls and suberin lamellae in the secondary cell walls, in the endo- and exodermis are not perfect barriers and unable to completely block the transport of water and some solute transport into the stele. Recent research on water and solute transport of roots with and without exodermis triggered the importance of the extension of conventional CTM adding resistances that arrange in series (epidermis, exodermis, mid-cortex, endodermis, and pericycle. The extension of the model may answer current questions about the applicability of CTM for composite water and solute transport of roots that contain complex anatomical structures with heterogeneous cell layers.
Nonvolatile resistive switching in Pt/laALO3/srTiO3 heterostructures
Wu, S.
2013-12-12
Resistive switching heterojunctions, which are promising for nonvolatile memory applications, usually share a capacitorlike metal-oxide-metal configuration. Here, we report on the nonvolatile resistive switching in Pt/LaAlO3/SrTiO3 heterostructures, where the conducting layer near the LaAlO3/SrTiO3 interface serves as the "unconventional"bottom electrode although both oxides are band insulators. Interestingly, the switching between low-resistance and high-resistance states is accompanied by reversible transitions between tunneling and Ohmic characteristics in the current transport perpendicular to the planes of the heterojunctions. We propose that the observed resistive switching is likely caused by the electric-field-induced drift of charged oxygen vacancies across the LaAlO3/SrTiO3 interface and the creation of defect-induced gap states within the ultrathin LaAlO3 layer. These metal-oxide-oxide heterojunctions with atomically smooth interfaces and defect-controlled transport provide a platform for the development of nonvolatile oxide nanoelectronics that integrate logic and memory devices.
Surface electrical resistivity of insulators
International Nuclear Information System (INIS)
Senn, B. C.; Liesegang, J.
1996-01-01
A method is presented here for measuring surface charge decay, and theory has been developed so as to produce determinations of resistivity in the surface region of insulator films or wafers. This method incorporates the use of a coaxial cylindrical capacitor arrangement and an electrometer interfaced to a PC. The charge transport theory given here is based on Mott-Gurney diffusion, and allows easy interpretation of the experimental data, especially for the initial phase of surface charge decay. Resistivity measurements are presented for glass, mica, perspex and polyethylene, covering a range of 10 9 to 10 18 Ωm, as an illustration of the useful range of the instrument for static and antistatic materials, particularly in film or sheet form. Values for the surface charge diffusion constants of the materials are also presented. The charge transport theory has also been extended to allow the experimental and computational theoretical comparison of surface charge decay not only over the initial phase of charge decay, but also over longer times. The theoretical predictions show excellent agreement with experiment using the values for the diffusion constants referred to above
DEFF Research Database (Denmark)
Andersen, Vibeke; Østergaard, Mette; Christensen, Jane
2009-01-01
(rs5275) polymorphisms in the 3'-untranslated region. The polymorphisms were assessed together with lifestyle factors in a nested case-cohort study of 359 cases and a random cohort sample of 765 participants from the Danish prospective Diet, Cancer and Health study. Results Carriers of the variant......Background The xenobiotic transporters, Multidrug Resistance 1 (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) may restrict intestinal absorption of various carcinogens, including heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH). Cyclooxygenase-2 (COX-2) derived...... prostaglandins promote gastrointestinal carcinogenesis, affecting angiogenesis, apoptosis, and invasiveness. The aim of this study was to investigate if polymorphisms in these genes were associated with risk of colorectal cancer (CRC), and to investigate possible interactions with lifestyle factors...
Growth and characterization of Bi2Se3 crystals by chemical vapor transport
Directory of Open Access Journals (Sweden)
W. H. Jiao
2012-06-01
Full Text Available Regularly-shaped high-quality Bi2Se3 crystals were grown by a chemical vapor transport using iodine as the transport agent. In addition to exhibiting a characteristic Dirac cone for a topological insulator, the Bi2Se3 crystals show some outstanding properties including additional crystallographic surfaces, large residual resistance ratio (∼10, and high mobility (∼8000 cm2·V−1·s−1. The low-temperature resistivity abnormally increases with applying pressures up to 1.7 GPa, and no superconductivity was observed down to 0.4 K.
Magneto Transport of CVD Carbon in Artificial Opals
Wang, Lei; Yin, Ming; Arammash, Fauzi; Datta, Timir
2014-03-01
Magneto-transport of carbon inverse opal structures were investigated in the 2.5 to 300 K temperatures and magnetic fields in the 0-10T regime. Qualitatively, our observations lie between those reported by previous researchers. Over this temperature range, transport (in zero magnetic field) is non-metallic; the resistance decreased with rising temperature however the temperature dependent behavior is not activated, as observed with variable range hopping. In three-dimensions, such behavior can also be the result of weak localization and electron-electron interactions; in particular the change in conductivity is a polynomial in fractional powers of absolute temperature. At sub-helium temperature regimes the relative magneto resistance is measured to be ~ 0.1 percent per Tesla. Results of data analysis for several different scenarios will be reported. DOD award #60177-RT-H from the ARO.
Low-temperature ballistic transport in nanoscale epitaxial graphene cross junctions
Weingart, S.; Bock, C.; Kunze, U.; Speck, F.; Seyller, Th.; Ley, L.
2009-01-01
We report on the observation of inertial-ballistic transport in nanoscale cross junctions fabricated from epitaxial graphene grown on SiC(0001). Ballistic transport is indicated by a negative bend resistance of R12,43 ~ 170 ohm which is measured in a non-local, four-terminal configuration at 4.2 K and which vanishes as the temperature is increased above 80 K.
International Nuclear Information System (INIS)
Marignac, Y.; Coeytaux, X.; Large, J.H.
2004-09-01
This report concerns the safety and the protection of plutonium dioxide transported from Cogema La Hague to the mixed oxide fuel plant of Marcoule and Cadarache. The French approach of the transport safety is based on the combining of two essential principles: the first one affirms that the performances of the FS47 container in regard of containment (norms TS-R-1 from IAEA for the accidental conditions) is conceived to resist in any situation even terrorism or sabotage. In fact, the IAEA norm follows a probabilistic study without a voluntary attack such a terrorist one. The second principle rests on the ability to prevent the treat of terrorism acts, because of a secrecy policy on the plutonium transport. It appeared that the Green peace association has succeeded several times to know exactly the hours, the trips of the plutonium transport and this simple thing raises more questions than it solves. (N.C.)
DEFF Research Database (Denmark)
Stein, Ulrike; Lage, Hermann; Jordan, Andreas
2002-01-01
The impact of the ABC transporters breast cancer resistance protein/mitoxantrone resistance associated transporter (BCRP/MXR), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance gene-1/P-glycoprotein (MDR1/PGP) on the multidrug resistance (MDR) phenotype in chemoresistance...... expression of BCRP/MXR and of MRP1 were clearly enhanced (vs. parental and classical MDR lines). MDR1/PGP expression was distinctly elevated in the classical MDR subline EPG85-257RDB (vs. parental and atypical MDR sublines). In all thermoresistant counterparts basal expression of BCRP/MXR, MRP1 and MDR1/PGP...... was increased relative to thermosensitive sublines. Although it could be shown that the overexpressed ABC transporters were functionally active, however, no decreased drug accumulations of doxorubicin, mitoxantrone and rhodamine 123 were observed. Thus, expression of BCRP/MXR, MRP1 and MDR1/PGP was found...
Dahan, Arik; Sabit, Hairat; Amidon, Gordon L
2009-10-01
The purpose of this study was to thoroughly characterize the efflux transporters involved in the intestinal permeability of the oral microtubule polymerization inhibitor colchicine and to evaluate the role of these transporters in limiting its oral absorption. The effects of P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) inhibitors on colchicine bidirectional permeability were studied across Caco-2 cell monolayers, inhibiting one versus multiple transporters simultaneously. Colchicine permeability was then investigated in different regions of the rat small intestine by in situ single-pass perfusion. Correlation with the P-gp/MRP2 expression level throughout different intestinal segments was investigated by immunoblotting. P-gp inhibitors [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), verapamil, and quinidine], and MRP2 inhibitors [3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571), indomethacin, and p-aminohippuric acid (p-AH)] significantly increased apical (AP)-basolateral (BL) and decreased BL-AP Caco-2 transport in a concentration-dependent manner. No effect was obtained by the BCRP inhibitors fumitremorgin C (FTC) and pantoprazole. P-gp/MRP2 inhibitors combinations greatly reduced colchicine mucosal secretion, including complete abolishment of efflux (GF120918/MK571). Colchicine displayed low (versus metoprolol) and constant permeability along the rat small-intestine. GF120918 significantly increased colchicine permeability in the ileum with no effect in the jejunum, whereas MK571 augmented jejunal permeability without changing the ileal transport. The GF120918/MK571 combination caused an effect similar to that of MK571 alone in the jejunum and to that of GF120918 alone in the ileum. P-gp expression followed a gradient increasing from
Cnubben, N.H.; Wortelboer, H.M.; Zanden, J.J. van; Rietjens, I.M.; Bladeren, P.J. van
2005-01-01
Membrane transport proteins belonging to the ATP-binding cassette (ABC) family of transport proteins play a central role in the defence of organisms against toxic compounds, including anticancer drugs. However, for compounds that are designed to display a toxic effect, this defence system diminishes
Suppression of turbulent resistivity in turbulent Couette flow
Si, Jiahe; Colgate, Stirling A.; Sonnenfeld, Richard G.; Nornberg, Mark D.; Li, Hui; Colgate, Arthur S.; Westpfahl, David J.; Romero, Van D.; Martinic, Joe
2015-07-01
Turbulent transport in rapidly rotating shear flow very efficiently transports angular momentum, a critical feature of instabilities responsible both for the dynamics of accretion disks and the turbulent power dissipation in a centrifuge. Turbulent mixing can efficiently transport other quantities like heat and even magnetic flux by enhanced diffusion. This enhancement is particularly evident in homogeneous, isotropic turbulent flows of liquid metals. In the New Mexico dynamo experiment, the effective resistivity is measured using both differential rotation and pulsed magnetic field decay to demonstrate that at very high Reynolds number rotating shear flow can be described entirely by mean flow induction with very little contribution from correlated velocity fluctuations.
Suppression of turbulent resistivity in turbulent Couette flow
Energy Technology Data Exchange (ETDEWEB)
Si, Jiahe, E-mail: jsi@nmt.edu; Sonnenfeld, Richard G.; Colgate, Arthur S.; Westpfahl, David J.; Romero, Van D.; Martinic, Joe [New Mexico Institute of Mining and Technology, Socorro, New Mexico 87801 (United States); Colgate, Stirling A.; Li, Hui [Los Alamos National Laboratory, Los Alamos, New Mexico 87544 (United States); Nornberg, Mark D. [University of Wisconsin-Madison, Madison, Wisconsin 53706 (United States)
2015-07-15
Turbulent transport in rapidly rotating shear flow very efficiently transports angular momentum, a critical feature of instabilities responsible both for the dynamics of accretion disks and the turbulent power dissipation in a centrifuge. Turbulent mixing can efficiently transport other quantities like heat and even magnetic flux by enhanced diffusion. This enhancement is particularly evident in homogeneous, isotropic turbulent flows of liquid metals. In the New Mexico dynamo experiment, the effective resistivity is measured using both differential rotation and pulsed magnetic field decay to demonstrate that at very high Reynolds number rotating shear flow can be described entirely by mean flow induction with very little contribution from correlated velocity fluctuations.
Suppression of turbulent resistivity in turbulent Couette flow
International Nuclear Information System (INIS)
Si, Jiahe; Sonnenfeld, Richard G.; Colgate, Arthur S.; Westpfahl, David J.; Romero, Van D.; Martinic, Joe; Colgate, Stirling A.; Li, Hui; Nornberg, Mark D.
2015-01-01
Turbulent transport in rapidly rotating shear flow very efficiently transports angular momentum, a critical feature of instabilities responsible both for the dynamics of accretion disks and the turbulent power dissipation in a centrifuge. Turbulent mixing can efficiently transport other quantities like heat and even magnetic flux by enhanced diffusion. This enhancement is particularly evident in homogeneous, isotropic turbulent flows of liquid metals. In the New Mexico dynamo experiment, the effective resistivity is measured using both differential rotation and pulsed magnetic field decay to demonstrate that at very high Reynolds number rotating shear flow can be described entirely by mean flow induction with very little contribution from correlated velocity fluctuations
DEFF Research Database (Denmark)
Jovel, Irina Tatiana; Kofoed, Poul-Erik; Rombo, Lars
2015-01-01
BACKGROUND: Guinea-Bissau, West-Africa introduced artemether-lumefantrine in 2008 but quinine has also been commonly prescribed for treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes...... of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine are described. METHODS: Pfcrt K76T, pfmdr1 gene copy numbers, N86Y, Y184F and 1034-1246 sequences were determined using PCR-based methods. Blood samples came from virtually all (n=1806) children aged.......001). CONCLUSIONS: Following the discontinuation of an effective chloroquine regimen highly artemether-lumefantrine susceptible P. falciparum (with pfcrt 76T) accumulated possibly due to suboptimal use of quinine and despite a fitness cost linked to 76T....
Remy, Estelle; Duque, Paula
2014-01-01
Higher plants possess a multitude of Multiple Drug Resistance (MDR) transporter homologs that group into three distinct and ubiquitous families—the ATP-Binding Cassette (ABC) superfamily, the Major Facilitator Superfamily (MFS), and the Multidrug And Toxic compound Extrusion (MATE) family. As in other organisms, such as fungi, mammals, and bacteria, MDR transporters make a primary contribution to cellular detoxification processes in plants, mainly through the extrusion of toxic compounds from the cell or their sequestration in the central vacuole. This review aims at summarizing the currently available information on the in vivo roles of MDR transporters in plant systems. Taken together, these data clearly indicate that the biological functions of ABC, MFS, and MATE carriers are not restricted to xenobiotic and metal detoxification. Importantly, the activity of plant MDR transporters also mediates biotic stress resistance and is instrumental in numerous physiological processes essential for optimal plant growth and development, including the regulation of ion homeostasis and polar transport of the phytohormone auxin. PMID:24910617
Plutonium accident resistant container project
International Nuclear Information System (INIS)
Andersen, J.A.
1978-05-01
The PARC (plutonium accident resistant container) project resulted in the design, development, and certification testing of a crashworthy air-transportable plutonium package (shipping container) for certification by the USNRC. This PAT-1 (plutonium air transportable) package survives a very severe sequential test program of impact, crush, puncture, slash, burn, and water immersion. There is also an individual hydrostatic pressure test. The package has a payload mass capacity of 2 kg of PuO2 and a thermal capacity of 25 watts. The design rationale for very high energy absorption (impact, crush, puncture, and slash protection) with residual high-level fire protection, resulted in a reasonalby small air-transportable package, advancing the packaging state-of-art. Optimization design iterations were utilized in the areas of impact energy absorption and stress and thermal analysis. Package test results are presented in relation to radioactive materials containment acceptance criteria, shielding and criticality standards
Data showing the circumvention of oxaliplatin resistance by vatalanib in colon cancer.
To, Kenneth K W; Poon, Daniel C; Wei, Yuming; Wang, Fang; Lin, Ge; Fu, Li-Wu
2016-06-01
We have recently reported that vatalanib, an orally active small molecule multi-tyrosine kinase inhibitor (Hess-Stumpp et al., 2005 [1]), can sensitize multidrug resistant (MDR) colon cancer cells to chemotherapy under hypoxia by inhibiting two MDR transporters ABCB1 and ABCG2 (To et al., 2015 [2]). This data article describes the possible circumvention of resistance to specifically platinum (Pt)-based anticancer drugs by vatalanib via inhibition of two other efflux transporters ABCC2 and ATP7A. Data from the flow cytometric transporter efflux assay showed specific inhibition of ABCC2 activity by vatalanib in stable transfected cells and ABCC2-overexpressing oxaliplatin-resistant colon cancer cells HCT116/Oxa. We also performed the transporter ABCC2 ATPase assay and showed an increase in ATP hydrolysis by ABCC2 in the presence of vatalanib. ATP7A mRNA expression was also shown to be upregulated in HCT116/Oxa cells. Vatalanib was shown to suppress this upregulated ATP7A expression. Data from the cellular Pt accumulation assay showed a lower Pt accumulation in HCT116/Oxa cells than the parental sensitive HCT116 cells. Vatalanib was shown to increase cellular Pt accumulation in a concentration-dependent manner. Combination of oxaliplatin and vatalanib was shown to restore the suppressed apoptosis in HCT116/Oxa cells.
Data showing the circumvention of oxaliplatin resistance by vatalanib in colon cancer
Directory of Open Access Journals (Sweden)
Kenneth K.W. To
2016-06-01
Full Text Available We have recently reported that vatalanib, an orally active small molecule multi-tyrosine kinase inhibitor (Hess-Stumpp et al., 2005 [1], can sensitize multidrug resistant (MDR colon cancer cells to chemotherapy under hypoxia by inhibiting two MDR transporters ABCB1 and ABCG2 (To et al., 2015 [2]. This data article describes the possible circumvention of resistance to specifically platinum (Pt-based anticancer drugs by vatalanib via inhibition of two other efflux transporters ABCC2 and ATP7A. Data from the flow cytometric transporter efflux assay showed specific inhibition of ABCC2 activity by vatalanib in stable transfected cells and ABCC2-overexpressing oxaliplatin-resistant colon cancer cells HCT116/Oxa. We also performed the transporter ABCC2 ATPase assay and showed an increase in ATP hydrolysis by ABCC2 in the presence of vatalanib. ATP7A mRNA expression was also shown to be upregulated in HCT116/Oxa cells. Vatalanib was shown to suppress this upregulated ATP7A expression. Data from the cellular Pt accumulation assay showed a lower Pt accumulation in HCT116/Oxa cells than the parental sensitive HCT116 cells. Vatalanib was shown to increase cellular Pt accumulation in a concentration-dependent manner. Combination of oxaliplatin and vatalanib was shown to restore the suppressed apoptosis in HCT116/Oxa cells.
Fukuchi, Junichi; Hiipakka, Richard A; Kokontis, John M; Nishimura, Kazuhiro; Igarashi, Kazuei; Liao, Shutsung
2004-07-16
Identification of the polyamine transporter gene will be useful for modulating polyamine accumulation in cells and should be a good target for controlling cell proliferation. Polyamine transport activity in mammalian cells is critical for accumulation of the polyamine analog methylglyoxal bis(guanylhydrazone) (MGBG) that induces apoptosis, although a gene responsible for transport activity has not been identified. Using a retroviral gene trap screen, we generated MGBG-resistant Chinese hamster ovary (CHO) cells to identify genes involved in polyamine transport activity. One gene identified by the method encodes TATA-binding protein-associated factor 7 (TAF7), which functions not only as one of the TAFs, but also a coactivator for c-Jun. TAF7-deficient cells had decreased capacity for polyamine uptake (20% of CHO cells), decreased AP-1 activation, as well as resistance to MGBG-induced apoptosis. Stable expression of TAF7 in TAF7-deficient cells restored transport activity (55% of CHO cells), AP-1 gene transactivation (100% of CHO cells), and sensitivity to MGBG-induced apoptosis. Overexpression of TAF7 in CHO cells did not increase transport activity, suggesting that TAF7 may be involved in the maintenance of basal activity. c-Jun NH2-terminal kinase inhibitors blocked MGBG-induced apoptosis without alteration of polyamine transport. Decreased TAF7 expression, by RNA interference, in androgen-independent human prostate cancer LN-CaP104-R1 cells resulted in lower polyamine transport activity (25% of control) and resistance to MGBG-induced growth arrest. Taken together, these results reveal a physiological function of TAF7 as a basal regulator for mammalian polyamine transport activity and MGBG-induced apoptosis.
Electronic transport and lasing in microstructures
International Nuclear Information System (INIS)
Lax, M.
1992-01-01
We consider the interaction of hot carriers with hot phonons in a quantum well. Transport is considered in the transverse direction and tunneling through the well barriers. Time-dependent transport effects down to the femto-second regime are included, as are strong and/or microwave fields, with negative resistance effects. Resonant tunneling assisted by phonon relaxation and infra-red radiation will be explored. The limitations on transmission of information due to partition noise, as influenced by the design of semiconductor feedback lasers will be considered. The use of light scattering and decision theory to detect shell-like aerosols is examined
Transport simulations TFTR: Theoretically-based transport models and current scaling
International Nuclear Information System (INIS)
Redi, M.H.; Cummings, J.C.; Bush, C.E.; Fredrickson, E.; Grek, B.; Hahm, T.S.; Hill, K.W.; Johnson, D.W.; Mansfield, D.K.; Park, H.; Scott, S.D.; Stratton, B.C.; Synakowski, E.J.; Tang, W.M.; Taylor, G.
1991-12-01
In order to study the microscopic physics underlying observed L-mode current scaling, 1-1/2-d BALDUR has been used to simulate density and temperature profiles for high and low current, neutral beam heated discharges on TFTR with several semi-empirical, theoretically-based models previously compared for TFTR, including several versions of trapped electron drift wave driven transport. Experiments at TFTR, JET and D3-D show that I p scaling of τ E does not arise from edge modes as previously thought, and is most likely to arise from nonlocal processes or from the I p -dependence of local plasma core transport. Consistent with this, it is found that strong current scaling does not arise from any of several edge models of resistive ballooning. Simulations with the profile consistent drift wave model and with a new model for toroidal collisionless trapped electron mode core transport in a multimode formalism, lead to strong current scaling of τ E for the L-mode cases on TFTR. None of the theoretically-based models succeeded in simulating the measured temperature and density profiles for both high and low current experiments
Zhou, Tian; Hu, Minlu; Pearlman, Andrew; Patton, Dorothy; Rohan, Lisa
2014-11-01
Antiretroviral drug absorption and disposition in cervicovaginal tissue is important for the effectiveness of vaginally or orally administered drug products in preexposure prophylaxis (PrEP) of HIV-1 sexual transmission to women. Therefore, it is imperative to understand critical determinants of cervicovaginal tissue pharmacokinetics. This study aimed to examine the mRNA expression and protein localization of three efflux transporters, P-glycoprotein (P-gp), multidrug resistance-associated protein 4 (MRP4), and breast cancer resistance protein (BCRP), in the lower genital tract of premenopausal women and pigtailed macaques. Along the human lower genital tract, the three transporters were moderately to highly expressed compared to colorectal tissue and liver, as revealed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). In a given genital tract segment, the transporter with the highest expression level was either BCRP or P-gp, while MRP4 was always expressed at the lowest level among the three transporters tested. The immunohistochemical staining showed that P-gp and MRP4 were localized in multiple cell types including epithelial cells and vascular endothelial cells. BCRP was predominantly localized in the vascular endothelial cells. Differences in transporter mRNA level and localization were observed among endocervix, ectocervix, and vagina. Compared to human tissues, the macaque cervicovaginal tissues displayed comparable expression and localization patterns of the three transporters, although subtle differences were observed between the two species. The role of these cervicovaginal transporters in drug absorption and disposition warrants further studies. The resemblance between human and pigtailed macaque in transporter expression and localization suggests the utility of the macaque model in the studies of human cervicovaginal transporters.
Splice form variant and amino acid changes in MDR49 confers DDT resistance in transgenic Drosophila.
Seong, Keon Mook; Sun, Weilin; Clark, John M; Pittendrigh, Barry R
2016-03-22
The ATP-binding cassette (ABC) transporters represent a superfamily of proteins that have important physiological roles in both prokaryotes and eukaryotes. In insects, ABC transporters have previously been implicated in insecticide resistance. The 91-R strain of Drosophila melanogaster has been intensely selected with DDT over six decades. A recent selective sweeps analysis of 91-R implicated the potential role of MDR49, an ABC transporter, in DDT resistance, however, to date the details of how MDR49 may play a role in resistance have not been elucidated. In this study, we investigated the impact of structural changes and an alternative splicing event in MDR49 on DDT-resistance in 91-R, as compared to the DDT susceptible strain 91-C. We observed three amino acid differences in MDR49 when 91-R was compared with 91-C, and only one isoform (MDR49B) was implicated in DDT resistance. A transgenic Drosophila strain containing the 91-R-MDR49B isoform had a significantly higher LD50 value as compared to the 91-C-MDR49B isoform at the early time points (6 h to 12 h) during DDT exposure. Our data support the hypothesis that the MDR49B isoform, with three amino acid mutations, plays a role in the early aspects of DDT resistance in 91-R.
Energetics of turbulent transport processes in tokamaks
International Nuclear Information System (INIS)
Haas, F.A.; Thyagaraja, A.
1987-01-01
The effect of electromagnetic turbulence on electrons and ions under Tokamak conditions is considered using a kinetic description. Taking the magnetic fluctuation spectrum as given, the density fluctuation spectrum is self-consistently calculated taking account of quasi-neutrality. The calculation is valid for arbitrary collisionality and appropriate to low frequencies typical of experiment. In addition to the usual enhancement of the radial electron energy transport, it is found that the turbulent fluctuations can heat the plasma at rates comparable to ordinary ohmic heating under well-defined conditions. Interestingly, electromagnetic turbulence appears to imply only an insignificant correction to the toroidal resistance of the plasma as estimated from Spitzer resistivity. The scalings of anomalous transport, fluctuations and heating with temperature and plasma volume are investigated. The assumption that the magnetic fluctuation spectrum of the turbulence is invariant under a wide range of conditions is shown to result in interesting consequences for JET-like plasmas. (author)
Urban risks of truck transport of radioactive material
International Nuclear Information System (INIS)
Mills, G.S.; Neuhauser, K.S.
1998-01-01
Truck transport of radioactive material (RAM), e.g., spent nuclear fuel (SNF), normally maximizes use of Interstate highways, which are safer and more efficient for truck transport in general. In the estimation of transportation risks, population bordering a route is a direct factor in determining consequences and an indirect factor in determining exposure times, accident probabilities and severities, and other parameters. Proposals to transport RAM may draw intense resistance from stakeholders based on concern for population concentrations along urban segments but the length of a route segment is also a determinative factor in estimating the transport risks. To quantify the relative importance of these two factors, a potential route for transport of SNF (strict use of Interstate highways) was selected and compared with a modified version that bypassed urban areas. The RADTRAN 4 code for transportation risk assessment, which was developed at Sandia National Laboratories, was used in the present study to assess the relative risks of SNF transportation for alternative routes. The results suggest that emphasis on Interstate highways minimizes total route and urban segment risks
Non-diffusive transport in 3-D pressure driven plasma turbulence
International Nuclear Information System (INIS)
Del-Castillo-Negrete, D.; Carreras, B.A.; Lynch, V.
2005-01-01
Numerical evidence of non-diffusive transport in 3-dimensional, resistive, pressure-gradient-driven plasma turbulence is presented. It is shown that the probability density function (pdf) of tracers is strongly non-Gaussian and exhibits algebraic decaying tails. To describe these results, a transport model using fractional derivative operators in proposed. The model incorporates in a unified way non-locality (i.e., non-Fickian transport), memory effects (i.e., non-Markovian transport), and non-diffusive scaling features known to be present in fusion plasmas. There is quantitative agreement between the model and the turbulent transport numerical calculations. In particular, the model reproduces the shape and space-time scaling of the pdf, and the super-diffusive scaling of the moments. (author)
Lara, Flavio Alves; Pohl, Paula C.; Gandara, Ana Caroline; Ferreira, Jessica da Silva; Nascimento-Silva, Maria Clara; Bechara, Gervásio Henrique; Sorgine, Marcos H. F.; Almeida, Igor C.; Vaz, Itabajara da Silva; Oliveira, Pedro L.
2015-01-01
In ticks, the digestion of blood occurs intracellularly and proteolytic digestion of hemoglobin takes place in a dedicated type of lysosome, the digest vesicle, followed by transfer of the heme moiety of hemoglobin to a specialized organelle that accumulates large heme aggregates, called hemosomes. In the present work, we studied the uptake of fluorescent metalloporphyrins, used as heme analogs, and amitraz, one of the most regularly used acaricides to control cattle tick infestations, by Rhipicephalus (Boophilus) microplus midgut cells. Both compounds were taken up by midgut cells in vitro and accumulated inside the hemosomes. Transport of both molecules was sensitive to cyclosporine A (CsA), a well-known inhibitor of ATP binding cassette (ABC) transporters. Rhodamine 123, a fluorescent probe that is also a recognized ABC substrate, was similarly directed to the hemosome in a CsA-sensitive manner. Using an antibody against conserved domain of PgP-1-type ABC transporter, we were able to immunolocalize PgP-1 in the digest vesicle membranes. Comparison between two R. microplus strains that were resistant and susceptible to amitraz revealed that the resistant strain detoxified both amitraz and Sn-Pp IX more efficiently than the susceptible strain, a process that was also sensitive to CsA. A transcript containing an ABC transporter signature exhibited 2.5-fold increased expression in the amitraz-resistant strain when compared with the susceptible strain. RNAi-induced down-regulation of this ABC transporter led to the accumulation of metalloporphyrin in the digestive vacuole, interrupting heme traffic to the hemosome. This evidence further confirms that this transcript codes for a heme transporter. This is the first report of heme transport in a blood-feeding organism. While the primary physiological function of the hemosome is to detoxify heme and attenuate its toxicity, we suggest that the use of this acaricide detoxification pathway by ticks may represent a new
Directory of Open Access Journals (Sweden)
Flavio Alves Lara
Full Text Available In ticks, the digestion of blood occurs intracellularly and proteolytic digestion of hemoglobin takes place in a dedicated type of lysosome, the digest vesicle, followed by transfer of the heme moiety of hemoglobin to a specialized organelle that accumulates large heme aggregates, called hemosomes. In the present work, we studied the uptake of fluorescent metalloporphyrins, used as heme analogs, and amitraz, one of the most regularly used acaricides to control cattle tick infestations, by Rhipicephalus (Boophilus microplus midgut cells. Both compounds were taken up by midgut cells in vitro and accumulated inside the hemosomes. Transport of both molecules was sensitive to cyclosporine A (CsA, a well-known inhibitor of ATP binding cassette (ABC transporters. Rhodamine 123, a fluorescent probe that is also a recognized ABC substrate, was similarly directed to the hemosome in a CsA-sensitive manner. Using an antibody against conserved domain of PgP-1-type ABC transporter, we were able to immunolocalize PgP-1 in the digest vesicle membranes. Comparison between two R. microplus strains that were resistant and susceptible to amitraz revealed that the resistant strain detoxified both amitraz and Sn-Pp IX more efficiently than the susceptible strain, a process that was also sensitive to CsA. A transcript containing an ABC transporter signature exhibited 2.5-fold increased expression in the amitraz-resistant strain when compared with the susceptible strain. RNAi-induced down-regulation of this ABC transporter led to the accumulation of metalloporphyrin in the digestive vacuole, interrupting heme traffic to the hemosome. This evidence further confirms that this transcript codes for a heme transporter. This is the first report of heme transport in a blood-feeding organism. While the primary physiological function of the hemosome is to detoxify heme and attenuate its toxicity, we suggest that the use of this acaricide detoxification pathway by ticks may
Mechanical Properties and Thermal Shock Resistance Analysis of BNNT/Si3N4 Composites
Wang, Shouren; Wang, Gaoqi; Wen, Daosheng; Yang, Xuefeng; Yang, Liying; Guo, Peiquan
2018-04-01
BNNT/Si3N4 ceramic composites with different weight amount of BNNT fabricated by hot isostatic pressing were introduced. The mechanical properties and thermal shock resistance of the composites were investigated. The results showed that BNNT-added ceramic composites have a finer and more uniform microstructure than that of BNNT-free Si3N4 ceramic because of the retarding effect of BNNT on Si3N4 grain growth. The addition of 1.5 wt.% BNNT results in simultaneous increase in flexural strength, fracture toughness, and thermal shock resistance. The analysis of the results indicates that BNNT brings many thermal transport channels in the microstructure, increasing the efficiency of thermal transport, therefore results in increase of thermal shock resistance. In addition, BNNT improves the residual flexural strength of composites by crack deflection, bridging, branching and pinning, which increase the crack propagation resistance.
Rijpma, S.R.; Velden, M. van der; Gonzalez-Pons, M.; Annoura, T.; Schaijk, B.C.L. van; Gemert, G.J.A. van; Heuvel, J.M.W. van den; Ramesar, J.; Chevalley-Maurel, S.; Ploemen, I.H.; Khan, S.M.; Franetich, J.F.; Mazier, D.; Wilt, J.H.W. de; Serrano, A.E.; Russel, F.G.; Janse, C.J.; Sauerwein, R.W.; Koenderink, J.B.; Franke-Fayard, B.M.
2016-01-01
Multidrug resistance-associated proteins (MRPs) belong to the C-family of ATP-binding cassette (ABC) transport proteins and are known to transport a variety of physiologically important compounds and to be involved in the extrusion of pharmaceuticals. Rodent malaria parasites encode a single ABC
Reasons of chlorella strain's resistance to physical and chemical factors of environment
Energy Technology Data Exchange (ETDEWEB)
Apasheva, L M; Bujiashvilie, D M; Naydich, V I; Shevchenko, V A
1979-07-01
Under environmental pollution it is necessary to study the reasons of an organism's resistance as well as the specificity of it. Some chlorella strains were under the influence of uv- and x-irradiation, heat treatment, cadmium salts, insecticide, and detergent. It was shown that cells which were resistant to physical factors were resistant to chemical intoxication, as well. The positive correlation between resistance of strains and the described influences and the levels of endogenic thiols was found. The second reason for higher resistance is an increase of free radicals' concentration. It is linked with increasing P/sub 700/ quantity of electron-transport chains that make possible higher levels of photosynthetic reactions of resistant cells.
Resistance switching memory in perovskite oxides
International Nuclear Information System (INIS)
Yan, Z.B.; Liu, J.-M.
2015-01-01
The resistance switching behavior has recently attracted great attentions for its application as resistive random access memories (RRAMs) due to a variety of advantages such as simple structure, high-density, high-speed and low-power. As a leading storage media, the transition metal perovskite oxide owns the strong correlation of electrons and the stable crystal structure, which brings out multifunctionality such as ferroelectric, multiferroic, superconductor, and colossal magnetoresistance/electroresistance effect, etc. The existence of rich electronic phases, metal–insulator transition and the nonstoichiometric oxygen in perovskite oxide provides good platforms to insight into the resistive switching mechanisms. In this review, we first introduce the general characteristics of the resistance switching effects, the operation methods and the storage media. Then, the experimental evidences of conductive filaments, the transport and switching mechanisms, and the memory performances and enhancing methods of perovskite oxide based filamentary RRAM cells have been summarized and discussed. Subsequently, the switching mechanisms and the performances of the uniform RRAM cells associating with the carrier trapping/detrapping and the ferroelectric polarization switching have been discussed. Finally, the advices and outlook for further investigating the resistance switching and enhancing the memory performances are given
Survey of 1 1/2D transport codes
International Nuclear Information System (INIS)
Grad, H.
1978-10-01
A survey is given of a family of classical transport codes, recently termed ''1 1/2D'', which efficiently and accurately follow the evolution of plasma configurations on a long time scale, following coupled changes in plasma shape and topology with transport (but not wave motion). Codes have been constructed and operated (since 1974) which include various combinations of finite beta, general plasma cross-section and aspect, various topologies (Doublet, tearing, reversed-field mirror) including time dependent transitions in topology resulting from external coil variation and plasma transport, with models including (classical) tensor resistivity and heat flow as well as the adiabatic limiting case
Investigation of transport properties of colossal magnetoresistive materials
International Nuclear Information System (INIS)
Kaurav, Netram
2006-01-01
The transport properties, i.e. resistivity, heat capacity, thermal conductivity and optical conductivity have been theoretically analysed for colossal magnetoresistive materials within the framework of double exchange mechanism. Following an effective interaction potential, we deduce acoustic (optical) phonon modes, coupling strength for electron-phonon and phonon-impurities, the phonon (magnon) scattering rate and constants characterise the scattering of charge and heat carriers with various disorders in the crystal. The theoretical models have been developed to account the anomalies observed in the transport phenomenon. It is noticed that electron-electron, electron-phonon and electron-magnon interactions are essential in discussing the transport behaviour of doped magnetites. (author)
International Nuclear Information System (INIS)
Liu, Hongbing; He, Ayada; Du, Dong; Wang, Xin; Zhang, Haiquan
2014-01-01
Highlights: • A deceleration system for fuel transportation in a pebble bed reactor is designed. • Dynamic analysis and motion analysis of the deceleration process are conducted. • The effectiveness of the system is verified by the analysis and the experiment. • Some key design parameters are studied to achieve effective deceleration. • This research provides a guide for the design of a pebble bed reactor. - Abstract: The fuel elements cycle occurring inside and outside the core of a pebble bed reactor is carried out by pneumatic conveying. In some processes of conveyance, it is necessary to reduce the velocity of the moving fuel element in a short time to avoid damage to the fuel elements and the equipment. In this research, a deceleration system for near-diameter spheres in pipeline transportation based on the resistance of a pneumatic cushion is designed to achieve an effective and reliable deceleration process. Dynamic analysis and motion analysis of the deceleration process are conducted. The results show that when the fuel element is moving in the deceleration pipeline, the gas in the pipeline is compressed to create a pneumatic cushion which resists the movement of the fuel element. In this way, the velocity of the fuel element is decreased to below the target value. During this process, the deceleration is steady and reliable. On this basis some key design parameters are studied, such as the deceleration pipeline length, the ratio of the diameter of the fuel element to the internal diameter of the pipeline, etc. The experimental results are generally consistent with the analysis and demonstrate the considerable effectiveness of the deceleration process as well. This research provides a guide for the design of the fuel elements cycling system in a pebble bed reactor along with the optimization of its control
Contribution of AcrAB-ToIC to multidrug resistance in an Escherichia coli sequence type 131 isolate
Schuster, Sabine; Vavra, Martina; Schweigger, Tobias M.; Rossen, John W. A.; Matsumura, Yasufumi; Kern, Winfried V.
Drug efflux by resistance-nodulation-cell division (RND)-type transporters, such as AcrAB-ToIC of Escherichia can, is an important resistance mechanism in Gram-negative bacteria; however, its contribution to multidrug resistance (MDR) in clinical isolates is poorly defined. We inactivated acrB of a
Purves, Joanne; Thomas, Jamie; Riboldi, Gustavo P.; Zapotoczna, Marta; Tarrant, Emma; Andrew, Peter W.; Londoño, Alejandra; Planet, Paul J.; Geoghegan, Joan A.; Waldron, Kevin J.
2018-01-01
Summary Excess copper is highly toxic and forms part of the host innate immune system's antibacterial arsenal, accumulating at sites of infection and acting within macrophages to kill engulfed pathogens. We show for the first time that a novel, horizontally gene transferred copper resistance locus (copXL), uniquely associated with the SCCmec elements of the highly virulent, epidemic, community acquired methicillin resistant Staphylococcus aureus (CA‐MRSA) USA300, confers copper hyper‐resistance. These genes are additional to existing core genome copper resistance mechanisms, and are not found in typical S. aureus lineages, but are increasingly identified in emerging pathogenic isolates. Our data show that CopX, a putative P1B‐3‐ATPase efflux transporter, and CopL, a novel lipoprotein, confer copper hyper‐resistance compared to typical S. aureus strains. The copXL genes form an operon that is tightly repressed in low copper environments by the copper regulator CsoR. Significantly, CopX and CopL are important for S. aureus USA300 intracellular survival within macrophages. Therefore, the emergence of new S. aureus clones with the copXL locus has significant implications for public health because these genes confer increased resistance to antibacterial copper toxicity, enhancing bacterial fitness by altering S. aureus interaction with innate immunity. PMID:29521441
Metabolic Reprogramming During Multidrug Resistance in Leukemias
Directory of Open Access Journals (Sweden)
Raphael Silveira Vidal
2018-04-01
Full Text Available Cancer outcome has improved since introduction of target therapy. However, treatment success is still impaired by the same drug resistance mechanism of classical chemotherapy, known as multidrug resistance (MDR phenotype. This phenotype promotes resistance to drugs with different structures and mechanism of action. Recent reports have shown that resistance acquisition is coupled to metabolic reprogramming. High-gene expression, increase of active transport, and conservation of redox status are one of the few examples that increase energy and substrate demands. It is not clear if the role of this metabolic shift in the MDR phenotype is related to its maintenance or to its induction. Apart from the nature of this relation, the metabolism may represent a new target to avoid or to block the mechanism that has been impairing treatment success. In this mini-review, we discuss the relation between metabolism and MDR resistance focusing on the multiple non-metabolic functions that enzymes of the glycolytic pathway are known to display, with emphasis with the diverse activities of glyceraldehyde-3-phosphate dehydrogenase.
Visualization of multidrug resistance in vivo
International Nuclear Information System (INIS)
Hendrikse, N.H.; Franssen, E.J.F.; Graaf, W.T.A. van der; Vries, E.G.E. de; Vaalburg, W.
1999-01-01
Various mechanisms are involved in multidrug resistance (MDR) for chemotherapeutic drugs, such as the drug efflux pumps, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP). In this review the mechanisms involved in MDR are described and results are reviewed with particular attention to the in vivo imaging of Pgp and MRP. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However, these methods do not yield information about the dynamic function of Pgp and MRP in vivo. For the study of Pgp- and MRP-mediated transport, single-photon emission tomography (SPET) and positron emission tomography (PET) are available. Technetium-99m sestamibi is a substrate for Pgp and MRP, and has been used in clinical studies for tumour imaging, and to visualize blockade of Pgp-mediated transport after modulation of the Pgp pump. Other 99m Tc radiopharmaceuticals, such as 99m Tc-tetrofosmin and several 99 Tc-Q complexes, are also substrates for Pgp, but to date only results from in vitro and animal studies are available for these compounds. Several agents, including [ 11 C]colchicine, [ 11 C]verapamil and [ 11 C]daunorubicin, have been evaluated for the quantification of Pgp-mediated transport with PET in vivo. The results suggest that radiolabelled colchicine, verapamil and daunorubicin are feasible substrates with which to image Pgp function in tumours. Uptake of [ 11 C]colchicine and [ 11 C]verapamil is relatively high in the chest area, reducing the value of both tracers for monitoring Pgp-mediated drug transport in tumours located in this region. In addition, it has to be borne in mind that only comparison of Pgp-mediated transport of radioalabelled substrates in the absence and in the presence of Pgp blockade gives quantitative information on Pgp-mediated pharmacokinetics. Leukotrienes are specific substrates for MRP. Therefore, N-[ 11 C]acetyl-leukotriene E 4 provides an opportunity to study MRP
Isolation and characterization of multidrug-resistant side population ...
African Journals Online (AJOL)
Results: SP cells in the prostate cancer samples constituted 2.8 %, but fell to 0.6 % after treatment with ... tumor. Keywords: Side population cells, ABC transporters, Cancer stem cells, Chemotherapy, Prostate treatment failure, Tumor recurrence, Drug resistance ..... Identification of human brain tumour initiating cells.
Evaluation of corrosion resistance of various concrete reinforcing materials.
2013-06-01
The Vermont Agency of Transportation undertook a simple experiment to determine the corrosion : resistance ability of various reinforcing steels (rebar) that may be used in bridges and other concrete : structures. Eight types of rebar were used in th...
Nonvolatile Resistive Switching in Pt/LaAlO_{3}/SrTiO_{3} Heterostructures
Directory of Open Access Journals (Sweden)
Shuxiang Wu
2013-12-01
Full Text Available Resistive switching heterojunctions, which are promising for nonvolatile memory applications, usually share a capacitorlike metal-oxide-metal configuration. Here, we report on the nonvolatile resistive switching in Pt/LaAlO_{3}/SrTiO_{3} heterostructures, where the conducting layer near the LaAlO_{3}/SrTiO_{3} interface serves as the “unconventional” bottom electrode although both oxides are band insulators. Interestingly, the switching between low-resistance and high-resistance states is accompanied by reversible transitions between tunneling and Ohmic characteristics in the current transport perpendicular to the planes of the heterojunctions. We propose that the observed resistive switching is likely caused by the electric-field-induced drift of charged oxygen vacancies across the LaAlO_{3}/SrTiO_{3} interface and the creation of defect-induced gap states within the ultrathin LaAlO_{3} layer. These metal-oxide-oxide heterojunctions with atomically smooth interfaces and defect-controlled transport provide a platform for the development of nonvolatile oxide nanoelectronics that integrate logic and memory devices.
Charge transport through superconductor/Anderson-insulator interfaces
International Nuclear Information System (INIS)
Frydman, A.; Ovadyahu, Z.
1997-01-01
We report on a study of charge transport through superconductor-insulator-superconductor and normal metal endash insulator endash superconductor structures (SIS and NIS junctions, respectively) where the insulator is of the Anderson type. Devices which are characterized by a junction resistance larger than 10 kΩ show behavior which is typical of Giaever tunnel junctions. In structures having smaller resistance, several peculiar features are observed. In the SIS junctions, Josephson coupling is detected over distances much larger then the typical insulator localization length. In addition, a series of resistance peaks appears at voltages of 2Δ/n, where Δ is the superconducting gap. The NIS Junctions exhibit a large resistance dip at subgap bias. We discuss possible interpretations of these findings and suggest that they may result from the presence of high transmission channels through the barrier region. copyright 1997 The American Physical Society
Cho, Joung-min; Mori, Takehiko
2016-06-01
Transistors based on single-crystal films of 2-decyl-7-phenyl-[1]benzothieno[3,2-b][1]benzothiophene (Ph-BTBT-10) fabricated using the blade-coating method are investigated by the four-probe method down to low temperatures. The four-probe mobility is as large as 18 cm2/V s at room temperature, and increases to 45 cm2/V s at 80 K. At 60 K the two-probe mobility drops abruptly by about 50%, but the mobility drop is mostly attributed to the increase of the source resistance. The carrier transport in the present single-crystal film is regarded as essentially bandlike down to 30 K.
Magnetic fluctuation driven cross-field particle transport in the reversed-field pinch
International Nuclear Information System (INIS)
Scheffel, J.; Liu, D.
1997-01-01
Electrostatic and electromagnetic fluctuations generally cause cross-field particle transport in confined plasmas. Thus core localized turbulence must be kept at low levels for sufficient energy confinement in magnetic fusion plasmas. Reversed-field pinch (RFP) equilibria can, theoretically, be completely stable to ideal and resistive (tearing) magnetohydrodynamic (MHD) modes at zero beta. Unstable resistive interchange modes are, however, always present at experimentally relevant values of the poloidal beta β θ . An analytical quasilinear, ambipolar diffusion model is here used to model associated particle transport. The results indicate that core density fluctuations should not exceed a level of about 1% for plasmas of fusion interest. Parameters of experimentally relevant stationary states of the RFP were adjusted to minimize growth rates, using a fully resistive linearized MHD stability code. Density gradient effects are included through employing a parabolic density profile. The scaling of particle diffusion [D(r)∝λ 2 n 0.5 T/aB, where λ is the mode width] is such that the effects of particle transport are milder in present day RFP experiments than in future reactor-relevant plasmas. copyright 1997 American Institute of Physics
Multiple Drug Transport Pathways through Human P-Glycoprotein.
McCormick, James W; Vogel, Pia D; Wise, John G
2015-07-21
P-Glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11-12 Å through the plane of the membrane as P-gp progressed through a catalytic cycle. Methylpyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side-chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp is presented.
Crystal structure of the Alcanivorax borkumensis YdaH transporter reveals an unusual topology
Bolla, Jani Reddy; Su, Chih-Chia; Delmar, Jared A.; Radhakrishnan, Abhijith; Kumar, Nitin; Chou, Tsung-Han; Long, Feng; Rajashankar, Kanagalaghatta R.; Yu, Edward W.
2015-04-01
The potential of the folic acid biosynthesis pathway as a target for the development of antibiotics has been clinically validated. However, many pathogens have developed resistance to these antibiotics, prompting a re-evaluation of potential drug targets within the pathway. The ydaH gene of Alcanivorax borkumensis encodes an integral membrane protein of the AbgT family of transporters for which no structural information was available. Here we report the crystal structure of A. borkumensis YdaH, revealing a dimeric molecule with an architecture distinct from other families of transporters. YdaH is a bowl-shaped dimer with a solvent-filled basin extending from the cytoplasm to halfway across the membrane bilayer. Each subunit of the transporter contains nine transmembrane helices and two hairpins that suggest a plausible pathway for substrate transport. Further analyses also suggest that YdaH could act as an antibiotic efflux pump and mediate bacterial resistance to sulfonamide antimetabolite drugs.
Electrophoretic transport of biomolecules across liquid-liquid interfaces
Energy Technology Data Exchange (ETDEWEB)
Hahn, Thomas; Hardt, Steffen [Center of Smart Interfaces, TU Darmstadt, Petersenstrasse 32, D-64287 Darmstadt (Germany); Muenchow, Goetz, E-mail: hardt@csi.tu-darmstadt.de [Institut fuer Mikrotechnik Mainz GmbH, Carl-Zeiss-Strasse 18-20, D-55129 Mainz (Germany)
2011-05-11
The mass transfer resistance of a liquid-liquid interface in an aqueous two-phase system composed of poly(ethylene glycol) and dextran is investigated. Different types of proteins and DNA stained with fluorescent dyes serve as probes to study the transport processes close to the interface. A microfluidic device is employed to enable the electrophoretic transport of biomolecules from one phase to another. The results obtained for proteins can be explained solely via the different electrophoretic mobilities and different affinities of the molecules to the two phases, without any indications of a significant mass transfer resistance of the liquid-liquid interface. By contrast, DNA molecules adsorb to the interface and only desorb under an increased electric field strength. The desorption process carries the signature of a thermally activated escape from a metastable state, as reflected in the exponential decay of the fluorescence intensity at the interface as a function of time.
A novel marRAB operon contributes to the rifampicin resistance in Mycobacterium smegmatis.
Zhang, Haiwei; Gao, Long; Zhang, Jiaoling; Li, Weihui; Yang, Min; Zhang, Hua; Gao, Chunhui; He, Zheng-Guo
2014-01-01
The multiple-antibiotic resistance regulator (MarR) plays an important role in modulating bacterial antibiotic resistance. However, the regulatory model of the marRAB operon in mycobacteria remains to be characterized. Here we report that a MarR, encoded by Ms6508, and its marRAB operon specifically contribute to rifampicin (RIF) resistance in Mycobacterium smegmatis. We show that the MarR recognizes a conserved 21-bp palindromic motif and negatively regulates the expression of two ABC transporters in the operon, encoded by Ms6509-6510. Unlike other known drug efflux pumps, overexpression of these two ABC transporters unexpectedly increased RIF sensitivity and deletion of these two genes increased mycobacterial resistance to the antibiotic. No change can be detected for the sensitivity of recombinant mycobacterial strains to three other anti-TB drugs. Furthermore, HPLC experiments suggested that Ms6509-Ms6510 could pump RIF into the mycobacterial cells. These findings indicated that the mycobacterial MarR functions as a repressor and constitutively inhibits the expression of the marRAB operon, which specifically contributes to RIF resistance in M. smegmatis. Therefore, our data suggest a new regulatory mechanism of RIF resistance and also provide the new insight into the regulatory model of a marRAB operon in mycobacteria.
A Challenge to Improve High-Temperature Platinum Resistance Thermometer
Tanaka, Y.; Widiatmo, J. V.; Harada, K.; Kobayashi, T.; Yamazawa, K.
2017-05-01
High-temperature standard platinum resistance thermometers (HTSPRTs) are used to interpolate the international temperature scale of 1990 (ITS-90), especially for temperatures between the aluminum and the silver points. For this, long-term stability of the HTSPRT is essential. CHINO R800-3L type SPRT, which has a nominal resistance at the triple point of water (TPW) around 0.25 Ω , is the one developed earlier for the interpolation of the ITS-90 at this temperature range. Further development to this previous model has been carried out for the purpose of improving the thermal stability. The improvement was focused on reducing the effect coming from the difference in thermal expansion between platinum wire and the quartz frame on which the platinum wire is installed. New HTSPRTs were made by CHINO Corporation. Some series of tests were carried out at CHINO and at NMIJ. Initial tests after the HTSPRT fabrication were done at CHINO, where thermal cycles between 500°C and 980°C were applied to the HTSPRTs to see change in the resistances at the TPW (R_{TPW}) and at the gallium point (R_{Ga}). Repeated resistance measurements at the silver point (R_{Ag}) were performed after completing the thermal cycling test. Before and after every measurement at silver point, R_{TPW} was measured, while before and after every two silver point realization R_{Ga} were measured. After completing this test, the HTSPRTs were transported to NMIJ, where the same repeated measurements at the silver point were done at NMIJ. These were then repeated at CHINO and at NMIJ upon repeated transportation among the institutes, to evaluate some effect due to transportation. This paper reports the details of the above-mentioned tests, the results and the analysis.
Liu, Ping; Soupir, Michelle L.; Zwonitzer, Martha; Huss, Bridgette; Jarboe, Laura R.
2011-01-01
Surface water can be contaminated by bacteria from various sources, including manure from agricultural facilities. Attachment of these bacteria to soil and organic particles contributes to their transport through the environment, though the mechanism of attachment is unknown. As bacterial attachment to human tissues is known to be correlated with antibiotic resistance, we have investigated here the relationship between bacterial attachment to environmental particles and antibiotic resistance in agricultural isolates. We evaluated 203 Escherichia coli isolates collected from swine facilities for attachment to quartz, resistance to 13 antibiotics, and the presence of genes encoding 13 attachment factors. The genes encoding type I, EcpA, P pili, and Ag43 were detected, though none was significantly related to attachment. Quartz attachment was positively and significantly (P amoxicillin/streptomycin/tetracycline/sulfamethazine/tylosin/chlortetracycline and negatively and significantly (P < 0.0038) related to combined resistance to nalidixic acid/kanamycin/neomycin. These results provide clear evidence for a link between antibiotic resistance and attachment to quartz in agricultural isolates. We propose that this may be due to encoding by the responsible genes on a mobile genetic element. Further exploration of the relationship between antibiotic resistance and attachment to environmental particles will improve the understanding and modeling of environmental transport processes, with the goal of preventing human exposure to antibiotic-resistant or virulent microorganisms. PMID:21821756
Liu, Ping; Soupir, Michelle L; Zwonitzer, Martha; Huss, Bridgette; Jarboe, Laura R
2011-10-01
Surface water can be contaminated by bacteria from various sources, including manure from agricultural facilities. Attachment of these bacteria to soil and organic particles contributes to their transport through the environment, though the mechanism of attachment is unknown. As bacterial attachment to human tissues is known to be correlated with antibiotic resistance, we have investigated here the relationship between bacterial attachment to environmental particles and antibiotic resistance in agricultural isolates. We evaluated 203 Escherichia coli isolates collected from swine facilities for attachment to quartz, resistance to 13 antibiotics, and the presence of genes encoding 13 attachment factors. The genes encoding type I, EcpA, P pili, and Ag43 were detected, though none was significantly related to attachment. Quartz attachment was positively and significantly (P amoxicillin/streptomycin/tetracycline/sulfamethazine/tylosin/chlortetracycline and negatively and significantly (P < 0.0038) related to combined resistance to nalidixic acid/kanamycin/neomycin. These results provide clear evidence for a link between antibiotic resistance and attachment to quartz in agricultural isolates. We propose that this may be due to encoding by the responsible genes on a mobile genetic element. Further exploration of the relationship between antibiotic resistance and attachment to environmental particles will improve the understanding and modeling of environmental transport processes, with the goal of preventing human exposure to antibiotic-resistant or virulent microorganisms.
Role of multidrug resistance protein (MRP) in glutathione S-conjugate transport in mammalian cells
Müller, M.; de Vries, E. G.; Jansen, P. L.
1996-01-01
The human multidrug resistance protein (MRP), a 190-kDa member of the ABC-protein superfamily, is an ATP-dependent glutathione S-conjugate carrier (GS-X pump) and is present in membranes of many, if not all, cells. Overexpression of MRP in tumor cells contributes to resistance to natural product
Role of multidrug resistance protein (MRP) in glutathione S-conjugate transport in mammalian cells
Muller, M; deVries, EGE; Jansen, PLM
1996-01-01
The human multidrug resistance protein (MRP), a 190-kDa member of the ABC-protein superfamily, is an ATP-dependent glutathione S-conjugate carrier (GS-X pump) and is present in membranes of many, if not all, cells, Overexpression of MRP in tumor cells contributes to resistance to natural product
Rijpma, Sanna R; van der Velden, Maarten; Annoura, Takeshi; Matz, Joachim M; Kenthirapalan, Sanketha; Kooij, Taco W A; Matuschewski, Kai; van Gemert, Geert-Jan; van de Vegte-Bolmer, Marga; Siebelink-Stoter, Rianne; Graumans, Wouter; Ramesar, Jai; Klop, Onny; Russel, Frans G M; Sauerwein, Robert W; Janse, Chris J; Franke-Fayard, Blandine M; Koenderink, Jan B
2016-07-01
Multidrug resistance (MDR) proteins belong to the B subfamily of the ATP Binding Cassette (ABC) transporters, which export a wide range of compounds including pharmaceuticals. In this study, we used reverse genetics to study the role of all seven Plasmodium MDR proteins during the life cycle of malaria parasites. Four P. berghei genes (encoding MDR1, 4, 6 and 7) were refractory to deletion, indicating a vital role during blood stage multiplication and validating them as potential targets for antimalarial drugs. Mutants lacking expression of MDR2, MDR3 and MDR5 were generated in both P. berghei and P. falciparum, indicating a dispensable role for blood stage development. Whereas P. berghei mutants lacking MDR3 and MDR5 had a reduced blood stage multiplication in vivo, blood stage growth of P. falciparum mutants in vitro was not significantly different. Oocyst maturation and sporozoite formation in Plasmodium mutants lacking MDR2 or MDR5 was reduced. Sporozoites of these P. berghei mutants were capable of infecting mice and life cycle completion, indicating the absence of vital roles during liver stage development. Our results demonstrate vital and dispensable roles of MDR proteins during blood stages and an important function in sporogony for MDR2 and MDR5 in both Plasmodium species. © 2016 John Wiley & Sons Ltd.
Determination of the drag resistance coefficients of different vehicles
Fahsl, Christoph; Vogt, Patrik
2018-05-01
While it has been demonstrated how air resistance could be analyzed by using mobile devices, this paper demonstrates a method of how to determine the drag resistance coefficient c of a commercial automobile by using the acceleration sensor of a smartphone or tablet. In an academic context, the drag resistance is often mentioned, but little attention is paid to quantitative measurements. This experiment was driven by the fact that this physical value is most certainly neglected because of its difficult measurability. In addition to that, this experiment gives insights on how the aerodynamic factor of an automobile affects the energy dissipation and thus how much power is required by automobile transportation.
Detection of multidrug-resistant tuberculosis from stored DNA Samples: A multicenter study
Directory of Open Access Journals (Sweden)
Marie Sylvianne Rabodoarivelo
2018-01-01
Full Text Available Background: In low-income countries, rapid detection of tuberculosis (TB drug resistance is often restricted by the difficulties of transporting and storing sputum samples from remote health centers to the reference laboratories where molecular tests are available. The aim of this study was to evaluate the performance of four transport and storage systems for molecular detection of rifampicin (RIF and isoniazid (INH resistance. Methods: This was a multicenter study. Molecular detection of RIF and INH resistance was performed directly from smear-positive TB sputa spotted on a slide, FTA card, GenoCard, and ethanol using the Genotype MTBDRplus assay. The performance of the DNA extraction method from each storage support to detect drug resistance was assessed by calculating their sensitivity and specificity compared to the phenotypic method. Results: From all sites, the overall sensitivity and specificity for RIF-resistance detection was 88% and 85%, respectively, for slides, 86% and 92%, respectively, for GenoCard, 87% and 89%, respectively, for FTA card, and 88% and 92%, respectively, for ethanol. For INH-resistance detection, the overall sensitivity and specificity was 82% and 90%, respectively, for slides, 85% and 96%, respectively, for GenoCard, 86% and 92%, respectively, for FTA card, and 86% and 94%, respectively, for ethanol. Conclusion: Smear slides and filter cards showed to be very useful tools to facilitate DNA extraction from sputum samples with the potential to accelerate the detection of drug resistance in remote areas.
Detection of multidrug-resistant tuberculosis from stored DNA Samples: A multicenter study.
Rabodoarivelo, Marie Sylvianne; Brandao, A; Cergole Novella, M C; C Bombonatte, A G; Imperiale, B; Rakotosamimanana, N; Morcillo, N; Rasolofo, V; Palomino, J C; Martin, A
2018-01-01
In low-income countries, rapid detection of tuberculosis (TB) drug resistance is often restricted by the difficulties of transporting and storing sputum samples from remote health centers to the reference laboratories where molecular tests are available. The aim of this study was to evaluate the performance of four transport and storage systems for molecular detection of rifampicin (RIF) and isoniazid (INH) resistance. This was a multicenter study. Molecular detection of RIF and INH resistance was performed directly from smear-positive TB sputa spotted on a slide, FTA card, GenoCard, and ethanol using the Genotype MTBDRplus assay. The performance of the DNA extraction method from each storage support to detect drug resistance was assessed by calculating their sensitivity and specificity compared to the phenotypic method. From all sites, the overall sensitivity and specificity for RIF-resistance detection was 88% and 85%, respectively, for slides, 86% and 92%, respectively, for GenoCard, 87% and 89%, respectively, for FTA card, and 88% and 92%, respectively, for ethanol. For INH-resistance detection, the overall sensitivity and specificity was 82% and 90%, respectively, for slides, 85% and 96%, respectively, for GenoCard, 86% and 92%, respectively, for FTA card, and 86% and 94%, respectively, for ethanol. Smear slides and filter cards showed to be very useful tools to facilitate DNA extraction from sputum samples with the potential to accelerate the detection of drug resistance in remote areas.
Plutonium accident resistant container project
International Nuclear Information System (INIS)
Andersen, J.A.
1978-09-01
The PARC (plutonium accident resistant container) project resulted in the design, development, and certification testing of a crashworthy air-transportable plutonium package (shipping container) for certification by the USNRC (Nuclear Regulatory Commission). This PAT-1 (plutonium air transportable) package survives a very severe sequential test program of impact, crush, puncture, slash, burn, and water immersion. There is also an individual hydrostatic pressure test. The package has a payload mass capacity of 2 kg of PuO 2 and a thermal capacity of 25 watts. The design rationale for very high energy absorption (impact, crush, puncture, and slash protection) with residual high-level fire protection, resulted in a reasonably small air-transportable package, advancing the packaging state-of-art. Optimization design iterations were utilized in the areas of impact energy absorption and stress and thermal analysis. Package test results are presented in relation to radioactive materials containment acceptance criteria, shielding and criticality standards
Drug Transporter Expression and Activity in Human Hepatoma HuH-7 Cells
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Elodie Jouan
2016-12-01
Full Text Available Human hepatoma cells may represent a valuable alternative to the use of human hepatocytes for studying hepatic drug transporters, which is now a regulatory issue during drug development. In the present work, we have characterized hepatic drug transporter expression, activity and regulation in human hepatoma HuH-7 cells, in order to determine the potential relevance of these cells for drug transport assays. HuH-7 cells displayed notable multidrug resistance-associated protein (MRP activity, presumed to reflect expression of various hepatic MRPs, including MRP2. By contrast, they failed to display functional activities of the uptake transporters sodium taurocholate co-transporting polypeptide (NTCP, organic anion-transporting polypeptides (OATPs and organic cation transporter 1 (OCT1, and of the canalicular transporters P-glycoprotein and breast cancer resistance protein (BCRP. Concomitantly, mRNA expressions of various sinusoidal and canalicular hepatic drug transporters were not detected (NTCP, OATP1B1, organic anion transporter 2 (OAT2, OCT1 and bile salt export pump or were found to be lower (OATP1B3, OATP2B1, multidrug and toxin extrusion protein 1, BCRP and MRP3 in hepatoma HuH-7 cells than those found in human hepatocytes, whereas other transporters such as OAT7, MRP4 and MRP5 were up-regulated. HuH-7 cells additionally exhibited farnesoid X receptor (FXR- and nuclear factor erythroid 2-related factor 2 (Nrf2-related up-regulation of some transporters. Such data indicate that HuH-7 cells, although expressing rather poorly some main hepatic drug transporters, may be useful for investigating interactions of drugs with MRPs, notably MRP2, and for studying FXR- or Nrf2-mediated gene regulation.
Ballistic Transport Exceeding 28 μm in CVD Grown Graphene.
Banszerus, Luca; Schmitz, Michael; Engels, Stephan; Goldsche, Matthias; Watanabe, Kenji; Taniguchi, Takashi; Beschoten, Bernd; Stampfer, Christoph
2016-02-10
We report on ballistic transport over more than 28 μm in graphene grown by chemical vapor deposition (CVD) that is fully encapsulated in hexagonal boron nitride. The structures are fabricated by an advanced dry van-der-Waals transfer method and exhibit carrier mobilities of up to three million cm(2)/(Vs). The ballistic nature of charge transport is probed by measuring the bend resistance in cross- and square-shaped devices. Temperature-dependent measurements furthermore prove that ballistic transport is maintained exceeding 1 μm up to 200 K.
Watson, Christopher P; Dogruel, Murat; Mihoreanu, Larisa; Begley, David J; Weksler, Babette B; Couraud, Pierre O; Romero, Ignacio A; Thomas, Sarah A
2012-02-03
Human African trypanosomiasis (HAT) is a parasitic disease affecting sub-Saharan Africa. The parasites are able to traverse the blood-brain barrier (BBB), which marks stage 2 (S2) of the disease. Delivery of anti-parasitic drugs across the BBB is key to treating S2 effectively and the difficulty in achieving this goal is likely to be a reason why some drugs require highly intensive treatment regimes to be effective. This study aimed to investigate not only the drug transport mechanisms utilised by nifurtimox at the BBB, but also the impact of nifurtimox-eflornithine combination therapy (NECT) and other anti-HAT drug combination therapies (CTs) on radiolabelled-nifurtimox delivery in an in vitro model of drug accumulation and the human BBB, the hCMEC/D3 cell line. We found that nifurtimox appeared to use several membrane transporters, in particular breast-cancer resistance protein (BCRP), to exit the BBB cells. The addition of eflornithine caused no change in the accumulation of nifurtimox, nor did the addition of clinically relevant doses of the other anti-HAT drugs suramin, nifurtimox or melarsoprol, but a significant increase was observed with the addition of pentamidine. The results provide evidence that anti-HAT drugs are interacting with membrane transporters at the human BBB and suggest that combination with known transport inhibitors could potentially improve their efficacy. Copyright © 2011 Elsevier B.V. All rights reserved.
Genome-wide re-sequencing of multidrug-resistant Mycobacterium leprae Airaku-3.
Singh, P; Benjak, A; Carat, S; Kai, M; Busso, P; Avanzi, C; Paniz-Mondolfi, A; Peter, C; Harshman, K; Rougemont, J; Matsuoka, M; Cole, S T
2014-10-01
Genotyping and molecular characterization of drug resistance mechanisms in Mycobacterium leprae enables disease transmission and drug resistance trends to be monitored. In the present study, we performed genome-wide analysis of Airaku-3, a multidrug-resistant strain with an unknown mechanism of resistance to rifampicin. We identified 12 unique non-synonymous single-nucleotide polymorphisms (SNPs) including two in the transporter-encoding ctpC and ctpI genes. In addition, two SNPs were found that improve the resolution of SNP-based genotyping, particularly for Venezuelan and South East Asian strains of M. leprae. © 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.
Nonlinear behavior of multiple-helicity resistive interchange modes near marginally stable states
International Nuclear Information System (INIS)
Sugama, Hideo; Nakajima, Noriyoshi; Wakatani, Masahiro.
1991-05-01
Nonlinear behavior of resistive interchange modes near marginally stable states is theoretically studied under the multiple-helicity condition. Reduced fluid equations in the sheared slab configuration are used in order to treat a local transport problem. With the use of the invariance property of local reduced fluid model equations under a transformation between the modes with different rational surfaces, weakly nonlinear theories for single-helicity modes by Hamaguchi and Nakajima are extended to the multiple-helicity case and applied to the resistive interchange modes. We derive the nonlinear amplitude equations of the multiple-helicity modes, from which the convective transport in the saturated state is obtained. It is shown how the convective transport is enhanced by nonlinear interaction between modes with different rational surfaces compared with the single-helicity case. We confirm that theoretical results are in good agreement with direct numerical simulations. (author)
Highly loaded behavior of kinesins increases the robustness of transport under high resisting loads.
Directory of Open Access Journals (Sweden)
Woochul Nam
2015-03-01
Full Text Available Kinesins are nano-sized biological motors which walk by repeating a mechanochemical cycle. A single kinesin molecule is able to transport its cargo about 1 μm in the absence of external loads. However, kinesins perform much longer range transport in cells by working collectively. This long range of transport by a team of kinesins is surprising because the motion of the cargo in cells can be hindered by other particles. To reveal how the kinesins are able to accomplish their tasks of transport in harsh intracellular circumstances, stochastic studies on the kinesin motion are performed by considering the binding and unbinding of kinesins to microtubules and their dependence on the force acting on kinesin molecules. The unbinding probabilities corresponding to each mechanochemical state of kinesin are modeled. The statistical characterization of the instants and locations of binding are captured by computing the probability of unbound kinesin being at given locations. It is predicted that a group of kinesins has a more efficient transport than a single kinesin from the perspective of velocity and run length. Particularly, when large loads are applied, the leading kinesin remains bound to the microtubule for long time which increases the chances of the other kinesins to bind to the microtubule. To predict effects of this behavior of the leading kinesin under large loads on the collective transport, the motion of the cargo is studied when the cargo confronts obstacles. The result suggests that the behavior of kinesins under large loads prevents the early termination of the transport which can be caused by the interference with the static or moving obstacles.
Insulin-stimulated glucose uptake in healthy and insulin-resistant skeletal muscle
DEFF Research Database (Denmark)
Deshmukh, Atul S
2016-01-01
transporter protein 4 (GLUT4) to the plasma membrane which leads to facilitated diffusion of glucose into the cell. Understanding the precise signaling events guiding insulin-stimulated glucose uptake is pivotal, because impairment in these signaling events leads to development of insulin resistance and type...... 2 diabetes. This review summarizes current understanding of insulin signaling pathways mediating glucose uptake in healthy and insulin-resistant skeletal muscle....
14 CFR 29.952 - Fuel system crash resistance.
2010-01-01
... AIRCRAFT AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Powerplant Fuel System § 29.952 Fuel system... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Fuel system crash resistance. 29.952... of fuel fires to occupants following an otherwise survivable impact (crash landing), the fuel systems...
Individual domain wall resistance in submicron ferromagnetic structures.
Danneau, R; Warin, P; Attané, J P; Petej, I; Beigné, C; Fermon, C; Klein, O; Marty, A; Ott, F; Samson, Y; Viret, M
2002-04-15
The resistance generated by individual domain walls is measured in a FePd nanostructure. Combining transport and magnetic imaging measurements, the intrinsic domain wall resistance is quantified. It is found positive and of a magnitude consistent with that predicted by models based on spin scattering effects within the walls. This magnetoresistance at a nanometer scale allows a direct counting of the number of walls inside the nanostructure. The effect is then used to measure changes in the magnetic configuration of submicron stripes under application of a magnetic field.
Ping, Linquan; Hou, Peng-Xiang; Liu, Chang; Li, Jincheng; Zhao, Yang; Zhang, Feng; Ma, Chaoqun; Tai, Kaiping; Cong, Hongtao; Cheng, Hui-Ming
2017-06-22
A vertically aligned carbon nanotube (VACNT) array is a promising candidate for a high-performance thermal interface material in high-power microprocessors due to its excellent thermal transport property. However, its rough and entangled free tips always cause poor interfacial contact, which results in serious contact resistance dominating the total thermal resistance. Here, we employed a thin carbon cover to restrain the disorderly growth of the free tips of a VACNT array. As a result, all the free tips are seamlessly connected by this thin carbon cover and the top surface of the array is smoothed. This unique structure guarantees the participation of all the carbon nanotubes in the array in the heat transport. Consequently the VACNT array grown on a Cu substrate shows a record low thermal resistance of 0.8 mm 2 K W -1 including the two-sided contact resistances, which is 4 times lower than the best result previously reported. Remarkably, the VACNT array can be easily peeled away from the Cu substrate and act as a thermal pad with excellent flexibility, adhesive ability and heat transport capability. As a result the CNT array with a thin carbon cover shows great potential for use as a high-performance flexible thermal interface material.
Hypoxic tumor environments exhibit disrupted collagen I fibers and low macromolecular transport.
Directory of Open Access Journals (Sweden)
Samata M Kakkad
Full Text Available Hypoxic tumor microenvironments result in an aggressive phenotype and resistance to therapy that lead to tumor progression, recurrence, and metastasis. While poor vascularization and the resultant inadequate drug delivery are known to contribute to drug resistance, the effect of hypoxia on molecular transport through the interstitium, and the role of the extracellular matrix (ECM in mediating this transport are unexplored. The dense mesh of fibers present in the ECM can especially influence the movement of macromolecules. Collagen 1 (Col1 fibers form a key component of the ECM in breast cancers. Here we characterized the influence of hypoxia on macromolecular transport in tumors, and the role of Col1 fibers in mediating this transport using an MDA-MB-231 breast cancer xenograft model engineered to express red fluorescent protein under hypoxia. Magnetic resonance imaging of macromolecular transport was combined with second harmonic generation microscopy of Col1 fibers. Hypoxic tumor regions displayed significantly decreased Col1 fiber density and volume, as well as significantly lower macromolecular draining and pooling rates, than normoxic regions. Regions adjacent to severely hypoxic areas revealed higher deposition of Col1 fibers and increased macromolecular transport. These data suggest that Col1 fibers may facilitate macromolecular transport in tumors, and their reduction in hypoxic regions may reduce this transport. Decreased macromolecular transport in hypoxic regions may also contribute to poor drug delivery and tumor recurrence in hypoxic regions. High Col1 fiber density observed around hypoxic regions may facilitate the escape of aggressive cancer cells from hypoxic regions.
Structures and transport dynamics of a Campylobacter jejuni multidrug efflux pump
Energy Technology Data Exchange (ETDEWEB)
Su, Chih-Chia; Yin, Linxiang; Kumar, Nitin; Dai, Lei; Radhakrishnan, Abhijith; Bolla, Jani Reddy; Lei, Hsiang-Ting; Chou, Tsung-Han; Delmar, Jared A.; Rajashankar, Kanagalaghatta R.; Zhang, Qijing; Shin, Yeon-Kyun; Yu, Edward W. (Cornell); (Iowa State)
2017-08-01
Resistance-nodulation-cell division efflux pumps are integral membrane proteins that catalyze the export of substrates across cell membranes. Within the hydrophobe-amphiphile efflux subfamily, these resistance-nodulation-cell division proteins largely form trimeric efflux pumps. The drug efflux process has been proposed to entail a synchronized motion between subunits of the trimer to advance the transport cycle, leading to the extrusion of drug molecules. Here we use X-ray crystallography and single-molecule fluorescence resonance energy transfer imaging to elucidate the structures and functional dynamics of the Campylobacter jejuni CmeB multidrug efflux pump. We find that the CmeB trimer displays a very unique conformation. A direct observation of transport dynamics in individual CmeB trimers embedded in membrane vesicles indicates that each CmeB subunit undergoes conformational transitions uncoordinated and independent of each other. On the basis of our findings and analyses, we propose a model for transport mechanism where CmeB protomers function independently within the trimer.
Directory of Open Access Journals (Sweden)
Ana M. Rule
Full Text Available Summary: Use of antimicrobial feed additives in food animal production is associated with selection for drug resistance in bacterial pathogens, which can then be released into the environment through occupational exposures, high volume ventilation of animal houses, and land application of animal wastes. We tested the hypothesis that current methods of transporting food animals from farms to slaughterhouses may result in pathogen releases and potential exposures of persons in vehicles traveling on the same road. Air and surface samples were taken from cars driving behind poultry trucks for 17 miles. Air conditioners and fans were turned off and windows fully opened. Background and blank samples were used for quality control. Samples were analyzed for susceptible and drug-resistant strains. Results indicate an increase in the number of total aerobic bacteria including both susceptible and drug-resistant enterococci isolated from air and surface samples, and suggest that food animal transport in open crates introduces a novel route of exposure to harmful microorganisms and may disseminate these pathogens into the general environment. These findings support the need for further exposure characterization, and attention to improving methods of food animal transport, especially in highly trafficked regions of high density farming such as the Delmarva Peninsula. Keywords: Antimicrobial resistance, CAFO, Bioaerosol, Food animal transport, Air sampling, Surface sampling
Lin, Shan-Hua; Kuo, Hui-Fen; Canivenc, Geneviève; Lin, Choun-Sea; Lepetit, Marc; Hsu, Po-Kai; Tillard, Pascal; Lin, Huey-Ling; Wang, Ya-Yun; Tsai, Chyn-Bey; Gojon, Alain; Tsay, Yi-Fang
2008-09-01
Little is known about the molecular and regulatory mechanisms of long-distance nitrate transport in higher plants. NRT1.5 is one of the 53 Arabidopsis thaliana nitrate transporter NRT1 (Peptide Transporter PTR) genes, of which two members, NRT1.1 (CHL1 for Chlorate resistant 1) and NRT1.2, have been shown to be involved in nitrate uptake. Functional analysis of cRNA-injected Xenopus laevis oocytes showed that NRT1.5 is a low-affinity, pH-dependent bidirectional nitrate transporter. Subcellular localization in plant protoplasts and in planta promoter-beta-glucuronidase analysis, as well as in situ hybridization, showed that NRT1.5 is located in the plasma membrane and is expressed in root pericycle cells close to the xylem. Knockdown or knockout mutations of NRT1.5 reduced the amount of nitrate transported from the root to the shoot, suggesting that NRT1.5 participates in root xylem loading of nitrate. However, root-to-shoot nitrate transport was not completely eliminated in the NRT1.5 knockout mutant, and reduction of NRT1.5 in the nrt1.1 background did not affect root-to-shoot nitrate transport. These data suggest that, in addition to that involving NRT1.5, another mechanism is responsible for xylem loading of nitrate. Further analyses of the nrt1.5 mutants revealed a regulatory loop between nitrate and potassium at the xylem transport step.
Jiang, Fangming; Peng, Peng
2016-01-01
Underutilization due to performance limitations imposed by species and charge transports is one of the key issues that persist with various lithium-ion batteries. To elucidate the relevant mechanisms, two groups of characteristic parameters were proposed. The first group contains three characteristic time parameters, namely: (1) te, which characterizes the Li-ion transport rate in the electrolyte phase, (2) ts, characterizing the lithium diffusion rate in the solid active materials, and (3) tc, describing the local Li-ion depletion rate in electrolyte phase at the electrolyte/electrode interface due to electrochemical reactions. The second group contains two electric resistance parameters: Re and Rs, which represent respectively, the equivalent ionic transport resistance and the effective electronic transport resistance in the electrode. Electrochemical modeling and simulations to the discharge process of LiCoO2 cells reveal that: (1) if te, ts and tc are on the same order of magnitude, the species transports may not cause any performance limitations to the battery; (2) the underlying mechanisms of performance limitations due to thick electrode, high-rate operation, and large-sized active material particles as well as effects of charge transports are revealed. The findings may be used as quantitative guidelines in the development and design of more advanced Li-ion batteries. PMID:27599870
Gellatly, Kyle J; Yoon, Kyong Sup; Doherty, Jeffery J; Sun, Weilin; Pittendrigh, Barry R; Clark, J Marshall
2015-06-01
4,4'-dichlorodiphenyltrichloroethane (DDT) has been re-recommended by the World Health Organization for malaria mosquito control. Previous DDT use has resulted in resistance, and with continued use resistance will increase in terms of level and extent. Drosophila melanogaster is a model dipteran that has many available genetic tools, numerous studies done on insecticide resistance mechanisms, and is related to malaria mosquitoes allowing for extrapolation. The 91-R strain of D. melanogaster is highly resistant to DDT (>1500-fold), however, there is no mechanistic scheme that accounts for this level of resistance. Recently, reduced penetration, increased detoxification, and direct excretion have been identified as resistance mechanisms in the 91-R strain. Their interactions, however, remain unclear. Use of UAS-RNAi transgenic lines of D. melanogaster allowed for the targeted knockdown of genes putatively involved in DDT resistance and has validated the role of several cuticular proteins (Cyp4g1 and Lcp1), cytochrome P450 monooxygenases (Cyp6g1 and Cyp12d1), and ATP binding cassette transporters (Mdr50, Mdr65, and Mrp1) involved in DDT resistance. Further, increased sensitivity to DDT in the 91-R strain after intra-abdominal dsRNA injection for Mdr50, Mdr65, and Mrp1 was determined by a DDT contact bioassay, directly implicating these genes in DDT efflux and resistance. Copyright © 2015 Elsevier Inc. All rights reserved.
Energy Technology Data Exchange (ETDEWEB)
Bhattacharjee, Sourav, E-mail: sourav.bhattacharjee@wur.nl [Wageningen University, Laboratory of Organic Chemistry (Netherlands); Opstal, Edward J. van; Alink, Gerrit M. [Wageningen University, Division of Toxicology (Netherlands); Marcelis, Antonius T. M.; Zuilhof, Han [Wageningen University, Laboratory of Organic Chemistry (Netherlands); Rietjens, Ivonne M. C. M. [Wageningen University, Division of Toxicology (Netherlands)
2013-06-15
The surface charge-dependent transport of polymeric nanoparticles (PNPs) across Caco-2 monolayers grown on transwell culture systems as an in vitro model for intestinal transport was tested. The transport of well-characterized, monodisperse, and fluorescent tri-block copolymer nanoparticles (TCNPs/size {approx}45 nm) and polystyrene nanoparticles (PSNPs/size {approx}50 nm), with different surface charges (positive and negative), was quantified. The positive PNPs showed a higher intracellular uptake and flux across the Caco-2 monolayers than the negative PNPs. Multidrug resistance/P-glycoprotein (MDR1/P-gp), a specific ATP-binding cassette (ABC) transporter, was found to play a major role in the cellular efflux of positive PNPs, whereas the multidrug resistance protein 1 took part in the efflux of negative PNPs from Caco-2 cells. The positive PNPs also caused an increased cellular uptake and apical to basolateral transport of the carcinogen PhIP across the Caco-2 monolayer. The flavonoid quercetin, which is known to interact with ABC transporters, promoted the intracellular uptake of different PNPs and interfered with the normal distribution patterns of PNPs in the transwell system. These results indicate that PNPs display surface charge-specific interactions with ABC transporters and can even affect the bioavailability of toxic food-borne compounds (like pro-carcinogens).
Bhattacharjee, Sourav; van Opstal, Edward J.; Alink, Gerrit M.; Marcelis, Antonius T. M.; Zuilhof, Han; Rietjens, Ivonne M. C. M.
2013-06-01
The surface charge-dependent transport of polymeric nanoparticles (PNPs) across Caco-2 monolayers grown on transwell culture systems as an in vitro model for intestinal transport was tested. The transport of well-characterized, monodisperse, and fluorescent tri-block copolymer nanoparticles (TCNPs/size 45 nm) and polystyrene nanoparticles (PSNPs/size 50 nm), with different surface charges (positive and negative), was quantified. The positive PNPs showed a higher intracellular uptake and flux across the Caco-2 monolayers than the negative PNPs. Multidrug resistance/P-glycoprotein (MDR1/P-gp), a specific ATP-binding cassette (ABC) transporter, was found to play a major role in the cellular efflux of positive PNPs, whereas the multidrug resistance protein 1 took part in the efflux of negative PNPs from Caco-2 cells. The positive PNPs also caused an increased cellular uptake and apical to basolateral transport of the carcinogen PhIP across the Caco-2 monolayer. The flavonoid quercetin, which is known to interact with ABC transporters, promoted the intracellular uptake of different PNPs and interfered with the normal distribution patterns of PNPs in the transwell system. These results indicate that PNPs display surface charge-specific interactions with ABC transporters and can even affect the bioavailability of toxic food-borne compounds (like pro-carcinogens).
International Nuclear Information System (INIS)
Bhattacharjee, Sourav; Opstal, Edward J. van; Alink, Gerrit M.; Marcelis, Antonius T. M.; Zuilhof, Han; Rietjens, Ivonne M. C. M.
2013-01-01
The surface charge-dependent transport of polymeric nanoparticles (PNPs) across Caco-2 monolayers grown on transwell culture systems as an in vitro model for intestinal transport was tested. The transport of well-characterized, monodisperse, and fluorescent tri-block copolymer nanoparticles (TCNPs/size ∼45 nm) and polystyrene nanoparticles (PSNPs/size ∼50 nm), with different surface charges (positive and negative), was quantified. The positive PNPs showed a higher intracellular uptake and flux across the Caco-2 monolayers than the negative PNPs. Multidrug resistance/P-glycoprotein (MDR1/P-gp), a specific ATP-binding cassette (ABC) transporter, was found to play a major role in the cellular efflux of positive PNPs, whereas the multidrug resistance protein 1 took part in the efflux of negative PNPs from Caco-2 cells. The positive PNPs also caused an increased cellular uptake and apical to basolateral transport of the carcinogen PhIP across the Caco-2 monolayer. The flavonoid quercetin, which is known to interact with ABC transporters, promoted the intracellular uptake of different PNPs and interfered with the normal distribution patterns of PNPs in the transwell system. These results indicate that PNPs display surface charge-specific interactions with ABC transporters and can even affect the bioavailability of toxic food-borne compounds (like pro-carcinogens).
Mendes, Â; Martins da Costa, P; Rego, D; Beça, N; Alves, C; Moreira, T; Conceição, T; Aires-de-Sousa, M
2015-08-01
To analyse the contamination of public transports by Staphylococcus aureus and assess its carriage by biomedical students, focussing on the point-prevalence, related risk factors and molecular characterization of methicillin-resistant strains. Cross-sectional survey. Methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) isolated from handrails of buses (n = 112) and trains (n = 79) circulating in Porto and from nasal swabs of local university students (n = 475) were quantified, characterized by molecular typing methods and related to possible risk factors. The MRSA prevalence in buses (16.1%) was not significantly different from trains (8.9%). There was also no identifiable association between the counts of MSSA and MRSA in buses and trains and the number of travellers in each sampling day, specific routes (including those passing by main hospitals) or other risk factors. Of the students, 37.1% carried S. aureus, and having a part-time job or smoking were found to be risk factors for carriage. EMRSA-15 (ST22-SCCmecIVh) was the prevalent MRSA clonal lineage, found not only in the buses (n = 14) and trains (n = 2) but also in the single MRSA-carrier among the students. The characteristics of the community-associated Southwest Pacific MRSA clone were found in a single ST30-IVa isolate, which may suggest a recent SCCmec acquisition by an MSSA background in the community. The spread of EMRSA-15, a common hospital-associated lineage, among different public transports and as a nasal coloniser is of concern and warrants adequate public health control measures. Copyright © 2015 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.
System for calibration of SPEAR transport line toroids
International Nuclear Information System (INIS)
Huang, T.V.; Smith, H.; Crook, K.
1977-01-01
A one nanosecond pulse generator was developed for calibration of the intensity monitors (toroids) in the SPEAR transport lines. The generator, located at the toroid, is simple, low cost and resistant to radiation. The generator and its connection to the standard SLAC toroid calibration system are described
Electrical Transport and Magnetoresistance in Single-Wall Carbon Nanotubes Films
Directory of Open Access Journals (Sweden)
Vitaly KSENEVICH
2014-06-01
Full Text Available Electrical transport properties and magnetoresistance of single-wall carbon nanotubes (SWCNT films were investigated within temperature range (2 – 300 K and in magnetic fields up to 8 T. A crossover between metallic (dR/dT > 0 and non-metallic (dR/dT < 0 temperature dependence of the resistance as well as low-temperature saturation of the resistance in high bias regime indicated on the diminishing of role of the contact barriers between individual nanotubes essential for the charge transport in SWCNT arrays. The magnetoresistance (MR data demonstrated influence of weak localization and electron-electron interactions on charge transport properties in SWCNT films. The low-field negative MR with positive upturn was observed at low temperatures. At T > 10 K only negative MR was observed in the whole range of available magnetic fields. The negative MR can be approximated using 1D weak localization (WL model. The low temperature positive MR is induced by contribution from electron-electron interactions. DOI: http://dx.doi.org/10.5755/j01.ms.20.2.6311
Validation of transport models using additive flux minimization technique
Energy Technology Data Exchange (ETDEWEB)
Pankin, A. Y.; Kruger, S. E. [Tech-X Corporation, 5621 Arapahoe Ave., Boulder, Colorado 80303 (United States); Groebner, R. J. [General Atomics, San Diego, California 92121 (United States); Hakim, A. [Princeton Plasma Physics Laboratory, Princeton, New Jersey 08543-0451 (United States); Kritz, A. H.; Rafiq, T. [Department of Physics, Lehigh University, Bethlehem, Pennsylvania 18015 (United States)
2013-10-15
A new additive flux minimization technique is proposed for carrying out the verification and validation (V and V) of anomalous transport models. In this approach, the plasma profiles are computed in time dependent predictive simulations in which an additional effective diffusivity is varied. The goal is to obtain an optimal match between the computed and experimental profile. This new technique has several advantages over traditional V and V methods for transport models in tokamaks and takes advantage of uncertainty quantification methods developed by the applied math community. As a demonstration of its efficiency, the technique is applied to the hypothesis that the paleoclassical density transport dominates in the plasma edge region in DIII-D tokamak discharges. A simplified version of the paleoclassical model that utilizes the Spitzer resistivity for the parallel neoclassical resistivity and neglects the trapped particle effects is tested in this paper. It is shown that a contribution to density transport, in addition to the paleoclassical density transport, is needed in order to describe the experimental profiles. It is found that more additional diffusivity is needed at the top of the H-mode pedestal, and almost no additional diffusivity is needed at the pedestal bottom. The implementation of this V and V technique uses the FACETS::Core transport solver and the DAKOTA toolkit for design optimization and uncertainty quantification. The FACETS::Core solver is used for advancing the plasma density profiles. The DAKOTA toolkit is used for the optimization of plasma profiles and the computation of the additional diffusivity that is required for the predicted density profile to match the experimental profile.
Validation of transport models using additive flux minimization technique
International Nuclear Information System (INIS)
Pankin, A. Y.; Kruger, S. E.; Groebner, R. J.; Hakim, A.; Kritz, A. H.; Rafiq, T.
2013-01-01
A new additive flux minimization technique is proposed for carrying out the verification and validation (V and V) of anomalous transport models. In this approach, the plasma profiles are computed in time dependent predictive simulations in which an additional effective diffusivity is varied. The goal is to obtain an optimal match between the computed and experimental profile. This new technique has several advantages over traditional V and V methods for transport models in tokamaks and takes advantage of uncertainty quantification methods developed by the applied math community. As a demonstration of its efficiency, the technique is applied to the hypothesis that the paleoclassical density transport dominates in the plasma edge region in DIII-D tokamak discharges. A simplified version of the paleoclassical model that utilizes the Spitzer resistivity for the parallel neoclassical resistivity and neglects the trapped particle effects is tested in this paper. It is shown that a contribution to density transport, in addition to the paleoclassical density transport, is needed in order to describe the experimental profiles. It is found that more additional diffusivity is needed at the top of the H-mode pedestal, and almost no additional diffusivity is needed at the pedestal bottom. The implementation of this V and V technique uses the FACETS::Core transport solver and the DAKOTA toolkit for design optimization and uncertainty quantification. The FACETS::Core solver is used for advancing the plasma density profiles. The DAKOTA toolkit is used for the optimization of plasma profiles and the computation of the additional diffusivity that is required for the predicted density profile to match the experimental profile
Influence of intermartensitic transitions on transport properties of Ni$_{2.16}Mn_{0.84}$Ga alloy
Khovailo, V V; Wedel, C; Takagi, T; Abe, T; Sugiyama, K
2004-01-01
Magnetic, transport, and x-ray diffraction measurements of ferromagnetic shape memory alloy Ni$_{2.16}$Mn$_{0.84}$Ga revealed that this alloy undergoes an intermartensitic transition upon cooling, whereas no such a transition is observed upon subsequent heating. The difference in the modulation of the martensite forming upon cooling from the high-temperature austenitic state [5-layered (5M) martensite], and the martensite forming upon the intermartensitic transition [7-layered (7M) martensite] strongly affects the magnetic and transport properties of the alloy and results in a large thermal hysteresis of the resistivity $\\rho$ and magnetization $M$. The intermartensitic transition has an especially marked influence on the transport properties, as is evident from a large difference in the resistivity of the 5M and 7M martensite, $(\\rho_{\\mathrm{5M}} - \\rho_{\\mathrm{7M}})/\\rho _{\\mathrm{5M}} \\approx 15%$, which is larger than the jump of resistivity at the martensitic transition from the cubic austenitic phase ...
Expression of the human multidrug transporter in insect cells by a recombinant baculovirus
International Nuclear Information System (INIS)
Germann, U.A.; Willingham, M.C.; Pastan, I.; Gottesman, M.M.
1990-01-01
The plasma membrane associated human multidrug resistance (MDR1) gene product, known as the 170-kDa P-glycoprotein or the multidrug transporter, acts as an ATP-dependent efflux pump for various cytotoxic agents. The authors expressed recombinant human multidrug transporter in a baculovirus expression system to obtain large quantities and further investigate its structure and mechanism of action. MDR1 cDNA was inserted into the genome of the Autographa californica nuclear polyhedrosis virus under the control of the polyhedrin promoter. Spodoptera frugiperda insect cells synthesized high levels of recombinant multidrug transporter 2-3 days after infection. The transporter was localized by immunocytochemical methods on the external surface of the plasma membranes, in the Golgi apparatus, and within the nuclear envelope. The human multidrug transporter expressed in insect cells is not susceptible to endoglycosidase F treatment and has a lower apparent molecular weight of 140,000, corresponding to the nonglycosylated precursor of its authentic counterpart expressed in multidrug-resistant cells. Labeling experiments showed that the recombinant multidrug transporter is phosphorylated and can be photoaffinity labeled by [ 3 H]azidopine, presumably at the same two sites as the native protein. Various drugs and reversing agents compete with the [ 3 H]azidopine binding reaction when added in excess, indicating that the recombinant human multidrug transporter expressed in insect cells is functionally similar to its authentic counterpart
Hegedüs, Csilla; Truta-Feles, Krisztina; Antalffy, Géza; Várady, György; Német, Katalin; Ozvegy-Laczka, Csilla; Kéri, György; Orfi, László; Szakács, Gergely; Settleman, Jeffrey; Váradi, András; Sarkadi, Balázs
2012-08-01
Human ABCG2 is a plasma membrane glycoprotein that provides physiological protection against xenobiotics. ABCG2 also significantly influences biodistribution of drugs through pharmacological tissue barriers and confers multidrug resistance to cancer cells. Moreover, ABCG2 is the molecular determinant of the side population that is characteristically enriched in normal and cancer stem cells. Numerous tumors depend on unregulated EGFR signaling, thus inhibition of this receptor by small molecular weight inhibitors such as gefitinib, and the novel second generation agents vandetanib, pelitinib and neratinib, is a promising therapeutic option. In the present study, we provide detailed biochemical characterization regarding the interaction of these EGFR inhibitors with ABCG2. We show that ABCG2 confers resistance to gefitinib and pelitinib, whereas the intracellular action of vandetanib and neratinib is unaltered by the presence of the transporter. At higher concentrations, however, all these EGFR inhibitors inhibit ABCG2 function, thereby promoting accumulation of ABCG2 substrate drugs. We also report enhanced expression of ABCG2 in gefitinib-resistant non-small cell lung cancer cells, suggesting potential clinical relevance of ABCG2 in acquired drug resistance. Since ABCG2 has important impact on both the pharmacological properties and anti-cancer efficiencies of drugs, our results regarding the novel EGFR inhibitors should provide useful information about their therapeutic applicability against ABCG2-expressing cancer cells depending on EGFR signaling. In addition, the finding that these EGFR inhibitors efficiently block ABCG2 function may help to design novel drug-combination therapeutic strategies. Copyright © 2012 Elsevier Inc. All rights reserved.
Lebedeva, Irina V; Pande, Praveen; Patton, Wayne F
2011-01-01
An underlying mechanism for multi drug resistance (MDR) is up-regulation of the transmembrane ATP-binding cassette (ABC) transporter proteins. ABC transporters also determine the general fate and effect of pharmaceutical agents in the body. The three major types of ABC transporters are MDR1 (P-gp, P-glycoprotein, ABCB1), MRP1/2 (ABCC1/2) and BCRP/MXR (ABCG2) proteins. Flow cytometry (FCM) allows determination of the functional expression levels of ABC transporters in live cells, but most dyes used as indicators (rhodamine 123, DiOC(2)(3), calcein-AM) have limited applicability as they do not detect all three major types of ABC transporters. Dyes with broad coverage (such as doxorubicin, daunorubicin and mitoxantrone) lack sensitivity due to overall dimness and thus may yield a significant percentage of false negative results. We describe two novel fluorescent probes that are substrates for all three common types of ABC transporters and can serve as indicators of MDR in flow cytometry assays using live cells. The probes exhibit fast internalization, favorable uptake/efflux kinetics and high sensitivity of MDR detection, as established by multidrug resistance activity factor (MAF) values and Kolmogorov-Smirnov statistical analysis. Used in combination with general or specific inhibitors of ABC transporters, both dyes readily identify functional efflux and are capable of detecting small levels of efflux as well as defining the type of multidrug resistance. The assay can be applied to the screening of putative modulators of ABC transporters, facilitating rapid, reproducible, specific and relatively simple functional detection of ABC transporter activity, and ready implementation on widely available instruments.