Download or read book Investigating the Druggability and Biological Roles of Apicomplexan AP2 Transcription Factors in the Human Malaria Parasite Plasmodium Falciparum written by Timothy Russell and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Plasmodium falciparum, the most virulent of the human infectious malaria parasites, caused over 600,000 deaths in 2020. Alarmingly, malaria deaths have increased since 2019 and resistance has been reported for every antimalarial drug deployed to date. Regulation of gene expression is critical for P. falciparum to complete its complex life cycle, which includes stages in the human host and Anopheles mosquito vector. Gene regulation in malaria parasites is primarily driven by the Apicomplexan AP2 (ApiAP2) proteins, a single expanded family of sequence specific DNA binding transcription factors. ApiAP2 proteins are plant derived and therefore have no homologs encoded in the human or mosquito genomes, making them potential drug targets. In order to exploit ApiAP2 proteins as antimalarial intervention targets, it is important to both identify ApiAP2 inhibitors and to probe the biological function of ApiAP2 proteins. In this thesis work, ApiAP2 proteins have been investigated to assess their biological functions and druggability. In Chapter 2, putative competitors of DNA binding by the ApiAP2 protein AP2-EXP were selected using an in silico screen. Several compounds were found to inhibit ApiAP2 DNA binding in vitro using DNA gel-shifts. An ApiAP2 competitor compound was then leveraged for use as a chemical genetic tool to interrogate the function of AP2-EXP. In Chapter 3, a potential cooperative interaction between the ApiAP2 proteins PfAP2-I and PfAP2-G during P. falciparum sexual development was interrogated by mapping the DNA binding occupancy of each protein. PfAP2-I genomic occupancy changes in the presence of PfAP2-G, indicating for the first time a causal relationship between two P. falciparum transcription factors that regulates DNA binding specificity. PfAP2-I and PfAP2-G co-occupancy coincides with the activation of P. falciparum sexual stage genes. In Chapter 4, the first indications of the gene regulatory functions of the ApiAP2 proteins PfAP2-HS and PfAP2-O3 were uncovered by mapping their genome-wide DNA binding occupancies. PfAP2-HS was found to regulate a transcription program that is required for P. falciparum to survive febrile host temperatures, while PfAP2-O3 primarily occupies the gene bodies of loci encoding tRNA and rRNA during sexual development. In aggregate, this thesis work describes efforts to further understand the unique ApiAP2 transcription factor proteins in the human malaria parasite P. falciparum.
Download or read book Investigation of ApiAP2 Transcription Factor PF3D7 0420300 in Plasmodium Falciparum written by Erin Kelly and published by . This book was released on 2021 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is an incredibly devastating disease, infecting more than 200 million people and causing over 400,000 deaths annually. The disease malaria is caused by a unicellular eukaryotic parasite from the genus Plasmodium, with P. falciparum being the most virulent.1As of now, there is no vaccine against this parasite, and many antimalarials that once were successful have begun to fail due to drug resistance. It is of the utmost importance to further investigate the Plasmodium falciparum parasite in order to discern potential new drug or vaccine targets. This is not an easy feat, for P. falciparum is an extremely complex organism. This parasite is transferred from a mosquito to humans, initially inhabiting the human hepatocytes then the human erythrocytes for much of the infection. Recently, the whole genome of P. falciparum had been sequenced, leading to further discoveries of genetic components including transcriptional regulators. Uniquely, much of the parasite's life is regulated by a major family of sequence-specific transcription factors known as the ApiAP2 proteins. There are only 27 known ApiAP2 proteins, and moreover, these proteins only contain plant homology, making them a good potential future vaccine or drug target. Additionally, the ApiAP2 expression is highly regulated in a cascading manner throughout the intraerythrocytic life cycle. This fact points to the importance of the regulators, however, only a handful of these proteins have been fully characterized. This project aims to characterize the role of the ApiAP2 protein, PF3D7_0420300. Very little is known about this protein; however, PF3D7_0420300 has been predicted to be essential, thus investigation into this protein could yield information critical in identifying the next major drug target. To characterize this protein, a tagged line as well as a conditional knock down system must be generated. I used several methods to accomplish this: FKBP destabilization domain, glmS ribozyme cleavage, and CRISPR/Cas9 gene editing. The establishment of these parasite lines is a great advancement in and of itself, and this progress may allow for a future researcher to continue the critical characterization of PF3D7_0420300.
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 Discovering the Multi faceted Roles of Ubiquitylation Within the Human Malaria Parasite Plasmodium Falciparum written by Duk-Won Doug Chung and published by . This book was released on 2012 with total page 401 pages. Available in PDF, EPUB and Kindle. Book excerpt: Overall, our investigation validates the importance of ubiquitylation within the Plasmodium biology and also highlights a few potential antimalarial drug targets that are specific to the deadly parasite.
Download or read book Exploring Regulators of Sexual Differentiation and Blood Stage Development in Malaria Parasites written by Joshua Rice and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The recently discovered Apicomplexan AP2 (ApiAP2) family of proteins is the best-studied group of transcription factors in Plasmodium falciparum, the causative agent of human malaria. While different ApiAP2s have been recognized to regulate transcription in every stage of P. falciparum development, two of these proteins--PfAP2-G and PF14-0633--are of particular interest for their roles in gametocytogenesis and blood stage cytoadherence, respectively. The goals of this study were to observe the expression of AP2-G relative to gametocyte formation and to study the relationship between PF14_0633 expression and cytoadherence. In order to accomplish these goals, a green fluorescent protein tag was to be used to monitor the expression of AP2-G, while a glmS ribozyme tag was chosen to modulate levels of PF14_0633 expression. AP2-G was successfully tagged with GFP but transfection of multiple parasite lines proved ineffective, making phenotypic observation impossible. The process of tagging PF14_0633 is currently underway with early success, but time constraints have hindered the completion of this experiment.
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 The Role of Autophagy in the Human Malaria Parasite Plasmodium Falciparum written by Serena Stacie Cervantes and published by . This book was released on 2013 with total page 395 pages. Available in PDF, EPUB and Kindle. Book excerpt: The human malaria parasite remains a major public health burden in developing nations. Despite many years of research, the mechanisms controlling gene expression in the parasite are still poorly understood. While the P. falciparum genome lacks more than fifty percent of the transcription factors anticipated to regulate its 6372 genes, it encodes a large amount of genes involved in RNA metabolism and chromatin remodeling. Furthermore, preliminary data in the laboratory showed extensive nucleosome remodeling during the parasite's asexual cycle. Therefore, we hypothesized that change in chromatin structure plays an important role in controlling parasite development. To understand the role of histone post-translational modifications (PTMs) in transcriptional regulation and histone turnover, we used a shotgun proteomic approach. A total of 246 histone PTMs were identified with 126 being novel. Parasite histones were highly acetylated and methylation marks associated with transcriptional silencing were detected at low levels. To elucidate the mechanism regulating histone turnover, we treated parasite cultures with inhibitors of two distinct pathways that degrade bulk amounts of protein; the ubiquitin-proteasome system and the autophagosome-lysosome pathway. Parasites treated with inhibitors of the autophagy pathway displayed an accumulation of histone protein. The autophagy pathway was overlooked in the parasite; thus, we investigated it at the comparative genomic, cellular, biological and genetic levels. PfATG8, an autophagosome membrane marker, was detected throughout the erythrocytic stages in the apicoplast and the cytoplasm. Proteins associated with PfAtg8 were isolated by immunoprecipitation and identified by mass spectrometry. Gene ontology enrichment showed an enrichment of proteins involved with the digestive food vacuole, the phagolysosome, and the nucleus. In summary, we determined that the autophagy pathway is multifunctional and is likely involved in vesicle traffic, apicoplast biogenesis, and protein catabolism. To further validate its role in histone turnover, we took a cellular approach and colocalized histones and PfATG8 vesicles. Collectively, our work provides key information of mechanism regulating epigenetic and its effects on gene expression in the human malaria parasite.
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 Evolution Of Life Histories written by Derek Roff and published by Springer Science & Business Media. This book was released on 1993-04-30 with total page 554 pages. Available in PDF, EPUB and Kindle. Book excerpt: There are many different types of organisms in the world: they differ in size, physiology, appearance, and life history. The challenge for evolutionary biology is to explain how such diversity arises. The Evolution of Life Histories does this by showing that natural selection is the principal underlying force molding life history variation. The book describes in particular the ways in which variation can be analyzed and predicted. It covers both the genetic and optimization approaches to life history analysis and gives an overview of the general framework of life history theory and the mathematical tools by which predictions can be made and tested. Factors affecting the age schedule of birth and death and the costs of reproduction are discussed. The Evolution of Life Histories concentrates on those theoretical developments that have been tested experimentally. It will interest both students and professionals in evolution, evolutionary ecology, mathematical and theoretical biology, and zoology and entomology.
Download or read book The Anopheline Mosquito written by R. C. Dauglish and published by . This book was released on 1911 with total page 48 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book The Biology of Trypanosomes written by Leslie Hudson and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 189 pages. Available in PDF, EPUB and Kindle. Book excerpt: African and South American trypanosomiases are notable features of clinical and veterinary practice in their respective endemic areas and, as such, are of considerable economic importance. Scientifically, however, their importance ex tends beyond their clinical significance, as the trypano somes are intriguing and easily manipulated models for the study of the control of gene expression, membrane chemistry, proliferation and differentiation. It is clear from the scientific press that the rate of advance has "hotted" up in these areas of trypanosome research over the past 5 years and so a single-topic volume within the scope of the present series seemed timely. As ever, the final admix ture of review topics was a compromise between what was appropriate and what was available - fortunately with the former in vast excess. I should like to highlight two omissions, made for en tirely different reasons. The first is a detailed treatment of the molecular biology of the variant surface glycopro teins of the African trypanosomes (in particular Trypano soma brucei and T. equiperdum). This topic has been the subject of several reviews, for example, BORST and CROSS (1982)1 and TURNER (1982)2, and so was excluded from the present volume. The second omission is a review of the first-class work on genetic recombination from the group of Dr. Leo Jenni at the Schweizerisches Tropeninsti tut, Basel. This group has used isoenzyme markers to show that T.
Download or read book Methods to Assess DNA Damage and Repair written by Robert G. Tardiff and published by . This book was released on 1994-08-16 with total page 300 pages. Available in PDF, EPUB and Kindle. Book excerpt: Integrates data obtained from a variety of disciplines to evaluate the current state of knowledge regarding defense mechanisms and applies this information to estimate health risks to humans exposed to substances that alter genetic material. Recognized experts document, to a large extent, which carcinogens can cause injury to human beings and their surroundings, providing guidance for the structured acquisition of key information to reduce cancer risks throughout the environment.
Download or read book Bioactive Compounds from Natural Sources Second Edition written by Corrado Tringali and published by CRC Press. This book was released on 2011-09-27 with total page 650 pages. Available in PDF, EPUB and Kindle. Book excerpt: The first edition of Bioactive Compounds from Natural Sources was published in a period of renewed attention to biologically active compounds of natural origin. This trend has continued and intensified—natural products are again under the spotlight, in particular for their possible pharmacological applications. Largely focusing on natural products as lead compounds in drug discovery, Bioactive Compounds from Natural Sources, Second Edition: Natural Products as Lead Compounds in Drug Discovery is actually a completely new volume containing surveys of selected recent advances in an interdisciplinary area covering chemistry of natural products, medicinal chemistry, biochemistry, and other related topics. Written by some of the most reputed scientists in the field, this second edition includes new chapters from authors who contributed to the first edition as well as many chapters compiled by new authors. Introducing the reader to strategies and methods in the search for bioactive natural products, this book covers topics including: Natural sources of bioactive compounds such as aquatic cyanobacteria, filamentous fungi, and tropical plants, The tremendous potentiality of metabolic engineering of natural products biosynthesis The contribution of emerging or developing technologies to the study of bioactive natural compounds, namely computational methods and circular dichroism The potential of natural or natural-derived compounds for specific therapeutic applications: treatment of viral diseases, regulation of hypoxia-inducible factor, antimalarials, modulation of angiogenesis, and antitumor and wound-healing activity Selected examples of natural product families and related synthetic analogues, namely polyphenols and campthotecins Compiled for researchers and Ph.D. students working in interdisciplinary fields, this book will also be appreciated by readers without a background in chemistry interested in bioactive natural products, their biological and pharmacological properties, and their possible use as chemopreventive or chemotherapeutic agents. Conversely, the biological and pharmacological data and methods are accessible by chemists.
Download or read book Gene Essentiality written by Long Jason Lu and published by Humana. This book was released on 2016-10-05 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume opens by covering two main types of approaches widely used to determine essential genes: single-gene knockouts and transposon mutagenesis, in both prokaryotes and Candida albicans. Given the significant advancement in the computational predictions of microbial essential genes, the second half of the book examines four main types of approaches: comparative genomics, supervised machine learning, constraint-based methods, and corrections of transposon mutagenesis data, as well as databases and servers that are often used in studying gene essentiality. Written in the highly successful Methods in Molecular Biology series format, chapters include an introduction 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 up-to-date, Gene Essentiality: Methods and Protocols will aid researchers who wish to further our knowledge in this vital field of study.
Download or read book Metabolic and Bioenergetic Drivers of Neurodegenerative Disease Treating Neurodegenerative Diseases as Metabolic Diseases written by and published by Academic Press. This book was released on 2020-09-08 with total page 320 pages. Available in PDF, EPUB and Kindle. Book excerpt: Metabolic Drivers and Bioenergetic Components of Neurodegenerative Disease reviews how the different aspects of metabolic dysfunction and consequent pathology associated with neurodegenerative diseases, including Alzheimer's and Parkinson's, can be targeted by novel treatment approaches. Topics covered include Cellular Senescence in Aging and Age-Related Disorders: Implications for Neurodegenerative Diseases; Repurposing GLP1 agonists for Neurodegenerative Diseases; Ketotherapeutics for Neurodegenerative Diseases; Enhancing Mitophagy as a Therapeutic Approach for Neurodegenerative Diseases; Harnessing Neurogenesis in the Adult Brain - A Role in Type 2 Diabetes Mellitus and Alzheimer's disease; and much more. Summarizes the impact of the metabolic hypothesis on underlying mechanisms of neurodegenerative diseases Presents novel, potential treatment strategies based on the metabolic hypothesis for neurodegenerative diseases.
Download or read book Fragment based Approaches in Drug Discovery written by Wolfgang Jahnke and published by John Wiley & Sons. This book was released on 2006-12-13 with total page 391 pages. Available in PDF, EPUB and Kindle. Book excerpt: This first systematic summary of the impact of fragment-based approaches on the drug development process provides essential information that was previously unavailable. Adopting a practice-oriented approach, this represents a book by professionals for professionals, tailor-made for drug developers in the pharma and biotech sector who need to keep up-to-date on the latest technologies and strategies in pharmaceutical ligand design. The book is clearly divided into three sections on ligand design, spectroscopic techniques, and screening and drug discovery, backed by numerous case studies.
Download or read book Lipid Modifications of Proteins written by Patrick J. Casey and published by Academic Press. This book was released on 1995-05-16 with total page 808 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume is organized around the three major classes of lipids that have been identified in covalent attachment to proteins in eukaryotic cells: isoprenoids, saturated fatty acyl groups and glycosylphosphatidylinositol ( GPI ).
