1,720,972 research outputs found
Clinically Relevant Models of Cardiac Function using Human Stem Cell-derived Cardiomyocytes
Get PDFCardiovascular diseases pose a significant healthcare burden, however, development of effective therapeutics has stagnated, with many recent clinical trials resulting in failure. Moreover, unexpected drug-induced cardiotoxicity contributes to a high attrition rate for all drugs, irrespective of disease indication. These issues largely stem from challenges in modeling the heart’s complex structure and dynamic function in preclinical settings. Emulating key cardiac mechanobiological aspects at a scale sufficient for drug development has been difficult. Human-based preclinical models are needed to reduce the reliance on animals, and mitigate problems arising from cardiological species differences. This research is aimed to broaden our understanding of how human stem cell-derived cardiomyocyte in vitro models can potentially improve downstream clinical translation by incorporating physiologically-relevant high-content study designs. Chapter 2 describes a novel high-throughput testing platform designed to comprehensively evaluate cardiomyocyte contractile function. A machine learning-based classifier to predict drug candidate cardioactivity was developed, illustrating how cardioactivity may be identified earlier in the drug development process to mitigate potential downstream toxicity issues. Using the new analysis platform, cardiac microenvironment biomechanical features were recapitulated in vitro, revealing how mechanical stress present in heart disease may affect drug response. Cardiomyocyte mechanobiology was further explored in Chapter 3 by investigating proteins involved in cardiac force-sensing. Specifically, the integrin-linked kinase adaptor protein beta-parvin was shown to regulate cardiomyocyte structure and function in response to mechanical stress, presenting a potential therapeutic target for cardiac fibrosis and heart failure. Chapter 4 focuses on local anesthetic cardiotoxicity, as a clinically-relevant example of inadvertent drug-induced toxicity. Cardiomyocyte calcium dynamics were found to differentiate the toxicity mechanisms between anesthetics with distinct clinical toxicity profiles, revealing potential anesthetic-specific treatment strategies. These findings were replicated in rodent experiments in vivo, emphasizing the translational utility of stem cell-derived cardiomyocyte models.
In summary, the conducted research demonstrates how stem cell-derived cardiomyocyte models can recapitulate key aspects of heart disease pathology and physiologic responses to cardiotropic drugs. The experimental approach described here provides an efficient framework to discover new cardiac therapeutic targets, and investigate cardiotoxicity mechanisms for existing drugs, with the ultimate goal of developing safer and more effective medications.Ph.D
Development and Application of Novel in Vitro Assays to Advance Drug Discovery for Arrhythmogenic Cardiomyopathy and Respiratory Syncytial Virus Infection
Get PDFThe research described in this thesis is focused on the development of in vitro assays to better study human disease and advance drug discovery, specifically in the context of arrhythmogenic cardiomyopathy (ACM) and respiratory syncytial virus (RSV) infection. Despite the functional distinction between these diseases, they both share the issue of inadequate treatment options for patients. Dysfunction of gap junctions is thought to underlie the development of fatal ventricular arrhythmias early in ACM disease progression. Existing methods of studying gap junction function are low-throughput, technically challenging, and have poor reproducibility. Chapter II outlines the development of a robotic cell microinjection assay to quantify gap junction permeability. Human cardiomyocytes with knockdown of PKP2, a protein commonly mutated in ACM, were screened against a library of drugs using the robotic assay. Five compounds were found to enhance gap junction function in vitro, one of which reduced beating irregularity in a mouse model of ACM. Respiratory syncytial virus (RSV) is the leading cause of acute respiratory tract infections necessitating hospitalization in infants and young children. There are currently no vaccines for the virus and treatment options are limited to supportive care. Chapter III describes the development of a high content assay to rapidly quantify RSV infection rates. Application of this assay towards drug screening led to the identification of several viral inhibitors and host pathways targeted by the virus. Functional enrichment analyses revealed an interaction between the virus and lipid metabolic pathways, prompting further investigation into the antiviral mechanism of statins–a top screening hit. Chapter IV takes a closer look at the function of statins and mevalonate pathway metabolites during viral infection. Statins were shown to inhibit RSV through a combination of cholesterol and isoprenoid-mediated effects. Notably, statin treatment negated virus-induced increases to the prenylation and activation of Rho GTPases. A primary outcome of the conducted research was the identification therapeutic drugs and pathways for two unique diseases with limited treatment options. The obtained results also highlight the utility of each assay, and demonstrate the potential of applying this work towards future studies on other viral or gap junction-mediated diseases.Ph.D
The Effect of Morphine on Glioblastoma Metabolism and Growth via Inhibition of Wild-Type IDH1
No full textGliomas, the most common cancers of the central nervous system, are categorized into grades I-IV to denote varying degrees of aggression. Low-grade gliomas often have a mutation in the key metabolic enzyme isocitrate dehydrogenase 1 (IDH1), causing the production of 2-hydroxyglutarate (2HG). The IDH1 mutation and 2HG production induce metabolic dysregulation, epigenetic modifications, and slower proliferating cells. Despite therapeutic interventions with antineoplastic agents like temozolomide (TMZ), patients with high-grade gliomas (GBMs) face a median survival of 12 to 14 months. Effective pain management, often involving opioids such as morphine, is paramount for individuals with GBM tumors. Although morphine's impact on cancer progression has been extensively studied, limited attention has been devoted to its specific effects on GBM metabolism. This thesis unravels the intricate relationship between morphine, GBM metabolism, and cell growth.
In the first data chapter, morphine is established as a mixed partial inhibitor of wild-type IDH1, elevating 2HG levels in IDH1 wild-type GBM cells. In vitro exploration via targeted metabolomics and quantification of mitochondrial health metrics exhibits morphine-induced disruptions across various metabolic pathways, including the pentose phosphate pathway, glutaminolysis, and Warburg metabolism. Morphine induces heightened oxidative stress and diminished mitochondrial basal respiration. The following chapter examines the impact of morphine on GBM growth dynamics and motility. The findings demonstrate that morphine reduces proliferation rate, enhances apoptosis, and impedes migration and invasion. Concomitant treatment with morphine and TMZ potentiates the anti-neoplastic effects of TMZ by elevating genomic instability, leading to increased apoptosis. In the final data chapter, the investigation extends to a xenograft mouse model. Morphine-treated mice exhibit tumors approximately threefold smaller than the control group, with elevated 2HG levels and dysregulation of metabolic pathways associated with IDH1 mutations.
The in vivo and in vitro phenotypic changes induced by morphine mirror those observed in low-grade gliomas with the IDH1 mutation. Considering the beneficial phenotype associated with IDH1 mutations in gliomas, treatment of IDH1 wild-type gliomas with morphine may improve prognosis. Given the variety of available pain management options, this research emphasizes the need for personalized pain management regimens in cancer care and underscores morphine's potential to improve GBM patient prognosis.Ph.D
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
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
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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