University of Kentucky

About: University of Kentucky is a education organization based out in Lexington, Kentucky, United States. It is known for research contribution in the topics: Population & Poison control. The organization has 43933 authors who have published 92195 publications receiving 3256087 citations. The organization is also known as: UK.

Central hypotensive effects of the alpha2a-adrenergic receptor subtype.

Abstract: α 2 -Adrenergic receptors (α 2 ARs) present in the brainstem decrease blood pressure and are targets for clinically effective antihypertensive drugs. The existence of three α 2 AR subtypes, the lack of subtype-specific ligands, and the cross-reactivity of α 2 AR agonists with imidazoline receptors has precluded an understanding of the role of individual α 2 AR subtypes in the hypotensive response. Gene targeting was used to introduce a point mutation into the α 2a AR subtype in the mouse genome. The hypotensive response to α 2 AR agonists was lost in the mutant mice, demonstrating that the α 2a AR subtype plays a principal role in this response.

Construct Validity: Advances in Theory and Methodology

Abstract: Measures of psychological constructs are validated by testing whether they relate to measures of other constructs as specified by theory. Each test of relations between measures reflects on the validity of both the measures and the theory driving the test. Construct validation concerns the simultaneous process of measure and theory validation. In this article, we review the recent history of validation efforts in clinical psychological science that has led to this perspective, and we review the following recent advances in validation theory and methodology of importance for clinical researchers. These are: the emergence of nonjustificationist philosophy of science; an increasing appreciation for theory and the need for informative tests of construct validity; valid construct representation in experimental psychopathology; the need to avoid representing multidimensional constructs with a single score; and the emergence of effective new statistical tools for the evaluation of convergent and discriminant val...

mTORC1 and mTORC2 regulate EMT, motility and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways

Abstract: Activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling is associated with growth and progression of colorectal cancer (CRC). We have previously shown that the mammalian target of rapamycin (mTOR) kinase, a downstream effector of PI3K/Akt signaling, regulates tumorigenesis of CRC. However, the contribution of mTOR and its interaction partners towards regulating CRC progression and metastasis remains poorly understood. We found that increased expression of mTOR, Raptor and Rictor mRNA was noted with advanced stages of CRC suggesting that mTOR signaling may be associated with CRC progression and metastasis. mTOR, Raptor and Rictor protein levels were also significantly elevated in primary CRCs (stage IV) and their matched distant metastasis compared to normal colon. Inhibition of mTOR signaling, using rapamycin or stable inhibition of mTORC1 (Raptor) and mTORC2 (Rictor), attenuated migration and invasion of CRCs. Furthermore, knockdown of mTORC1 and mTORC2 induced a mesenchymal-epithelial transition and enhanced chemosensitivity of CRCs to oxaliplatin. We observed increased cell-cell contact as well as decreased actin cytoskeletal remodeling concomitant with decreased activation of the small GTPases, RhoA and Rac1, upon inhibition of both mTORC1 and mTORC2. Finally, establishment of CRC metastasis in vivo was completely abolished with targeted inhibition of mTORC1 and mTORC2 irrespective of the site of colonization. Our findings support a role for elevated mTORC1 and mTORC2 activity in regulating EMT, motility and metastasis of CRCs via RhoA and Rac1 signaling. These findings provide the rationale for including mTOR kinase inhibitors, which inhibit both mTORC1 and mTORC2, as part of the therapeutic regimen for CRC patients.