Life Sciences Commons^™

Parasite Of The Month. Hepatocystis, Imran Ejotre, Deeann Reeder, Kai Matuschewski, Juliane Schaer

Faculty Journal Articles

No abstract provided.

Plasmodium Para-Aminobenzoate Synthesis And Salvage Resolve Avoidance Of Folate Competition And Adaptation To Host Diet, Joachim Michael Matz, Mutsumi Watanabe, Mofolusho Falade, Takayuki Tohge, Rainer Hoefgen, Kai Matuschewski

Pharmaceutical Sciences Faculty Publications

Folate metabolism is essential for DNA synthesis and a validated drug target in fast-growing cell populations, including tumors and malaria parasites. Genome data suggest that Plasmodium has retained its capacity to generate folates de novo. However, the metabolic plasticity of folate uptake and biosynthesis by the malaria parasite remains unresolved. Here, we demonstrate that Plasmodium uses an aminodeoxychorismate synthase and an aminodeoxychorismate lyase to promote the biogenesis of the central folate precursor para-aminobenzoate (pABA) in the cytoplasm. We show that the parasite depends on de novo folate synthesis only when dietary intake of pABA by …

A Potent Antimalarial Benzoxaborole Targets A Plasmodium Falciparum Cleavage And Polyadenylation Specificity Factor Homologue., Ebere Sonoiki, Caroline L. Ng, Marcus C. S. Lee, Denghui Guo, Yong-Kang Zhang, Yasheen Zhou, M. R. K. Alley, Vida Ahyong, Laura M. Sanz, Maria Jose Lafuente-Monasterio, Chen Dong, Patrick G. Schupp, Jiri Gut, Jenny Legac, Roland A. Cooper, Francisco-Javier Gamo, Joseph Derisi, Yvonne R. Freund, David A. Fidock, Philip J. Rosenthal

Natural Sciences and Mathematics | Faculty Scholarship

Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg-1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these …

Environmental Data Analysis And Remote Sensing For Early Detection Of Dengue And Malaria, Md Zahidur Rahman, Leonid Roytman, Abdelhamid Kadik, Dilara A. Rosy

Publications and Research

Malaria and dengue fever are the two most common mosquito-transmitted diseases, leading to millions of serious illnesses and deaths each year. Because the mosquito vectors are sensitive to environmental conditions such as temperature, precipitation, and humidity, it is possible to map areas currently or imminently at high risk for disease outbreaks using satellite remote sensing. In this paper we propose the development of an operational geospatial system for malaria and dengue fever early warning; this can be done by bringing together geographic information system (GIS) tools, artificial neural networks (ANN) for efficient pattern recognition, the best available ground-based epidemiological and …

The Armadillo Repeat Protein Pf16 Is Essential For Flagellar Structure And Function In Plasmodium Male Gametes, Ursula Straschil, Arthur M. Talman, David J. P. Ferguson, Karen A. Bunting, Zhengyao Xu, Elizabeth Bailes, Robert E. Sinden, Anthony A. Holder, Elizabeth F. Smith

Dartmouth Scholarship

Malaria, caused by the apicomplexan parasite Plasmodium, threatens 40% of the world's population. Transmission between vertebrate and insect hosts depends on the sexual stages of the life-cycle. The male gamete of Plasmodium parasite is the only developmental stage that possesses a flagellum. Very little is known about the identity or function of proteins in the parasite's flagellar biology. Here, we characterise a Plasmodium PF16 homologue using reverse genetics in the mouse malaria parasite Plasmodium berghei. PF16 is a conserved Armadillo-repeat protein that regulates flagellar structure and motility in organisms as diverse as green algae and mice. We show that …

Chloroquine Susceptibility And Reversibility In A Plasmodium Falciparum Genetic Cross, Jigar J. Patel, Drew Thacker, John C. Tan, Perri Pleeter, Lisa Checkley, Joseph M. Gonzales, Bingbing Deng, Paul D. Roepe, Roland A. Cooper, Michael T. Ferdig

Biological Sciences Faculty Publications

Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT) are major determinants of verapamil (VP)-reversible CQ resistance (CQR). In the presence of mutant PfCRT, additional genes contribute to the wide range of CQ susceptibilities observed. It is not known if these genes influence mechanisms of chemosensitization by CQR reversal agents. Using quantitative trait locus (QTL) mapping of progeny clones from the HB3 x Dd2 cross, we show that the P. falciparum multidrug resistance gene 1 (pfmdr1) interacts with the South-East Asia-derived mutant pfcrt haplotype to modulate CQR levels. A novel chromosome 7 locus is predicted to contribute …

Quantitative Dissection Of Clone-Specific Growth Rates In Cultured Malaria Parasites, Heather B. Reilly Ayala, Hongjian Wang, John A. Steuter, Anastasia M. Marx, Michael T. Ferdig

Faculty Publications - Department of Biological & Molecular Science

Measurement of parasite proliferation in cultured red blood cells underpins many facets of malaria research, from drug sensitivity assays to assessing the impact of experimentally altered genes on parasite growth, virulence, and fitness. Pioneering efforts to grow Plasmodium falciparum in cultured red blood cells revolutionized malaria research and spurred the development of semi-high throughput growth assays using radio-labeled hypoxanthine, an essential nucleic acid precursor, as a reporter of whole-cycle proliferation (Trager and Jensen, 1976; Desjardins et al., 1979). Use of hypoxanthine (Hx) and other surrogate readouts of whole-cycle proliferation remains the dominant choice in malaria research. While amenable to high-throughput …

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, David J. Hinrichs, Rolf Winter, Michael Riscoe

Biological Sciences Faculty Publications

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). Isobolograrn 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 …

Intellectual Property Management Strategies To Accelerate The Development And Access Of Vaccines And Diagnostics: Case Studies On Pandemic Influenza, Malaria And Sars, Anatole Krattiger, Stanley P. Kowalski, Robert Eiss, Anthony Taubman

Law Faculty Scholarship

Achieving global access to vaccines, diagnostics, and pharmaceuticals remains a challenge. Throughout the developing world, intellectual property (IP) constraints complicate access to critically essential medical technologies and products. Vaccines for malaria and pandemic strains of influenza, as well as diagnostic and vaccine technologies for SARS, are not only relevant to global public health but are particularly critical to the needs of developing countries. A global access solution is urgently needed. This article offers a timely case‐by‐case analysis of preliminary patent landscape surveys and formulates options via patent pools and other forms of creative IP management to accelerate development and access. …

Dr. Nott's Theory Of Insect Causation Of Disease, William A. Riley

Harold W. Manter Laboratory: Library Materials

Excerpt:

The danger in using isolated sentences from an article as a basis for interpreting the author's theories, is generally recognized, but sometimes the most careful workers fall into the trap. Once the mistaken interpretation is published, it may be copied over and over again until it rises to the dignity of a dogma.

A striking illustration is afforded by the practical unanimity with which writers on the subject of insects and disease credit Dr. Josiah Nott with being the earliest to formulate definitely the theory of mosquito transmission of yellow fever.

Nuttall, in his classic monograph On the Role …