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Proteomics-Based Approaches to Identify and Characterize Molecular Glues
No full textDespite advances in proteomics techniques, the rational discovery of non-degrader molecular glues and their targets remains challenging. In Chapter 1, I describe the BioTAC system, an unbiased ligand-guided proximity labeling method, and showcase its ability to robustly identify small molecule targets and interactomes, including complex partners of non-degrader molecular glues. In Chapter 2, I present a detailed method development guide to implementing the BioTAC system for compounds and proteins of interest. In Chapter 3, I develop a chemoproteomics-based pipeline to identify new covalent ligand-protein binding sites for structure-interactome relationship studies, and characterize a reactive cysteine-containing hub protein as an amenable target for non-degrader molecular glue development
Synthesis of Alpha-Synuclein Proteolytic Targeting Chimeras and Selective Tau Tubulin Kinase I Inhibitors
Get PDFMisfolded alpha-synuclein has been identified as a potential target to developing disease modifying or preventative therapies for Parkinson’s Disease. Proteolytic Targeting Chimeras (PROTACs) have been demonstrated as chemical tools and selective degraders for protein targets in neurodegenerative diseases. PROTACs have already been demonstrated as chemical tools and selective degraders for other neurodegenerative diseases such as targeting tau protein for Frontal Temporal Dementia. Taking previously known binders of alpha-synuclein and proteasomal ligand recruiters a library of PROTACs was synthesized in addition to small molecule degraders with a guanosine-derived autophagy tag, or Autophagy Targeting Chimera (AUTAC), as an alternative form of degradation. Successful development of a selective and potent degrader would allow a better understanding of alpha-synuclein and its role in Parkinson’s Disease. Hyperphosphorylation of Tau is a hallmark of many neurodegenerative diseases. Tau Tubulin Kinase 1 (TTBK1) is involved in tau phosphorylation and has been indicated to phosphorylate tau at pathologically relevant sites making it a promising drug target. Small molecule inhibitors exist that can inhibit TTBK1 with off target affects on TTBK2 which has important functions throughout the nervous system. Utilizing known crystal structures of TTBK1 and TTBK2, selective small molecules were synthesized taking advantage of a peripheral lysine residue which can covalently react with a flour sulfonyl moiety. Using this strategy, separation of TTBK1 and 2 would allow for detailed understanding of their separate and overlapping substrates and biological functions
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Developing a Generalizable Approach to Improve the Blood Brain Barrier Permeability of Proteolysis Targeting Chimeras through Prodrugs
No full textProteolysis targeting chimeras (PROTACs) are a promising class of molecular probes that can elicit degradation of classically undruggable targets. This capability comes with a large size (>1000Da), and thus reduced cell permeability: this extends to the blood brain barrier (BBB), effectively limiting the employment of PROTACs as in vivo probes for pharmacologically relevant targets that lie in the central nervous system. Strategies for small molecule inhibitors generally cannot be applied to PROTACs due to their large size, however one such approach that shows promise is the prodrug approach, in which a labile attachment known as a promoiety is attached to a pharmacologically active site of a drug with the purpose of improving physicochemical properties. To date, no studies exist which utilize the prodrug approach as a means of improving the BBB permeability of PROTACs. The work herein describes our efforts to develop a generalizable strategy to improve the BBB permeability of PROTACs through the prodrug approach, as to expand the degradable proteome into the CNS
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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