67 research outputs found
Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.
PurposeThe phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established.MethodsWe analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations.ResultsWe determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding.ConclusionThese findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196
Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity
Endothelial cellâcell junctions regulate vascular permeability, vasculogenesis, and angiogenesis. Familial cerebral cavernous malformations (CCMs) in humans result from mutations of CCM2 (malcavernin, OSM, MGC4607), PDCD10 (CCM3), or KRIT1 (CCM1), a Rap1 effector which stabilizes endothelial cellâcell junctions. Homozygous loss of KRIT1 or CCM2 produces lethal vascular phenotypes in mice and zebrafish. We report that the physical interaction of KRIT1 and CCM2 proteins is required for endothelial cellâcell junctional localization, and lack of either protein destabilizes barrier function by sustaining activity of RhoA and its effector Rho kinase (ROCK). Protein haploinsufficient Krit1+/â or Ccm2+/â mouse endothelial cells manifested increased monolayer permeability in vitro, and both Krit1+/â and Ccm2+/â mice exhibited increased vascular leak in vivo, reversible by fasudil, a ROCK inhibitor. Furthermore, we show that ROCK hyperactivity occurs in sporadic and familial human CCM endothelium as judged by increased phosphorylation of myosin light chain. These data establish that KRIT1âCCM2 interaction regulates vascular barrier function by suppressing Rho/ROCK signaling and that this pathway is dysregulated in human CCM endothelium, and they suggest that fasudil could ameliorate both CCM disease and vascular leak
Crop Updates 2005 - Geraldton
This session covers seventeen papers from different authors
2005 Seasonal Outlook, David Stephens and Nicola Telcik, Department of Agriculture
Horses for Courses â using the best tools to manage climate risk, Cameron Weeks, Mingenew-Irwin Group / Planfarm and Richard Quinlan, Planfarm Agronomy
Global influences driving Australian agriculture, Tony Harman, Australian Government Department of Agriculture, Fisheries and Forestry
Wheat yield and quality improvements â where have they come from and can we have more? Wal Anderson, Department of Agriculture
Rotations for nematode management, Vivien A. Vanstone, Sean J. Kelly, Helen F. Hunter and Mena C. Gilchrist, Department of Agriculture
Integrate strategies to manage stripe rust risk, Ciara Beard, Geoff Thomas, Robert Loughman, Kith Jayasena and Manisha Shenkar, Department of Agriculture
Frequency of herbicide resistance in wild radish populations across the WA wheatbelt, Dr Michael Walsh, Mechelle Owen and Prof. Stephen Powels, University of Western Australia
The incidence and severity of wild radish resistance in the NAR â results from an in-situ survey, Rob Grima and Andrew Blake, Elders Limited
Stubble management: the pros and cons of different methods, Bill Bowden, Department of Agriculture, Mike Collins WANTFA
Effectiveness of Zinc Application Methods in Wheat, Luigi Moreschi, CSBP
Know your Mo, Douglas Hamilton, Department of Agriculture
Atrazine contamination of groundwater in the agricultural region of Western Australia, Russell Speed1, Neil Rothnie2, John Simons1, Ted Spadek2, and John Moore1, 1Department of Agriculture, 2Chemistry Centre (W.A.)
Comparison of canola varieties in the Northern Agricultural Region in 2004, Graham Walton Department of Agriculture
Pasture rotations are a promising option for sandplain production, Nadine Eva, Department of Agriculture
Zone management can improve profit on sandplain, Bindi Webb, Damian Shepherd, Department of Agriculture, David Forrester, Davejeff Farms, casuarinas via Geraldton, Peter Tozer, Department of Agriculture
Crop leftovers: whatâs in stubble for sheep? Roy Butler and Keith Croker, Department of Agriculture
Realising Rural Equity, Nathan Windebank, Australian Agricultural Contracts Limite
Changing perspectives on the internationalization of R&D and innovation by multinational enterprises: a review of the literature
Internationalization of R&D and innovation by Multinational Enterprises (MNEs) has undergone a gradual and comprehensive change in perspective over the past 50 years. From sporadic works in the late 1950s and in the 1960s, it became a systematically analysed topic in the 1970s, starting with pioneering reports and âfoundation textsâ. Our review unfolds the theoretical and empirical evolution of the literature from dyadic interpretations of centralization versus decentralization of R&D by MNEs to more comprehensive frameworks, wherein established MNEs from Advanced Economies still play a pivotal role, but new players and places also emerge in the global generation and diffusion of knowledge. Hence views of R&D internationalization increasingly rely on concepts, ideas and methods from IB and other related disciplines such as industrial organization, international economics and economic geography. Two main findings are highlighted. First, scholarly research pays an increasing attention to the network-like characteristics of international R&D activities. Second, different streams of literature have emphasized the role of location- specific factors in R&D internationalization. The increasing emphasis on these aspects has created new research opportunities in some key areas, including inter alia: cross-border knowledge sourcing strategies, changes in the geography of R&D and innovation, and the international fragmentation of production and R&D activities
Cerebral Cavernous Malformations: Somatic Mutations in Vascular Endothelial Cells
OBJECTIVE: Germline mutations in three genes have been found in familial cases of cerebral cavernous malformations (CCM). We previously discovered somatic and germline truncating mutations in the KRIT1 gene supporting the âtwo-hitâ mechanism of CCM lesion formation in a single lesion. The purpose of this study was to screen for somatic, nonheritable, mutations in three more lesions from different patients and identify the cell type(s) in which somatic mutations occur. METHODS: Somatic mutations were sought in DNA from three surgically excised, fresh-frozen CCM lesions by cloning and screening PCR products generated from KRIT1 or PDCD10 coding regions. Laser capture microdissection (LCM) was used to isolated endothelial and nonendothelial cells in order to determine if somatic mutations were found in endothelial cells. RESULTS: A CCM lesion harbored somatic and germline KRIT1 mutations on different chromosomes and are therefore biallelic. Both mutations are predicted to truncate the protein. The KRIT1 somatic mutations (novel c.1800delG mutation and previously identified 34 nucleotide deletion) in CCMs from two different patients were only found in the vascular endothelial cells lining caverns. No obvious somatic mutations were identified in the two other lesions; however, the results were inconclusive possibly due to the technical limitations or the fact that these specimens had a small proportion of vascular endothelial cells lining pristine caverns. CONCLUSION: The âtwo-hitâ mechanism occurs in vascular endothelial cells lining CCM caverns from two patients with somatic and Hispanic-American KRIT1 germline mutations. Methods for somatic mutation detection should focus on vascular endothelial cells lining pristine caverns
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