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      Transcriptional Abnormalities of Hamstring Muscle Contractures in Children with Cerebral Palsy

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          Abstract

          Cerebral palsy (CP) is an upper motor neuron disease that results in a spectrum of movement disorders. Secondary to the neurological lesion, muscles from patients with CP are often spastic and form debilitating contractures that limit range of motion and joint function. With no genetic component, the pathology of skeletal muscle in CP is a response to aberrant complex neurological input in ways that are not fully understood. This study was designed to gain further understanding of the skeletal muscle response in CP using transcriptional profiling correlated with functional measures to broadly investigate muscle adaptations leading to mechanical deficits.

          Biospsies were obtained from both the gracilis and semitendinosus muscles from a cohort of patients with CP (n = 10) and typically developing patients (n = 10) undergoing surgery. Biopsies were obtained to define the unique expression profile of the contractures and passive mechanical testing was conducted to determine stiffness values in previously published work. Affymetrix HG-U133A 2.0 chips (n = 40) generated expression data, which was validated for selected transcripts using quantitative real-time PCR. Chips were clustered based on their expression and those from patients with CP clustered separately. Significant genes were determined conservatively based on the overlap of three summarization algorithms (n = 1,398). Significantly altered genes were analyzed for over-representation among gene ontologies and muscle specific networks.

          The majority of altered transcripts were related to increased extracellular matrix expression in CP and a decrease in metabolism and ubiquitin ligase activity. The increase in extracellular matrix products was correlated with mechanical measures demonstrating the importance in disability. These data lay a framework for further studies and development of novel therapies.

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          Most cited references47

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          Integration of biological networks and gene expression data using Cytoscape.

          Cytoscape is a free software package for visualizing, modeling and analyzing molecular and genetic interaction networks. This protocol explains how to use Cytoscape to analyze the results of mRNA expression profiling, and other functional genomics and proteomics experiments, in the context of an interaction network obtained for genes of interest. Five major steps are described: (i) obtaining a gene or protein network, (ii) displaying the network using layout algorithms, (iii) integrating with gene expression and other functional attributes, (iv) identifying putative complexes and functional modules and (v) identifying enriched Gene Ontology annotations in the network. These steps provide a broad sample of the types of analyses performed by Cytoscape.
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            Development and reliability of a system to classify gross motor function in children with cerebral palsy.

            To address the need for a standardized system to classify the gross motor function of children with cerebral palsy, the authors developed a five-level classification system analogous to the staging and grading systems used in medicine. Nominal group process and Delphi survey consensus methods were used to examine content validity and revise the classification system until consensus among 48 experts (physical therapists, occupational therapists, and developmental pediatricians with expertise in cerebral palsy) was achieved. Interrater reliability (kappa) was 0.55 for children less than 2 years of age and 0.75 for children 2 to 12 years of age. The classification system has application for clinical practice, research, teaching, and administration.
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              Molecular diversity of myofibrillar proteins: gene regulation and functional significance.

              Myofibrillar proteins exist as multiple isoforms that derive from multigene (isogene) families. Additional isoforms, including products of tropomyosin, myosin light chain 1 fast, troponin T, titin, and nebulin genes, can be generated from the same gene through alternative splicing or use of alternative promoters. Myofibrillar protein isogenes are differentially expressed in various muscle types and fiber types but can be coexpressed within the same fiber. Isogenes are regulated by transcriptional and posttranscriptional mechanisms; however, specific regulatory sequences and transcriptional factors have not yet been identified. The pattern of isogene expression varies during muscle development in relation to the different origin of myogenic cells and primary/secondary fiber generations and is affected by neural and hormonal influences. The variable expression of myofibrillar protein isoforms is a major determinant of the contractile properties of skeletal muscle fibers. The diversity among isomyosins is related to the differences in the parameters of chemomechanical transduction as ATP hydrolysis rate and shortening velocity. Troponin and tropomyosin isoforms determine the variable sensitivity to calcium, whereas titin isoforms dictate the elastic properties of muscle fibers at rest. Both myosin and troponin isoforms contribute to the differences in the resistance to fatigue of muscle fibers.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                16 August 2012
                : 7
                : 8
                : e40686
                Affiliations
                [1 ]Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America
                [2 ]Department of Orthopedic Surgery, Rady Children's Hospital, San Diego, California, United States of America
                [3 ]Department of Orthopedic Surgery, University of California San Diego, La Jolla, California, United States of America
                [4 ]Department of Veterans Affairs, Medical Center, San Diego, California, United States of America
                University of Pittsburgh, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: LRS HGC SS RLL. Performed the experiments: LRS HGC. Analyzed the data: LRS SS RLL. Contributed reagents/materials/analysis tools: HGC SS. Wrote the paper: LRS SS HGC RLL.

                Article
                PONE-D-12-01683
                10.1371/journal.pone.0040686
                3431909
                22956992
                c9ff3a22-b119-4446-8ef2-31b3eb2417e5
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 January 2012
                : 13 June 2012
                Page count
                Pages: 13
                Funding
                This work was supported by the National Institutes of Health [grant number AR057393]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Musculoskeletal System
                Muscle
                Muscle Biochemistry
                Muscle Components
                Muscle Functions
                Muscle Types
                Computational Biology
                Microarrays
                Molecular Cell Biology
                Cellular Types
                Muscle Fibers
                Muscle Cells
                Gene Expression
                Medicine
                Neurology
                Cerebral Palsy
                Neuromuscular Diseases

                Uncategorized
                Uncategorized

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