Download or read book Genomics and Transcriptomics Approaches to Understanding Drug Resistance Mechanisms in the Malaria Parasite Plasmodium Falciparum written by Justin Allan Gibbons and published by . This book was released on 2019 with total page 184 pages. Available in PDF, EPUB and Kindle. Book excerpt: The malaria parasite Plasmodium falciparum is responsible for about 500,000 deaths a year and is evolving resistance to the front-line treatment of artemisinin-based combination therapy. Resistance is currently confined to South East Asia, however millions of lives will be at risk if resistance spreads to Africa. Understanding the mechanism of resistance to artemisinins would aid containment strategies to prevent the spread of artemisinin resistance. There is also an urgent need to accelerate drug discovery since drug resistance has already been documented to all existing antimalarials. Here, I report on our efforts to understand the function of the gene k13, the gene with the strongest association with artemisinin resistance, and the potential genetic mechanisms associated with resistance to atovaquone, another widely used antimalarial. To precisely study the transcriptome characteristics of an isogenic k13 dysregulation mutant and wild type strain, I developed a new computational algorithm called Dephasing Identifier (DI) that is capable of identifying the genes dysregulated in cell cycle shifts. DI is designed to solve the problem of pinpointing important patterns in complex genomics data with temporal sequences that cannot be resolved by standard pair-wise comparison methods, by using an innovative method that leverages external reference data for systematic comparisons. In the k13 study, I demonstrated that the algorithm identifies co- regulated gene sets that have consistent annotated functions. The DI algorithm successfully identified aberrantly early DNA replication as the driving process of transcriptome changes in the mutant. To understand genome-wide changes that occurred in a set of atovaquone resistance stains, I analyzed whole genome sequencing data previously generated for a P. falciparum strain that underwent in vitro atovaquone selection to create atovaquone resistant strains. I systematically analyzed the genomes of these strains to search for significant genetic changes associated with atovaquone resistance; and used stringent criteria to identify genes involved in regulating transcription and protein modifications as acquiring non- synonymous mutations. Additionally, copy number variations in plasmepsin genes, a family known to be involved in resistance, were found in the resistant strains. In summary, genomics and transcriptomics technologies can be used to rapidly identify resistance mechanisms allowing for faster adjustment of current containment strategies. Future research on the critical targets identified in this study can aid new drug discovery efforts and novel control strategies.

Download or read book Integrated Omics Approaches to Infectious Diseases written by Saif Hameed and published by Springer Nature. This book was released on 2021-07-18 with total page 538 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book examines applications of multi-omics approaches for understanding disease etiology, pathogenesis, host-pathogen interactions. It also analyzes the genetics, immunological and metabolic mechanisms underlying the infections. The book also explores genomics, transcriptomics, translational-omics, and metabolomics approaches to understand the pathogenesis and identify potential drug targets. It reviews the role of epigenetic reprogramming in shaping the host-pathogen interactions and presents bioinformatics application in the identification of drug targets. Further, it examines the potential applications of RNA sequencing and non-coding RNA profiling to identify the pathogenesis. Lastly, it offers the current challenges, technological advances, and prospects of using multi-omics technologies in infectious biology.

Download or read book Plasmodium Evolution and Drug Resistance in Vitro and in Populations Using Whole Genome Technologies written by Neekesh Vijay Dharia and published by . This book was released on 2009 with total page 328 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria remains a significant worldwide cause of morbidity and mortality. As drug resistance is widespread, there is a need to identify the mechanisms of action and resistance of current and novel compounds to leverage this knowledge for monitoring the emergence of resistance and to accelerate development of new drugs. Using a genomics approach, we show how whole-genome microarrays and deep sequencing can be used to advance our understanding of parasite biology. First, a custom high-density tiling array for Plasmodium falciparum was developed and validated, detecting nearly all mutations in the parasite genome. This technology was used to show that in vitro-derived P. falciparum parasites resistant to fosmidomycin have acquired of extra copies of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, the presumed target. Second, we describe how whole-genome microarray analysis of 14 P. falciparum patient isolates from the Peruvian Amazon led to the discovery of clindamycin resistance, which is used for malaria treatment in Peru. We discovered a highly related parasite population in this region and identified the progeny of a natural cross. Additionally, we identified the genomic deletion of an important antigen for rapid diagnostic tests for malaria. Third, we describe using a custom microarray-based approach as well as deep sequencing for the study of a patient-derived P. vivax isolate. We show that microarray-based methods can detect thousands of SNPs in a patient isolate of P. vivax and the utility of whole-genome methods for genetic diversity studies. Last, we discuss ongoing work to characterize the mechanisms of action or resistance to several antimalarial compounds: piperaquine, decoquinate, mupirocin, and thiaisoleucine. The work described here provides a framework for future studies of in vitro drug resistance in and populations of malaria parasites.

Download or read book Malaria Drugs Disease and Post genomic Biology written by David Sullivan and published by Springer Science & Business Media. This book was released on 2006-01-09 with total page 447 pages. Available in PDF, EPUB and Kindle. Book excerpt: Despite rapid increases in knowledge, malaria continues to kill more than a million people each year and causes symptomatic disease in a further 300 million individuals. This volume brings some of the world's best investigators to describe recent advances in both the scientific and clinical aspects of malaria, and bridges between the two.

Download or read book Proteomic Approaches to Studying Drug Targets and Resistance in Plasmodium written by and published by . This book was released on 2004 with total page 12 pages. Available in PDF, EPUB and Kindle. Book excerpt: Ever increasing drug resistance by Plasmodium falciparum, the most virulent of human malaria parasites, is creating new challenges in malaria chemotherapy. The entire genome sequences of P. falciparum and the rodent malaria parasite, P. yoelii are now available. Extensive genome sequence data from other Plasmodium species including another important human malaria parasite, P. vivax are also available. Powerful research techniques coupled to genomic resources are needed to help identify new drug and vaccine targets against malaria. Applied to Plasmodium, proteomics combines high-resolution protein or peptide separation with mass spectrometry and computer software to rapidly identify large numbers of proteins expressed from various stages of parasite development. Proteomic methods can be applied to study sub-cellular localization, cell function, organelle composition, changes in protein expression patterns in response to drug exposure, drug-protein binding and validation of data from genomic annotation and transcript expression studies. Recent high-throughput proteomic approaches have provided a wealth of protein expression data on P. falciparum, while smaller-scale studies examining specific drug-related hypotheses are also appearing. Of particular interest is the study of mechanisms of action and resistance of drugs such as the quinolines, whose targets currently may not be predictable from genomic data. Coupling the Plasmodium sequence data with bioinformatics, proteomics and RNA transcript expression profiling opens unprecedented opportunities for exploring new malaria control strategies. This review will focus on pharmacological research in malaria and other intracellular parasites using proteomic techniques, emphasizing resources and strategies available for Plasmodium.

Download or read book Identification and Characterization of Novel Drug Resistance Loci in Plasmodium Falciparum written by Daria Natalie Van Tyne and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria has plagued mankind for millennia. Antimalarial drug use over the last century has generated highly drug-resistant parasites, which amplify the burden of this disease and pose a serious obstacle to control efforts. This dissertation is motivated by the simple fact that malaria parasites have become resistant to nearly every antimalarial drug that has ever been used, yet the precise genetic mechanisms of parasite drug resistance remain largely unknown. Our work pairs genomics-age technologies with molecular biology, genetics and molecular epidemiology in order to identify and characterize novel genes that contribute to drug resistance in P. falciparum.

Download or read book Dissecting Mechanisms of Antimalarials Using CRISPR Cas9 Editing in Plasmodium Falciparum written by SooNee Tan and published by . This book was released on 2019 with total page 123 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria, caused by Plasmodium infections, continues to be a global disease of public health importance with 300 million annual cases and about 500,000 deaths. Continual emergence of resistance to commonly used antimalarials underscores the importance of finding new drug targets and new antimalarial drugs. Previously, the Rathod lab has established systematic approaches to study targets of antimalarials and resistance mechanisms with the use of in vitro selection methods and deep sequencing of selected mutants. There are some limitations with these approaches as deep sequencing data does not reveal the stepwise mechanism of mutagenesis and mutations observed from the sequencing result might not associate with the resistance phenotype. This thesis has multiple projects aimed to expand the molecular toolbox with genome manipulation using CRISPR/Cas9 technique. It will complement the current tools that we have in performing target identification/validation as well as understanding the mechanism of mutagenesis in malaria parasites. Ciprofloxacin is an antibacterial known to target bacterial DNA Gyrase. In some instances, ciprofloxacin has been used for malaria prophylaxis but little is known about the mode-of-action of ciprofloxacin in malaria parasites. In the first project, we aim to understand the essentiality of Plasmodium falciparum DNA gyrase A subunit (PfGyrA) and its relationship with ciprofloxacin. Based on bioinformatics analyses, PfGyr A and B subunits are known to contain apicoplast-targeting signals. To test the predicted localization of this enzyme in the apicoplast and the function of this enzyme at the subcellular level, a CRISPR/Cas9 gene-editing tool was used to disrupt PfGyrA. It is known that isopentenyl pyrophosphate (IPP) rescues malaria parasites from apicoplast-targeting inhibitors and indeed successful growth of Pf[delta]GyrA required chemical rescue with IPP. PfGyrA disruption was accompanied by loss of the plastid acyl-carrier protein (ACP) immunouorescnce and the plastid genome. Drug sensitivity assays revealed that a Pf[delta]GyrA clone, supplemented with IPP was less sensitive to antibacterial compounds (doxycycline and ciprofloxacin) but not the nuclear topoisomerase inhibitor (etoposide). In addition, at high concentrations, ciprofloxacin continued to inhibit IPP-rescued Pf[delta]GyrA suggesting that this drug has an additional target in P. falciparum. We concluded that PfGyrA is an apicoplast enzyme in malaria parasite and it is essential for blood-stage parasites. In the future, untangling the two possible inhibitory functions of ciprofloxacin in malaria parasites may reveal a new and important drug target. The second project aim involves target validation of a tetrahydroquinolone compound, BMS-388891. Previous publications from the lab showed that resistance to BMS-388891 arises from a single point mutation in either the protein farnesyl transferase (PFT) alpha or beta subunit. Although results indicated that a single point mutation on the PfPFT enzyme led to BMS-3888891 resistant parasites, whole genome sequencing on those mutants have yet to be done. To test that a single mutation is sufficient for parasite acquisition of resistance to BMS-388891, gene alteration with CRISPR/Cas9 tool was utilized to introduce a point mutation (Y837N, Y837S, or Y837C) on the PFT-[Beta]-subunit. The CRISPR-modified mutant parasites have shown an increase of 10-20 fold resistance to BMS-388891. This data is the first to formally demonstrate that a single point mutation on the Pfpft-[Beta]-subunit is sufficient for parasites to confer resistance to BMS-388891 compound. There are very few validated compound to target relationships and CRISPR/Cas9 technique will be a valuable tool in the malaria field. The third project aim involves the understanding of the mechanism of mutagenesis in malaria parasites. While it is known that amplification and point mutation are the possible outcomes of resistance selection, the order of the processes is less understood. Recent work by Guler et. al. points to a novel step-wise amplification mechanism in the malarial parasite response to DSM1 selection pressure. In these selected parasites, 25-30 kb regions surrounding the Pfdhodh locus were amplified. Taking advantage of the highly amplified Pfdhodh locus, we were able to introduce Pfpft-[alpha]-subunit into this region. This sets up future studies for us to dissect the step-wise resistance mechanism in malaria parasites. Overall, the utilization of CRISPR/Cas9 tool has allowed us to efficiently perform gene knockout, gene alteration and gene translocation. These applications not only enable us to prove for the first time the importance of the PfGyrA enzyme but also to directly confirm the causality of specific point mutations in BMS-388891 resistant parasites. The addition of CRISPR/Cas9 gene-editing to our systematic approach toolbox will ultimately aid in our understanding of how mutagenesis occurs in malaria parasites and allow us to expand our knowledge in the mode-of-action of different antimalarials in P. falciparum.

Download or read book New Strategies for Drug Discovery and Development for Plasmodium Falciparum written by and published by . This book was released on 2000 with total page 33 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria continues as a major health threat throughout the tropical world and potential demand for antimalarials is higher than for any other medication yet the world faces a crisis-drug resistance is emerging and spreading faster than drugs are being developed and the flow in the pipeline of new drugs has all but stopped. This represents a particular threat to the US Military. In a short time there may be parts of the world where no effective antimalarial drug is available. The recent emergence of multidrug resistant malaria parasites has intensified this problem. Recognizing this emerging crisis, it is necessary to identify new strategies for the identification and development of new antimalarials. The goal of this work is the development of a framework for antimalarial drug development into the 21st century. A new strategy for drug development is urgently needed. Current drugs are based on a small number of target molecules or lead compounds and in most cases the target of drug action is yet to be identified. Resistance is emerging rapidly and the mechanisms of resistance are poorly understood. The identification of new targets or new candidate drugs based on an understanding of the parasite biology are key elements in this new strategy. Clearly the development of a new antimalarial will require both basic and applied research working in concert with one another. The goal of this work is to use a molecular genetic approach both in the identification of new drug targets and in the investigation of mechanisms of drug resistance. The research has focused on the two objectives, namely the analysis of critical genes in the Plasmodium falciparum for their role in drug resistance and as potential new drug targets, including the analysis of gene expression in response to drug treatment using the method of Serial Analysis of Gene Expression and the use of DNA Chip technology in the analysis of the yeast heterologous system.

Download or read book Plasmodium Falciparum Functional Genomics written by Jason Andrew Young and published by ProQuest. This book was released on 2007 with total page 384 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is a devastating disease that afflicts hundreds of millions of people worldwide each year. The recent availability of the genome sequence and several transcriptome and proteome datasets for Plasmodium falciparum, the agent responsible for the most lethal form of the disease, promises to accelerate the pace of malaria research. However, functional genomic methods must first be developed that are capable of converting the wealth of information contained within these large datasets into high-quality, testable hypotheses that lead to biologically relevant conclusions. For this purpose, we have developed functional genomic methods that use P. falciparum transcriptome datasets to elucidate malaria parasite gene function and transcriptional control mechanisms. First, I will describe a knowledge-based clustering algorithm we developed called Ontology-based Pattern Identification (OPI) that uses microarray-generated transcriptome data to rapidly predict gene function on a genome-wide basis. OPI analysis of transcriptome data from P. falciparum asexual, sporozoite, and high-purity stage I-V gametocytes using Gene Ontology annotations as a guide resulted in the identification of 381 functionally enriched gene clusters. These results shed light on the components of molecular mechanisms underlying parasite sexual development, as well as a multitude of other malaria parasite biological processes. Second, I will describe an algorithm we developed called Gene Enrichment Motif Searching (GEMS), designed specifically for the identification of cis -regulatory elements in the extremely AT-rich parasite genome. When applied to 21 OPI clusters, GEMS identified 34 putative cis -regulatory motifs associated with a variety of parasite processes including sexual development, cell invasion, antigenic variation and protein biosynthesis. These data, along with results from subsequent experimental characterization of several of these putative cis -regulatory elements using reporter gene assays, electrophoretic mobility shift assays, and DNA-affinity purification experiments suggest cis -regulatory element mediated transcriptional regulation plays an important role in the overall control of P. falciparum gene expression. The functional genomics approaches developed herein will aid to lay the groundwork for future research towards developing novel therapeutics against malaria.

Download or read book Global Technical Strategy for Malaria 2016 2030 written by World Health Organization and published by World Health Organization. This book was released on 2015-11-04 with total page 35 pages. Available in PDF, EPUB and Kindle. Book excerpt: The World Health Organization's Global Technical Strategy for Malaria 2016- 2030 has been developed with the aim to help countries to reduce the human suffering caused by the world's deadliest mosquito-borne disease. Adopted by the World Health Assembly in May 2015 it provides comprehensive technical guidance to countries and development partners for the next 15 years emphasizing the importance of scaling up malaria responses and moving towards elimination. It also highlights the urgent need to increase investments across all interventions - including preventive measures diagnostic testing treatment and disease surveillance- as well as in harnessing innovation and expanding research. By adopting this strategy WHO Member States have endorsed the bold vision of a world free of malaria and set the ambitious new target of reducing the global malaria burden by 90% by 2030. They also agreed to strengthen health systems address emerging multi-drug and insecticide resistance and intensify national cross-border and regional efforts to scale up malaria responses to protect everyone at risk.

Download or read book Readings in Machine Learning written by Jude W. Shavlik and published by Morgan Kaufmann. This book was released on 1990 with total page 868 pages. Available in PDF, EPUB and Kindle. Book excerpt: The ability to learn is a fundamental characteristic of intelligent behavior. Consequently, machine learning has been a focus of artificial intelligence since the beginnings of AI in the 1950s. The 1980s saw tremendous growth in the field, and this growth promises to continue with valuable contributions to science, engineering, and business. Readings in Machine Learning collects the best of the published machine learning literature, including papers that address a wide range of learning tasks, and that introduce a variety of techniques for giving machines the ability to learn. The editors, in cooperation with a group of expert referees, have chosen important papers that empirically study, theoretically analyze, or psychologically justify machine learning algorithms. The papers are grouped into a dozen categories, each of which is introduced by the editors.

Download or read book Advances in Malaria Research written by Deepak Gaur and published by John Wiley & Sons. This book was released on 2016-12-27 with total page 611 pages. Available in PDF, EPUB and Kindle. Book excerpt: Thoroughly reviews our current understanding of malarial biology Explores the subject with insights from post-genomic technologies Looks broadly at the disease, vectors of infection, and treatment and prevention strategies A timely publication with chapters written by global researchers leaders

Download or read book Drug Resistance in Leishmania Parasites written by Alicia Ponte-Sucre and published by Springer Science & Business Media. This book was released on 2012-09-04 with total page 458 pages. Available in PDF, EPUB and Kindle. Book excerpt: One of the main problems concerning therapeutic tools for the treatment of parasitic diseases, including leishmaniasis, is that some field parasites are naturally resistant to the classical drugs; additionally, current therapies may select parasites prone to be resistant to the applied drugs. These features are (at least partially) responsible for the disappointing persistence of the disease and resultant deaths worldwide. This book provides a comprehensive view of the pathology of the disease itself, and of parasitic drug resistance, its molecular basis, consequences and possible treatments. Scientists both from academic fields and from the industry involved in biomedical research and drug design, will find in this book a valuable and fundamental guide that conveys the knowledge needed to understand and to improve the success in combating this disease worldwide.

Download or read book Resistance of Malaria Parasites to Drugs written by World Health Organization. Scientific Group on Resistance of Malaria Parasites to Drugs and published by . This book was released on 1965 with total page 76 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Malaria Control and Elimination written by Frédéric Ariey and published by Methods in Molecular Biology. This book was released on 2020-07-17 with total page 341 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Genes and Genomes written by R.S. Verma and published by Elsevier. This book was released on 1998-06-03 with total page 281 pages. Available in PDF, EPUB and Kindle. Book excerpt: The laws of inheritance were considered quite superficial until 1903, when the chromosome theory of heredity was established by Sutton and Boveri. The discovery of the double helix and the genetic code led to our understanding of gene structure and function. For the past quarter of a century, remarkable progress has been made in the characterization of the human genome in order to search for coherent views of genes. The unit of inheritance termed factor or gene, once upon a time thought to be a trivial an imaginary entity, is now perceived clearly as the precise unit of inheritance that has continually deluged us with amazement by its complex identity and behaviour, sometimes bypassing the university of Mendel's law. The aim of the fifth volume, entitled Genes and Genomes, is to cover the topics ranging from the structure of DNA itself to the structure of the complete genome, along with everything in between, encompassing 12 chapters. These chapters relate much of the information accumulated on the role of DNA in the organization of genes and genomes per se. Several distinguished scientists, all pre-eminent authorities in each field to share their expertise. Obviously, since the historical report on the double helix configuration in 1953, voluminous reports on the meteoric advances in genetics have been accumulated, and to cover every account in a single volume format would be a Herculean task. Therefore, only a few topics are chosen, which are of great interest to molecular geneticists. This volume is intended for advanced graduate students who would wish to keep abreast with the most recent trends in genome biology.

Download or read book Bioinformatics and Drug Discovery written by Richard S. Larson and published by . This book was released on 2012 with total page 374 pages. Available in PDF, EPUB and Kindle. Book excerpt: Recent advances in drug discovery have been rapid. The second edition of Bioinformatics and Drug Discovery has been completely updated to include topics that range from new technologies in target identification, genomic analysis, cheminformatics, protein analysis, and network or pathway analysis. Each chapter provides an extended introduction that describes the theory and application of the technology. In the second part of each chapter, detailed procedures related to the use of these technologies and software have been incorporated. Written in the highly successful Methods in Molecular Biology series format, the chapters include the kind of detailed description and implementation advice that is crucial for getting optimal results in the laboratory. Thorough and intuitive, Bioinformatics and Drug Discovery, Second Edition seeks to aid scientists in the further study of the rapidly expanding field of drug discovery.