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      Gene alterations in monocytes are pathogenic factors for immunoglobulin a nephropathy by bioinformatics analysis of microarray data

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          Abstract

          Background

          Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulopathy worldwide. The study aimed to provide potential molecular biomarkers for IgAN management.

          Methods

          The public gene expression profiling GSE58539 was utilized, which contained 17 monocytes samples (8 monocytes samples isolated from IgAN patients and 9 monocytes samples isolated from healthy blood donors). Firstly, differentially expressed genes (DEGs) between the two kinds of samples were identified by limma package. Afterwards, pathway enrichment analysis was implemented. Thereafter, protein-protein interaction (PPI) network was constructed and key nodes in PPI network were predicted using four network centrality analyses. Ultimately, gene functional interaction (FI) was constructed according to expressions in each sample, and then module network was extracted from FI network.

          Results

          A total of 678 DEGs were screened out, of these, 72 DEGs were identified as crucial nodes in PPI network that could well distinguish IgAN and healthy samples. In particular, IL6, TNF, IL1B, PRKACA and CCL20 were closely related to pathways such as hematopoietic cell lineage, apoptosis and Toll-like receptor (TLR) signaling pathway. Moreover, 12 genes in the FI network belonged to the 72 identified key nodes, such as CCL20, HDAC10, FPR2 and PRKACA, which were also key genes in 4 module networks.

          Conclusions

          Several crucial genes were identified in monocytes of IgAN patients, such as IL6, TNF, IL1B, CCL20, PRKACA, FPR2 and HDAC10. These genes might co-involve in pathways such as TLR and apoptosis signaling during IgAN progression.

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          Most cited references32

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          Evaluation of time profile reconstruction from complex two-color microarray designs

          Background As an alternative to the frequently used "reference design" for two-channel microarrays, other designs have been proposed. These designs have been shown to be more profitable from a theoretical point of view (more replicates of the conditions of interest for the same number of arrays). However, the interpretation of the measurements is less straightforward and a reconstruction method is needed to convert the observed ratios into the genuine profile of interest (e.g. a time profile). The potential advantages of using these alternative designs thus largely depend on the success of the profile reconstruction. Therefore, we compared to what extent different linear models agree with each other in reconstructing expression ratios and corresponding time profiles from a complex design. Results On average the correlation between the estimated ratios was high, and all methods agreed with each other in predicting the same profile, especially for genes of which the expression profile showed a large variance across the different time points. Assessing the similarity in profile shape, it appears that, the more similar the underlying principles of the methods (model and input data), the more similar their results. Methods with a dye effect seemed more robust against array failure. The influence of a different normalization was not drastic and independent of the method used. Conclusion Including a dye effect such as in the methods lmbr_dye, anovaFix and anovaMix compensates for residual dye related inconsistencies in the data and renders the results more robust against array failure. Including random effects requires more parameters to be estimated and is only advised when a design is used with a sufficient number of replicates. Because of this, we believe lmbr_dye, anovaFix and anovaMix are most appropriate for practical use.
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            Network analysis of protein structures identifies functional residues.

            Identifying active site residues strictly from protein three-dimensional structure is a difficult task, especially for proteins that have few or no homologues. We transformed protein structures into residue interaction graphs (RIGs), where amino acid residues are graph nodes and their interactions with each other are the graph edges. We found that active site, ligand-binding and evolutionary conserved residues, typically have high closeness values. Residues with high closeness values interact directly or by a few intermediates with all other residues of the protein. Combining closeness and surface accessibility identified active site residues in 70% of 178 representative structures. Detailed structural analysis of specific enzymes also located other types of functional residues. These include the substrate binding sites of acetylcholinesterases and subtilisin, and the regions whose structural changes activate MAP kinase and glycogen phosphorylase. Our approach uses single protein structures, and does not rely on sequence conservation, comparison to other similar structures or any prior knowledge. Residue closeness is distinct from various sequence and structure measures and can thus complement them in identifying key protein residues. Closeness integrates the effect of the entire protein on single residues. Such natural structural design may be evolutionary maintained to preserve interaction redundancy and contribute to optimal setting of functional sites.
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              Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.

              Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol-producing adrenal adenomas is not well understood.
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                Author and article information

                Contributors
                +86-010-84013142 , zhongjieliuLZJ@163.com
                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central (London )
                1471-2369
                20 July 2018
                20 July 2018
                2018
                : 19
                : 184
                Affiliations
                [1 ]ISNI 0000 0001 1431 9176, GRID grid.24695.3c, Department of Nephropathy, , Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, ; Beijng, 100078 China
                [2 ]GRID grid.412073.3, Department of Urology, , Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, ; Beijng, 100700 China
                [3 ]GRID grid.412073.3, Department of Nephropathy and Endocrinology, , Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, ; No. 5 Haiyuncang, Dongcheng District, Beijng City, 100700 China
                Article
                944
                10.1186/s12882-018-0944-z
                6053766
                30029622
                d2393a2b-1db5-4740-bd60-5fa28e743b82
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 8 December 2017
                : 7 June 2018
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Nephrology
                immunoglobulin a nephropathy,network centrality analysis,functional interaction,toll-like receptor signaling,apoptosis

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