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Vincent L.G.,University of California at San Diego | Engler A.J.,Sanford Consortium for Regenerative Medicine
Nature Materials | Year: 2013

Jason Burdick and colleagues have demonstrated that the differentiation of mesenchymal stem cells (MSCs) encapsulated in degradable, covalently crosslinked hyaluronic hydrogels is mediated by degradation-specific traction stresses. To make their gels degradable, the researchers first incorporated both methacrylate and maleimide functional groups onto the hyaluronic backbone, and used the reactions of the maleimide groups with the thiols on degradable peptides to form a primary gel. The gel could then be covalently crosslinked by radical polymerization of the methacrylate groups in the presence of both a photoinitiator and ultraviolet light. When using the degradable hydrogel, Burdick and co-authors found that local degradability was needed for entrapped cells to be able to rearrange their cytoskeletal structure and undergo osteogenesis. The findings from Burdick and colleagues support the notion that, unlike in two dimensions, in three dimensions matrix-driven cell tension drives cell fate irrespective of cell morphology and spread area.

Cheng J.,Japan National Cardiovascular Center Research Institute | Morisaki H.,Japan National Cardiovascular Center Research Institute | Sugimoto N.,Japan National Cardiovascular Center Research Institute | Sugimoto N.,Osaka University | And 17 more authors.
Molecular Genetics and Metabolism Reports | Year: 2014

Mutation of the AMP deaminase 1 (AMPD1) gene, the predominate AMPD gene expressed in skeletal muscle, is one of the most common inherited defects in the Caucasian population; 2-3% of individuals in this ethnic group are homozygous for defects in the AMPD1 gene. Several studies of human subjects have reported variable results with some studies suggesting this gene defect may cause symptoms of a metabolic myopathy and/or easy fatigability while others indicate individuals with this inherited defect are completely asymptomatic. Because of confounding problems in assessing muscle symptoms and performance in human subjects with different genetic backgrounds and different environmental experiences such as prior exercise conditioning and diet, a strain of inbred mice with selective disruption of the AMPD1 was developed to study the consequences of muscle AMPD deficiency in isolation. Studies reported here demonstrate that these animals are a good metabolic phenocopy of human AMPD1 deficiency but they exhibit no abnormalities in muscle performance in three different exercise protocols. © 2013 The Authors.

Akizu N.,University of California at San Diego | Cantagrel V.,University of California at San Diego | Cantagrel V.,French Institute of Health and Medical Research | Schroth J.,University of California at San Diego | And 25 more authors.
Cell | Year: 2013

Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease. © 2013 Elsevier Inc.

Cheng J.,Shantou University | Morisaki H.,Japan National Cardiovascular Center Research Institute | Toyama K.,Osaka University of Pharmaceutical Sciences | Sugimoto N.,Osaka University of Pharmaceutical Sciences | And 5 more authors.
BMC Endocrine Disorders | Year: 2015

Background: Insulin resistance is one of the hallmark manifestations of obesity and Type II diabetes and reversal of this pathogenic abnormality is an attractive target for new therapies for Type II diabetes. A recent report that metformin, a drug known to reverse insulin resistance, demonstrated in vitro the metformin can inhibit AMP deaminase (AMPD) activity. Skeletal muscle is one of the primary organs contributing to insulin resistance and that the AMPD1 gene is selectively expressed at high levels in skeletal muscle. Methods: Recognizing the background above, we asked if genetic disruption of the AMPD1 gene might ameliorate the manifestations of insulin resistance. AMPD1 deficient homozygous mice and control mice fed normal chow diet or a high-fat diet, and blood analysis, glucose tolerance test and insulin tolerance test were performed. Also, skeletal muscle metabolism and gene expression including nucleotide levels and activation of AMP activated protein kinase (AMP kinase) were evaluated in both conditions. Results: Disruption of the AMPD1 gene leads to a less severe state of insulin resistance, improved glucose tolerance and enhanced insulin clearance in mice fed a high fat diet. Given the central role of AMP kinase in insulin action, and its response to changes in AMP concentrations in the cell, we examined the skeletal muscle of the AMPD1 deficient mice and found that they have greater AMP kinase activity as evidenced by higher levels of phosphorylated AMP kinase. Conclusions: Taken together these data suggest that AMPD may be a new drug target for the reversal of insulin resistance and the treatment of Type II diabetes. © 2014 Cheng et al.; licensee BioMed Central Ltd.

Dai J.,Huazhong University of Science and Technology | Dai J.,University of California at San Diego | Chiu Y.-J.,University of California at San Diego | Lian I.,Sanford Consortium for Regenerative Medicine | And 3 more authors.
Journal of Micromechanics and Microengineering | Year: 2016

Early signs of diseases can be revealed from cell detection in biofluids, such as detection of white blood cells (WBCs) in the peritoneal fluid for peritonitis. A lab-on-a-chip microfluidic device offers an attractive platform for such applications because of its small size, low cost, and ease of use provided the device can meet the performance requirements which many existing LoC devices fail to satisfy. We report an integrated microfluidic device capable of accurately counting low concentration of white blood cells in peritoneal fluid at 150 μl min-1 to offer an accurate (<3% error) and fast (∼10 min/run) WBC count. Utilizing the self-regulating hydrodynamic properties and a unique architecture in the design, the device can achieve higher flow rate (500-1000 μl min-1), continuous running for over 5 h without clogging, as well as excellent signal quality for unambiguous WBC count and WBC classification for certain diseases. These properties make the device a promising candidate for point-of-care applications. © 2016 IOP Publishing Ltd.

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