1,720,990 research outputs found
Analogues and molecular tools of natural compounds targeting the OSBP protein : synthesis and biological validation
No full textLes ORPphilines sont un ensemble de molécules naturelles possédant une activité antitumorale ciblée, agissant via un mécanisme d'action original et inédit en inhibant l'OSBP (OxySterol Binding Protein), une protéine impliquée dans le transport intracellulaire du cholestérol. Bien que l'OSBP soit ciblée par les ORPphilines, son rôle direct dans le traitement du cancer n'a jamais été confirmé. Par ailleurs, cette protéine joue un rôle dans la réplication de nombreux types de virus et constitue une cible prometteuse pour le développement de nouveaux agents antiviraux, bien qu'à l'heure actuelle, les inhibiteurs connus d'OSBP soient trop fortement cytotoxiques pour une application dans ce domaine.Dans ce contexte, une nouvelle ORPphiline, la macarangine B, a récemment été isolée dans l'équipe. Cette molécule, cent fois moins cytotoxique que les ORPphilines, conserve cependant de fortes propriétés antivirales, notamment contre les virus du zika et de la dengue. Ce composé a également permis de mettre en lumière une décorrélation entre l'inhibition d'OSBP et la mort cellulaire, suggérant l'implication d'autres partenaires protéiques dans la cytotoxicité induite par les ORPphilines. Bien que prometteuse, la macarangine B est cependant faiblement disponible dans la nature, ce qui a motivé notre équipe à développer sa synthèse totale à partir d'une flavone naturelle commerciale. Ainsi, des études complémentaires ont pu être réalisées, mettant en évidence la faible stabilité métabolique de ce composé, ce qui a freiné les perspectives d'utilisation en tant qu'agent antiviral. Le premier objectif de ma thèse a donc été de synthétiser une bibliothèque d'analogues afin d'établir les relations structure-activité et d'obtenir un lead actif et stable métaboliquement. En parallèle, notre équipe s'est intéressée ces dernières années au développement de molécules anticancéreuses dérivées des schweinfurthines (SWs), une famille de molécule représentante des ORPphilines. Pour aller plus loin dans l'élaboration de molécules bioactives, nous avons conçu des molécules bifonctionnelles de type PROTACs dérivées des SWs, une stratégie prometteuse en oncologie. Outre les applications thérapeutiques, la conception d'outils moléculaires dérivés des ORPphilines peut également être envisagée afin de décrypter leur mécanisme d'action. Le dernier projet de cette thèse a donc été de développer des sondes moléculaires pour permettre l'extraction et l'identification des protéines potentiellement responsables de la mort cellulaire. L'utilisation de ces composés, suivie d'une étude protéomique, a ainsi permis d'établir une première liste de partenaires protéiques potentiels. Avec ces différentes approches, nous espérons décrypter le mécanisme d'action des ORPphilines et ainsi développer des traitements plus efficaces et mieux ciblés pour aider à lutter contre le cancer et les infections virales.ORPphilins are a group of natural molecules with targeted anti-tumor activity, acting through an original and novel mechanism of action by inhibiting OSBP (OxySterol Binding Protein), a protein involved in intracellular cholesterol transport. Although OSBP is targeted by ORPphilins, its direct role in cancer treatment has never been confirmed. On the other hand, this protein plays a role in the replication of many types of virus and is a promising target for the development of new antiviral agents, although at present, known OSBP inhibitors are too strongly cytotoxic for application in this field.In this context, a new ORPphilin member, macarangin B, was recently isolated by the team. This molecule, a hundred times less cytotoxic than ORPphilins, nevertheless retains strong antiviral properties, notably against zika and dengue viruses. This compound also revealed a decorrelation between OSBP inhibition and cell death, suggesting the involvement of other protein partners in ORPphilin-induced cytotoxicity. Although promising, macarangin B is not widely available in nature, which motivated our team to develop its total synthesis from a natural commercial flavone. Complementary studies were then carried out, highlighting the compound's low metabolic stability, which hampered prospects for its use as an antiviral agent. The first objective of my thesis was therefore to synthesize a library of analogues in order to establish structure-activity relationships and obtain an active, metabolically stable lead.In parallel, in recent years our team has focused on the development of anti-cancer molecules derived from schweinfurthins (SWs), a family of molecules representing the ORPphilins. To take the development of bioactive compounds a step further, we have designed bifunctional PROTACs derived from SWs, a promising strategy in oncology. In addition to therapeutic applications, the design of molecular tools derived from ORPphilins can also be envisaged in order to decipher their mechanism of action. The third project of this thesis was therefore to develop molecular probes to enable the extraction and identification of proteins potentially responsible for cell death. The use of these compounds, followed by a proteomic study, has enabled us to draw up an initial list of potential protein partners. With these different approaches, we hope to decipher the mechanism of action of ORPphilins and thus develop more effective, better-targeted treatments to help fight cancer and viral infections
Design of antiviral cyclopeptides inspired by a natural product
No full textSelon l'OMS, les arbovirus tels que le virus Zika, la dengue ou le chikungunya représentent un enjeu majeur de santé publique, provoquant régulièrement des épidémies marquées par des symptômes parfois sévères. En collaboration avec le laboratoire PIMIT, nous avons réalisé un criblage de l'extractothèque de plantes de l'ICSN, aboutissant à la découverte d'une nouvelle famille de cyclo-peptides possédant de puissantes propriétés antivirales. Pour identifier un candidat biodisponible par voie orale en vue d'essais in vivo, j'ai d'abord mis au point une méthode de synthèse efficace pour accéder à ce type de composés. La préparation de certains acides aminés non canoniques a d'abord été développée avant de réaliser la synthèse totale de deux molécules naturelles par SPPS. En s'appuyant sur cette stratégie de synthèse, nous avons ensuite élaboré une bibliothèque de 36 analogues en modifiant quatre positions du cyclopeptide naturel chef de file. Les résultats des tests d'activité antivirale nous ont permis de mettre en évidence de solides données de relations structure-activité (RSA), complétées par des études pharmacocinétiques. Ces résultats nous ont orientés vers la sélection d'acides aminés clés pour la conception de nouveaux cyclopeptides antiviraux biodisponibles par voie orale, inspirés de la structure d'un produit naturel.According to the WHO, arboviruses such as Zika virus, dengue, and chikungunya represent a major public health challenge, frequently causing outbreaks with sometimes severe symptoms. In collaboration with the PIMIT laboratory, we performed a screening of the ICSN plant extract library, leading to the discovery of a new family of cyclopeptides with potent antiviral properties. To identify an orally bioavailable candidate for in vivo trials, I first developed an efficient synthetic route to access these types of compounds. The preparation of two non-canonical amino acids was initially developed before completing the total synthesis of two natural molecules via SPPS. Building on this synthetic strategy, we then created a library of 36 analogs by modifying four positions on the lead natural cyclopeptide. The antiviral activity results highlighted strong structure-activity relationship (SAR) data, complemented by pharmacokinetic studies. These findings guided us in selecting key amino acids for designing new orally bioavailable antiviral cyclopeptides derived from nature
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
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
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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