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      Age-related neurodegenerative disease associated pathways identified in retinal and vitreous proteome from human glaucoma eyes

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          Glaucoma is a chronic disease that shares many similarities with other neurodegenerative disorders of the central nervous system. This study was designed to evaluate the association between glaucoma and other neurodegenerative disorders by investigating glaucoma-associated protein changes in the retina and vitreous humour. The multiplexed Tandem Mass Tag based proteomics (TMT-MS3) was carried out on retinal tissue and vitreous humour fluid collected from glaucoma patients and age-matched controls followed by functional pathway and protein network interaction analysis. About 5000 proteins were quantified from retinal tissue and vitreous fluid of glaucoma and control eyes. Of the differentially regulated proteins, 122 were found linked with pathophysiology of Alzheimer’s disease (AD). Pathway analyses of differentially regulated proteins indicate defects in mitochondrial oxidative phosphorylation machinery. The classical complement pathway associated proteins were activated in the glaucoma samples suggesting an innate inflammatory response. The majority of common differentially regulated proteins in both tissues were members of functional protein networks associated brain changes in AD and other chronic degenerative conditions. Identification of previously reported and novel pathways in glaucoma that overlap with other CNS neurodegenerative disorders promises to provide renewed understanding of the aetiology and pathogenesis of age related neurodegenerative diseases.

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          Mitochondria and apoptosis.

          A variety of key events in apoptosis focus on mitochondria, including the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered cellular oxidation-reduction, and participation of pro- and antiapoptotic Bcl-2 family proteins. The different signals that converge on mitochondria to trigger or inhibit these events and their downstream effects delineate several major pathways in physiological cell death.
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            MultiNotch MS3 Enables Accurate, Sensitive, and Multiplexed Detection of Differential Expression across Cancer Cell Line Proteomes

            Multiplexed quantitation via isobaric chemical tags (e.g., tandem mass tags (TMT) and isobaric tags for relative and absolute quantitation (iTRAQ)) has the potential to revolutionize quantitative proteomics. However, until recently the utility of these tags was questionable due to reporter ion ratio distortion resulting from fragmentation of coisolated interfering species. These interfering signals can be negated through additional gas-phase manipulations (e.g., MS/MS/MS (MS3) and proton-transfer reactions (PTR)). These methods, however, have a significant sensitivity penalty. Using isolation waveforms with multiple frequency notches (i.e., synchronous precursor selection, SPS), we coisolated and cofragmented multiple MS2 fragment ions, thereby increasing the number of reporter ions in the MS3 spectrum 10-fold over the standard MS3 method (i.e., MultiNotch MS3). By increasing the reporter ion signals, this method improves the dynamic range of reporter ion quantitation, reduces reporter ion signal variance, and ultimately produces more high-quality quantitative measurements. To demonstrate utility, we analyzed biological triplicates of eight colon cancer cell lines using the MultiNotch MS3 method. Across all the replicates we quantified 8 378 proteins in union and 6 168 proteins in common. Taking into account that each of these quantified proteins contains eight distinct cell-line measurements, this data set encompasses 174 704 quantitative ratios each measured in triplicate across the biological replicates. Herein, we demonstrate that the MultiNotch MS3 method uniquely combines multiplexing capacity with quantitative sensitivity and accuracy, drastically increasing the informational value obtainable from proteomic experiments.
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              Bidirectional relation between inflammation and coagulation.

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                Author and article information

                Contributors
                mehdi.mirzaei@mq.edu.au
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                4 October 2017
                4 October 2017
                2017
                : 7
                Affiliations
                [1 ]ISNI 0000 0001 2158 5405, GRID grid.1004.5, Department of Chemistry and Biomolecular Sciences, Macquarie University, ; Sydney, NSW Australia
                [2 ]ISNI 0000 0004 0389 4302, GRID grid.1038.a, School of Medical Sciences, Edith Cowan University, ; Joondalup, WA Australia
                [3 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Cell Biology, Harvard Medical School, ; Boston, Massachusetts USA
                [4 ]ISNI 0000 0001 2097 5006, GRID grid.16750.35, Department of Molecular Biology, Princeton University, ; Princeton, New Jersey USA
                [5 ]ISNI 0000 0001 2158 5405, GRID grid.1004.5, Faculty of Medicine and Health Sciences, Macquarie University, ; Sydney, NSW Australia
                [6 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, ; Sydney, Australia
                [7 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Save Sight Institute, Sydney University, ; Sydney, NSW Australia
                [8 ]GRID grid.417689.5, Department of Molecular Systems Biology, Cell Science Research Center, Royan, Institute for Stem Cell Biology and Technology, ACECR, ; Tehran, Iran
                [9 ]ISNI 0000 0001 2158 5405, GRID grid.1004.5, Australian Proteome Analysis Facility, Macquarie University, ; Sydney, NSW Australia
                Article
                12858
                10.1038/s41598-017-12858-7
                5627288
                28978942
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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