1,721,031 research outputs found
Developing Serum-stabilized Cationic Liposome-DNA Particles for Gene Therapy by Preformed Vesicles and Ethanol Method
No full textOptimization of lipid nanoparticles containing small molecule drugs and genetic drugs
No full textLipid-based nanoparticle (LNP) drug delivery vehicles can be used for in vivo delivery of a variety of bioactive molecules including nucleic acid polymers and small molecule drugs for applications ranging from improving the efficacy of anticancer drugs to enabling gene therapies. While liposomal systems containing small molecule drugs can be designed to be relatively nontoxic and long circulating, the ability to trigger rapid release of drug cargo at the target site remains elusive, severely limiting their therapeutic index. The first objective of this thesis is to develop lipid nanoparticles that can release a larger payload at the target site to improve their overall efficacy. Despite more than 30 years of experimentation, triggered release systems for liposomes containing anticancer drugs that leak contents in response to local heating or irradiation have failed to result in clinically approved applications. Chapters 3 and 4 of this thesis focus on incorporating photoswitchable lipids or metal nanoparticles into previously well-established liposomes, making
them responsive to externally applied radiation such as laser light to trigger drug release. These
novel liposomal systems have similar size and drug encapsulation properties as parent systems,
while also exhibiting triggered release properties.
Additionally, systems currently being used for delivery of genetic drugs such as RNAbased
drugs only result in effective gene silencing or gene expression in the liver. The second objective of this thesis is to develop transfection competent long circulating systems that can transfect extra-hepatic tissues following intravenous administration. Chapter 5 of this dissertation describes an attempt to increase the proportion of so-called “helper” lipids in LNP formulations containing mRNA. It is shown that high (40 mol%) levels of helper lipids such as egg sphingomyelin (ESM) can result in improved gene expression both in vitro and in vivo, particularly in extrahepatic tissues such as bone marrow. This ability is attributed to the unique morphology of these LNP systems which exhibit a “solid” hydrophobic core surrounded by a lipid bilayer. Such systems allow improved distribution to extrahepatic tissues due to an enhanced circulation lifetime.Medicine, Faculty ofBiochemistry and Molecular Biology, Department ofGraduat
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Optimizing systems to enable genetic engineering of transfusable platelets
No full textPlatelet transfusions are essential for managing bleeding and hemostatic dysfunction, but may become ineffective during certain circumstances such as in trauma. Optimizing systems that can enhance the hemostatic potential of platelets could lead to increased efficacy of transfusions and improve patient outcomes. Modifying transfusable donor platelets to express therapeutic proteins is the most direct method to enhance platelets. However, no appropriate methods exist for genetically modifying platelets collected from blood donors. This thesis showed that platelet-optimized lipid nanoparticles containing mRNA (mRNA-LNP) enable exogenous protein expression in human and rat platelets. Exogenous protein expression did not appear to require, nor correlate with platelet activation. Transfected platelets retained hemostatic function and accumulated in regions of vascular damage after transfusion into rats with hemorrhagic shock. These results suggest that platelets can be genetically modified without impairing hemostasis, where further optimization can expand the therapeutic potential of platelets. Engineering the platelet precursor cells, megakaryocytes (MKs), can also yield modified platelets, but can only currently be achieved through viral vectors. No methods currently exist to genetically modify MKs with non-viral techniques. mRNA-LNP represent a scalable strategy to transfect and modify MKs with a variety of nucleic acid payloads. This thesis showed that the clinically approved mRNA-LNP can transfect cord-blood derived MKs without affecting MK maturation. Expression of the coagulation factor VII (FVII) also decreased clot time in FVII-deficient plasma when assessed through rotational thromboelastometry. This was the first study to demonstrate LNP transfection of in vitro cultured MKs. Optimizing LNP further can create highly potent systems that may enable improved transfection of both platelets and MKs. This thesis showed that formulating LNP in the presence of high concentration pH 4 buffer can induce “bleb” structures and improve the transfection potency both in vitro and in vivo. Induction of bleb structure and improved potency is dependent on the type of pH 4 buffer employed, and the improved transfection potencies can be partially attributed to enhanced integrity of the encapsulated mRNA. These results suggest that enhanced transfection can be achieved by optimizing formulation parameters to improve mRNA stability through formation of bleb structures.Applied Science, Faculty ofBiochemistry and Molecular Biology, Department ofGraduat
Variations on the Author
Full text link“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
Full text linkWe 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
Full text linkWe 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
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