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1.  Amyotrophic Lateral Sclerosis Multiprotein Biomarkers in Peripheral Blood Mononuclear Cells 
PLoS ONE  2011;6(10):e25545.
Background
Amyotrophic lateral sclerosis (ALS) is a fatal progressive motor neuron disease, for which there are still no diagnostic/prognostic test and therapy. Specific molecular biomarkers are urgently needed to facilitate clinical studies and speed up the development of effective treatments.
Methodology/Principal Findings
We used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC), a panel of protein biomarkers that are closely associated with ALS. Validations and a longitudinal study were performed by immunoassays on a selected number of proteins. The same proteins were also measured in PBMC and spinal cord of a G93A SOD1 transgenic rat model. We identified combinations of protein biomarkers that can distinguish, with high discriminatory power, ALS patients from healthy controls (98%), and from patients with neurological disorders that may resemble ALS (91%), between two levels of disease severity (90%), and a number of translational biomarkers, that link responses between human and animal model. We demonstrated that TDP-43, cyclophilin A and ERp57 associate with disease progression in a longitudinal study. Moreover, the protein profile changes detected in peripheral blood mononuclear cells of ALS patients are suggestive of possible intracellular pathogenic mechanisms such as endoplasmic reticulum stress, nitrative stress, disturbances in redox regulation and RNA processing.
Conclusions/Significance
Our results indicate that PBMC multiprotein biomarkers could contribute to determine amyotrophic lateral sclerosis diagnosis, differential diagnosis, disease severity and progression, and may help to elucidate pathogenic mechanisms.
doi:10.1371/journal.pone.0025545
PMCID: PMC3187793  PMID: 21998667
2.  The Protein Interaction Network of the Epithelial Junctional Complex: A System-Level Analysis 
Molecular Biology of the Cell  2008;19(12):5409-5421.
To acquire system-level understanding of the intercellular junctional complex, protein–protein interactions occurring at the junctions of simple epithelial cells have been examined by network analysis. Although proper hubs (i.e., very rare proteins with exceedingly high connectivity) were absent from the junctional network, the most connected (albeit nonhub) proteins displayed a significant association with essential genes and contributed to the “small world” properties of the network (as shown by in vivo and in silico deletion, respectively). In addition, compared with a random network, the junctional network had greater tendency to form modules and subnets of densely interconnected proteins. Module analysis highlighted general organizing principles of the junctional complex. In particular, two major modules (corresponding to the tight junctions and to the adherens junctions/desmosomes) were linked preferentially to two other modules that acted as structural and signaling platforms.
doi:10.1091/mbc.E08-05-0477
PMCID: PMC2592657  PMID: 18923145
3.  Network analysis of cell adhesion 
Complex systems consisting of diverse interlinked elements are often represented as networks and are described according to the principles of network analysis. Among the networks of biological interest, several protein-protein interactomes have been reported in recent years, mostly in conjunction with high-throughput assays and extensive efforts of literature mining. The resulting global networks display well-defined topological properties and provide a comprehensive view of all the biological contexts in which a given interactome is involved. Global networks, however, do not provide enough information about the specific contexts, such as biological processes and subcellular compartments in which the individual interactions occur. Thus, to glean additional insights, it is often advantageous to extract context-defined local subnetworks from the global networks. Our recently published network analysis of the cell-cell adhesome, i.e., the protein-protein interaction subnetwork that underlies both the biological process of cell-cell adhesion and the subcellular compartment of the apical junctions in human epithelial cells, is an example of such context-defined approaches.
PMCID: PMC2649292  PMID: 19704858
systems biology; network analysis; protein-protein interactions; cell adhesion; cell-cell junctions; tight junctions; adherens junctions; desmosomes and focal adhesions

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