1,720,956 research outputs found
Characterisation of a type II functionally-deficient variant of alpha-1-antitrypsin discovered in the general population
Get PDFLung disease in alpha-1-antitrypsin deficiency (AATD) results from dysregulated proteolytic
activity, mainly by neutrophil elastase (HNE), in the lung parenchyma. This is the result of a
substantial reduction of circulating alpha-1-antitrypsin (AAT) and the presence in the plasma
of inactive polymers of AAT. Moreover, some AAT mutants have reduced intrinsic activity
toward HNE, as demonstrated for the common Z mutant, as well as for other rarer variants.
Here we report the identification and characterisation of the novel AAT reactive centre loop
variant Gly349Arg (p.G373R) present in the ExAC database. This AAT variant is secreted at
normal levels in cellular models of AATD but shows a severe reduction in anti-HNE activity.
Biochemical and molecular dynamics studies suggest it exhibits unfavourable RCL presentation
to cognate proteases and compromised insertion of the RCL into β-sheet A. Identification
of a fully dysfunctional AAT mutant that does not show a secretory defect underlines the importance
of accurate genotyping of patients with pulmonary AATD manifestations regardless of
the presence of normal levels of AAT in the circulation. This subtype of disease is reminiscent
of dysfunctional phenotypes in anti-thrombin and C1-inibitor deficiencies so, accordingly, we
classify this variant as the first pure functionally-deficient (type II) AATD mutant
Susceptibility of alpha-1 antitrypsin deficiency variants to polymer-blocking therapy
No full textThe Z variant (Glu342Lys) causes alpha-1 antitrypsin (AAT) to self-assemble into polymer chains that accumulate within hepatocytes, causing liver disease and exposing a cryptic epitope recognized by the 2C1 monoclonal antibody (mAb). They can be blocked by the small molecule GSK716 (‘716) that stabilizes an intermediate on the polymerization pathway. We have characterized 23 mutants of AAT in a cellular model to establish: (a) their ability to form intracellular polymers, (b) whether polymer formation could be prevented by ‘716, and (c) whether the polymers expose the 2C1 cryptic epitope. Most of the variants, including Mprocida (Leu41Pro), Mherleen (Pro369Leu), Mduarte (Asp256Val), Lfrankfurt (Pro255Thr), Yorzinuovi (Pro391His), Mwurzburg (Pro369Ser), and p.289S accumulated as intracellular polymers. Eleven formed polymers that were resistant to ‘716, including Mprocida, Mmalton (ΔPhe51), Lfrankfurt, Mduarte, S (Glu264Val), Mherleen, and Yorzinuovi. The ‘716 resistant mutants localize to a region of the AAT molecule separate from the binding site of the small molecule and form polymers that are less well recognized by the 2C1 mAb. They are fully recognized by a novel 8A7 mAb that we developed to have a broader specificity. Our data suggest that individuals with these mutations are unlikely to benefit from treatment with ‘716 or its derivatives
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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