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    Development of therapeutic bioconjugates for neuroprotection in ischemic stroke.

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    This thesis is written based on the INRS Guide-2019, article-based version in order to fulfill the last requirement of the PhD program. It consists of an abstract (English and French versions), synopsis (required when a thesis or dissertation is written in English), general introduction, general discussion and conclusion, bibliography, and appendix which will be further discussed in below. Synopsis: Includes the main points discussed in the document and explains the working hypotheses, research objectives, methodology, and results in much more detail than the abstract does. Chapter 1: Consists of a review of literature about the ischemia, glutamate excitotoxicity, and enzymatic glutamate degradation approaches. This chapter concludes with a contextualization. Of note, some sections of this chapter are published as part of a manuscript accepted for publication in Biomaterials (Appendix C). Chapter 2: Presents concepts related to PEGylation, its benefits and its drawbacks. This chapter ends with a research proposal, the main hypothesis, and objectives. The figures used in Chapter 1 and 2 are either from the literature or made by me (with BioRender) in order to provide further explanation. Chapter 3: Published as Zaghmi, A.; Mendez-Villuendas, E.; Greschner, A. A.; Liu, J. Y.; de Haan, H. W.; Gauthier, M. A., Mechanisms of activity loss for a multi-PEGylated protein by experiment and simulation. Mater Today Chem 2019, 12, 121-131. I was responsible for data collection and analysis as well as the manuscript composition and revision. Andrea A Greschner contributed to manuscript edits and assisted with the PEGylation experiments. Jun Yang Liu was a summer student under my supervision who assisted with some measures of the enzyme activities. Eduardo Mendez-Villuendas performed the simulations with the help and supervision of Hendrick W de Haan. Marc A Gauthier was the supervisory author and was involved with concept formation, manuscript composition and revision. This Chapter starts with a brief contextualization and finishes with a preliminary study introducing the following paper. Chapter 4: Accepted as Zaghmi, A.; Dopico-López, A.; Pérez-Mato M.; Iglesias-Rey R.; Hervella P.; Greschner A. A.; Bugallo-Casal A.; Da Silva A.; Gutiérrez-Fernández M.; Castillo J.; Campos Pérez F.; Gauthier, M. A., Sustained blood glutamate scavenging enhances protection in ischemic stroke. Commun Biol 2020. I participated in the design and conception of the study, carried out most experiments (synthesis, characterisation, and purification of the bioconjugates; in vivo experiences including the functional tests). I also wrote and revised the manuscript. Antonio Dopico-López contributed with the production of the ischemic rat model. María Pérez-Mato contributed with the production of the ischemic rat model and commented on the manuscript at all stages. Ramón Iglesias-Rey and Pablo Hervella helped with technical assistance (mainly for MRI). Francisco Campos Pérez participated to the design and conception of the study, results discussion, and commented on the manuscript at all stages. Marc A. Gauthier was the supervisory author and was involved with concept formation and manuscript composition and revision. Chapter 5: General discussion, conclusion and perspectives. Summarizes the main elements of the articles and how they are related. This discussion also presents the contribution of this thesis to the field, as well as the limitations of this work. Both are framed with possible future directions that can be explored. Chapter 6: Appendix. Contains additional information to complement the body of the text and includes elements that are essential to the understanding of the thesis or to support its argumentation. It further presents scientific papers in which I am first author. - Appendix A: Supplementary information of Paper 1. - Appendix B: Supplementary information of Paper 2. - Appendix C: Review paper, accepted as Zaghmi, A.; Drouin-Ouellet J.; Brambilla, D.; and Gauthier, M. A., Treating Brain Diseases using Systemic Parenterally-administered Protein Therapeutics: Dysfunction of the Brain Barriers and Potential Strategies. Biomaterials 2020. - Appendix D: Data in Brief paper, published as Zaghmi, A.; Greschner, A. A.; Mendez Villuendas, E.; Liu, J. Y.; de Haan, H. W.; Gauthier, M. A., Determination of the degree of PEGylation of protein bioconjugates using data from proton nuclear magnetic resonance spectroscopy. Data Brief 2019, 25. - Appendix E: Book Chapter, published as Zaghmi, A.; Greschner, A. A.; Gauthier, M. A., In vivo properties of therapeutic bioconjugates composed of proteins and architecturally/functionally complex polymers. Polymer-Protein Conjugates: From PEGylation and Beyond 2020, 389-406. Chapter 7: Contains the bibliography used in this thesis. It should be noted that the references used for each scientific paper are included in this chapter (except for Appendix D and E)

    Going Beyond Counting First Authors in Author Co-citation Analysis

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    The 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

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    “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

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    We 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

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    We 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

    Author Index

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    koamabayili/VECTRON-author-checklist: VECTRON author checklist

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    We 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

    PLGA matrix - composition affects the therapeutic properties of nanocurcumin: Potential application in Alzheimer’s disease

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    Curcumin, a neuroprotective agent with promising therapeutic approach has poor brain bioavailability. Herein, we demonstrate that curcumin - encapsulated poly (lactide - co - glycolide) (PLGA) 50:50 nanoparticles (NPs - Cur 50:50) are able to prevent the phosphorylation of Akt and Tau proteins in SK - N - SH cells induced by H2O2 and display higher anti - inflammatory and antioxidant activities than free curcumin. PLGA can display various physicochemical and degradation characteristics for controlled drug release applications according to the matrix used. We demonstrate that the release of curcumin entrapped into a PLGA 50:50 matrix (NPs - Cur 50:50) is faster than into PLGA 65:35. We have studied the effects of the PLGA matrix on the expression of some key antioxidant - and neuroprotective - related genes such as apolipoprotein E (APOE), apolipoprotein J (APOJ), thioredoxin (TRX), glutaredoxin (GLRX), and the repressor element - 1 silencing transcription factor (REST). NPs - Cur induced the elevation of GLRX and TRX while decreasing APOJ mRNA levels and had no effect on APOE and REST expressions. In the presence of H2O2, both NPs - Cur matrices are more efficient than free curcumin to prevent the induction of these genes. Higher uptake was found with NPs - Cur 50:50 than NPs - Cur 65:35. By using PLGA nanoparticles loaded with the fluorescent Lumogen Red, we demonstrated that PLGA nanoparticles are indeed taken up by neuronal cells. These data highlight the importance of polymer composition in the therapeutic properties of the nanodrug delivery systems. Moreover, our study demonstrated that NPs - Cur enhance the action of curcumin on several pathways implicated in the pathophysiology of AD. Overall, these results suggest that PLGA nanoparticles are a promising strategy for the brain delivery of drugs for the treatment of AD.</p
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