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      A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum

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          Abstract

          Malaria liver stages represent an ideal therapeutic target with a bottleneck in parasite load and reduced clinical symptoms; however, current in vitro pre-erythrocytic (PE) models for Plasmodium vivax and P. falciparum lack the efficiency necessary for rapid identification and effective evaluation of new vaccines and drugs, especially targeting late liver-stage development and hypnozoites. Herein we report the development of a 384-well plate culture system using commercially available materials, including cryopreserved primary human hepatocytes. Hepatocyte physiology is maintained for at least 30 days and supports development of P. vivax hypnozoites and complete maturation of P. vivax and P. falciparum schizonts. Our multimodal analysis in antimalarial therapeutic research identifies important PE inhibition mechanisms: immune antibodies against sporozoite surface proteins functionally inhibit liver stage development and ion homeostasis is essential for schizont and hypnozoite viability. This model can be implemented in laboratories in disease-endemic areas to accelerate vaccine and drug discovery research.

          Abstract

          Currently available platforms to study liver stage of Plasmodium species have limitations. Here, the authors show that primary human hepatocyte cultures in 384-well format support hypnozoite and other liver stage development and are suitable for drug and antibody screens.

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          Most cited references79

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          Fiji: an open-source platform for biological-image analysis.

          Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.
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            A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays.

            The ability to identify active compounds (³hits²) from large chemical libraries accurately and rapidly has been the ultimate goal in developing high-throughput screening (HTS) assays. The ability to identify hits from a particular HTS assay depends largely on the suitability or quality of the assay used in the screening. The criteria or parameters for evaluating the ³suitability² of an HTS assay for hit identification are not well defined and hence it still remains difficult to compare the quality of assays directly. In this report, a screening window coefficient, called ³Z-factor,² is defined. This coefficient is reflective of both the assay signal dynamic range and the data variation associated with the signal measurements, and therefore is suitable for assay quality assessment. The Z-factor is a dimensionless, simple statistical characteristic for each HTS assay. The Z-factor provides a useful tool for comparison and evaluation of the quality of assays, and can be utilized in assay optimization and validation.
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              Vivax malaria: neglected and not benign.

              Plasmodium vivax threatens almost 40% of the world's population, resulting in 132-391 million clinical infections each year. Most of these cases originate from Southeast Asia and the Western Pacific, although a significant number also occurs in Africa and South America. Although often regarded as causing a benign and self-limiting infection, there is increasing evidence that the overall burden, economic impact, and severity of disease from P. vivax have been underestimated. Malaria control strategies have had limited success and are confounded by the lack of access to reliable diagnosis, emergence of multidrug resistant isolates, the parasite's ability to transmit early in the course of disease and relapse from dormant liver stages at varying time intervals after the initial infection. Progress in reducing the burden of disease will require improved access to reliable diagnosis and effective treatment of both blood-stage and latent parasites, and more detailed characterization of the epidemiology, morbidity, and economic impact of vivax malaria. Without these, vivax malaria will continue to be neglected by ministries of health, policy makers, researchers, and funding bodies.
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                Author and article information

                Contributors
                jadams3@health.usf.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                9 May 2018
                9 May 2018
                2018
                : 9
                : 1837
                Affiliations
                [1 ]ISNI 0000 0001 2353 285X, GRID grid.170693.a, Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, , University of South Florida, ; 3720 Spectrum Blvd 404, Tampa, FL 33612 USA
                [2 ]ISNI 0000 0004 1936 738X, GRID grid.213876.9, Center for Tropical and Emerging Global Diseases, , University of Georgia, ; 500 DW Brooks Dr. Suite 370, Athens, GA 30602 USA
                [3 ]ISNI 0000 0004 0419 1772, GRID grid.413910.e, Department of Entomology, , Armed Forces Research Institute of Medical Sciences (AFRIMS), ; 315/6 Rajvithi Rd, Bangkok, 10400 Thailand
                [4 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, , University of Oxford, ; Oxford, UK
                [5 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Shoklo Malaria Research Unit, Mahidol Oxford Research Unit, , Faculty of Tropical Medicine, Mahidol University, ; 68/30 Bantung Rd, Mae Sot, Tak 63110 Thailand
                [6 ]ISNI 0000 0001 0036 4726, GRID grid.420210.5, Malaria Vaccine Branch, , Walter Reed Army Institute of Research, ; 503 Robert Grant Ave, Silver Spring, MD 20910 USA
                [7 ]GRID grid.418537.c, Malaria Molecular Epidemiology Unit, , Institut Pasteur du Cambodge, ; 5 Boulevard Monivong-PO Box 983, Phnom Penh, 12 201 Cambodia
                [8 ]ISNI 0000 0004 4902 4281, GRID grid.423305.3, California Institute for Biomedical Research (Calibr), ; 11119N. Torrey Pines Rd, Suite 100, La Jolla, CA 92037 USA
                [9 ]ISNI 0000 0004 0432 5267, GRID grid.452605.0, Medicines for Malaria Venture, ; Pré-Bois Rd 20, Meyrin, 1215 Switzerland
                [10 ]Center for Infectious Disease Research, 307 Westlake Ave N Suite 500, Seattle, WA 98109 USA
                Author information
                http://orcid.org/0000-0001-6917-3485
                http://orcid.org/0000-0002-9560-5656
                http://orcid.org/0000-0002-7951-0745
                http://orcid.org/0000-0001-8982-4169
                http://orcid.org/0000-0002-0238-965X
                http://orcid.org/0000-0003-3707-7979
                Article
                4221
                10.1038/s41467-018-04221-9
                5943321
                29743474
                f98c3ea5-99ef-4763-8c2b-71a24beaceaf
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 8 January 2018
                : 10 April 2018
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