NCS-1 Inhibits insulin stimulated GLUT4 translocation in 3T3L1 adipocytes through a phosphatidylinositol 4-kinase dependent pathway

Expression of NCS-1 (neuronal calcium sensor-1, also termed frequenin) in 3T3L1 adipocytes strongly inhibited insulin-stimulated translocation of GLUT4 and insulin-responsive aminopeptidase. The effect of NCS-1 was specific for GLUT4 and the insulin-responsive aminopeptidase translocation as there was no effect on the trafficking of the cation-independent mannose 6-phosphate receptor or the GLUT1 glucose transporter isoform. Moreover, NCS-1 showed partial colocalization with GLUT4-EGFP in the perinuclear region. The inhibitory action of NCS-1 was independent of calcium sequestration since neither treatment with ionomycin nor endothelin-1, both of which elevated the intracellular calcium concentration, restored insulin-stimulated GLUT4 translocation. Furthermore, NCS-1 did not alter the insulin-stimulated protein kinase B (PKB/Akt) phosphorylation or the recruitment of Cbl to the plasma membrane. In contrast, expression of the NCS-1 effector phosphatidylinositol 4-kinase (PI 4-kinase) inhibited insulin-stimulated GLUT4 translocation, whereas co-transfection with an inactive PI 4-kinase mutant prevented the NCS-1-induced inhibition. These data demonstrate that PI 4-kinase functions to negatively regulate GLUT4 translocation through its interaction with NCS-1

Louis de La Forge and the ‘Non-Transfer Argument’ for Occasionalism

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Does Continuous Creation Entail Occasionalism? Malebranche (and Descartes)

‘God needs no instruments to act,’ Malebranche writes in Search 6.2.3; “it suffices that He wills in order that a thing be, because it is a contradiction that He should will and that what He wills should not happen. Therefore, His power is His will” (450). After nearly identical language in Treatise 1.12, Malebranche writes that “[God's] wills are necessarily efficacious … His power differs not at all from His will” (116). God exercises His causal power, here, via His volitions; what He causes depends not merely on the fact that He wills, but specifically (since volitions are intentional states) on the content of His volitions, on “what He wills.” Yet despite the obviously key role the ordinary notion of volitional content plays for Malebranche, recent writers have paid surprisingly little attention either to it or its exegetical implications. I hope partly to rectify this situation here.The plan of this paper is this:(I) to borrow current work in the philosophy of mind to sketch the notion of an incomplete volition, i.e. one whose content is ‘incomplete’ in a sense to be explained;(II) to note that Malebranche accepts and uses something like this notion;</jats:p

Malebranche on Ideas

In this paper I offer an interpretation of Malebranche's conception of ideas. This is no easy matter. Malebranche says so many different things about ideas that it is daunting to try to weave them all together. To make matters worse, some of the things he says are not very clear. Worse still, some of the things he says are not obviously consistent with each other or with other Malebranchean doctrines. It is not surprising, therefore, that his account of ideas came under attack from the beginning, and continues to be attacked to this day. It is with trepidation, then, that I offer any interpretation at all. It is with even greater trepidation that I suggest that this interpretation affords Malebranche a clear and coherent theory of ideas, one that is consistent with the rest of his philosophy, has its primitives in the right places, and may even satisfactorily address the common charges laid against him.</jats:p