Electrophoresis of a dielectric droplet with constant surface charge density.

Electrophoresis of a dielectric fluid droplet with constant surface charge density is investigated theoretically in this study. A pseudo-spectral method based on Chebyshev polynomials is adopted to solve the governing electrokinetic equations. It is found, among other things, that the larger the electrolyte strength in the ambient solution is, the slower the droplet moves in general. This is due to the strong screening effect of the large amount of indifferent counterions in the neighborhood of the droplet, with no reinforcement of potential-determining ions adsorbing to the droplet surface. The droplet comes to a complete halt eventually. Critical points are discovered for highly charged droplets, at which the droplet surface becomes immobile and the interior fluid stops recirculating. The droplet moves like a rigid particle with constant mobility regardless of its viscosity, a situation referred to as the "solidification phenomenon." The deadlock between the spinning motions on the charged droplet surface induced by the electric driving force and the hydrodynamic driving force respectively is responsible for this peculiar phenomenon. This is also observed for a dielectric droplet with constant surface electric potential. We demonstrate here that it occurs in the constant surface charge density situation as well.

Diffusiophoresis of a Weakly Charged Liquid Metal Droplet.

Diffusiophoresis of a weakly charged liquid metal droplet (LMD) is investigated theoretically, motivated by its potential application in drug delivery. A general analytical formula valid for weakly charged condition is adopted to explore the droplet phoretic behavior. We determined that a liquid metal droplet, which is a special category of the conducting droplet in general, always moves up along the chemical gradient in sole chemiphoresis, contrary to a dielectric droplet where the droplet tends to move down the chemical gradient most of the time. This suggests a therapeutic nanomedicine such as a gallium LMD is inherently superior to a corresponding dielectric liposome droplet in drug delivery in terms of self-guiding to its desired destination. The droplet moving direction can still be manipulated via the polarity dependence; however, there should be an induced diffusion potential present in the electrolyte solution under consideration, which spontaneously generates an extra electrophoresis component. Moreover, the smaller the conducting liquid metal droplet is, the faster it moves in general, which means a smaller LMD nanomedicine is preferred. These findings demonstrate the superior features of an LMD nanomedicine in drug delivery.

Verbal problem-solving in agenesis of the corpus callosum: Analysis using semantic similarity.

OBJECTIVE: Previous studies demonstrated that individuals with agenesis of the corpus callosum (AgCC) experience difficulties in novel and complex problem-solving. The present study investigated verbal problem-solving, deductive reasoning, and semantic inference in AgCC. METHOD: Capacity for semantic inference was tested in 25 individuals with AgCC and normal-range intelligence compared to 29 neurotypical controls. The Word Context Test (WCT) of Delis-Kaplan Executive Function System was used, employing a novel method of analysis (semantic similarity) to detect trial-by-trial progress toward a solution. RESULTS: With respect to the typical WCT scores, persons with AgCC had fewer total consecutive correct responses. In addition, semantic similarity to the correct word was significantly lower overall in persons with AgCC than in controls. CONCLUSION: These findings indicated that individuals with AgCC who have intelligence in the normal range are less able at the WCT taking all trials into account, although they often solve the problem eventually. This outcome is consistent with previous research indicating that callosal absence in AgCC results in a restricted imagination for possibilities, limiting their problem-solving and inferential capacities. The results also highlight the usefulness of semantic similarity as a means of scoring the WCT. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Metabolic consequences of treatment with AKT inhibitor perifosine in breast cancer cells.

Activation of the PI3K/Akt pathway is associated with the development of numerous human cancers. As a result, many emerging therapies target this pathway. Previous studies have shown that targeting the PI3K/Akt pathway at the level of PI3K is associated with a drop in phosphocholine (PCho) and a reduction in hyperpolarized lactate production. However, the consequences of targeting downstream of PI3K at the level of Akt have not been investigated. Perifosine is an anticancer alkylphospholipid used in clinical trials. It acts by inhibiting phosphorylation of Akt and has been shown to inhibit CTP-phosphocholine cytidyltransferase (CT). The goal of this study was to identify the MRS-detectable metabolic consequences of treatment with perifosine in MCF-7 breast cancer cells. We found that perifosine treatment led to a 51 ± 5% drop in PCho from 30 ± 5 to 15 ± 1 fmol/cell and a comparable drop in de novo synthesized PCho. This was associated with a drop in choline kinase (ChoK) activity and ChoKα expression. CT inhibition could not be ruled out but likely did not contribute to the change in PCho. We also found that intracellular lactate levels decreased from 2.7 ± 0.5 to 1.5 ± 0.3 fmol/cell and extracellular lactate levels dropped by a similar extent. These findings were consistent with a drop in lactate dehydrogenase expression and associated with a drop in activity of the hypoxia inducible factor (HIF)-1α. The drops in PCho and lactate production following perifosine treatment are therefore mediated downstream of Akt by the drop in HIF-1α, which serves as the transcription factor for both ChoK and lactate dehydrogenase. The metabolic changes were confirmed in a second breast cancer cell line, MDA-MB-231. Taken together, these findings indicate that PCho and lactate can serve as noninvasive metabolic biomarkers for monitoring the effects of inhibitors that target the PI3K/Akt pathway, independent of the step that leads to inhibition of HIF-1α.

Awareness of consequences in agenesis of the corpus callosum: Semantic analysis of responses.

OBJECTIVE: Agenesis of the corpus callosum (AgCC) in individuals with general intelligence within the normal range results in a syndrome of mild to moderate deficiencies in cognitive, emotional, and social functioning that are still being explored. Anecdotal accounts from families suggest that these cognitive and psychosocial deficiencies affect the ability of these individuals to anticipate the consequences of their decisions and behaviors. This research was designed to clarify the nature of social and emotional cognition in AgCC with respect to imagination of the consequences of decisions by assessing responses from the Awareness of Consequences Scale (AOCS). METHOD: Verbal AOCS responses from persons with AgCC and age and IQ-matched neurotypical controls were scored in the normal manner, and also subjected to semantic analyses using both latent semantic analysis and Linguistic Inquiry and Word Count. RESULTS: It was found that, relative to neurotypical controls, individuals with AgCC scored significantly lower on the typical scoring of the AOCS, had nontypical semantic content in their responses, and used fewer emotion and cognitive content (insight) words. These results were apparent in responses to the three most complex of the AOCS scenarios. CONCLUSIONS: Results were consistent with the hypothesis that persons with AgCC are deficient in the capacity to imagine the emotional and cognitive consequences of potential actions on others. particularly in the face of greater situational and social complexity. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

2-Arachidonylglyceryl ether and abnormal cannabidiol-induced vascular smooth muscle relaxation in rabbit pulmonary arteries via receptor-pertussis toxin sensitive G proteins-ERK1/2 signaling.

The receptor(s) used by cannabinoids to relax vascular smooth muscle is unknown. Here, we investigated the effects of 2-arachidonylglyceryl ether (2-AG ether), a metabolically stable endocannabinoid, and abnormal cannabidiol (abn-CBD) on relaxation of permeabilized pulmonary arterial strips monitored with force, and on extracellular signal-regulated mitogen-activated protein kinases (ERK1/2) phosphorylation in permeabilized vascular smooth muscle cells using immunoblotting. We found that 2-AG ether and abn-CBD caused relaxation and increased phosphorylation of ERK1/2. 2-AG ether effects were completely abolished by N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), and N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A), and partially blocked by (-)-1.3-dimethoxy-2-(3-3,4-trans-p-menthadien-(1,8)-yl)-orcinol (O-1918). In contrast, abn-CBD effects were completely abolished by O-1918, and only partially blocked by AM251, and SR141716A. Both 2-AG ether and abn-CBD effects were partially blocked by pertussis toxin, an inhibitor of Gi/o proteins. PD98059, an inhibitor of mitogen activated protein kinase kinase (MEK), completely abolished the relaxation, but only partially blocked the increased phosphorylation of ERK1/2 by 2-AG ether. In contrast, abn-CBD-induced relaxation was partially blocked and the increased phosphorylation of ERK1/2 was abolished by PD98059. These findings suggest that 2-AG ether and abn-CBD-induced vascular smooth muscle relaxation are mediated by the cannabinoid CB1 receptor, and the abn-CBD receptor, respectively, and are modulated by cross-talk between the receptors. These responses occur mainly by coupling to pertussis toxin sensitive G proteins, but also, in part independent of these G proteins, which have been classically thought to initiate MEK/ERK1/2 signaling to relax vascular smooth muscle.

Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation.

The protumorigenic functions for autophagy are largely attributed to its ability to promote cancer cell survival in response to diverse stresses. Here we demonstrate an unexpected connection between autophagy and glucose metabolism that facilitates adhesion-independent transformation driven by a strong oncogenic insult-mutationally active Ras. In cells ectopically expressing oncogenic H-Ras as well as human cancer cell lines harboring endogenous K-Ras mutations, autophagy is induced following extracellular matrix detachment. Inhibiting autophagy due to the genetic deletion or RNA interference-mediated depletion of multiple autophagy regulators attenuates Ras-mediated adhesion-independent transformation and proliferation as well as reduces glycolytic capacity. Furthermore, in contrast to autophagy-competent cells, both proliferation and transformation in autophagy-deficient cells expressing oncogenic Ras are insensitive to reductions in glucose availability. Overall, increased glycolysis in autophagy-competent cells facilitates Ras-mediated adhesion-independent transformation, suggesting a unique mechanism by which autophagy may promote Ras-driven tumor growth in specific metabolic contexts.

Role of protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and mitogen-activated protein kinases in volatile anesthetic-induced relaxation in newborn rabbit pulmonary artery.

BACKGROUND: This study examined the responsiveness of skinned pulmonary arteries from newborn rabbit to volatile anesthetics and the role of protein kinase C (PKC), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and the downstream effectors, mitogen-activated protein kinases (ERK1/2 and p38). METHODS: Pulmonary arterial strips from 9- to 12-day-old rabbits were mounted on force transducers and treated with saponin ("skinned" strips). The skinned strips were activated by pCa 6.3 until force reached a steady state (control). Isoflurane or halothane was then administered. The result (test) was expressed as a percentage of the control. Inhibitors included bisindolylmaleimide (Ca2+-dependent and -independent PKC), Gö6976 (Ca2+-dependent PKC), CKIINtide (CaMKII), KN-93 (CaMKII), PD98059 (MEK/ERK1/2), and SB203580 (p38). RESULTS: The anesthetics dose-dependently decreased pCa-induced force (4-32% for 1-5% isoflurane; 17-76% for 1-3% halothane). The inhibitors of PKC (bisindolylmaleimide and Gö6976) and MEK/ERK1/2 (PD98059) completely prevented the relaxation induced by 3% isoflurane and partially prevented that induced by 2% and 3% halothane with the same effective inhibitor concentrations. In contrast, the effective concentration of CaMKII inhibitors was a direct function of the anesthetic concentration for different inhibitors (KN-93 for isoflurane and CKIINtide for halothane), and that of the p38 inhibitor (SB20358) was a direct function of both anesthetics. CONCLUSIONS: In Ca2+-clamped skinned pulmonary arterial strips from newborn rabbits, the anesthetics induce relaxation, which is prevented by the PKC inhibitors MEK/ERK/12, CaMKII, and p38. It is proposed that the anesthetic-induced relaxation is via cPKC/MEK/ERK1/2 and CaMKII/p38 pathways and, in addition, via CaMKII-p/MLCK-p(-)/MLC-p(-) for halothane.

Ca(2+)-calmodulin-dependent protein kinase II plays a major role in halothane-induced dose-dependent relaxation in the skinned pulmonary artery.

BACKGROUND: Previously, the authors have shown in Ca(2+)-clamped skinned arterial strips that protein kinase C (PKC) plays a role in 3% halothane- or isoflurane-increased force. PKC in the pulmonary artery and Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) in the femoral artery have been implicated in isoflurane-induced relaxation. For this study, the authors used clinical concentrations of halothane to examine the role of PKC and CaMKII in the halothane-induced biphasic effect on contraction in skinned pulmonary arterial strips. METHODS: Rabbit pulmonary arterial strips were mounted on force transducers and treated with saponin to make the sarcolemma permeable ("skinning"). Skinned strips were activated by low Ca(2+) (pCa 6.3) buffered with 7 mm EGTA, or the PKC activator phorbol-12,13-dibutyrate (PDBu, 1 microm) until force reached a steady state (control). Halothane (1, 2, and 3%) was administered, and the force was observed at peak and 15 min (test results). Ca(2+) ionophore (A23187, 10 microm) and inhibitors were preincubated in a relaxing solution and present in subsequent contracting solutions. Inhibitors were bisindolylmaleimide and Gö6976 for PKC, and KN-93 and the inhibitor protein (CKIINtide) for CaMKII. RESULTS: Halothane (1-3%) dose-dependently caused an initial increase (18-35%) and a subsequent decrease (48-68%) in pCa 6.3-induced force. Bisindolylmaleimide, 3 and 10 microm, completely blocked the increase in force at 2% and 3% halothane, respectively. CKIINtide, 0.1 microm, reduced the force at 3% halothane. The decrease in force at 1% and 2% halothane was partially prevented by 0.01 microm bisindolylmaleimide, and at 1, 2, and 3% halothane by 0.01, 0.1, and 1 microm CKIINtide, respectively. At 3% halothane, the increased force was abolished by A23187. In PDBu-induced force, 3% halothane-induced relaxation was also partially prevented by lower concentrations of KN-93 and CKIINtide. CONCLUSIONS: In skinned pulmonary arterial strips, the dose-dependent increase in force by halothane is associated with PKC activation, and that of decrease is associated with CaMKII activation.

Isoflurane activates PKC and Ca(2+) -calmodulin-dependent protein kinase II via MAP kinase signaling in cultured vascular smooth muscle cells.

BACKGROUND: Protein kinase C (PKC) and Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) have been implicated in isoflurane-increased force in skinned femoral arterial strips. The extracellular signal-regulated kinases (ERK1/2) of mitogen-activated protein kinase have been shown to be target effectors of PKC and CaMKII. This study examined the role of the ERK1/2 signaling pathway in isoflurane activation of PKC and CaMKII using cultured vascular smooth muscle cells. METHODS: Vascular smooth muscle cells were prepared by cell migration from isolated rabbit femoral arterial segments. Growth of passage of vascular smooth muscle cells (80-90% confluence, passage 5-10) was arrested for 48 h before experiments, during which time phorbol 1,3-diaceylester treatment was used to down-regulate PKC. Cells were treated for 30 min with one of the inhibitors of mitogen-activated protein kinase kinase (PD98059), PKC (Go6976 and bisindolylmaleimide), or CaMKII (KN-93 and KN-62) at 10 microm. After administration of isoflurane, vascular smooth muscle cells were frozen rapidly, homogenized, and centrifuged. The homogenates were used for identification of phosphorylated ERK1/2 or for further centrifugation to separate the membrane from the cytosol for identification of PKC isoforms (alpha and epsilon) by Western blotting. RESULTS: Isoflurane increased ERK1/2 phosphorylation in a dose-dependent manner and reached a plateau at 10 min. PD98059 or down-regulated PKC blocked the increase of phosphorylated ERK1/2 levels by isoflurane, and bisindolylmaleimide, KN-93, or KN-62, but not by Go6976 reduced levels of phosphorylated ERK1/2. The membrane fraction of PKC epsilon but not of PKC alpha was increased by isoflurane. CONCLUSIONS: ERK1/2 signaling is downstream of PKC and CaMKII activated by isoflurane in vascular smooth muscle cells.

Role of PKC in isoflurane-induced biphasic contraction in skinned pulmonary arterial strips.

BACKGROUND: Activation or inhibition of protein kinase C (PKC) has been implicated in the anesthetic-induced contraction or relaxation of different types of arteries. In skinned pulmonary arterial strips, the initial halothane-induced contraction has been attributed to PKC activation, but the subsequent relaxation has not. Whether isoflurane has a similar biphasic effect is not known. This study examined the role of PKC and its isoforms in the effect of isoflurane on pulmonary artery. METHODS: Rabbit pulmonary arterial strips were mounted on force transducers and treated with saponin to make the sarcolemma permeable ("skinned" strips). Skinned strips were activated by low Ca(2+) (pCa 6.5 or pCa 6.3 buffered with 7 mm EGTA) or the PKC activator phorbol-12,13-dibutyrate (1 microm) until force reached a steady state (control). Various concentrations of isoflurane (test) were administered, and force was observed at time intervals up to 60 min. The PKC inhibitors (bisindolylmaleimide and Go6976 from 0.1 to 10 microm) were preincubated in a relaxing solution and the subsequent contracting solutions. The results were expressed as a percentage of control, with P < 0.05 considered significant for statistical comparison between the tests and time controls. RESULTS: In a dose-dependent fashion, isoflurane (1-5%) initially increased (5-40%) and then decreased (3-70%) the Ca(2+)- or phorbol-12,13-dibutyrate (pCa 6.7 buffer)-activated force. The increased in force caused by isoflurane was partially reduced by 3 and 10 microm bisindolylmaleimide, but not by Go6976. Isoflurane-induced relaxation was partially prevented by both inhibitors at 0.1 and 0.3 microm. CONCLUSIONS: Isoflurane causes biphasic effects in skinned pulmonary arterial strips that may be in part mediated by different isoforms of PKC.