1,723,495 research outputs found
Bioactivation of GPR40 Agonist MK-8666: Formation of Protein Adducts in Vitro from Reactive Acyl Glucuronide and Acyl CoA Thioester
No full textMK-8666, a selective
GPR40 agonist developed for the treatment
of type 2 diabetes mellitus, was discontinued in phase I clinical
trials due to liver safety concerns. To address whether chemically
reactive metabolites played a causative role in the observed drug
induced liver injury (DILI), we characterized the metabolism, covalent
binding to proteins, and amino acid targets of MK-8666 in rat and
human hepatocytes or cofactor-fortified liver microsomes. MK-8666
was primarily metabolized to an acyl glucuronide in hepatocytes of
both species and a taurine conjugate in rat hepatocytes. Similar levels
of covalent binding to proteins were observed in rat and human hepatocytes
following incubation with [3H]MK-8666. After protease digestion
of hepatocyte pellets, amino acid adducts A1, A2, and A3 were identified
as transacylated products with lysine, serine, and cysteine residues,
respectively. Amino acid adducts A4a–c were identified as glycation
adducts resulting from rearrangement of MK-8666–1-O-β-acyl
glucuronide to ring-opened aldehydes which further condensed with
lysine residues of proteins into imine adducts. Adducts A1–A3
and A4a–c were detected in rat and human liver microsomes fortified
with UDPGA. Adducts A1–A3 were detected in rat and human liver
microsomes fortified with CoA and ATP. Additionally, a trace amount
of CoA thioester metabolite of MK-8666 and its transacylated GSH adduct
were detected in human liver microsomes fortified with CoA, ATP, and
GSH. Higher levels of covalent binding to protein were observed when
[3H]MK-8666 was incubated in liver microsomes supplemented
with CoA and ATP compared to UDPGA. Addition of GSH attenuated levels
of CoA thioester-mediated covalent binding by 41–45%. Collectively,
these studies indicated that metabolism of the −COOH moiety
of MK-8666 can form a reactive acyl glucuronide and an acyl CoA thioester,
which covalently modifies proteins and may represent one causative
mechanism of the observed DILI
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
Unlocking and securing ecological infrastructure investments : the needs and willingness to invest and institutional support mechanisms used
Full text linkCITATION: Mbopha, M.S. et al. 2021. Unlocking and securing ecological infrastructure investments: The needs and willingness to
invest and institutional support mechanisms used. South African Journal of Science, 117(9/10)#8666:1-9. https://doi.org/10.17159/sajs.2021/8666.The original publication is available at https://www.sajs.co.za/Ecological infrastructure (EI) is a natural and near-natural functioning ecosystem that delivers a range
of essential services to humankind. Examples include mountain catchments, wetlands, coastal dunes,
and riparian corridors. In a world where EI is underinvested, rapid degradation and threats such as
unsustainable veld-fire regimes, droughts, climate change, and invasive alien plants persist in dominating
the ecological landscape. In South Africa, there are government programmes that encourage the
restoration, rehabilitation and protection of EI. However, inadequate funding allocations constrain scalingup
and thus necessitate the unlocking of public and private sector investments to augment resources
for ecosystem-based management interventions. A systematic literature review was conducted at a
global scale to (1) understand the drivers behind EI investments, (2) understand the willingness and
desire of private landowners and land users to participate and contribute to EI investments and (3)
identify institutional support mechanisms used to encourage investments. Results suggest that the need
to invest is driven by growing degradation of EI and the urgency to meet environmental sustainability
goals. The willingness to invest is stimulated by the use of economic-based policies and compensatory
mechanisms. Public–private partnerships, public policy, and market-based conservation instruments
are institutional arrangements executed to protect EI. These include processes and systems used by the
institutions to legislate and manage interventions towards fulfilling the conservation objective. Our review
contributes to the EI investment research agenda by recommending coordinated efforts to encourage EI
investment from both public and private partners. These measures will help to secure financial resources
and mobilise investments beyond monetary terms by coordinating planning and developing capacity and
reform policies.https://sajs.co.za/article/view/8666Publishers versio
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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