Uremic cardiomyopathy is characterised by loss of the cardioprotective effects of insulin

Chronic kidney disease is associated with a unique cardiomyopathy, characterised by a combination of structural and cellular remodelling, and an enhanced susceptibility to ischaemia-reperfusion injury. This may represent dysfunction of the reperfusion injury salvage kinase pathway, due to insulin resistance. Aims: The susceptibility of the uraemic heart to ischaemia-reperfusion injury and the cardioprotective effects of insulin and rosiglitazone were investigated. Methods and Results: Uraemia was induced in Sprague-Dawley rats by subtotal nephrectomy. Functional recovery from ischaemia was investigated in vitro in control and uraemic hearts ±insulin ±rosiglitazone. The response of myocardial oxidative metabolism to insulin was determined by 13C NMR spectroscopy. Activation of reperfusion injury salvage kinase pathway intermediates (Akt and GSK3β) were assessed by SDS-PAGE and immuno-precipitation. Insulin improved post-ischaemic rate pressure product in control but not uraemic hearts, (recovered rate pressure product (%), control 59.6±10.7 vs 88.9±8.5, p<0.05; uraemic 19.3±4.6 vs 28.5±10.4, p=ns). Rosiglitazone resensitised uraemic hearts to insulin-mediated cardio-protection (recovered rate pressure product (%) 12.7±7.0 vs. 61.8±15.9, p<0.05). Myocardial carbohydrate metabolism remained responsive to insulin in uraemic hearts. Uraemia was associated with increased phosphorylation of Akt (1.00±0.08 vs. 1.31±0.11, p<0.05) in normoxia, but no change in post-ischaemic phosphorylation of Akt or GSK3β. Akt2 isoform expression was decreased post-ischaemia in uraemic hearts (p<0.05). Conclusion: Uraemia is associated with enhanced susceptibility to ischaemia-reperfusion injury and a loss of insulin-mediated cardio-protection, which can be restored by administration of rosiglitazone. Altered Akt2 expression in uraemic hearts post ischaemia-reperfusion and impaired activation of reperfusion injury salvage kinase pathway may underlie these findings

Galaxy Deployments at Indiana University

A short overview of the different Galaxy instances at IU.This material is based upon work supported by the National Science Foundation under Grant No. ABI-1062432, Craig Stewart, PI. William Barnett, Matthew Hahn, and Michael Lynch, co-PIs. This work was supported in part by the Lilly Endowment, Inc. and the Indiana University Pervasive Technology Institute. Any opinions presented here are those of the presenter(s) and do not necessarily represent the opinions of the National Science Foundation or any other funding agencies

Mutations in valosin-containing protein (VCP) decrease ADP/ATP translocation across the mitochondrial membrane and impair energy metabolism in human neurons

Mutations in the gene encoding valosin-containing protein (VCP) lead to multisystem proteinopathies including frontotemporal dementia. We have previously shown that patient-derived VCP mutant fibroblasts exhibit lower mitochondrial membrane potential, uncoupled respiration, and reduced ATP levels. This study addresses the underlying basis for mitochondrial uncoupling using VCP knockdown neuroblastoma cell lines, induced pluripotent stem cells (iPSCs), and iPSC-derived cortical neurons from patients with pathogenic mutations in VCP. Using fluorescent live cell imaging and respiration analysis we demonstrate a VCP mutation/knockdown-induced dysregulation in the adenine nucleotide translocase, which results in a slower rate of ADP or ATP translocation across the mitochondrial membranes. This deregulation can explain the mitochondrial uncoupling and lower ATP levels in VCP mutation-bearing neurons via reduced ADP availability for ATP synthesis. This study provides evidence for a role of adenine nucleotide translocase in the mechanism underlying altered mitochondrial function in VCP-related degeneration, and this new insight may inform efforts to better understand and manage neurodegenerative disease and other proteinopathies

National Resources for Computationally Intensive Genomics

Poster presented at Plant and Animal Genome Conference, 2015, on January 12th 2015 in San Diego CA.This material is based upon work supported by the National Science Foundation under Grant No. ABI-1062432, Craig Stewart, PI. William Barnett, Matthew Hahn, and Michael Lynch, co-PIs. This work was supported in part by the Lilly Endowment, Inc. and the Indiana University Pervasive Technology Institute. Any opinions presented here are those of the presenter(s) and do not necessarily represent the opinions of the National Science Foundation or any other funding agencies

Galaxy Deployment on Heterogenous Hardware

Talk presented at Galaxy Community Conference 2014, June 30 - July 2, 2014. Video is available at URL: https://wiki.galaxyproject.org/Events/GCC2014/Abstracts/Talks#Galaxy_Deployment_on_Heterogenous_HardwareIndiana University, like many institutions, houses a heterogenous mixture of compute resources. In addition to university resources, the National Center for Genome Analysis Support, the Extreme Science and Engineering Discovery Environment, and the Open Science Grid all provide resources to biologists with NSF affiliations. Such a diverse mixture of compute power and services could be applied to address the equally diverse set of problems and needs in the bioinformatics field. Many software suites are well suited for large numbers of fast CPUS, such as phylogenetic tree building algorithms. De novo assembly problems really crave a machine with lots of RAM to spare. Alignment and mapping problems where each input is a separate invocation lend themselves perfectly to high-throughput, heavily distributed compute systems. Galaxy is a web interface that acts as a mediator between the biologist and the underlying hardware and software - in an ideal setup, Galaxy would be able to delegate work to the best suited underlying infrastructure. We present an instance of Galaxy at Indiana University, installed and maintained by NCGAS, that takes advantage of a variety of compute resources to increase utilization and efficiency. The OSG is a distributed grid through which Blast jobs can be run. IU, NCGAS and XSEDE jointly support Mason, a 512Gb/node system. For IU users, Big Red 2 is the first university-owned petaFLOPS machine. Connecting these resources to Galaxy and using the best tool for the job results in the best performance and utilization - everyone wins.This material is based upon work supported by the National Science Foundation under Grant No. ABI-1062432, Craig Stewart, PI. William Barnett, Matthew Hahn, and Michael Lynch, co-PIs. This work was supported in part by the Lilly Endowment, Inc. and the Indiana University Pervasive Technology Institute. Any opinions presented here are those of the presenter(s) and do not necessarily represent the opinions of the National Science Foundation or any other funding agencie

The advanced cyberinfrastructure research and education facilitators virtual residency: Toward a national cyberinfrastructure workforce

An Advanced Cyberinfrastructure Research and Education Facilitator (ACI-REF) works directly with researchers to advance the computing- and data-intensive aspects of their research, helping them to make effective use of Cyberinfrastructure (CI). The University of Oklahoma (OU) is leading a national "virtual residency" program to prepare ACI-REFs to provide CI facilitation to the diverse populations of Science, Technology, Engineering and Mathematics (STEM) researchers that they serve. Until recently, CI Facilitators have had no education or training program; the Virtual Residency program addresses this national need by providing: (1) training, specifically (a) summer workshops and (b) third party training opportunity alerts; (2) a community of CI Facilitators, enabled by (c) a biweekly conference call and (d) a mailing list

Cyberinfrastructure Resources for Genomics Research

New DNA sequencing technologies are generating more sequence data, faster, and cheaper. But there is a catch: the sequences are shorter and the nucleotide identification has higher error rates, meaning that the computational challenge of assembling a full genome from sequence data is also greater. In this poster, we examine cyberinfrastructure resources available to researchers undertaking genomics work, and present a case study that illustrates how one lab is currently making use of these resources.This material is based upon work supported by the National Science Foundation under Grant No. ABI-1062432, Craig Stewart, PI. William Barnett, Matthew Hahn, and Michael Lynch, co-PIs. This work was supported in part by the Lilly Endowment, Inc. and the Indiana University Pervasive Technology Institute. Any opinions presented here are those of the presenter(s) and do not necessarily represent the opinions of the National Science Foundation or any other funding agencie

Intro to Using Galaxy for Bioinformatics

Talk given at IU Galaxy for Bioinformatics Workshop 09/17/13This material is based upon work supported by the National Science Foundation under Grant No. ABI-1062432, Craig Stewart, PI. William Barnett, Matthew Hahn, and Michael Lynch, co-PIs. This work was supported in part by the Lilly Endowment, Inc. and the Indiana University Pervasive Technology Institute. Any opinions presented here are those of the presenter(s) and do not necessarily represent the opinions of the National Science Foundation or any other funding agencie

RNA-Seq Demo on Galaxy

Talk given at the IU Bioinformatics Clinic, July 2014.This material is based upon work supported by the National Science Foundation under Grant No. ABI-1062432, Craig Stewart, PI. William Barnett, Matthew Hahn, and Michael Lynch, co-PIs. This work was supported in part by the Lilly Endowment, Inc. and the Indiana University Pervasive Technology Institute. Any opinions presented here are those of the presenter(s) and do not necessarily represent the opinions of the National Science Foundation or any other funding agencie

RNA-Seq Demo on Galaxy

Workshop given during the 2015 Bioinformatics Clinic at Indiana University, August 2015This material is based upon work supported by the National Science Foundation under Grant No. ABI-1062432, Craig Stewart, PI. William Barnett, Matthew Hahn, and Michael Lynch, co-PIs. This work was supported in part by the Lilly Endowment, Inc. and the Indiana University Pervasive Technology Institute. Any opinions presented here are those of the presenter(s) and do not necessarily represent the opinions of the National Science Foundation or any other funding agencies