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Full-Text Articles in Medicine and Health Sciences

Dsarm/Sarm1 Is Required For Activation Of An Injury-Induced Axon Death Pathway, Jeannette Osterloh, Jing Yang, Timothy Rooney, A. Fox, Robert Adalbert, Eric Powell, Amy Sheehan, Michelle Avery, Rachel Hackett, Mary Logan, Jennifer Macdonald, Jennifer Ziegenfuss, Stefan Milde, Ying-Ju Hou, Carl Nathan, Aihao Ding, Robert Brown, Laura Comforti, Michael Coleman, Marc Tessier-Lavigne, Stephan Zuchner, Marc Freeman Dec 2012

Dsarm/Sarm1 Is Required For Activation Of An Injury-Induced Axon Death Pathway, Jeannette Osterloh, Jing Yang, Timothy Rooney, A. Fox, Robert Adalbert, Eric Powell, Amy Sheehan, Michelle Avery, Rachel Hackett, Mary Logan, Jennifer Macdonald, Jennifer Ziegenfuss, Stefan Milde, Ying-Ju Hou, Carl Nathan, Aihao Ding, Robert Brown, Laura Comforti, Michael Coleman, Marc Tessier-Lavigne, Stephan Zuchner, Marc Freeman

Dr Robert Brown

Axonal and synaptic degeneration is a hallmark of peripheral neuropathy, brain injury, and neurodegenerative disease. Axonal degeneration has been proposed to be mediated by an active autodestruction program, akin to apoptotic cell death; however, loss-of-function mutations capable of potently blocking axon self-destruction have not been described. Here, we show that loss of the Drosophila Toll receptor adaptor dSarm (sterile alpha/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously suppresses Wallerian degeneration for weeks after axotomy. Severed mouse Sarm1 null axons exhibit remarkable long-term survival both in vivo and in vitro, indicating that Sarm1 prodegenerative signaling is conserved in mammals. Our results provide direct …


Targeted Mutation Of Mouse Skeletal Muscle Sodium Channel Produces Myotonia And Potassium-Sensitive Weakness, Lawrence Hayward, Joanna Kim, Ming-Yang Lee, Hongru Zhou, Ji Kim, Kumudini Misra, Mohammad Salajegheh, Fen-Fen Wu, Shinji Matsuda, Valerie Reid, Didier Cros, Eric Hoffman, Jean-Marc Renaud, Stephen Cannon, Robert Brown Dec 2012

Targeted Mutation Of Mouse Skeletal Muscle Sodium Channel Produces Myotonia And Potassium-Sensitive Weakness, Lawrence Hayward, Joanna Kim, Ming-Yang Lee, Hongru Zhou, Ji Kim, Kumudini Misra, Mohammad Salajegheh, Fen-Fen Wu, Shinji Matsuda, Valerie Reid, Didier Cros, Eric Hoffman, Jean-Marc Renaud, Stephen Cannon, Robert Brown

Dr Robert Brown

Hyperkalemic periodic paralysis (HyperKPP) produces myotonia and attacks of muscle weakness triggered by rest after exercise or by K+ ingestion. We introduced a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene encoding the skeletal muscle voltage-gated Na+ channel NaV1.4. Mice heterozygous for this mutation exhibited prominent myotonia at rest and muscle fiber-type switching to a more oxidative phenotype compared with controls. Isolated mutant extensor digitorum longus muscles were abnormally sensitive to the Na+/K+ pump inhibitor ouabain and exhibited age-dependent changes, including delayed relaxation and altered generation of tetanic force. Moreover, rapid and sustained weakness …


Loss-Of-Function Variants In Endothelial Lipase Are A Cause Of Elevated Hdl Cholesterol In Humans, Andrew Edmondson, Robert Brown, Sekar Kathiresan, L. Cupples, Serkalem Demissie, Alisa Manning, Majken Jensen, Eric Rimm, Jian Wang, Amrith Rodrigues, Vaneeta Bamba, Sumeet Khetarpal, Megan Wolfe, Stephanie Derohannessian, Mingyao Li, Muredach Reilly, Jens Aberle, David Evans, Robert Hegele, Daniel Rader Dec 2012

Loss-Of-Function Variants In Endothelial Lipase Are A Cause Of Elevated Hdl Cholesterol In Humans, Andrew Edmondson, Robert Brown, Sekar Kathiresan, L. Cupples, Serkalem Demissie, Alisa Manning, Majken Jensen, Eric Rimm, Jian Wang, Amrith Rodrigues, Vaneeta Bamba, Sumeet Khetarpal, Megan Wolfe, Stephanie Derohannessian, Mingyao Li, Muredach Reilly, Jens Aberle, David Evans, Robert Hegele, Daniel Rader

Dr Robert Brown

Elevated plasma concentrations of HDL cholesterol (HDL-C) are associated with protection from atherosclerotic cardiovascular disease. Animal models indicate that decreased expression of endothelial lipase (LIPG) is inversely associated with HDL-C levels, and genome-wide association studies have identified LIPG variants as being associated with HDL-C levels in humans. We hypothesized that loss-of-function mutations in LIPG may result in elevated HDL-C and therefore performed deep resequencing of LIPG exons in cases with elevated HDL-C levels and controls with decreased HDL-C levels. We identified a significant excess of nonsynonymous LIPG variants unique to cases with elevated HDL-C. In vitro lipase activity assays demonstrated …