1,721,013 research outputs found
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
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DECIPHERING AND TARGETING TRANSMEMBRANE ALLOSTERIC SITES OF GPCRS TACKLING CHALLENGES WITH PHYSICS-BASED METHODS AND ARTIFICIAL INTELLIGENCE
Full text linkG protein-coupled receptors, a class of membrane-embedded proteins, constitute therapeutic targets for ~ 35 % of FDA-approved drugs. Recent breakthroughs in the structural biology of GPCRs reveal novel transmembrane lipid-facing allosteric binding pockets distinct from the orthosteric site. Interestingly, the ligands bound to these sites are significantly exposed to the surrounding lipid bilayer. For a ligand to bind to these lipid-exposed sites, it must first partition before diffusing laterally to the binding site. However, there is a lack of clear mechanistic understanding of how these sites function, including how these allosteric ligands access these binding pockets and the relative enthalpic and entropic contributions of the membrane lipids in access, binding, and stability at the transmembrane sites. Because these lipid-exposed sites are novel, there haven't been any large-scale studies characterizing them in different membrane-embedded proteins and how they compare to conventional pockets exposed to the aqueous bulk.Additionally, there is no information on how traditional metrics for estimating important drug discovery parameters, such as druggability for soluble proteins' binding pockets, translate to these unique membrane-embedded sites. Furthermore, predicting the permeability of transmembrane ligands, an essential part of in silico drug discovery workflows for developing compounds that bind to these lipid-exposed sites, is computationally expensive and time-consuming. All these hinder the rational, high throughput design of allosteric ligands, making the development process tedious and costly.The background, significance, knowledge gaps, hypothesis, and specific aims of the dissertation work are outlined in Chapter 1. Chapter 2 elucidates the binding process of the CB1R negative allosteric modulator (NAM), ORG27569, to its transmembrane allosteric site, including the role of membrane lipids in this process. Additionally, a retrospective analysis of the effect of ligand-lipid interactions was carried out using a series of the NAM's analogs. This was the first study to characterize the entire binding process of an allosteric ligand to a site embedded deep in the bilayer. We found that the membrane lipids contribute significantly to the binding and eventual stability of allosteric ligands and can also help improve druggability predictions at these lipid-exposed sites. Also, specific ligand-lipid interactions can affect measurable parameters such as binding affinity and cooperativity. Chapter 3 focuses on the differences between transmembrane sites and soluble proteins' binding pockets, the interplay between these properties, and druggability predictions. This is the first large-scale analysis of transmembrane binding sites and how they compare to soluble protein sites. We observed that these pockets have distinct properties, and the current metrics do not work well in predicting druggability for transmembrane sites. Chapter 4 implements a generative AI model, denoising diffusion probabilistic model (DDPM), to reduce the computational time for predicting the membrane permeability of drugs by one-third. By combining just one-third of the original umbrella sampling simulations and the DDPM, we could reproduce the solvation-free energy profile, orientation angle, and other important features identical to those obtained from traditional methods.This dissertation provides unique insights into the access and binding of transmembrane ligands to lipid-exposed pockets and the participation of membrane lipids in facilitating access and subsequent stability after binding, laying a framework for future rational design for transmembrane ligands. The differences elucidated between transmembrane and soluble protein binding sites and the subsequent effect on predicting druggability have huge implications for designing future drug discovery workflows. This work also showcases the potential of generative AI to accelerate drug discovery and development by reducing the required computational time for predicting the membrane permeability of drugs and biologically relevant chemical species
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OCULAR AND SYSTEMIC METABOLOMIC/GENOMIC DYSREGULATION IN THE VIGABATRIN INDUCED HYPERGABAERGIC STATE
Full text linkThe antiepileptic agent vigabatrin (VGB; SabrilR) is effective in treating infantile spasms and focal-onset seizures. VGB directly targets the metabolic pathway of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), via irreversible inhibition of GABA-transaminase (GABA-T) and ensuant increase of CNS GABA. VGB is administered as a racemic mixture of the R-(-) and S-(+) isomers; only the S-(+) enantiomer is active. Unfortunately, VGB carries a significant risk of use-limiting ocular toxicity, manifesting as permanent peripheral visual field constriction (pVFC) in a subpopulation of patients. Here we demonstrate that adult VGB-treated mice accumulate the active isomer preferentially in the retina and visual cortex. This accumulation is accompanied by altered amino acid profiles, including retinal GABA and 2-aminoadipic acid (AADA), the latter a glial toxin. Brain amino acid alterations during VGB administration included elevated GABA, β-alanine, carnosine, ornithine, and AADA (the latter in the visual cortex). VGB-induced metabolic abnormalities were compared to those found in the autopsied brain of a patient with succinic semialdehyde dehydrogenase deficiency (SSADHD), which is the enzyme directly following GABA-T and responsible for the final conversion of the GABA carbon skeleton to succinate. Retinal transcriptome analysis in VGB-treated animals revealed dysregulation of signaling, including the pathway of phototransduction. This work provides a tissue-specific platform from which to further evaluate VGB’s mechanism of action for adverse retinal toxicity, and the potential for drug development to mitigate this side effect
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POTENTIAL INTERACTIONS OF CANNABINOIDS AND THEIR METABOLITES ON MAJOR DRUG METABOLIZING ENZYMES IMPLICATION ON CO-USE OF TOBACCO AND CANNABIS
Full text linkCannabis-based products have seen increased usage in many parts of the world and in the US, including increases in co-usage with tobacco products. This has led to a need for a more comprehensive understanding of cannabis constituents and their potential for cannabis-drug interactions (CDI) as well as cannabis-tobacco interactions (CTI). While (−)-trans-Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are major cannabinoids present in cannabis, the THC metabolites 11-hydroxy-∆9-tetra-hydrocannabinol (11-OH-THC), 11-COO-Δ9-THC (THC-COOH), and 11-COO-Δ9-THC-glucuronide (THC-COO-Gluc) are found in plasma at higher concentrations than cannabinoids in cannabis users. To better understand the potential for CDI and CTI, the inhibitory potential of cannabinoids and metabolites on Phase I [(cytochrome P450 (CYP)] and Phase II [UDP-glucuronosyltransferase (UGT)] enzymes and on the nicotine metabolism pathway were investigated. In vitro assays demonstrated that the major THC metabolites 11-OH-THC and THC-COO-Gluc competitively inhibited CYP2B6, CYP2C9, and CYP2D6. Basic static modeling populated with these data were indicative of the possibility of pharmacokinetic interactions in vivo. Major UGTs were also inhibited by cannabinoids, though no inhibition was observed by THC metabolites. The highest inhibition was observed for CBD against UGTs 1A9, 2B4,1A6, and 2B7.. Potent inhibition of UGT1A9 and UGT2B7 was also demonstrated by THC and CBN. Significant inhibition of nicotine metabolism pathways by CBD and 7-OH-CBD was also observed. CBD and 7-OH-CBD inhibited nicotine metabolism to cotinine and nornicotine in CYP2A6 and CYP2B6-overexpressing microsomes, cotinine metabolism to trans-3’-hydroxycotinine (3HC) in CYP2A6 overexpressing microsomes, and 3HC to 3HC-glucuronide in UGT1A9-overexpressing microsomes. The findings presented in this dissertation suggest that circulating cannabinoids and their metabolites may be inhibiting major CYP and UGT enzymes in users of cannabis products, potentially resulting in CDIs. In addition, cannabinoids like CBD and 7-OH-CBD inhibit nicotine metabolism, potentially decreasing the desire to smoke more cigarettes in smokers who are co-users of cannabis products due to higher endogenous nicotine levels, suggesting that cannabinoids could be important as smoking cessation agents. These findings will help clinicians and researchers identify prescription medications that may have adverse effects when combined with cannabis products
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
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