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Metabolic Modeling of Inborn Errors of Metabolism: Carnitine Palmitoyltransferase II Deficiency and Respiratory Chain Complex I Deficiency
No full textThe research goal was to assess the current capabilities of a metabolic modeling environment to support exploration of inborn errors of metabolism (IEMs); and to assess whether, drawing on evidence from published studies of EMs, the current capabilities of this modeling environment correlate with clinical measures of energy production, fatty acid oxidation, accumulation of toxic by-products of defective metabolism, and mitigation via therapeutic agents.
IEMs comprise several hundred disorders of energy production, often with significant impact on morbidity and mortality. Despite advances in genomic medicine, currently the majority of therapeutic options for IEMs are supportive only, and most only weakly evidenced. Metabolic modeling could potentially offer an in silico alternative for exploring therapeutic possibilities.
This research established models of two inborn errors of metabolism (IEMs), carnitine palmitoyltransferase (CPT) II deficiency and respiratory chain complex I deficiency, allowing exploration of combinations of IEMs at different degrees of enzyme deficiency. It utilized a modified version of the human metabolic network reconstruction, Recon 2, which includes known metabolic reactions and metabolites in human cells, and which allows constraint-based modeling within a computational and mathematical representation of human metabolism. It utilized the Matlab-based COBRA (Constraint-based Reconstruction and Analysis) Toolbox 2.0, and a customized suite of functions, to model ATP production, long-chain fatty acid oxidation (LCFA), and acylcarnitine accumulation in response to varying defect levels, inputs and a simulated candidate therapy.
Following significant curation of the metabolic network reconstruction and customization of COBRA/Matlab functions, this study demonstrated that ATP production and LCFA oxidation were within expected ranges, and correlated with clinical data for enzyme deficiencies, while acylcarnitine accumulation inversely correlated with the degree of enzyme deficiency; and that it was possible to simulate upregulation of enzyme activity with a therapeutic agent.
Results of the curation effort contributed to development of an updated version of the metabolic reconstruction Recon 2. Customization of modeling approaches resulted in a suite of re-usable Matlab functions and scripts usable with COBRA Toolbox methods available for further exploration of IEMs.
While this research points to potentially greater suitability of kinetic modeling for some aspects of metabolic modeling of IEMs, it helps to demonstrate potential viability of constraint-based steady state modeling as a means to explore some clinically relevant measures of metabolic function for single and combined inborn errors of metabolism.Metabolic modeling; flux-balance analysis; constraint-based modeling; inborn errors of metabolism; IEM; carnitine palmitoyltransferase II deficiency; CPT II deficiency; respiratory chain complex I deficiency; metabolic network reconstruction; COBRA Toolbox 2; Recon 2; Recon 2.2; synergistic heterozygosit
Rapid cloning of random mutagenesis libraries using PTO-QuickStep
No full textPTO-QuickStep is a quick and easy molecular cloning technique that allows seamless point integration of a DNA fragment, encoding either a tag or a protein, into any position within a target plasmid. The entire process is conducted in a time-efficient and cost-effective manner, without the need of DNA gel purification and enzymatic restriction and ligation. PTO-QuickStep further innovates protein engineering by providing the possibility of integrating a random mutagenesis step (e.g., error-prone PCR) into the workflow, without compromising the time duration required. Random mutagenesis libraries can be quickly and efficiently cloned into a plasmid of interest, thereby accelerating directed evolution. On top of that, PTO-QuickStep can be utilized for rapid integration of noncoding DNA fragments to modify existing plasmids, making it an excellent tool for synthetic biologists
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
libAnnotationSBML: A library for exploiting SBML annotations
No full textThe Systems Biology Markup Language (SBML) is an established community XML format for the markup of biochemical models. With the introduction of SBML level 2 version 3, specific model entities, such as species or reactions, can now be annotated using ontological terms. These annotations, which are encoded using the resource description framework (RDF), provide the facility to specify definite terms to individual components, allowing software to unambiguously identify such components and thus link the models to existing data resources. libSBML is an application programming interface library for the manipulation of SBML files. While libSBML provides the facilities for reading and writing such annotations from and to models, it is beyond the scope of libSBML to provide interpretation of these terms. The libAnnotationSBML library introduced here acts as a layer on top of libSBML linking SBML annotations to the web services that describe these ontological terms. Two applications that use this library are described: SbmlSynonymExtractor finds name synonyms of SBML model entities and SbmlReactionBalancer checks SBML files to determine whether specifed reactions are elementally balanced. © 2009 The Author(s)
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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