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https://www.readbyqxmd.com/read/28446690/antimalarial-efficacy-of-mmv390048-an-inhibitor-of-plasmodium-phosphatidylinositol-4-kinase
#1
Tanya Paquet, Claire Le Manach, Diego González Cabrera, Yassir Younis, Philipp P Henrich, Tara S Abraham, Marcus C S Lee, Rajshekhar Basak, Sonja Ghidelli-Disse, María José Lafuente-Monasterio, Marcus Bantscheff, Andrea Ruecker, Andrew M Blagborough, Sara E Zakutansky, Anne-Marie Zeeman, Karen L White, David M Shackleford, Janne Mannila, Julia Morizzi, Christian Scheurer, Iñigo Angulo-Barturen, María Santos Martínez, Santiago Ferrer, Laura María Sanz, Francisco Javier Gamo, Janette Reader, Mariette Botha, Koen J Dechering, Robert W Sauerwein, Anchalee Tungtaeng, Pattaraporn Vanachayangkul, Chek Shik Lim, Jeremy Burrows, Michael J Witty, Kennan C Marsh, Christophe Bodenreider, Rosemary Rochford, Suresh M Solapure, María Belén Jiménez-Díaz, Sergio Wittlin, Susan A Charman, Cristina Donini, Brice Campo, Lyn-Marie Birkholtz, Kirsten K Hanson, Gerard Drewes, Clemens H M Kocken, Michael J Delves, Didier Leroy, David A Fidock, David Waterson, Leslie J Street, Kelly Chibale
As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model...
April 26, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28437083/dual-plug-and-display-synthetic-assembly-using-orthogonal-reactive-proteins-for-twin-antigen-immunization
#2
Karl Brune, Can Buldun, Yuanyuan Li, Iona Taylor, Florian Brod, Sumi Biswas, Mark Howarth
Engineering modular platforms to control biomolecular architecture can advance both the understanding and manipulation of biological systems. Icosahedral particles uniformly displaying single antigens stimulate potent immune activation and have been successful in various licensed vaccines. However, it remains challenging to display multiple antigens on a single particle, to induce broader immunity protective across strains or even against distinct diseases. Here we design a dually-addressable synthetic nanoparticle, by engineering the multimerizing coiled-coil IMX313 and two orthogonally-reactive split proteins...
April 24, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28431639/advances-in-molecular-diagnosis-of-malaria
#3
Zhi Zheng, Zhibin Cheng
Malaria is a mosquito-borne disease caused by five species of Plasmodium parasites. Accurate diagnosis of malaria plays an essential part in malaria control. With traditional diagnostic methodologies, malaria control programs have achieved remarkable success during the past decade, and are now heading toward malaria elimination in many areas. This new situation, however, calls for novel diagnostics with improved sensitivity, throughput, and reduced cost for active screening of malaria parasites, as all transfected individuals have to be identified in order to block transmission...
2017: Advances in Clinical Chemistry
https://www.readbyqxmd.com/read/28407766/novel-lead-structures-with-both-plasmodium-falciparum-gametocytocidal-and-asexual-blood-stage-activity-identified-from-high-throughput-compound-screening
#4
Wei Sun, Xiuli Huang, Hao Li, Gregory Tawa, Ethan Fisher, Takeshi Q Tanaka, Paul Shinn, Wenwei Huang, Kim C Williamson, Wei Zheng
BACKGROUND: Blocking malaria transmission is an important step in eradicating malaria. In the field, transmission requires the production of sexual stage Plasmodium parasites, called gametocytes, which are not effectively killed by the commonly used anti-malarials allowing individuals to remain infectious after clearance of asexual parasites. METHODS: To identify new gametocytocidal compounds, a library of 45,056 compounds with diverse structures was screened using a high throughput gametocyte viability assay...
April 13, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28378767/the-need-to-compare-assessing-the-level-of-agreement-of-three-high-throughput-assays-against-plasmodium-falciparum-mature-gametocytes
#5
Leonardo Lucantoni, Sasdekumar Loganathan, Vicky M Avery
Whole-cell High-Throughput Screening (HTS) is a key tool for the discovery of much needed malaria transmission blocking drugs. Discrepancies in the reported outcomes from various HTS Plasmodium falciparum gametocytocidal assays hinder the direct comparison of data and ultimately the interpretation of the transmission blocking potential of hits. To dissect the underlying determinants of such discrepancies and assess the impact that assay-specific factors have on transmission-blocking predictivity, a 39-compound subset from the Medicines for Malaria Venture Malaria Box was tested in parallel against three distinct mature stage gametocytocidal assays, under strictly controlled parasitological, chemical, temporal and analytical conditions resembling the standard membrane feeding assay (SMFA)...
April 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28377572/salivary-gland-maturation-and-duct-formation-in-the-african-malaria-mosquito-anopheles-gambiae
#6
Michael B Wells, Jordan Villamor, Deborah J Andrew
Mosquito-borne diseases cause one million deaths and hundreds of millions of human infections yearly. With all such diseases, the pathogen must traverse the mosquito salivary gland (SG) for transmission to a new host, making the SGs ideal targets for genetic strategies to block transmission. Prior studies have elucidated details of SG structure by light and electron microscopy and have deeply explored the salivary transcriptome and proteome. Very little is known, however, about how the unique functional architecture of mosquito SGs is achieved...
April 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28376897/a-novel-model-fitted-to-multiple-life-stages-of-malaria-for-assessing-efficacy-of-transmission-blocking-interventions
#7
Ellie Sherrard-Smith, Thomas S Churcher, Leanna M Upton, Katarzyna A Sala, Sara E Zakutansky, Hannah C Slater, Andrew M Blagborough, Michael Betancourt
BACKGROUND: Transmission-blocking interventions (TBIs) aim to eliminate malaria by reducing transmission of the parasite between the host and the invertebrate vector. TBIs include transmission-blocking drugs and vaccines that, when given to humans, are taken up by mosquitoes and inhibit parasitic development within the vector. Accurate methodologies are key to assess TBI efficacy to ensure that only the most potent candidates progress to expensive and time-consuming clinical trials. Measuring intervention efficacy can be problematic because there is substantial variation in the number of parasites in both the host and vector populations, which can impact transmission even in laboratory settings...
April 4, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28357366/inhibition-of-zika-virus-by-wolbachia-in-aedes-aegypti
#8
COMMENT
Eric Pearce Caragata, Heverton Leandro Carneiro Dutra, Luciano Andrade Moreira
Through association with cases of microcephaly in 2015, Zika virus (ZIKV) has transitioned from a relatively unknown mosquito-transmitted pathogen to a global health emergency, emphasizing the need to improve existing mosquito control programs to prevent future disease outbreaks. The response to Zika must involve a paradigm shift from traditional to novel methods of mosquito control, and according to the World Health Organization should incorporate the release of mosquitoes infected with the bacterial endosymbiont Wolbachiapipientis...
June 27, 2016: Microbial Cell
https://www.readbyqxmd.com/read/28357319/phylogenetic-profiles-of-all-membrane-transport-proteins
#9
January Weiner, Taco W A Kooij
In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right...
August 30, 2016: Microbial Cell
https://www.readbyqxmd.com/read/28348156/a-bioluminescence-method-for-in-vitro-screening-of-plasmodium-transmission-blocking-compounds
#10
Raquel Azevedo, Marija Markovic, Marta Machado, Blandine Franke-Fayard, António M Mendes, Miguel Prudêncio
The sporogonic stage of the life cycle of Plasmodium spp., the causative agents of malaria, occurs inside the parasite's mosquito vector, where a process of fertilization, meiosis and mitotic divisions culminates in the generation of large numbers of mammalian-infective sporozoites. Efforts to cultivate Plasmodium mosquito stages in vitro have proved challenging and yielded only moderate success. Here, we describe a methodology that simplifies the in vitro screening of much-needed transmission blocking (TB) compounds employing a bioluminescence-based method to monitor the in vitro development of sporogonic stages of the rodent malaria parasite, P...
March 27, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28306665/molecular-mechanisms-that-mediate-invasion-and-egress-of-malaria-parasites-from-red-blood-cells
#11
Aditi Alaganan, Pallavi Singh, Chetan E Chitnis
PURPOSE OF REVIEW: Malaria parasites invade and multiply in diverse host cells during their complex life cycle. Some blood stage parasites transform into male and female gametocytes that are transmitted by female anopheline mosquitoes. The gametocytes are activated in the mosquito midgut to form male and female gametes, which egress from RBCs to mate and form a zygote. Here, we will review our current understanding of the molecular mechanisms that mediate invasion and egress by malaria parasites at different life cycle stages...
May 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28289025/age-weight-and-cyp2d6-genotype-are-major-determinants-of-primaquine-pharmacokinetics-in-african-children
#12
Bronner P Gonçalves, Helmi Pett, Alfred B Tiono, Daryl Murry, Sodiomon Sirima, Mikko Niemi, Teun Bousema, Chris Drakeley, Rob Ter Heine
Low dose primaquine is recommended to prevent Plasmodium falciparum malaria transmission in areas threatened by artemisinin resistance and areas aiming for malaria elimination. Community treatment campaigns with artemisinin-based combination therapy in combination with the gametocytocidal primaquine dose target all age groups but no studies thus far have assessed the pharmacokinetics of this gametocytocidal drug in African children. We recruited forty children participating in a primaquine efficacy trial in Burkina Faso to study primaquine pharmacokinetics...
March 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28279180/primaquine-thiazolidinones-block-malaria-transmission-and-development-of-the-liver-exoerythrocytic-forms
#13
Anna Caroline C Aguiar, Flávio Jr B Figueiredo, Patrícia D Neuenfeldt, Tony H Katsuragawa, Bruna B Drawanz, Wilson Cunico, Photini Sinnis, Fidel Zavala, Antoniana U Krettli
BACKGROUND: Primaquine is an anti-malarial used to prevent Plasmodium vivax relapses and malaria transmission. However, PQ metabolites cause haemolysis in patients deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD). Fifteen PQ-thiazolidinone derivatives, synthesized through one-post reactions from primaquine, arenealdehydes and mercaptoacetic acid, were evaluated in parallel in several biological assays, including ability to block malaria transmission to mosquitoes. RESULTS: All primaquine derivatives (PQ-TZs) exhibited lower cell toxicity than primaquine; none caused haemolysis to normal or G6PD-deficient human erythrocytes in vitro...
March 9, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28211852/plasmodium-falciparum-crk4-directs-continuous-rounds-of-dna-replication-during-schizogony
#14
Markus Ganter, Jonathan M Goldberg, Jeffrey D Dvorin, Joao A Paulo, Jonas G King, Abhai K Tripathi, Aditya S Paul, Jing Yang, Isabelle Coppens, Rays H Y Jiang, Brendan Elsworth, David A Baker, Rhoel R Dinglasan, Steven P Gygi, Manoj T Duraisingh
Plasmodium parasites, the causative agents of malaria, have evolved a unique cell division cycle in the clinically relevant asexual blood stage of infection(1). DNA replication commences approximately halfway through the intracellular development following invasion and parasite growth. The schizont stage is associated with multiple rounds of DNA replication and nuclear division without cytokinesis, resulting in a multinucleated cell. Nuclei divide asynchronously through schizogony, with only the final round of DNA replication and segregation being synchronous and coordinated with daughter cell assembly(2,3)...
February 17, 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28209188/erratum-to-characterization-of-a-plasmodium-berghei-sexual-stage-antigen-pbph-as-a-new-candidate-for-malaria-transmission-blocking-vaccine
#15
Xu Kou, Wenqi Zheng, Feng Du, Fei Liu, Meilian Wang, Qi Fan, Liwang Cui, Enjie Luo, Yaming Cao
No abstract text is available yet for this article.
February 16, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/28159753/requirements-for-driving-antipathogen-effector-genes-into-populations-of-disease-vectors-by-homing
#16
Andrea Beaghton, Andrew Hammond, Tony Nolan, Andrea Crisanti, H Charles J Godfray, Austin Burt
There is a need for new interventions against the ongoing burden of vector-borne diseases such as malaria and dengue. One suggestion has been to develop genes encoding effector molecules that block parasite development within the vector, and then use the nuclease-based homing reaction as a form of gene drive to spread those genes through target populations. If the effector gene reduces the fitness of the mosquito and does not contribute to the drive, then loss-of-function mutations in the effector will eventually replace functional copies, but protection may nonetheless persist sufficiently long to provide a public health benefit...
April 2017: Genetics
https://www.readbyqxmd.com/read/28091576/adjuvant-and-carrier-protein-dependent-t-cell-priming-promotes-a-robust-antibody-response-against-the-plasmodium-falciparum-pfs25-vaccine-candidate
#17
Andrea J Radtke, Charles F Anderson, Nicolas Riteau, Kelly Rausch, Puthupparampil Scaria, Emily R Kelnhofer, Randall F Howard, Alan Sher, Ronald N Germain, Patrick Duffy
Humoral immune responses have the potential to maintain protective antibody levels for years due to the immunoglobulin-secreting activity of long-lived plasma cells (LLPCs). However, many subunit vaccines under development fail to generate robust LLPC responses, and therefore a variety of strategies are being employed to overcome this limitation, including conjugation to carrier proteins and/or formulation with potent adjuvants. Pfs25, an antigen expressed on malaria zygotes and ookinetes, is a leading transmission blocking vaccine (TBV) candidate for Plasmodium falciparum...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28087198/cloning-characterization-and-transmission-blocking-potential-of-midgut-carboxypeptidase-a-in-anopheles-stephensi
#18
V VenkatRao, Surendra K Kumar, P Sridevi, Vijaykumar Yogesh Muley, R K Chaitanya
Transmission-blocking vaccines (TBV) interrupt malaria parasite transmission and hence form an important component for malaria eradication. Mosquito midgut exopeptidases such as aminopeptidase N & carboxypeptidase B have demonstrated TBV potential. In the present study, we cloned and characterized carboxypeptidase A (CPA) from the midgut of an important malarial vector, Anopheles stephensi. ClustalW amino acid alignment and in silico 3-dimensional structure analysis of CPA predicted the presence of active sites involved in zinc and substrate binding that are conserved among all the known mosquito species...
April 2017: Acta Tropica
https://www.readbyqxmd.com/read/28057055/functional-characterization-of-plasmodium-berghei-psop25-during-ookinete-development-and-as-a-malaria-transmission-blocking-vaccine-candidate
#19
Wenqi Zheng, Fei Liu, Yiwen He, Qingyang Liu, Gregory B Humphreys, Takafumi Tsuboi, Qi Fan, Enjie Luo, Yaming Cao, Liwang Cui
BACKGROUND: Plasmodium ookinete surface proteins as post-fertilization target antigens are potential malaria transmission-blocking vaccine (TBV) candidates. Putative secreted ookinete protein 25 (PSOP25) is a highly conserved ookinete surface protein, and has been shown to be a promising novel TBV target. Here, we further investigated the TBV activities of the full-length recombinant PSOP25 (rPSOP25) protein in Plasmodium berghei, and characterized the potential functions of PSOP25 during the P...
January 5, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/28043395/artesunate-tafenoquine-combination-therapy-promotes-clearance-and-abrogates-transmission-of-the-avian-malaria-parasite-plasmodium-gallinaceum
#20
Suchada Tasai, Tawee Saiwichai, Morakot Kaewthamasorn, Sonthaya Tiawsirisup, Prayute Buddhirakkul, Sirintip Chaichalotornkul, Sittiporn Pattaradilokrat
Clinical manifestations of malaria infection in vertebrate hosts arise from the multiplication of the asexual stage parasites in the blood, while the gametocytes are responsible for the transmission of the disease. Antimalarial drugs that target the blood stage parasites and transmissible gametocytes are rare, but are essentially needed for the effective control of malaria and for limiting the spread of resistance. Artemisinin and its derivatives are the current first-line antimalarials that are effective against the blood stage parasites and gametocytes, but resistance to artemisinin has now emerged and spread in various malaria endemic areas...
January 15, 2017: Veterinary Parasitology
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