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Selected Works

Roland A. Cooper

Articles 1 - 23 of 23

Full-Text Articles in Life Sciences

Genome-Wide Compensatory Changes Accompany Drug-Selected Mutations In The Plasmodium Falciparum Crt Gene, Hongying Jiang, Jigar J. Patel, Ming Yi, Jianbing Mu, Jinhui Ding, Robert Stephens, Roland A. Cooper, Michael T. Ferdig, Xin-Zhuan Su May 2016

Genome-Wide Compensatory Changes Accompany Drug-Selected Mutations In The Plasmodium Falciparum Crt Gene, Hongying Jiang, Jigar J. Patel, Ming Yi, Jianbing Mu, Jinhui Ding, Robert Stephens, Roland A. Cooper, Michael T. Ferdig, Xin-Zhuan Su

Roland A. Cooper

Mutations in PfCRT (Plasmodium falciparum chloroquine-resistant transporter), particularly the substitution at amino acid position 76, confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. Moreover, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). Reemergence of CQ sensitive parasites after cessation of CQ use indicates that changes in PfCRT are deleterious to the parasite. Some CQR parasites, however, persist in the …

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Mutation In The Plasmodium Falciparum Crt Protein Determines The Stereospecific Activity Of Antimalarial Cinchona Alkaloids, Carol E. Griffin, Jonathan M. Hoke, Upeka Samarakoon, Junhui Duan, Jianbing Mu, Michael T. Ferdig, David C. Warhurst, Roland Cooper Oct 2015

Mutation In The Plasmodium Falciparum Crt Protein Determines The Stereospecific Activity Of Antimalarial Cinchona Alkaloids, Carol E. Griffin, Jonathan M. Hoke, Upeka Samarakoon, Junhui Duan, Jianbing Mu, Michael T. Ferdig, David C. Warhurst, Roland Cooper

Roland A. Cooper

The Cinchona alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (-)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (-)-isomers in vitro and in vivo against Plasmodium falciparum malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparum chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward P. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the in vitro susceptibility …

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Accumulation Of Artemisinin Trioxane Derivatives Within Neutral Lipids Of Plasmodium Falciparum Malaria Parasites Is Endoperoxide-Dependent, Carmony L. Hartwig, Andrew S. Rosenthal, John D'Angelo, Carol E. Griffin, Gary H. Posner, Roland A. Cooper Oct 2015

Accumulation Of Artemisinin Trioxane Derivatives Within Neutral Lipids Of Plasmodium Falciparum Malaria Parasites Is Endoperoxide-Dependent, Carmony L. Hartwig, Andrew S. Rosenthal, John D'Angelo, Carol E. Griffin, Gary H. Posner, Roland A. Cooper

Roland A. Cooper

The antimalarial trioxanes, exemplified by the naturally occurring sesquiterpene lactone artemisinin and its semi-synthetic derivatives, contain an endoperoxide pharmacophore that lends tremendous potency against Plasmodium parasites. Despite decades of research, their mechanism of action remains unresolved. A leading model of anti-plasmodial activity hypothesizes that iron-mediated cleavage of the endoperoxide bridge generates cytotoxic drug metabolites capable of damaging cellular macromolecules. To probe the malarial targets of the endoperoxide drugs, we studied the distribution of fluorescent dansyl trioxane derivatives in living, intraerythrocytic-stage Plasmodium falciparum parasites using microscopic imaging. The fluorescent trioxanes rapidly accumulated in parasitized erythrocytes, localizing within digestive vacuole-associated neutral lipid …

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Genome-Wide Compensatory Changes Accompany Drugselected Mutations In The Plasmodium Falciparum Crt Gene, Hongying Jiang, Jigar J. Patel, Ming Yi, Jianbing Mu, Jinhui Ding, Robert Stephens, Roland Cooper, Michael T. Ferdig, Xin-Zhuan Su Oct 2015

Genome-Wide Compensatory Changes Accompany Drugselected Mutations In The Plasmodium Falciparum Crt Gene, Hongying Jiang, Jigar J. Patel, Ming Yi, Jianbing Mu, Jinhui Ding, Robert Stephens, Roland Cooper, Michael T. Ferdig, Xin-Zhuan Su

Roland A. Cooper

Mutations in PfCRT (Plasmodium falciparum chloroquine-resistant transporter), particularly the substitution at amino acid position 76, confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. Moreover, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). Reemergence of CQ sensitive parasites after cessation of CQ use indicates that changes in PfCRT are deleterious to the parasite. Some CQR parasites, however, persist in the field and grow well …

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Design, Synthesis, And Evaluation Of 10-N-Substituted Acridones As Novel Chemosensitizers In Plasmodium Falciparum, Jane X. Kelly, Martin J. Smilkstein, Roland A. Cooper, Kristin D. Lane, Robert A. Johnson, Aaron Janowsky, Rozalia A. Dodean, Rolf Winter, Michael Riscoe Oct 2015

Design, Synthesis, And Evaluation Of 10-N-Substituted Acridones As Novel Chemosensitizers In Plasmodium Falciparum, Jane X. Kelly, Martin J. Smilkstein, Roland A. Cooper, Kristin D. Lane, Robert A. Johnson, Aaron Janowsky, Rozalia A. Dodean, Rolf Winter, Michael Riscoe

Roland A. Cooper

A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive …

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Detection Of Panulirus Argus Virus 1 In Caribbean Spiny Lobsters, Megan M. Montgomery-Fullerton, Roland Cooper, Kathryn M. Kauffman, Jeffrey D. Shields, Robert E. Ratzlaff Oct 2015

Detection Of Panulirus Argus Virus 1 In Caribbean Spiny Lobsters, Megan M. Montgomery-Fullerton, Roland Cooper, Kathryn M. Kauffman, Jeffrey D. Shields, Robert E. Ratzlaff

Roland A. Cooper

Panulirus argus Virus 1 (PaV1) is a pathogenic virus that infects Caribbean spiny lobsters P. argus in the Florida Keys. We have developed a PCR detection assay for PaV1 for the purpose of studying the natural history of the virus and for monitoring the prevalence of infection. The detection of the virus in hemolymph and other tissues is based on the PCR amplification of a 499 bp product using specific primers designed from a cloned fragment of the PaV1 genome. The sensitivity limit for the assay was 1.2 fg of purified viral DNA. The PaV1 primers did not react with …

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Detection Of Panulirus Argus Virus 1 (Pav1) In The Caribbean Spiny Lobster Using Fluorescence In Situ Hybridization (Fish), Caiwen Li, Jeffrey D. Shields, Hamish J. Small, Kimberly S. Reece, Carmony L. Hartwig, Roland A. Cooper, Robert E. Ratzlaff Oct 2015

Detection Of Panulirus Argus Virus 1 (Pav1) In The Caribbean Spiny Lobster Using Fluorescence In Situ Hybridization (Fish), Caiwen Li, Jeffrey D. Shields, Hamish J. Small, Kimberly S. Reece, Carmony L. Hartwig, Roland A. Cooper, Robert E. Ratzlaff

Roland A. Cooper

Panulirus argus Virus 1 (PaV1) is the first virus known to be pathogenic to a wild lobster. It infects the Caribbean spiny lobster P. argus from the Florida Keys, and has a predilection for juveniles. The monitoring of the virus in wild populations and study of its behavior in the laboratory require the development of reliable diagnostic tools. A sensitive and specific fluorescence in situ hybridization (FISH) assay was developed for detection of PaV1. The lower detection limit using a 110 bp DNA probe in a dot-blot hybridization for PaV1 DNA was 10 pg of cloned template PaV1 DNA and …

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Burrow Morphology And Behavior Of The Mud Shrimp Upogebia Omissa (Decapoda: Thalassinidea: Upogebiidae), Vania Rodrigues Coelho, Roland Arthur Cooper, Sergio De Almeida Rodrigues Oct 2015

Burrow Morphology And Behavior Of The Mud Shrimp Upogebia Omissa (Decapoda: Thalassinidea: Upogebiidae), Vania Rodrigues Coelho, Roland Arthur Cooper, Sergio De Almeida Rodrigues

Roland A. Cooper

The burrow morphology, burrowing behavior and feeding mechanisms of the thalassinidean shrimp Upogebia omissa were studied. Twenty burrow casts were made in situ with epoxy resin, and an overall 'Y' shape was most frequently observed. Several burrows consisted of a single, oblique tunnel; burrow diameter was positively correlated with burrow length, maximum depth and distance between openings. Additionally, burrow length was positively associated with maximum depth, indicating that as burrow length increased burrow depth increased; i.e. burrows spread vertically rather than horizontally. Total sediment displacement by the burrows accounted for 2.6 % of sediment to a depth of 30 cm. …

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Investigating The Antimalarial Action Of 1,2,4-Trioxolanes With Fluorescent Chemical Probes, Carmony L. Hartwig, Erica M. W. Lauterwasser, Sumit S. Mahajan, Jonathan M. Hoke, Roland Cooper, Adam R. Renslo Dec 2012

Investigating The Antimalarial Action Of 1,2,4-Trioxolanes With Fluorescent Chemical Probes, Carmony L. Hartwig, Erica M. W. Lauterwasser, Sumit S. Mahajan, Jonathan M. Hoke, Roland Cooper, Adam R. Renslo

Roland A. Cooper

The 1,2,4-trioxolanes are a new class of synthetic peroxidic antimalarials currently in human clinical trials. The well known reactivity of the 1,2,4-trioxolane ring towards inorganic ferrous iron and ferrous iron heme is proposed to play a role in the antimalarial action of this class of compounds. We have designed structurally relevant fluorescent chemical probes to study the sub-cellular localization of 1,2,4-trioxolanes in cultured Plasmodium falciparum parasites. Microscopy experiments revealed that a probe fluorescently labeled on the adamantane ring accumulated specifically in digestive vacuole-associated neutral lipid bodies within the parasite while an isosteric, but non-peroxidic congener did not. Probes fluorescently labeled …

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Artemether-Lumefantrine Selects For Malaria Parasites With Decreased Lumefantrine Sensitivity Although Parasites Remain Sensitive To This Regimen In Tororo, Uganda, P. Tumwebaze, J. Bloome, O. Byaruhanga, C. Nakazibwe, A. Walakira, J. Okiring, S. L. Nsobya, Roland A. Cooper, P. J. Rosenthal Nov 2012

Artemether-Lumefantrine Selects For Malaria Parasites With Decreased Lumefantrine Sensitivity Although Parasites Remain Sensitive To This Regimen In Tororo, Uganda, P. Tumwebaze, J. Bloome, O. Byaruhanga, C. Nakazibwe, A. Walakira, J. Okiring, S. L. Nsobya, Roland A. Cooper, P. J. Rosenthal

Roland A. Cooper

Artemisinin-based combination therapies (ACTs) may select for malaria parasites with decreased drug sensitivity. We studied the sensitivity of parasites from children enrolled in treatment and prevention trials in Tororo, Uganda from June, 2010 to February, 2012. When Plasmodium falciparum malaria was diagnosed, blood was obtained, parasites (286 isolates) were cultured with serial dilutions of chloroquine (CQ), monodesethylamodiaquine (AQ), quinine (QN), dihydroartemisinin (DHA), lumefantrine (LM), or piperaquine (PQ) for 72 h, and ex vivo sensitivities were assessed by HRP-2-based ELISA. Sensitivities (nM) to CQ (median IC50 486.2; IQR 206.5-748.8), AQ (83.3; 58.4-132.4), PQ (20.3; 7.6-47.5) and QN (126.4; 74.9-196.3) varied widely; …

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Molecular Action Of 1,2,4-Trioxolanes In Plasmodium Falciparum, R. A. Cooper, C. L. Hartwig, E. Lauterwasser, S. Mahajan, M. Hoke, A. Renslo Dec 2011

Molecular Action Of 1,2,4-Trioxolanes In Plasmodium Falciparum, R. A. Cooper, C. L. Hartwig, E. Lauterwasser, S. Mahajan, M. Hoke, A. Renslo

Roland A. Cooper

No abstract provided.

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Ex Vivo Drug Sensitivity Of Malaria Parasites Under Selective Pressure In Tororo, Uganda, P. K. Tumebaze, O. Byaruhanga, J. Okiring, S. L. Nsobya, R. A. Cooper, P. J. Rosenthal Nov 2011

Ex Vivo Drug Sensitivity Of Malaria Parasites Under Selective Pressure In Tororo, Uganda, P. K. Tumebaze, O. Byaruhanga, J. Okiring, S. L. Nsobya, R. A. Cooper, P. J. Rosenthal

Roland A. Cooper

Artemisinin-based combination therapies (ACTs) are standard treatments for uncomplicated malaria in Africa. ACTs provide highly effective treatment, and regular use may offer protection against malaria in high risk populations. However, increased use of ACTs may select for parasites with decreased sensitivity. We studied the ex vivo sensitivity of malaria parasites collected from children enrolled in treatment and prevention trials in Tororo, Uganda from June, 2010 to August, 2011. When P. falciparum malaria was diagnosed, blood was obtained, parasites were cultured with serial dilutions of chloroquine (CQ), monodesethylamodiaquine (AQ), quinine (QN), dihydroartemisinin (DHA), lumefantrine (LM), and piperaquine (PQ) for 72 hours, …

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Discovery Of Dual Function Acridones As A New Antimalarial Chemotype, Jane X. Kelly, Martin J. Smilkstein, Reto Brun, Sergio Wittlin, Roland A. Cooper, Kristin D. Lane, Aaron Janowsky, Robert A. Johnson, Rozalia A. Dodean, Rolf Winter, David J. Hinrichs, Michael K. Riscoe May 2009

Discovery Of Dual Function Acridones As A New Antimalarial Chemotype, Jane X. Kelly, Martin J. Smilkstein, Reto Brun, Sergio Wittlin, Roland A. Cooper, Kristin D. Lane, Aaron Janowsky, Robert A. Johnson, Rozalia A. Dodean, Rolf Winter, David J. Hinrichs, Michael K. Riscoe

Roland A. Cooper

Preventing and delaying the emergence of drug resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug-resistant malaria. Haem remains an immutable and vulnerable target, because it is not parasite-encoded and its detoxification during haemoglobin degradation, critical to parasite survival, can be subverted by drug-haem interaction as in the case of quinolines and many other drugs. Here we describe a new antimalarial chemotype that combines the haem-targeting character of acridones, together with a chemosensitizing component that counteracts resistance to quinoline antimalarial …

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Stage Independent Chloroquine Resistance And Chloroquine Toxicity Revealed Via Spinning Disk Confocal Microscopy, Bojana Gligorijevic, Kyle Purdy, David A. Elliott, Roland A. Cooper, Paul D. Roepe Apr 2008

Stage Independent Chloroquine Resistance And Chloroquine Toxicity Revealed Via Spinning Disk Confocal Microscopy, Bojana Gligorijevic, Kyle Purdy, David A. Elliott, Roland A. Cooper, Paul D. Roepe

Roland A. Cooper

We previously customized a Nipkow spinning disk confocal microscope (SDCM) to acquire 4D data for live, intraerythrocytic malarial parasites [Gligorijevic B, McAllister R, Urbach JS, Roepe, PD. Spinning disk confocal microscopy of live, intraerythrocytic malarial parasites. 1. Quantification of hemozoin development for drug sensitive versus resistant malaria. Biochemistry 2006;45:12400-10]. We reported that chloroquine (CQ) treatment did not appear to affect progress through the cell cycle, and suggested that toxicity may be manifested post-schizogony. We now use SDCM, synchronized cell culture and continuous vs. bolus drug dosing to investigate stage specific CQ effects in detail. We develop a novel, extremely rapid …

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Pfcg2, A Plasmodium Falciparum Protein Peripherally Associated With The Parasitophorous Vacuolar Membrane, Is Expressed In The Period Of Maximum Hemoglobin Uptake And Digestion By Trophozoites, Roland A. Cooper, Janni Papakrivos, Kristen D. Lane, Hisashi Fujioka, Klaus Lingelbach, Thomas E. Wellems Nov 2005

Pfcg2, A Plasmodium Falciparum Protein Peripherally Associated With The Parasitophorous Vacuolar Membrane, Is Expressed In The Period Of Maximum Hemoglobin Uptake And Digestion By Trophozoites, Roland A. Cooper, Janni Papakrivos, Kristen D. Lane, Hisashi Fujioka, Klaus Lingelbach, Thomas E. Wellems

Roland A. Cooper

A Plasmodium falciparum gene closely linked to the chloroquine resistance locus encodes PfCG2, a predicted 320-330kDa protein. In the parasitized erythrocyte, PfCG2 expression rises sharply in the trophozoite stage and is detected in electron-dense patches along the parasitophorous vacuolar membrane (PVM), in the cytoplasm and in the digestive vacuole (DV). Results of extraction and partitioning experiments show that PfCG2 is a peripheral membrane protein. Exposure of trophozoite-infected erythrocytes to trypsin-containing buffer after streptolysin O permeabilization indicates that PfCG2 is exposed to the erythrocyte cytosol at the outer face of the PVM. PfCG2 is highly susceptible to hydrolysis by aspartic and …

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Pfcrt Is More Than The Plasmodium Falciparum Chloroquine Resistance Gene: A Functional And Evolutionary Perspective, Roland A. Cooper, Carmony L. Hartwig, Michael T. Ferdig May 2005

Pfcrt Is More Than The Plasmodium Falciparum Chloroquine Resistance Gene: A Functional And Evolutionary Perspective, Roland A. Cooper, Carmony L. Hartwig, Michael T. Ferdig

Roland A. Cooper

Genetic, physiological and pharmacological studies are gradually revealing the molecular basis of chloroquine resistance (CQR) in the malaria parasite, Plasmodium falciparum. Recent highlights include the discovery of a key gene associated with resistance, pfcrt (Plasmodium falciparum chloroquine resistance transporter; PfCRT), encoding a novel transporter, and the characterization of global selective sweeps of haplotypes containing a K76T amino acid change within this protein. Little is known about the cellular mechanism by which resistant parasites escape the effects of chloroquine (CQ), one of the most promising drugs ever deployed, due in part to an unresolved mechanism of action. The worldwide spread of …

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Proteomic Approaches To Studying Drug Targets And Resistance In Plasmodium, R. A. Cooper, D. J. Carucci Feb 2004

Proteomic Approaches To Studying Drug Targets And Resistance In Plasmodium, R. A. Cooper, D. J. Carucci

Roland A. Cooper

Ever increasing drug resistance by Plasmodium falciparum, the most virulent of human malaria parasites, is creating new challenges in malaria chemotherapy. The entire genome sequences of P. falciparum and the rodent malaria parasite, P. yoelii yoelii are now available. Extensive genome sequence data from other Plasmodium species including another important human malaria parasite, P. vivax are also available. Powerful research techniques coupled to genomic resources are needed to help identify new drug and vaccine targets against malaria. Applied to Plasmodium, proteomics combines high-resolution protein or peptide separation with mass spectrometry and computer software to rapidly identify large numbers of proteins …

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Plasmepsin 4, The Food Vacuole Aspartic Proteinase Found In All Plasmodium Spp. Infecting Man, John B. Dame, Charles A. Yowell, Levi Omara-Opyene, Jane M. Carlton, Roland A. Cooper, Tang Li Jul 2003

Plasmepsin 4, The Food Vacuole Aspartic Proteinase Found In All Plasmodium Spp. Infecting Man, John B. Dame, Charles A. Yowell, Levi Omara-Opyene, Jane M. Carlton, Roland A. Cooper, Tang Li

Roland A. Cooper

Plasmepsins are aspartic proteinases of the malaria parasite, and seven groups of plasmepsins have been identified by comparing genomic sequence data available for the genes encoding these enzymes from Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium berghei, and Plasmodium yoelii. The food vacuole plasmepsins typified by plasmepsin 4 from P. falciparum (PfPM4) constitute one of these groups. Genes encoding the ortholog of PfPM4 have been cloned from Plasmodium ovale, Plasmodium malariae, and P. vivax. In addition, P. falciparum contains three paralagous food vacuole plasmepsins or plasmepsin-like enzymes that appear to have arisen by gene duplication, plasmepsins 1 (PfPM1), 2 (PfPM2) …

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Genetic Diversity And Chloroquine Selective Sweeps In Plasmodium Falciparum, John C. Wootton, Xiaorong Feng, Michael T. Ferdig, Roland A. Cooper, Jianbing Mu, Dror I. Baruch, Alan J. Magill, Xin-Zhuan Su Jul 2002

Genetic Diversity And Chloroquine Selective Sweeps In Plasmodium Falciparum, John C. Wootton, Xiaorong Feng, Michael T. Ferdig, Roland A. Cooper, Jianbing Mu, Dror I. Baruch, Alan J. Magill, Xin-Zhuan Su

Roland A. Cooper

Widespread use of antimalarial agents can profoundly influence the evolution of the human malaria parasite Plasmodium falciparum. Recent selective sweeps for drug-resistant genotypes may have restricted the genetic diversity of this parasite, resembling effects attributed in current debates to a historic population bottleneck. Chloroquine-resistant (CQR) parasites were initially reported about 45 years ago from two foci in southeast Asia and South America, but the number of CQR founder mutations and the impact of chlorquine on parasite genomes worldwide have been difficult to evaluate. Using 342 highly polymorphic microsatellite markers from a genetic map, here we show that the level of …

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Alternative Mutations At Position 76 Of The Vacuolar Transmembrane Protein Pfcrt Are Associated With Chloroquine Resistance And Unique Stereospecific Quinine And Quinidine Responses In Plasmodium Falciparum, Roland A. Cooper, Michael T. Ferdig, Xin-Zhuan Su, Lyann M. B. Ursos, Jiabing Mu, Takashi Nomura, David A. Fidock, Paul D. Roepe, Thomas E. Wellems Dec 2001

Alternative Mutations At Position 76 Of The Vacuolar Transmembrane Protein Pfcrt Are Associated With Chloroquine Resistance And Unique Stereospecific Quinine And Quinidine Responses In Plasmodium Falciparum, Roland A. Cooper, Michael T. Ferdig, Xin-Zhuan Su, Lyann M. B. Ursos, Jiabing Mu, Takashi Nomura, David A. Fidock, Paul D. Roepe, Thomas E. Wellems

Roland A. Cooper

Chloroquine resistance (CQR) in Plasmodium falciparum is associated with multiple mutations in the digestive vacuole membrane protein PfCRT. The chloroquine-sensitive (CQS) 106/1 line of P. falciparum has six of seven PfCRT mutations consistently found in CQR parasites from Asia and Africa. The missing mutation at position 76 (K76T in reported population surveys) may therefore be critical to CQR. To test this hypothesis, we exposed 106/1 populations (10(9)-10(10) parasites) to a chloroquine (CQ) concentration lethal to CQS parasites. In multiple independent experiments, surviving CQR parasites were detected in the cultures after 28 to 42 days. These parasites showed novel K76N or …

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P. Falciparum Cg2, Linked To Chloroquine Resistance, Does Not Resemble Na+/H+ Exchangers, Thomas E. Wellems, John C. Wootton, Hisashi Fujioka, Xin-Zhuan Su, Roland Cooper, Dror Baruch, David A. Frock Aug 1998

P. Falciparum Cg2, Linked To Chloroquine Resistance, Does Not Resemble Na+/H+ Exchangers, Thomas E. Wellems, John C. Wootton, Hisashi Fujioka, Xin-Zhuan Su, Roland Cooper, Dror Baruch, David A. Frock

Roland A. Cooper

Understanding the molecular basis for chloroquine resistance in Plasmodium falciparum will provide important support for the development of new therapies and prophylactic measures against malaria. Complementary genetic and biochemical investigations should discriminate among current theories and pinpoint the functional determinants of resistance. With this in mind Sanchez et al. 1998 have proposed that the P. falciparum cg2 gene, linked by Su et al. 1997 to chloroquine resistance, may encode a sodium/hydrogen exchanger (NHE) responsible for drug transport. Here, we present evidence against this proposal. Detailed reanalysis of the CG2 sequence fails to support the claims for significant similarity to functional …

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Preparative Separation Of Pyrrolizidine Alkaloids By High-Speed Counter-Current Chromatography, Roland A. Cooper, Rion J. Bowers, Carla J. Beckham, Ryan J. Huxtable Apr 1996

Preparative Separation Of Pyrrolizidine Alkaloids By High-Speed Counter-Current Chromatography, Roland A. Cooper, Rion J. Bowers, Carla J. Beckham, Ryan J. Huxtable

Roland A. Cooper

We have applied a high-speed counter-current chromatography (CCC) technique to the separation and purification of pyrrolizidine alkaloids from Amsinckia tessellata, Symphytum spp., Trichodesma incanum (Boraginaceae), and Senecio douglasii var. longilobus (Asteraceae). Alkaloidal fractions were separated in a solvent system composed of a chloroform mobile phase and 0.2 M potassium phosphate buffer, of an optimum pH, as the stationary phase. Up to 800 mg of sample could be successfully separated in a single run, with excellent resolution of alkaloids. Lycopsamine and several of its acetylated derivatives were resolved from alkaloidal fractions of Amsinckia and Symphytum. However, diastereomeric pairs such as 7-acetyl-lycopsamine …

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The Comparative Metabolism Of The Four Pyrrolizidine Alkaloids, Seneciphylline, Retrorsine, Monocrotaline, And Trichodesmine In The Isolated, Perfused Rat Liver., C. C. Yan, R. A. Cooper, R. J. Huxtable Jul 1995

The Comparative Metabolism Of The Four Pyrrolizidine Alkaloids, Seneciphylline, Retrorsine, Monocrotaline, And Trichodesmine In The Isolated, Perfused Rat Liver., C. C. Yan, R. A. Cooper, R. J. Huxtable

Roland A. Cooper

Despite their similarity in structure, pyrrolizidine alkaloids (PAs) vary in their LD50s and in the organs in which toxicity is expressed. We have examined whether there are differences in the metabolism of certain PAs that are associated with these quantitative and qualitative differences in toxicity. Isolated rat livers were perfused with one of four PAs (seneciphylline, retrorsine, monocrotaline, and trichodesmine) at 0.5 mM for 1 hr, and the pyrrolic metabolites determined that were released into perfusate and bile or bound in the liver. The proportion of the PA removed by the liver varied from 93% for retrorsine to 55% for …

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