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Search Results: 1 - 10 of 94461 matches for " Joseph W. Fowble "
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A Genetically Hard-Wired Metabolic Transcriptome in Plasmodium falciparum Fails to Mount Protective Responses to Lethal Antifolates
Karthikeyan Ganesan equal contributor,Napawan Ponmee equal contributor,Lei Jiang,Joseph W. Fowble,John White,Sumalee Kamchonwongpaisan,Yongyuth Yuthavong,Prapon Wilairat,Pradipsinh K. Rathod
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.1000214
Abstract: Genome sequences of Plasmodium falciparum allow for global analysis of drug responses to antimalarial agents. It was of interest to learn how DNA microarrays may be used to study drug action in malaria parasites. In one large, tightly controlled study involving 123 microarray hybridizations between cDNA from isogenic drug-sensitive and drug-resistant parasites, a lethal antifolate (WR99210) failed to over-produce RNA for the genetically proven principal target, dihydrofolate reductase-thymidylate synthase (DHFR-TS). This transcriptional rigidity carried over to metabolically related RNA encoding folate and pyrimidine biosynthesis, as well as to the rest of the parasite genome. No genes were reproducibly up-regulated by more than 2-fold until 24 h after initial drug exposure, even though clonal viability decreased by 50% within 6 h. We predicted and showed that while the parasites do not mount protective transcriptional responses to antifolates in real time, P. falciparum cells transfected with human DHFR gene, and adapted to long-term WR99210 exposure, adjusted the hard-wired transcriptome itself to thrive in the presence of the drug. A system-wide incapacity for changing RNA levels in response to specific metabolic perturbations may contribute to selective vulnerabilities of Plasmodium falciparum to lethal antimetabolites. In addition, such regulation affects how DNA microarrays are used to understand the mode of action of antimetabolites.
Novel Triazine JPC-2067-B Inhibits Toxoplasma gondii In Vitro and In Vivo
Ernest J. Mui,Guy A. Schiehser,Wilbur K. Milhous,Honghue Hsu,Craig W. Roberts,Michael Kirisits,Stephen Muench,David Rice,J. P. Dubey,Joseph W. Fowble,Pradipsinh K. Rathod,Sherry F. Queener,Susan R. Liu,David P. Jacobus,Rima McLeod
PLOS Neglected Tropical Diseases , 2008, DOI: 10.1371/journal.pntd.0000190
Abstract: Background and Methodology Toxoplasma gondii causes substantial morbidity, mortality, and costs for healthcare in the developed and developing world. Current medicines are not well tolerated and cause hypersensitivity reactions. The dihydrotriazine JPC-2067-B (4, 6-diamino-1, 2-dihydro-2, 2-dimethyl-1-(3′(2-chloro-, 4-trifluoromethoxyphenoxy)propyloxy)-1, 3, 5-triazine), which inhibits dihydrofolate reductase (DHFR), is highly effective against Plasmodium falciparum, Plasmodium vivax, and apicomplexans related to T. gondii. JPC-2067-B is the primary metabolite of the orally active biguanide JPC-2056 1-(3′-(2-chloro-4-trifluoromethoxyphenyl?oxy)propyloxy)- 5-isopropylbiguanide, which is being advanced to clinical trials for malaria. Efficacy of the prodrug JPC-2056 and the active metabolite JPC-2067-B against T. gondii and T. gondii DHFR as well as toxicity toward mammalian cells were tested. Principal Findings and Conclusions Herein, we found that JPC-2067-B is highly effective against T. gondii. We demonstrate that JPC-2067-B inhibits T. gondii growth in culture (IC50 20 nM), inhibits the purified enzyme (IC50 6.5 nM), is more efficacious than pyrimethamine, and is cidal in vitro. JPC-2067-B administered parenterally and the orally administered pro-drug (JPC-2056) are also effective against T. gondii tachyzoites in vivo. A molecular model of T. gondii DHFR-TS complexed with JPC-2067-B was developed. We found that the three main parasite clonal types and isolates from South and Central America, the United States, Canada, China, and Sri Lanka have the same amino acid sequences preserving key binding sites for the triazine. Significance JPC-2056/JPC-2067-B have potential to be more effective and possibly less toxic treatments for toxoplasmosis than currently available medicines.
Enriching Stakeholder Theory: Student Identity of Higher Education  [PDF]
Joseph W. C. Lau
American Journal of Industrial and Business Management (AJIBM) , 2014, DOI: 10.4236/ajibm.2014.412082
Abstract: While students commonly assume the identity of being key stakeholders of higher education, the present article explores the possible complications stemmed from such key identity. Stakeholder theory has its strengths attributed by its conceptual breath and versatility; the limits of the theory arise for the same merit. Making reference to the theory with no restrains leads reasonably to the conclusion that the educational institute is unwilling to take measure closely to the long term effect, tangible or intangible, of such approach. Providing multiple perspectives on the identity of students are observed, an enrichment of stakeholder theory catering student identity is necessary.
Spontaneous Pneumomediastinum from Running Sprints
Joseph W. Turban
Case Reports in Medicine , 2010, DOI: 10.1155/2010/927467
Abstract: Spontaneous pneumomediastinum (SPM) is a fairly rare condition, caused by increased intrathoracic pressure, leading to free air in the mediastinal structures. Underlying lung conditions are associated with increased incidence of SPM, including asthma, interstitial lung disease, pneumonia, bullous lung, and radiation therapy for lung cancer. It is often preceded by Valsalva maneuvers, vomiting, coughing, asthma exacerbation, sneezing, childbirth, or intense physical activity. A case of SPM is presented in a 15-year-old male, who complained of throat pain and dyspnea while running sprints at football practice. Workup revealed SPM, and he was subsequently admitted and treated conservatively. His symptoms resolved in 2 days and he was discharged and suffered no further recurrences. In contrast to secondary pneumomediastinum, SPM is usually a benign condition although life-threatening conditions can rarely arise. Differentiating between these two conditions has important prognostic indications. There is a paucity of prospectively collected data regarding SPM, and considerable variation in recommendations concerning the extent of workup.
An Analytical Study of Smooth Solutions of the Bl?tekj?r Hydrodynamic Model of Electron Transport
Joseph W. Jerome
VLSI Design , 2002, DOI: 10.1080/1065514021000012345
Abstract: We study the Bløtekjær hydrodynamic model from the standpoint of local well-posedness. We employ analytical methods, originally introduced by T. Kato for complex systems, to obtain the existence of unique local smooth solutions of the Cauchy problem, with smooth initial data. The time interval is invariant with respect to vanishing heat flux. The model is self-consistent, and is developed for onevalley electron carriers only. A symmetrizer is introduced for the system, and regularization is employed to avoid the formation of singularities due to vacuum regions. In the regime studied, it is not possible for shocks to form.
Analytical and Computational Advances for Hydrodynamic Models of Classical and Quantum Charge Transport
Joseph W. Jerome
VLSI Design , 2000, DOI: 10.1155/2000/94851
Abstract: In recent years, substantial advances have been made in understanding hydrodynamic models, both from the standpoint of analytical infrastructure, as well as the parameters which play a decisive effect in the behavior of such models. Both classical and quantum hydrodynamic models have been studied in depth. In this survey paper, we describe several results of this type. We include, for example, well-posedness for both classical and quantum reduced models, and the relaxation drift–diffusion limit as examples of analytical results. As examples of computational results, we include some discussion of effective algorithms, but most importantly, some information gleaned from extensive simulation. In particular, we present our findings of the prominent role played by the mobilities in the classical models, and the role of hysteresis in the quantum models. All models are self-consistent. Included is discussion of recent analytical results on the use of Maxwell’s equations. Benchmark devices are utilized: the MESFET transistor and the n+/n/n+ diode for classical transport, and the resonant tunneling diode for quantum transport. Some comparison with the linear Boltzmann transport equation is included.
Tissue Engineering Options for Ligament Healing
Joseph W. Freeman
Bone and Tissue Regeneration Insights , 2012,
Abstract: The anterior cruciate ligament (ACL) is one of five ligaments in the knee that are important for stability and kinematics. It is also the most commonly injured ligament of the knee and due to its poor healing potential, severe damage warrants surgical intervention including complete replacement. Ligaments are longitudinally arranged, complex tissues; the mechanical properties of ligaments are a direct result of their components and the arrangement of these components in the tissue. It is these mechanics that have made ligaments so difficult to replace. Past ACL replacements have had many limitations that prevented their extensive use. These limitations range from mechanical fatigue over time to fraying of the device after implantation. In light of these problems, investigators have begun to pursue a host of new techniques to create a range of viable options for the repair, replacement, and/or regeneration of the ACL. These options include tissue engineered scaffolds with novel designs and specially treated transplanted tissues. In this article, the composition, arrangement, and mechanics of the ACL will be discussed in order to elucidate important aspects of ACL repair; past replacements will also be discussed. Afterwards, novel replacement options that look to solve problems faced by older replacement options will be presented. These devices use a wide variety of materials and designs to replicate ligament mechanics and allow for new tissue regeneration.
Using a Level-Set Model to Generate Artwork from Digital Images
Joseph W Wilder
International Journal of Mathematics and Soft Computing , 2013,
Abstract: The use of mathematics and computers in the generation of art is an ever growing field. This work concerns the development of an algorithm based on the solution of a partial differential equation that can be used with digital images to generate art-like drawings. This modified model uses a conceptual framework that includes local and global perspectives to determine which aspects of the objects in the image should be included in the drawing. This novel inclusion of both of these perspectives results in drawings with enhanced art-like qualities compared with those utilizing a single perspective.
Students Prefer Audience Response System for Lecture Evaluation
Joseph W Turban
International Journal of Emerging Technologies in Learning (iJET) , 2011, DOI: 10.3991/ijet.v6i4.1743
Abstract: Objectives: Student evaluation of courses is an important component of overall course evaluation. The extent of student participation in the evaluation may be related to the ease of the evaluation process. The standard evaluation format is a paper form. This study examines medical students preference of utilizing Audience Response System compared to a paper method. Methods: Following several medical school lectures, students were queried if they preferred Audience Response System versus a paper method, and if they would prefer using Audience Response System more for future course evaluations. Results: 391 students were queried. Overall response rate was 94%. Using a five point Likert scale, 299 out of 361 (82%) responded they agreed, or strongly agreed with the statement “We should use ARS more. . .” When asked which format they preferred to use for evaluation, 299/367 (81%) responded Audience Response System, 31 (8%) preferred paper, and 37 (10%) were not sure, or had no opinion (chi squared = 378.936, df2, p<0.0001). Conclusion: The medical students surveyed showed a strong preference for utilizing Audience Response System as a course evaluation modality, and desired its continued use in medical school. Audience Response System should be pursued as a lecture evaluation modality, and its use in medical school education should be encouraged.
From Summetria to Symmetry: The Making of a Revolutionary Concept
Joseph W. Dauben
Aestimatio : Critical Reviews in the History of Science , 2009,
Abstract:
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