Download or read book Exploring Chromatin Organization and Regulation in Human Malaria Parasites written by Gayani Dinusha Batugedara and published by . This book was released on 2018 with total page 20 pages. Available in PDF, EPUB and Kindle. Book excerpt: Collectively, our data highlight the importance of spatial genome organization as a mechanism of transcriptional regulation in malaria parasites, and our work directly addresses one of the central outstanding questions in Plasmodium biology, namely, how a parasite with approximately 6,000 genes manages to control gene expression in a coordinated fashion using a limited number of transcription factors.
Download or read book An Exploration of Transcriptional Regulation in the Human Malaria Parasite Plasmodium Falciparum written by Xueqing Lu and published by . This book was released on 2017 with total page 211 pages. Available in PDF, EPUB and Kindle. Book excerpt: Approximately half of the world's population is at risk of malaria transmission, and this number can be expected to grow as drug resistant strains continue to develop. Among the human infectious Plasmodium species, Plasmodium falciparum causes the most severe and lethal form of malaria. This parasite has an extreme AT-rich genome and a complex life cycle that is likely to be regulated by coordinate changes in gene expression. However, the mechanisms behind this fine-tuned gene expression and regulation system remain elusive. For instance, only a limited number of transcription factors have been identified. Recent studies suggest that epigenetic and post-transcriptional regulation may be used as alternative regulation strategies to compensate for the lack of transcription factors in this parasite. Therefore, in this dissertation work, we further explored the transcriptome, epigenome, and the proteome to better understand the transcriptional mechanisms in P. falciparum. In chapter 1, we demonstrated that genes are usually defined by unique nucleosomal features and that nucleosome landscape alone could be used to identify novel genes in organisms with a nucleotide bias. Next, we investigated nascent RNA expression profiles and observed that the majority of genes are transcribed at the trophozoite stage in response to the open chromatin structure of that stage. These results helped us link chromatin reorganization events to transcriptional activity and highlighted the importance of epigenetic and post-transcriptional regulation in this parasite. Therefore, in the latter two chapters, we further examined the proteasome and transcriptome isolated from both nuclear and cytoplasmic fractions to identify potential chromatin regulators. As a result, we identified a large number of chromatin-associated proteins and lncRNAs that are likely to have important roles in chromatin regulation and post-transcriptional and translational regulations. Collectively, data and results from these studies will become stepping-stones for future malaria studies and further assist the identification of promising anti-malarial drug targets.
Download or read book DNA Sequence Context and the Chromatin Landscape Differentiate Sequence specific Transcription Factor Binding in the Human Malaria Parasite Plasmodium Falciparum written by Victoria Bonnell and published by . This book was released on 2023 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria, caused by protozoan parasites of the genus Plasmodium, remains a major global health burden, with 247 million cases and killing 619,000 in 2021 alone. In Plasmodium falciparum, the deadliest human malaria parasite, about 90% of the protein-coding genes are transcribed in a periodic fashion over the 48-hour intraerythrocytic development cycle (IDC), with the peak transcript abundance generally occurring just before the protein is required. The periodicity of transcription forms a genome-wide cascade of continuous gene expression, which is believed to be finely regulated by a limited number of transcriptional regulators, including the 30-member Apicomplexan APETALA2 (ApiAP2) family of sequence-specific transcription factors (TFs). Interestingly, this family of proteins has AP2 DNA-binding domains only evolutionarily conserved in plant-linage genomes and Apicomplexan parasites, making them potential drug targets for novel antimalarial therapeutics in humans. The current literature is focused only on identifying regulatory networks controlled by the ApiAP2 TFs; however, dissecting the molecular mechanisms of their genome-wide binding pattern is still understudied. Knowing mechanisms of binding site selection of putative drug targets is critical to identifying essential interactions or features to be blocked. This dissertation elucidates the biological function and binding specificity of a subset of ApiAP2 TFs, which each recognize similar DNA sequence motifs in vitro, along with their chromatin-remodeling interaction partners. This project applies in vitro, in vivo, and in silico approaches to identify how sequence preferences are established during parasite development by probing the effects of cis- and trans- regulation on TF binding, in addition to dissecting the function of these TFs in parasite development. In higher eukaryotes, TFs with similar binding preferences can carry out different regulatory functions in a given cell type, work synergistically or antagonistically, perform similar functions in different cell types, or can be fully redundant and only necessary in the event that the primary factor cannot function. The occurrence of multiple TFs recognizing similar DNA sequence motifs in P. falciparum is intriguing since functional gene redundancy is not often evolutionarily conserved in pathogens. Therefore, despite the similar DNA binding motifs of these proteins, we predict that they carry out distinct regulatory functions in the parasite. There are several established features investigated by this work that can modulate binding specificity of a TF such as: DNA sequence context/intrinsic DNA shape, interaction with cofactors, histone post-translational modification, and chromatin accessibility. It is critical to understand which features, or combinations thereof, influence binding specificity of transcriptional regulators in P. falciparum to inform future antimalarial drug development.
Download or read book Genome Engineering and Functional Gene Regulation Tools for the Study of Malaria Parasites written by Diana Alejandra Falla Castillo and published by . This book was released on 2018 with total page 201 pages. Available in PDF, EPUB and Kindle. Book excerpt: Plasmodium falciparum is the causative agent of the most severe form of human malaria, a mosquito-borne disease that remains a major global health problem. The efforts to create new antimalarial drugs and effective vaccines have been significantly hindered by the lack of robust tools for performing functional genetics in P. falciparum. The identification and characterization of essential functions for parasite survival are fundamental steps towards the creation of effective antimalarial therapies. In this work, we developed an integrated set of gene editing and functional gene regulation tools that enable the study of essential and non-essential genes in blood stage parasites. We first created a robust and versatile conditional expression system that uses a fusion of endogenous translational regulatory elements and synthetic RNA-protein modules to regulate gene expression in the parasite. Using this system, we achieved tight regulation of expression of reporter and essential antimalarial genes. Next, we created an integrated strategy that utilizes our conditional system together with a CRISPR-Cas9 gene editing system to identify and characterize the function of an essential RNA-Binding protein (RBP). We first determined the essentiality of our target protein using a two-step approach, in which a merodiploid line conditionally expresses an ectopic copy of the RBP and the native gene is disrupted using CRISPR technologies. This approach was next streamlined into a single-step methodology to genetically modify native loci to regulate expression from their promoters. We performed biochemical and biological characterization of this essential protein, and established the role of this RBP in cell cycle progression and parasite schizogony. Finally, to expand the repertoire of P.falciparum target loci, we implemented the editing activity of CRISPR-Cpfl, and showed high efficiency in the disruption of non-essential genes and genes located in AT-rich regions. We also integrated the Cpfl editing activity with our conditional system to achieve conditional regulation of native loci. This work combines genome-engineering technologies and regulatory systems designed to provide a robust platform for the identification and characterization of essential functions in human malarial parasites.
Download or read book Integrative Transcriptome and Phenome Analysis Reveals Unique Regulatory Cascades Controlling the Intraerythrocytic Asexual and Sexual Development of Human Malaria Parasites written by RieÌ8tte Andele̹ Van Biljon and published by . This book was released on 2019 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Plasmodium falciparum parasite, the major causative agent of malaria on the African continent, has evolved numerous cellular adaptations to effectively propagate its species. The parasite can proliferate asexually, producing mass amounts of progeny to subsist in the human host or differentiate into sexual forms (gametocytes) that, once mature, can transmit to a feeding Anopheles mosquito. Key to our ability to effectively develop chemical candidates that interfere with either of these processes is the identification and understanding of critical factors that regulate parasite development. This is particularly true for the development of antimalarials that can be used in malaria elimination strategies by targeting both parasite proliferation and transmission. We therefore hypothesized that parasite proliferation and differentiation use divergent mechanisms for gene expression that could be observed through a thorough investigation of the functional genome of these different parasite forms. This doctoral study therefore set out to increase our knowledge base on three crucial aspects of parasite development: 1) the atypical cell cycle that allows the rapid proliferation of asexual parasites; 2) the full molecular profile of gametocytogenesis enabling the cellular differentiation that allows the parasite to transmit; and 3) the metabolic differences between these proliferating and differentiating parasites that results from their strategy-specific mechanisms of developmental control. The atypical cell cycle of the parasite, associated with the massive cell number expansion in asexual development, is notoriously difficult to study. Here, we contributed a novel system by developing a cell cycle synchronization tool that reversibly blocks the development of asexual parasites at the G1/S transition. This results in an inescapable arrest of the cell cycle that is completely and functionally reversible; parasites re-initiate cell cycle progression and continue to S phase within 6 h. This system provided the opportunity to characterize cell cycle phases in the parasite and additionally evaluate molecular mechanisms associated with cell cycle arrest or re-initiation. During cell cycle arrest, the parasite enters a quiescent state reminiscent of a mitogen-activated restriction point. This arrest is unique and solely attributed to the removal of the specific mitogens within this system, polyamines. These analyses indicate the close interaction between transcriptional regulation and signal transduction cascades in the progression through the parasite℗þs cell cycle and for the first time highlight aspects of controlled cell cycle regulation in Plasmodium. In contrast to proliferation, the process of sexual differentiation only started receiving attention in the past few years. As such, we lack fundamental understanding of the mechanisms driving the unique gametocyte differentiation of P. falciparum parasites. This study contributes a detailed analysis of gametocyte differentiation that revealed distinct developmental transitions demarcating the start of gametocytogenesis, intermediate gametocyte development and finally maturation to produce the transmissible mature gametocytes. The study provides evidence for coordinated regulation of gene expression on a transcriptional level. We propose a model for regulation of gametocytogenesis in malaria parasites that involves active repression of gene sets mediated through epigenetics and RNA destabilization as well as active transcription of gene sets through successive ApiAP2 transcription factor activity. This data provides the most detailed framework of coordinated gene regulation events underlying development of P. falciparum gametocytes to date, a unique resource for the malaria community. The comprehensive and complex transcriptional regulation described for the proliferation and differentiation of the parasite led us to evaluate the functional consequence thereof. A whole cell phenotype microarray system was evaluated for its ability to measure the metabolic processes that define asexual and sexual stage metabolism as a functional consequence of changed gene expression profiles during proliferation and differentiation. The study provided metabolic profiles detailing carbon and nitrogen metabolism in asexual parasites, mature and immature gametocyte stages. The data highlighted dipeptide metabolism as a distinguishing feature in mature gametocytes and showed the presence of a low, delayed metabolic state concurrent with reduced transcriptional activity observed in this stage. These results show that gene expression changes associated with differentiation compared to proliferation translate to an observable metabolic phenotype and that transcriptional regulation shapes the molecular landscape underlying crucial events that enable the parasite℗þs intraerythrocytic asexual and sexual development.
Download or read book RNA Based Regulation in Human Health and Disease written by and published by Academic Press. This book was released on 2020-08-19 with total page 444 pages. Available in PDF, EPUB and Kindle. Book excerpt: RNA-based Regulation in Human Health and Disease offers an in-depth exploration of RNA mediated genome regulation at different hierarchies. Beginning with multitude of canonical and non-canonical RNA populations, especially noncoding RNA in human physiology and evolution, further sections examine the various classes of RNAs (from small to large noncoding and extracellular RNAs), functional categories of RNA regulation (RNA-binding proteins, alternative splicing, RNA editing, antisense transcripts and RNA G-quadruplexes), dynamic aspects of RNA regulation modulating physiological homeostasis (aging), role of RNA beyond humans, tools and technologies for RNA research (wet lab and computational) and future prospects for RNA-based diagnostics and therapeutics. One of the core strengths of the book includes spectrum of disease-specific chapters from experts in the field highlighting RNA-based regulation in metabolic & neurodegenerative disorders, cancer, inflammatory disease, viral and bacterial infections. We hope the book helps researchers, students and clinicians appreciate the role of RNA-based regulation in genome regulation, aiding the development of useful biomarkers for prognosis, diagnosis, and novel RNA-based therapeutics. Comprehensive information of non-canonical RNA-based genome regulation modulating human health and disease Defines RNA classes with special emphasis on unexplored world of noncoding RNA at different hierarchies Disease specific role of RNA - causal, prognostic, diagnostic and therapeutic Features contributions from leading experts in the field
Download or read book Apicomplexan Parasites written by Katja Becker and published by John Wiley & Sons. This book was released on 2011-01-19 with total page 548 pages. Available in PDF, EPUB and Kindle. Book excerpt: This handbook is the first dealing with the discovery of drugs directed against apicomplexan parasites. Amongst others, this group of endoparasites includes the causative agents of Malaria, Toxoplasmosis, and Babesiosis, the latter occurring mainly in animals. Written by renowned scientific experts from academia and industry, the book focuses on currentdrug development approaches for all apicomplexan diseases making it appealing to a large audience, ranging from research labs in academia to the human and veterinarian pharmaceutical industry. This work is the second volume of the new book series 'Drug Discovery in Infectious Diseases', edited by Prof. Dr Paul M. Selzer.
Download or read book The Malaria Genome Projects written by Irwin W. Sherman and published by World Scientific. This book was released on 2012 with total page 389 pages. Available in PDF, EPUB and Kindle. Book excerpt: The year 2012 marks the tenth anniversary of the announcement of the genome sequence of the human malaria parasite Plasmodium falciparum and that of its mosquito vector Anopheles. The genome sequences were a result of the Plasmodium falciparum Genome Project. This book covers in detail the biology of malaria parasites and the mosquitoes that transmit the disease, how the Genome Project came into being, the people who created it, and the cadre of scientists who are attempting to see the promise of the Project realized. The promise was: a more complete understanding of the genes of the parasite (and its vector) would provide a rational basis for the development of antimalarial drugs and vaccines, allow a better understanding of the regulation of the complex life cycle in the red blood and liver cells of the human, identify the genes the parasite uses to thwart the host immune response and the ways in which the parasite evades cure by drug treatments, as well as leading to more effective measures of control transmission. The hope was that cracking the genetic code of Plasmodium and Anopheles would reveal the biochemical Achilles heel of the parasite and its vector, leading to the development of novel drugs and better methods of control, and by finding the targets of protective immunity could result in the manufacture of effective vaccines. Through a historic approach, this book will allow for those new to the field, or those with insufficient background in the sciences, to have an easier entry point. Even scientists already working in the field may better appreciate how discoveries made in the past can impact the direction of future research.
Download or read book Rodent Malaria written by R. Killick-Kendrick and published by Elsevier. This book was released on 2012-12-02 with total page 435 pages. Available in PDF, EPUB and Kindle. Book excerpt: Rodent Malaria reviews significant findings concerning malaria parasites of rodents, including their taxonomy, zoogeography, and evolution, along with life cycles and morphology; genetics and biochemistry; and concomitant infections. This volume is organized into eight chapters and begins by sketching out the history of the discovery of rodent as well as aspects of parasitology, immunology, and chemotherapy. These concepts are investigated two decades following Ignace Vincke's major discovery and Meir Yoeli's successful establishment of the method of cyclical transmission of the parasite. The following chapters focus on the taxonomy and systematics of the subgenus Vinckeia, with reference to the concepts of species and subspecies of animals and the degree to which they apply to malaria parasites, in particular to those of rodents. The discussion then shifts to how the rodent malaria parasites provide a unique insight into the subcellular organization of Plasmodium species, the use of rodent malaria as an experimental model to study immunological responses, and infectious agents that interact with malaria parasites. The book concludes with a chapter on malaria chemotherapy, with emphasis on the value of rodent malaria in antimalarial drug screening and the use of antimalarial drugs as biological probes. This book will be of interest to protozoologists and physicians as well as those from other disciplines including biochemistry, immunology, pharmacology, cell biology, and genetics.
Download or read book Molecular Parasitology written by Julia Walochnik and published by Springer. This book was released on 2016-10-20 with total page 546 pages. Available in PDF, EPUB and Kindle. Book excerpt: In the past years, genome projects for numerous human parasites have been completed and now allow first in depth comparisons and evolutionary conclusions. The genomes of parasites reflect the coevolution with their host, metabolic capacities depending on their respective habitat in the host. Gut parasites usually have an anaerobic metabolism, while blood parasites have an aerobic metabolism, intracellular parasites escape the immune system, while extracellular parasites evade the immune system, usually by antigenic variation. Comprehensive genome data now being available allow us to address profound scientific questions, such as which traits enable the parasite to survive in the human host, which to cause disease and which can be used as drug targets. This book intends to give an overview of the state of knowledge on “the molecules” of protozoan parasites – on their genomes, proteomes, glycomes and lipidomes.
Download or read book Epigenetics of Infectious Diseases written by Walter Doerfler and published by Springer. This book was released on 2017-05-26 with total page 281 pages. Available in PDF, EPUB and Kindle. Book excerpt: The present volume of Epigenetics and Human Health is devoted to the patho-epigenetics of viral and microbial infections, an exiting new field of disease-related epigenetic research. As recognized during the past years, epigenetic reprogramming of pathogen and host genome functions – the latter frequently induced by pathogens – plays an important role in many infectious processes. Beyond their immediate relevance for pathogen proliferation and obligatorily associated symptoms, such alterations frequently contribute to severe additional complications, such as the development of immunodeficiency, cancer and various chronic disorders. This holds in particular for epigenetic dysregulation of host gene expression induced by latent infections. The present book summarizes current knowledge of the mechanisms underlying epigenetic changes caused by viral, bacterial, fungal and protozoan infections and their impact on human health.
Download or read book Current Topics in Malaria written by Alfonso J. Rodriguez-Morales and published by . This book was released on 2016-11-30 with total page 508 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Parasite Genomics written by Luis M. de Pablos and published by Humana. This book was released on 2021-07-28 with total page 336 pages. Available in PDF, EPUB and Kindle. Book excerpt: This detailed book provides a comprehensive series of innovative research techniques and methodologies applied to the parasite genomics research area, all applying different approaches to analyzing parasite genomes and furthering the study of genetic complexity and the mechanisms of regulation. Beginning with chapters on novel sequencing and the bioinformatics pipeline, the volume continues by exploring diagnostic approaches using genomic tools, host-parasite interactions, as well as the genomics of parasite-derived extracellular vesicles. Written for the highly successful Methods in Molecular Biology series, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Parasite Genomics: Methods and Protocols creates a detailed picture of genomic approaches for researchers seeking a better understanding of characterizing parasite nucleic acid content.
Download or read book Malaria Parasites written by Andrew P. Waters and published by Caister Academic Press Limited. This book was released on 2004 with total page 578 pages. Available in PDF, EPUB and Kindle. Book excerpt: The completion of the Plasmodium falciparum genome sequence in late 2002 heralded a new era in malaria research. The search began in earnest for new drugs and vaccines to combat malaria, a disease which afflicts up to 500 million people worldwide and is responsible for the deaths of more than one million people each year. The new genomic data is aiding a greater understanding of the living parasite and its interaction with the insect vector and human host. In this book internationally renowned experts provide up-to-date reviews of the most important aspects of post-genomic malaria research. Topics covered include: the P. falciparum genome and model parasites, bioinformatics and genome databases, microsatellite analysis, analysis of chromosome structure, cell cycle to RNA polymerase I and II mediated gene expression, role of the nuclear genome, the parasite surface and cell biology, and much more. The book is essential to all researchers working in this highly topical field and is recommended reading for scientists in other areas of biology and medicine.
Download or read book World Malaria Report 2018 written by World Health Organization and published by World Health Organization. This book was released on 2019-02-12 with total page 210 pages. Available in PDF, EPUB and Kindle. Book excerpt: This year s report shows that after an unprecedented period of success in global malaria control progress has stalled. Data from 2015?2017 highlight that no significant progress in reducing global malaria cases was made in this period. There were an estimated 219 million cases and 435 000 related deaths in 2017. The World malaria report 2018 draws on data from 90 countries and areas with ongoing malaria transmission. The information is supplemented by data from national household surveys and databases held by other organizations.
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 Comprehensive Analysis of Parasite Biology written by Sylke Müller and published by John Wiley & Sons. This book was released on 2016-07-19 with total page 576 pages. Available in PDF, EPUB and Kindle. Book excerpt: Written and edited by experts in the field, this book brings together the current state of the art in phenotypic and rational, target-based approaches to drug discovery against pathogenic protozoa. The chapters focus particularly on virtual compounds and high throughput screening, natural products, computer-assisted drug design, structure-based drug design, mechanism of action identification, and pathway modelling. Furthermore, state-of the art "omics" technologies are described and currently studied enzymatic drug targets are discussed. Mathematical, systems biology-based approaches are introduced as new methodologies for dissecting complex aspects of pathogen survival mechanisms and for target identification. In addition, recently developed anti-parasitic agents targeting particular pathways, which serve as lead compounds for further drug development, are presented.
