1,721,166 research outputs found
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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Target Identification and Validation of the Imidazolopiperazine Class of Antimalarials
No full textThe antimalarial resistance arms race is alive and well. In 2022, the Plasmodium genus of parasites were responsible for 249 million cases of malaria, 608,000 of which were fatal (WHO, 2023). This increase in cases is attributed to lack of an effective vaccine and restricted access to preventative and treatment measures coming after the COVID-19 pandemic, but especially to the ongoing development of antimalarial resistant parasites. Thus, there is a dire need to create medicines that possess novel modes of action. And if malaria were ever to be eradicated, we need those that inhibit parasite growth at every stage of their life cycle. So, how do we know which compounds exhibit antimalarial activity in a novel way?This dissertation highlights and applies strategies of antimalarial target identification. Chapter 1 describes omics approaches: in-vitro evolution and whole genome analysis, proteomic affinity chromatography, cellular thermal shift assay, metabolomic profiling. Chapter 2 uses these methods on imidazolopiperazines, a new class of antimalarials that possess a novel mode of action and are active against multiple stages of the parasite life cycle. Previous work evolving parasites against the GNF179 analog only presented multidrug resistance mechanisms; metabolomic profiling with the KAF156 analog did not present clear perturbations. Using proteomic affinity chromatography, thermal shift assay, and surface plasmon resonance, we identify GNF179 interaction with a putative dynamin-like GTPase. Having only been predicted to be essential in parasites, we also confirm that it is an essential P. falciparum gene via conditional knockdown. Molecular docking and GTPase activity assay suggest imidazolopiperazine binding to the N-terminal GTPase domain, yet a nonsense mutation that removes residues from the C-terminal end confers resistance. In Chapter 3, we investigate the significance of the transmembrane domains and C-terminal tail of this GTPase protein to imidazolopiperazine interaction. Through this research, we can better guide imidazolopiperazine development and anticipate resistant alleles
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Know thy Enemy: Exploring Pathogenic Evolution, Resistance, and Virulence in Plasmodium falciparum and Leptospira interrogans
Get PDFWe are in a constant battle against pathogens. Millions of individuals die every year due to inadequate diagnosis and emerging resistance to current therapeutics. Improvements in diagnosis and treatment strategies are needed, but these can be hindered by a lack of knowledge regarding a particular pathogen’s molecular and resistance mechanisms. Plasmodium and Leptospira are two such examples of widespread pathogenic organisms whose genomes are still poorly understood and additional knowledge is desperately needed to improve therapeutic strategies. This dissertation presents two evolution-based strategies that when coupled with whole genome sequencing can be used to identify virulence and resistance associated genes. These include a “forward” approach, which studies the development of resistance, and a “reverse” approach, which examines the loss of virulence. In Chapter 2, the forward approach is used to examine novel targetable pathways in Plasmodium falciparum. Selectively evolving resistance to 50 novel antimalarial compounds, we successfully identify potential targets to 21 compounds and eight novel gene targets. Additionally, this chapter examines resistance development patterns against the compound set, and identifies fast-killing compounds may result in a slower onset of clinical resistance. Chapter 3 focuses on PfCARL, one potential target identified in Chapter 2, which has been previously described as the target for KAF156, a drug currently in clinical trials. Our data demonstrate that pfcarl mutations confer resistance to two distinct compound classes – benzimidazolyl piperidines and imidazolopiperazines. However, these two classes appear to have different timing of action in the asexual blood stage and different potencies against the liver and sexual blood stages, suggesting pfcarl is a multidrug resistance gene rather than a common target. Finally, using the reverse approach, Chapter 4 identifies virulence-related genes in Leptospira by observing cumulative genomic changes occurring after serial in vitro passaging of a highly virulent Leptospira interrogans strain into a nearly avirulent isogenic derivative. Comparison between these two polyclonal strains identifies 15 non-synonymous single nucleotide variant (nsSNV) alleles that increased in frequency and 19 that decreased. These frequency changes likely contribute to the loss of virulence, and suggest new virulence-associated genes whose role in Leptospira pathogenesis should be further studied
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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Drug Target Discovery Using Designer Drug Sensitive Yeast
Get PDFDetermining the protein target(s) and mechanism(s) of drug candidates found in phenotypic screens is critical to subsequent structure-activity-based development and optimization, but existing methods for target identification are limited. Here we present a method that applies directed evolution to a genetically engineered, drug sensitive Saccharomyces cerevisiae strain. Whole genome sequencing of yeast clones that have evolved drug resistance, in concert with in vitro cell free assays and computer modeling, can be a useful tool for target identification and binding site characterization.To demonstrate the ease and utility of this method, we applied it to the identification of the molecular target and binding site of a range of cytotoxic molecular compounds with activity against eukaryotic pathogens and human cancers. These studies include known drug target combinations, as well as application to experimental compounds with unknown drug targets. As proof of concept, the method correctly identified the precise binding pocket of the protein synthesis inhibitor, cycloheximide, as the ribosomal protein Rpl28. We also correctly identified topoisomerase II inhibitor as the target of the human cancer chemotherapeutic, etoposide.We next used the method to identify novel drug target combinations, which were then validated using a combination of genetic, biochemical, structural and chemical structure activity relationships (SAR)-based assays. We identified a p-type ATPase, ScPma1, as the target of the spiroindolone antimalarials, of which KAE609 is currently in stage 2b clinical trials. We determined that the pre- clinical phenyl-amino-methyl-quinolinols (PAMQ) antimalarials inhibit the cyclic AMP signaling pathway, a mechanism of action that is different from existing commercial antimicrobials. We also demonstrated that MMV001239, a compound with antitrypanosomal activity, targets ScErg11, the yeast homolog of the T, cruzi Cyp51p, and a protein crucial for ergosterol biosynthesis. Taken together, our approach expands on the number of tools available for analyzing compound-target interactions and can be applied to studies of other eukaryotic antimicrobials and chemotherapeutics
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Battling Drug Resistance: A Tale of Two Pathogens
Get PDFHIV/AIDS, malaria, and tuberculosis are the world’s three deadliest infectious diseases of humans, often referred to as the ‘Big Three’. Together, they are responsible for more than 10% of all the deaths worldwide each year. What is perhaps most worrisome is the fact that the current therapies that treat these conditions are losing their efficacy due to the emergence of antimicrobial drug resistance. Accordingly, research is urgently needed to address the growing problem of drug resistance and to help drive the development of novel therapeutics. In the first chapter of this doctoral dissertation, three strategies to combat drug resistance are discussed: 1. Developing therapeutics that target host-derived factors, 2. Identifying new antimicrobial inhibitors, and 3. Investigating host-pathogen biology using systems analysis to drive the development of novel therapeutics. Examples of research utilizing these strategies are discussed in the following chapters, with a particular focus on two of the “Big Three” pathogens- HIV-1 and the malaria parasite, Plasmodium. The identification and characterization of a novel host factor that regulates HIV-1 reverse transcription is described in Chapter 2. In Chapter 3, the development of a high-throughput phenotypic assay to identify novel antimalarial drugs is discussed, and in Chapter 4, a broad review of systems biology-based research of host-parasite interactions (with an emphasis on Plasmodium) is included. The Appendix includes preliminary data and future aims for systems biology research aimed at understanding Plasmodium liver-stage development. Through the combination of these scientific efforts, we will surely strength our position in the ongoing battle against antimicrobial drug resistance
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Antimalarial Drug Discovery and Target Identification from Phenotypic High-throughput Screening Hits
Get PDFThe drive to propagate a species genes is among the strongest biological forces, shared by humans and pathogens alike. For pathogens like Plasmodium parasites, the etiological agent of human malaria, self-preservation comes at the cost of hundreds of thousands of human lives annually. Between 2000 and 2016, worldwide cases of malaria were progressively declining. Although there are many causes for the recent increase in global malaria cases, parasite drug resistance is a likely contributor. Thus, research is desperately needed to identify druggable targets and develop novel therapeutics capable of more than symptom alleviation. This dissertation highlights the use of key strategies that have resulted in new preclinical drug candidates, namely the systematic investigation of vast small molecule libraries. In Chapter 1, the investigation of more than 100 marine derived natural products identified six compounds with promising antiparasitic activity and selectivity relative to the host cell. Additionally, this chapter describes the successful target identification of choice screening hits, such as hectochlorin and its newly validated target, actin. In Chapter 2 high throughput screening methods are embraced to explore the activity of nearly 70,000 small molecules, testing them, with collaborators, against all malaria parasite stages that dwell in the human host. Hundreds of these molecules are discovered to have activity against one or more of these stages. Studies in collaboration with Manu Vanaerschot show the target of one such molecule acting within the mitochondrial electron transport chain, against cytochrome bc1. Despite affecting a well-characterized drug target in Plasmodium, this target rediscovery legitimizes our strategy for antimalarial hit selection from untested chemical libraries. Because drug target discovery is vital to the development of novel therapeutics, and can guide drug design to minimize the likelihood of off target effects, Chapter 3 describes the search for the target of a potent asexual blood stage (ABS) inhibitor. Here, the protein cytoplasmic isoleucyl-tRNA synthetase (PF3D7_1332900) is shown as the target of a drug-like scaffold, TCMDC-124553. This protein was previously shown to be critical in P. falciparum ABS, and our data also suggest it is essential in the liver stage of infection as well
Using experimental evolution to elucidate the genomic drivers of antimicrobial resistance in eukaryotic pathogens
Get PDFThe emergence of drug resistance in an ever-present threat to the successful treatment of infectious diseases. Microorganisms have an almost unparalleled abilityto divide rapidly to achieve large population numbers, introducing a potentially large number of random mutations into the population over time which can confer a distinct advantage (or disadvantage) depending on the environment and selection conditions. In vitro evolution combined with whole genome analysis is a powerful forward genetics tool used to study the development of antimicrobial resistance within a tightly controlled experimental environment (i.e. a tissue culture flask). This dissertation explores the use of this method to begin to collectively understand the genomic drivers of drug resistance across multiple eukaryotic microbes: the human malaria parasite Plasmodium falciparum, the toxoplasmosis-causing parasite Toxoplasma gondii, and the fungus and “model organism” Saccharomyces cerevisiae. We find that multidrug resistance mechanisms are major drivers of resistance for both P. falciparum and S. cerevisiae.In Chapter 2, in vitro evolution of resistance to the antimalarial clinical candidate DSM265 is shown to mirror the results of in vivo resistance development both in a murine model and in Phase 2a clinical trial data, thus supporting its value as a method toward understanding the mechanics of P. falciparum resistance development. Then in Chapter 3, the method is expanded to 113 different compound selections either performed within the Malaria Drug Accelerator Consortium or by other groups which have made their data publicly available. Here, we show that half of all compounds taken into selection yield parasites with mutations in multidrug resistance mechanisms.In Chapter 4, we explore how selections performed in T. gondii with the antimalarial drug Artemisinin differ from those performed in the malaria parasite. Both organisms are Apicomplexan parasites but parasitize their hosts in distinctly differentways. While the selections do not yield any homologous resistance genes, both yield mutations that are believed to be involved in each respective parasite’s stress response. Moreover, we find that a key shared feature is the multigenic nature of resistance to Artemisinin, which is likely tied to it mode of action.Finally, in Chapter 5, experimental evolution is applied at scale in S. cerevisiae to model resistance development in fungi. Selections with 80 different compounds yielded 355 compound-resistant clones and once again we identify a multidrug resistance mechanism that is strongly overrepresented across the dataset. The two Zn2C6 transcription factors YRR1 and YRM1, which are known to induce the pleiotropic drug response, were mutated 100 different times and conferred resistance to 19 structurally distinct compounds
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