Investigating the validity of current network analysis on static conglomerate networks by protein network stratification

<p>Abstract</p> <p>Background</p> <p>A molecular network perspective forms the foundation of systems biology. A common practice in analyzing protein-protein interaction (PPI) networks is to perform network analysis on a conglomerate network that is an assembly of all available binary interactions in a given organism from diverse data sources. Recent studies on network dynamics suggested that this approach might have ignored the dynamic nature of context-dependent molecular systems.</p> <p>Results</p> <p>In this study, we employed a network stratification strategy to investigate the validity of the current network analysis on conglomerate PPI networks. Using the genome-scale tissue- and condition-specific proteomics data in <it>Arabidopsis thaliana</it>, we present here the first systematic investigation into this question. We stratified a conglomerate <it>A. thaliana </it>PPI network into three levels of context-dependent subnetworks. We then focused on three types of most commonly conducted network analyses, i.e., topological, functional and modular analyses, and compared the results from these network analyses on the conglomerate network and five stratified context-dependent subnetworks corresponding to specific tissues.</p> <p>Conclusions</p> <p>We found that the results based on the conglomerate PPI network are often significantly different from those of context-dependent subnetworks corresponding to specific tissues or conditions. This conclusion depends neither on relatively arbitrary cutoffs (such as those defining network hubs or bottlenecks), nor on specific network clustering algorithms for module extraction, nor on the possible high false positive rates of binary interactions in PPI networks. We also found that our conclusions are likely to be valid in human PPI networks. Furthermore, network stratification may help resolve many controversies in current research of systems biology.</p

S151A δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice

So far, the role of mutations in the δ-sarcogylcan (Sgcd) gene in causing autosomal dominant dilated cardiomyopathy (DCM) remains inconclusive. A p.S151A missense mutation in exon 6 of the Sgcd gene was reported to cause severe isolated autosomal dominant DCM without affecting skeletal muscle. This is controversial to our previous findings in a large consanguineous family where this p.S151A mutation showed no relevance for cardiac disease. In this study, the potential of the p.S151A mutation to cause DCM was investigated by using two different approaches: (1) engineering and characterization of heterozygous knock-in (S151A-) mice carrying the p.S151A mutation and (2) evaluation of the potential of adeno-associated virus (AAV) 9-based cardiac-specific transfer of p.S151A-mutated Sgcd cDNA to rescue the cardiac phenotype in Sgcd-deficient (Sgcd-null) mice as it has been demonstrated for intact, wild-type Sgcd cDNA. Heterozygous S151A knock-in mice developed a rather mild phenotype of cardiomyopathy. Increased heart to body weight suggests cardiac enlargement in 1-year-old S151A knock-in mice. However, at this age cardiac function, assessed by echocardiography, is maintained and histopathology completely absent. Myocardial expression of p.S151A cDNA, similar to intact Sgcd cDNA, restores cardiac function, although not being able to prevent myocardial histopathology in Sgcd-null mice completely. Our results suggest that the p.S151A mutation causes a mild, subclinical phenotype of cardiomyopathy, which is prone to be overseen in patients carrying such sequence variants. Furthermore, this study shows the suitability of an AAV-mediated cardiac gene transfer approach to analyze whether a sequence variant is a disease-causing mutation

Left ventricular enlargement in coxsackievirus-B3 induced chronic myocarditis - ongoing inflammation and an imbalance of the matrix degrading system

Enteroviruses, especially Coxsackie B3 virus (CVB-3), cause acute viral myocarditis, but the detailed mechanisms leading to chronic left ventricular dysfunction and dilatation remain elusive. Myocardial tissues of CVB-3 infected and sham infected male swr/J mice were analyzed after hemodynamic evaluation on days 4, 7, and 28 p.i. by RT-PCR, gelatin zymography, ELISA, immunohisto-chemistry, sirius red staining, and luxol fast blue staining. In the early phase after infection an abnormal diastolic function was the main hemodynamic finding. CVB-3 infection caused impairment of left ventricular function combined with ventricular dilatation 7 and 28 days post-infection. These hemodynamic findings were associated with relevant upregulation of different cytokines (IL-1beta, IL-6, IL-10, INF-gamma, TNF-alpha) in the acute phase with persistent over-expression of IL-6, IL-10, and INF-gamma in the chronic phase. This virus induced myocardial inflammation was linked to a significant induced MMP/TIMP-system (MMP-2,-3,-8, TIMP-1, uPA, tPA - mRNA-expression, MMP-2-activity) in the acute and chronic phase leading to imbalance in the MMP/TIMP-ratio at day 28. This imbalance in the MMP/TIMP-system was significantly correlated to the development of ventricular dilatation. Viral persistence induces chronic myocardial inflammation and an imbalance of the matrix degrading system, associated with the development of left ventricular dysfunction and dilatation in chronic murine myocarditis

Inhibition of urokinase-type plasminogen activator or matrix metalloproteinases prevents cardiac injury and dysfunction during viral myocarditis

BACKGROUND: Acute viral myocarditis is an important cause of cardiac failure in young adults for which there is no effective treatment apart from general heart failure therapy. The present study tested the hypothesis that increased expression of the proteinases urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) is implicated in cardiac inflammation, injury, and subsequent failure during Coxsackievirus-B3 (CVB3)-induced myocarditis. METHODS AND RESULTS: First, we showed increased expression and activity of uPA and MMP-9 in wild-type mice at 7 days of CVB3-induced myocarditis. Targeted deletion of uPA, which resulted in reduced MMP activity and cytokine expression or inhibition of MMPs by adenoviral gene overexpression of tissue inhibitor of metalloproteinases-1, decreased cardiac inflammation and reduced myocardial necrosis at 7 days and decreased cardiac fibrosis at 35 days after CVB3 infection. Importantly, loss of uPA or MMP activity prevented CVB3-induced cardiac dilatation and dysfunction, as determined by serial echocardiography. CONCLUSIONS: Loss of uPA or MMP activity reduces the cardiac inflammatory response after CVB3 infection, thereby protecting against cardiac injury, dilatation, and failure during CVB3-induced myocarditi