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      Evaluation and Interpretation of Transcriptome Data Underlying Heterogeneous Chronic Obstructive Pulmonary Disease

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          Abstract

          Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease, featured by airflow obstruction. Recently, a comprehensive analysis of the transcriptome in lung tissue of COPD patients was performed, but the heterogeneity of the sample was not seriously considered in characterizing the mechanistic dysregulation of COPD. Here, we established a new transcriptome analysis pipeline using a deconvolution process to reduce the heterogeneity and clearly identified that these transcriptome data originated from the mild or moderate stage of COPD patients. Differentially expressed or co-expressed genes in the protein interaction subnetworks were linked with mitochondrial dysfunction and the immune response, as expected. Computational protein localization prediction revealed that 19 proteins showing changes in subcellular localization were mostly related to mitochondria, suggesting that mislocalization of mitochondria-targeting proteins plays an important role in COPD pathology. Our extensive evaluation of COPD transcriptome data could provide guidelines for analyzing heterogeneous gene expression profiles and classifying potential candidate genes that are responsible for the pathogenesis of COPD.

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          Most cited references22

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          Chronic obstructive pulmonary disease

          Summary Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow obstruction that is only partly reversible, inflammation in the airways, and systemic effects or comorbities. The main cause is smoking tobacco, but other factors have been identified. Several pathobiological processes interact on a complex background of genetic determinants, lung growth, and environmental stimuli. The disease is further aggravated by exacerbations, particularly in patients with severe disease, up to 78% of which are due to bacterial infections, viral infections, or both. Comorbidities include ischaemic heart disease, diabetes, and lung cancer. Bronchodilators constitute the mainstay of treatment: β2 agonists and long-acting anticholinergic agents are frequently used (the former often with inhaled corticosteroids). Besides improving symptoms, these treatments are also thought to lead to some degree of disease modification. Future research should be directed towards the development of agents that notably affect the course of disease.
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            Oxidative stress–induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease

            Background Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress–induced pathology. Objective We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. Methods Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. Results Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β–induced ASM cell proliferation and CXCL8 release. Conclusions Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD.
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              A data integration methodology for systems biology.

              Different experimental technologies measure different aspects of a system and to differing depth and breadth. High-throughput assays have inherently high false-positive and false-negative rates. Moreover, each technology includes systematic biases of a different nature. These differences make network reconstruction from multiple data sets difficult and error-prone. Additionally, because of the rapid rate of progress in biotechnology, there is usually no curated exemplar data set from which one might estimate data integration parameters. To address these concerns, we have developed data integration methods that can handle multiple data sets differing in statistical power, type, size, and network coverage without requiring a curated training data set. Our methodology is general in purpose and may be applied to integrate data from any existing and future technologies. Here we outline our methods and then demonstrate their performance by applying them to simulated data sets. The results show that these methods select true-positive data elements much more accurately than classical approaches. In an accompanying companion paper, we demonstrate the applicability of our approach to biological data. We have integrated our methodology into a free open source software package named POINTILLIST.
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                Author and article information

                Journal
                Genomics Inform
                Genomics Inform
                GNI
                Genomics & Informatics
                Korea Genome Organization
                1598-866X
                2234-0742
                March 2019
                31 March 2019
                : 17
                : 1
                : e2
                Affiliations
                [1 ]Department of Life Sciences, POSTECH, Pohang 37674, Korea
                [2 ]Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
                [3 ]Division of Integrative Biosciences and Biotechnology, POSTECH, Pohang 37674, Korea
                Author notes
                [* ]Corresponding author: E-mail: tyroh@ 123456postech.edu
                Author information
                http://orcid.org/0000-0002-6950-2848
                http://orcid.org/0000-0003-0116-4683
                http://orcid.org/0000-0001-5833-0844
                Article
                gi-2019-17-1-e2
                10.5808/GI.2019.17.1.e2
                6459164
                30929403
                29dc65cd-39f4-4110-8a46-18822e6468c4
                (c) 2019, Korea Genome Organization

                (CC) This is an open-access article distributed under the terms of the Creative Commons Attribution license( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 3 December 2018
                : 28 December 2018
                : 28 December 2018
                Categories
                Original Article

                Genetics
                chronic obstructive pulmonary disease,deconvolution,gene co-expression,gene heterogeneity,protein sublocalization

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