CALDAG 2012 PDF

Yesterday shares in ENK rose almost 20 per cent as it unveiled a deal to sell the non-core project. Caldag was put on care and maintenance last December after the company experienced persistent delays in getting a forestry permit. Following a strategic review at that time ENK - formerly known as European Nickel — refocused its efforts on the Acoje project in the Philippines. ENK has made rapid progress on Acoje since then.

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Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page. Free to read. When subjected to a laser injury thrombosis model, mice lacking STIM1 in platelets were characterized by the formation of unstable platelet-rich thrombi and delayed and reduced fibrin generation in injured arterioles. Platelet activation is triggered by various agonists including subendothelial collagens, the second wave mediators adenosine diphosphate ADP and thromboxane A 2 TxA 2 , and the protease thrombin [ 1 ].

DAG is critical for protein kinase C PKC activation, a key event in platelet granule release and integrin activation [ 2 ]. Crucial to this conversion is the scrambling of phosphatidyl serine PS from the inner to the outer membrane leaflet, a process that is mediated by transmembrane protein 16F [ 7 ]. CalDAG-GEFI activates the small GTPase Rap1, a central molecular switch that drives platelet activation by directly regulating integrin-mediated aggregation [ 9 , 12 , 13 ] and the release of autocrine agonists [ 11 ].

Store release depends on the formation of inositol 1,4,5-triphosphate IP 3 by PLC, which triggers the activation of IP3 receptors and thus opening of the pore. Discrepant results, however, were observed with regard to the importance of SOCE for thrombus formation under physiological flow conditions [ 23 ].

While platelet adhesion to collagen was significantly reduced in blood from chimeric mice lacking STIM1 or Orai1 in blood cells only, normal thrombus formation was observed under similar experimental conditions for platelets expressing an inactive mutant of Orai1 [ 22 ].

Blood was drawn from the retroorbital plexus into heparinized tubes. Platelet rich plasma PRP was prepared by centrifugation of heparinized blood at g for 5 minutes.

Platelets were activated with the indicated agonists in the presence of 0. The lysed cells were centrifuged at g and the supernatant was discarded carefully. The cells were washed with PBS, the supernatant was discarded carefully and the pellet was incubated for 5 minutes with 0.

Cells were immediately analyzed by flow cytometry. For the detection of intracellular proteins, washed platelets were fixed and permeabilised as described above, stained with FITC-labeled antibodies to VWF, fibrinogen, or P-selectin, and immediately analyzed. In vitro flow studies were performed in a microfluidic device fabricated in poly dimethylsiloxane PDMS. Fabrication of microfluidic devices and microfluidic collagen patterning were performed as previously described [ 25 ]. Platelet rich plasma PRP was obtained from heparinized blood.

Indicated doses of various agonists were added and transmission was recorded over 10 minutes on a Chrono-log 4-channel optical aggregation system Chrono-log, Havertown, PA. After incubation with horseradish peroxidase-coupled anti—rabbit antibodies Vector Laboratories , immunoreactivity was detected by Western Lightning enhanced chemiluminescence G-Biosciences.

Laser-induced thrombosis in the cremaster muscle microcirculation was performed as described previously [ 27 , 28 ]. No more than 5 arterioles were studied per mouse. All data were analyzed using Slidebook 4. A P value less than 0. Deficiency in platelet STIM1 was confirmed by western blotting and flow cytometry. Specific deletion of STIM1 in platelets did not affect peripheral platelet counts or platelet size not shown. Platelets were stained for von Willebrand factor VWF as a control right panel.

No significant differences were observed between the two groups. Traces are representative of 5 independent experiments. A Representative images taken at the indicated time points during the perfusion at arterial shear rates. Aside of integrin activation and granule release, calcium plays a crucial role for phosphatidyl serine PS exposure and the pro-coagulant response in activated platelets [ 7 , 22 , 23 ].

Together these studies suggested that the previously described anti-thrombotic phenotype of mice lacking functional platelet STIM1 may be due to an impaired contribution of platelets to thrombin generation at the site of injury rather than an impaired adhesive ability of these cells.

B, C PS exposure on platelets activated under static conditions. Early thrombi, however, were reversible and in most cases disappeared within one minute after laser injury Fig. C Representative images Green-platelets; Red-Fibrin. See supplemental Videos 1—3 for a better visualization of the differences in thrombus growth and stability observed in the respective study groups.

STIM1 was shown to be important for store-operated calcium entry in platelets and its deletion in mice led to protection from injury-induced thrombosis, presumably due to a defect in the adhesive function of STIM1-deficient platelets [ 21 ]. By contrast, our studies demonstrate that STIM1 is not critical for platelet aggregation both under static and flow conditions, while it plays an important role for the platelet pro-coagulant response.

When looking at aggregation and thrombus formation of STIM1-deficient platelets, we observed similarities and discrepancies to previous studies. In accordance with Varga-Szabo et al. Thus, in contrast to previous studies [ 21 , 23 ], our studies suggest only a minor role for STIM1 in platelet aggregation.

One potential explanation for the different phenotypes comes from methodological differences between the studies. For example, the microfluidic devices used for the respective studies are custom-made and thus may generate slightly different flow patterns. Variation may also derive from differences between the collagen preparations and the collagen coating procedures used to generate the pro-thrombotic surface. Both Varga-Szabo et al. There are drawbacks to both systems: the chimeric mice lack STIM1 in all blood cells, a potential limitation in assays monitoring thrombosis in whole blood.

Furthermore, lethal irradiation required for the generation of chimeric mice causes the systemic release of inflammatory mediators [ 30 ], which may adversely affect circulating platelets [ 31 ]. The platelet-specific, conditional deletion of STIM1 described here eliminates the above-mentioned complications.

Thus, the authors suggested that platelet SOCE could be redundant for the formation of fibrin-rich thrombi at injury sites where thrombin is present as a co-agonist.

Our studies argue against this conclusion. In a model of thrombin-dependent, localized thrombosis laser injury, Fig. Our results are also in line with studies on the adhesive and pro-coagulant properties of platelets isolated from patients with Scott syndrome [ 32 — 33 ]. However, platelet PS exposure and platelet-dependent fibrin formation is strongly impaired.

It is currently not clear how one molecule, Rap1, can regulate diverse cellular functions such as integrin-mediated adhesion and pro-coagulant response. Conflict of interest disclosure : S. Read article at publisher's site DOI : Cell Calcium , , 05 Oct Physiology Bethesda , 33 4 , 01 Jul Cited by 2 articles PMID: Ahmad F. J Am Heart Assoc , 7 13 , 23 Jun Blood Adv , 2 12 , 01 Jun Front Mol Neurosci , , 22 Mar This data has been text mined from the article, or deposited into data resources.

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J Biol Chem , 31 , 02 Jun Blood , 12 , 23 Jul Cited by 72 articles PMID: Blood , 4 , 07 Jun Bergmeier W , Stefanini L. J Thromb Haemost , 7 Suppl , 01 Jul Cited by 41 articles PMID: Stefanini L , Bergmeier W. Platelets , 21 4 , 01 Jan Review Free to read. Coronavirus: Find the latest articles and preprints.

Europe PMC requires Javascript to function effectively. Recent Activity. Recent history Saved searches. Ahmad F 1 ,. Boulaftali Y ,. Greene TK ,. Ouellette TD ,. M Poncz Search articles by 'M Poncz'. Poncz M ,. Feske S ,. W Bergmeier Search articles by 'W Bergmeier'. Bergmeier W. Affiliations 1 author 1. Share this article Share with email Share with twitter Share with linkedin Share with facebook.

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GRAFLEX SPEED GRAPHIC MANUAL PDF

European Nickel on track to fund project

Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page. Free to read. When subjected to a laser injury thrombosis model, mice lacking STIM1 in platelets were characterized by the formation of unstable platelet-rich thrombi and delayed and reduced fibrin generation in injured arterioles. Platelet activation is triggered by various agonists including subendothelial collagens, the second wave mediators adenosine diphosphate ADP and thromboxane A 2 TxA 2 , and the protease thrombin [ 1 ]. DAG is critical for protein kinase C PKC activation, a key event in platelet granule release and integrin activation [ 2 ].

R.G.DROMEY HOW TO SOLVE IT BY COMPUTER PDF

ENK receives US$6 million deposit from Caldag sale

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