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Your search keyword '"Dennis, E."' showing total 175 results
Start Over Author "Dennis, E." Journal proceedings of the national academy of sciences of the united states of america
175 results on '"Dennis, E."'

2. Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Author

Baragan˜a, Beatriz, Forte, Barbara, Choi, Ryan, Hewitt, Stephen Nakazawa, Bueren-Calabuig, Juan A., Pisco, Joa˜o Pedro, Peet, Caroline, Dranow, David M., Robinson, David A., Jansen, Chimed, Norcross, Neil R., Vinayak, Sumiti, Anderson, Mark, Brooks, Carrie F., Cooper, Caitlin A., Damerow, Sebastian, Delves, Michael, Dowers, Karen, Duffy, James, Edwards, Thomas E., Hallyburton, Irene, Horst, Benjamin G., Hulverson, Matthew A., Ferguson, Liam, Jiménez-Díaz, María Belén, Jumani, Rajiv S., Lorimer, Donald D., Love, Melissa S., Maher, Steven, Matthews, Holly, McNamara, Case W., Miller, Peter, O’Neill, Sandra, Ojo, Kayode K., Osuna-Cabello, Maria, Pinto, Erika, Post, John, Riley, Jennifer, Rottmann, Matthias, Sanz, Laura M., Scullion, Paul, Sharma, Arvind, Shepherd, Sharon M., Shishikura, Yoko, Simeons, Frederick R. C., Stebbins, Erin E., Stojanovski, Laste, Straschil, Ursula, Tamaki, Fabio K., Tamjar, Jevgenia, Torrie, Leah S., Vantaux, Amélie, Witkowski, Benoît, Wittlin, Sergio, Yogavel, Manickam, Zuccotto, Fabio, Angulo-Barturen, Iñigo, Sinden, Robert, Baum, Jake, Gamo, Francisco-Javier, Mäser, Pascal, Kyle, Dennis E., Winzeler, Elizabeth A., Myler, Peter J., Wyatt, Paul G., Floyd, David, Matthews, David, Sharma, Amit, Striepen, Boris, Huston, Christopher D., Gray, David W., Fairlamb, Alan H., Pisliakov, Andrei V., Walpole, Chris, Read, Kevin D., Van Voorhis, Wesley C., and Gilbert, Ian H.

Published
2019

3. (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Author

Jiménez-Díaz, María Belén, Ebert, Daniel, Salinas, Yandira, Pradhan, Anupam, Lehane, Adele M, Myrand-Lapierre, Marie-Eve, O’Loughlin, Kathleen G, Shackleford, David M, de Almeida, Mariana Justino, Carrillo, Angela K, Clark, Julie A, Dennis, Adelaide SM, Diep, Jonathon, Deng, Xiaoyan, Duffy, Sandra, Endsley, Aaron N, Fedewa, Greg, Guiguemde, W Armand, Gómez, María G, Holbrook, Gloria, Horst, Jeremy, Kim, Charles C, Liu, Jian, Lee, Marcus CS, Matheny, Amy, Martínez, María Santos, Miller, Gregory, Rodríguez-Alejandre, Ane, Sanz, Laura, Sigal, Martina, Spillman, Natalie J, Stein, Philip D, Wang, Zheng, Zhu, Fangyi, Waterson, David, Knapp, Spencer, Shelat, Anang, Avery, Vicky M, Fidock, David A, Gamo, Francisco-Javier, Charman, Susan A, Mirsalis, Jon C, Ma, Hongshen, Ferrer, Santiago, Kirk, Kiaran, Angulo-Barturen, Iñigo, Kyle, Dennis E, DeRisi, Joseph L, Floyd, David M, and Guy, R Kiplin

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Rare Diseases, Infectious Diseases, Orphan Drug, Malaria, Vector-Borne Diseases, Antimicrobial Resistance, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Antimalarials, Calcium-Transporting ATPases, Cellular Senescence, Drug Discovery, Drug Resistance, Erythrocytes, Flow Cytometry, Heterocyclic Compounds, 4 or More Rings, High-Throughput Screening Assays, Isoquinolines, Models, Molecular, Molecular Structure, Plasmodium, malaria, PfATP4, drug discovery
Abstract

Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na(+) levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na(+) homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.

Published
2014

11. Perturbative diffraction methods resolve a conformational switch that facilitates a two-step enzymatic mechanism.

Author

Greisman, Jack B., Dalton, Kevin M., Brookner, Dennis E., Klureza, Margaret A., Sheehan, Candice J., In-Sik Kim, Henning, Robert W., Russi, Silvia, and Hekstra, Doeke R.

Subjects
TETRAHYDROFOLATE dehydrogenase, COFACTORS (Biochemistry), ESCHERICHIA coli, X-ray diffraction, AMINO acids, X-ray crystallography
Abstract

Enzymes catalyze biochemical reactions through precise positioning of substrates, cofactors, and amino acids to modulate the transition-state free energy. However, the role of conformational dynamics remains poorly understood due to poor experimental access. This shortcoming is evident with Escherichia coli dihydrofolate reductase (DHFR), a model system for the role of protein dynamics in catalysis, for which it is unknown how the enzyme regulates the different active site environments required to facilitate proton and hydride transfer. Here, we describe ligand-, temperature-, and electric-field-based perturbations during X-ray diffraction experiments to map the conformational dynamics of the Michaelis complex of DHFR. We resolve coupled global and local motions and find that these motions are engaged by the protonated substrate to promote efficient catalysis. This result suggests a fundamental design principle for multistep enzymes in which pre-existing dynamics enable intermediates to drive rapid electrostatic reorganization to facilitate subsequent chemical steps. [ABSTRACT FROM AUTHOR]

Published
2024
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16. Mechanical signaling coordinates the embryonic heartbeat

Author

Chiou, Kevin K., Rocks, Jason W., Chen, Christina Yingxian, Cho, Sangkyun, Merkus, Koen E., Rajaratnam, Anjali, Robison, Patrick, Tewari, Manorama, Vogel, Kenneth, Majkut, Stephanie F., Prosser, Benjamin L., Discher, Dennis E., and Liu, Andrea J.

Published
2016

17. AIM2 sensors mediate immunity to

Author

Camila, Marques-da-Silva, Barun, Poudel, Rodrigo P, Baptista, Kristen, Peissig, Lisa S, Hancox, Justine C, Shiau, Lecia L, Pewe, Melanie J, Shears, Thirumala-Devi, Kanneganti, Photini, Sinnis, Dennis E, Kyle, Prajwal, Gurung, John T, Harty, and Samarchith P, Kurup

Subjects
DNA-Binding Proteins, Plasmodium, Liver, Caspases, Hepatocytes, Animals, Humans, Parasites, Malaria
Abstract

Malaria, caused by

Published
2023

27. The Feeding Biomechanics and Dietary Ecology of Australopithecus africanus

Author

Strait, David S., Weber, Gerhard W., Neubauer, Simon, Chalk, Janine, Richmond, Brian G., Lucas, Peter W., Spencer, Mark A., Schrein, Caitlin, Dechow, Paul C., Ross, Callum F., Grosse, Ian R., Wright, Barth W., Constantino, Paul, Wood, Bernard A., Lawn, Brian, Hylander, William L., Wang, Qian, Byron, Craig, Slice, Dennis E., Smith, Amanda L., and Pilbeam, David

Published
2009
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32. AIM2 sensors mediate immunity to Plasmodium infection in hepatocytes.

Author

Marques-da-Silva, Camila, Poudel, Barun, Baptista, Rodrigo P., Peissig, Kristen, Hancox, Lisa S., Shiau, Justine C., Pewe, Lecia L., Shears, Melanie J., Kanneganti, Thirumala-Devi, Sinnis, Photini, Kyle, Dennis E., Gurung, Prajwal, Harty, John T., and Kurup, Samarchith P.

Subjects
LIVER cells, PLASMODIUM, MALARIA prevention, NATURAL immunity, MEMBRANE proteins
Abstract

Malaria, caused by Plasmodium parasites is a severe disease affecting millions of people around the world. Plasmodium undergoes obligatory development and replication in the hepatocytes, before initiating the life-threatening blood-stage of malaria. Although the natural immune responses impeding Plasmodium infection and development in the liver are key to controlling clinical malaria and transmission, those remain relatively unknown. Here we demonstrate that the DNA of Plasmodium parasites is sensed by cytosolic AIM2 (absent in melanoma 2) receptors in the infected hepatocytes, resulting in Caspase-1 activation. Remarkably, Caspase-1 was observed to undergo unconventional proteolytic processing in hepatocytes, resulting in the activation of the membrane pore-forming protein, Gasdermin D, but not inflammasome-associated proinflammatory cytokines. Nevertheless, this resulted in the elimination of Plasmodium-infected hepatocytes and the control of malaria infection in the liver. Our study uncovers a pathway of natural immunity critical for the control of malaria in the liver. [ABSTRACT FROM AUTHOR]

Published
2023
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