Key Words: Akt Ⅲ PHLPP Ⅲ phosphatase Ⅲ heart Ⅲ protection N umerous studies have demonstrated that activation of Akt contributes to the cardioprotective effects of receptors tyrosine kinases, 1,2 glycoprotein 130 -linked receptors, [3][4][5] and G protein-coupled receptors. 6,7 These receptors activate phosphatidylinositol 3-kinase (PI3K) and the resultant increase in phosphatidylinositol (3,4,5) triphosphate (PIP 3 ) levels drives Akt translocation to the plasma membrane. Akt is subsequently activated through phosphorylation at Thr308 by the upstream kinase phosphoinositide-dependent kinase 1 (PDK1) and phosphorylation at Ser473 by a mechanism that depends on both TORC2 and the intrinsic catalytic activity of Akt. 8,9 The lipid phosphatase PTEN, which dephosphorylates PIP 3 to PIP 2 , has been shown to limit Akt activation by decreasing PIP 3 . Deletion or mutation of PTEN is observed in many types of tumors and is accompanied by high Akt activity. 10 A recent study identified a PH domain-only protein, PHLDA3, that competes with the PH domain of Akt for binding of PIP 3 . 11 These molecules regulate the activation of Akt via various mechanisms but far less is known about mechanisms involved in terminating Akt activity by its dephosphorylation.Protein phosphatase (PP)2A has been shown to dephosphorylate Akt at Thr308 and/or Ser473 in noncardiac cells. 12,13 A pharmacological study also suggests that in retina PP2B (calcineurin) can dephosphorylate Akt at both sites. 14 A more specific Akt-directed novel PP2C family member protein phosphatase, PHLPP (PH domain leucine-rich repeat protein phosphatase), [15][16][17] In cardiac myocytes, overexpression of PTEN has been shown to be proapoptotic, whereas genetic deletion of PTEN rescues hearts from ischemia/reperfusion (I/R) injury. 18,19 These data support observations made in noncardiac cells which demonstrate that modulation of Akt activity regulates cell survival. A recent article showed that either PP2A or PP2B (calcineurin) can dephosphorylate Akt and thereby, regulate insulin signaling in cardiomyocytes. 20 It has been generally believed that phosphatases such as PP2A and PP2B have poor substrate selectivity, eliciting dephosphorylation of diverse target molecules. In contrast, PHLPP has been reported to be a selective Akt phosphatase. [15][16][17] In this study, we demonstrate a role for endogenous PHLPP-1 in regulation of cardiomyocyte Akt activity and survival in vitro and in vivo.
MethodsPHLPP-1 knockout (KO) mice were generated in the C57BL/6 strain as described previously. 21 All mice used in the present study were male at 8 to 10 weeks of age. All procedures were performed in accordance with NIH Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee. To knockdown PHLPP-1, predesigned PHLPP-1 ONTARGETplus small interfering (si)RNA for rat and control siRNA were purchased from Thermo Scientific. NRVMs were transfected with siRNA using DharmaFECT-I transfection reagent (Thermo Scientific) based on ...
Most deceit-pollinated species involve floral dimorphisms characterized by the presence of rewarding male flowers and nonrewarding female flowers. It has been proposed that this polymorphism establishes the conditions for the action of frequency dependent selection (FDS). The tendency of foraging animals to aggregate in areas of high resource density suggests that pollination efficiency and fruit production may be positively influenced by flower density (density dependent selection, DDS). In this paper we offer a graphical model describing the effects of FDS and DDS on a monoecious species pollinated by deceit. We test the FDS and DDS assumptions and the predictions of the model using field observations and experimental populations of Begonia gracilis in which population sex ratio and flower density were controlled. We found a marked effect of both FDS and DDS on pollinator visitation, fruit-set, and on the probability of female flowers to setting fruits. We conclude that these two types of selection have had a strong influence on the evolution of deceit-pollinated species.
Apparent molar heat capacities at 25 °C of a series of
1-alcohols and three branched alcohols were determined
in mixtures of the type alcohol + (p wt % AOT +
n-decane) at R = 0 and 10, R being
the water−surfactant
molar ratio [W]/[S]. For methanol and 1-hexanol, the
measurements were done for different p values as
a
function of alcohol concentration. For all the other alcohols
p = 5. Heat capacities for the binary (AOT
+
nC10) and the ternary (AOT + W +
nC10) mixtures, as well as for 1-hexanol in a 5
wt % solution of dioctyl
succinate, were also measured at 25 °C. For all alcohols + AOT
+ n-decane, kinematic viscosities and
dynamic light scattering (DLS) were measured at 25 °C for
R = 10 and p = 13 as a function of
alcohol
concentration. DLS was also measured for the ternary mixture AOT
+ W + nC10 with R = 10 at 25
°C. A
reasonable molecular picture of the alcohol−AOT interactions in the
presence and absence of reverse micelles
emerges from the experimental DLS and heat capacity results, the latter
having been analyzed within the
Treszczanowicz−Kehiaian model framework. In the absence of
reverse micelles, all alcohols form complexes
with the free AOT molecules in the solution, a process that competes
with the alcohol self-association. The
alcohol−AOT complex is most probably formed via an interaction
between the hydroxyl group of the alcohol
and the ionic head of AOT. When reverse micelles are present, two
behaviors were found: (i) Methanol and
ethanol are located in the micelle water pool; at low AOT concentration
these alcohols only interact with
water, but at higher AOT concentration they also form a complex with
AOT molecules at the micellar interface.
(ii) For butanol, longer 1-alcohols, and the three branched
alcohols studied here two different processes
occur: AOT molecules are withdrawn from the micelles to be complexed
with alcohol molecules in the bulk
of the solution, and alcohol molecules penetrate the micellar shell,
where they also form a complex with
AOT.
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