Differential mechanisms of adenosine- and ATPγS-induced microvascular endothelial barrier strengthening.

Maintenance of the endothelial cell (EC) barrier is critical to vascular homeostasis and a loss of barrier integrity results in increased vascular permeability. While the mechanisms that govern increased EC permeability have been under intense investigation over the past several decades, the processes regulating the preservation/restoration of the EC barrier remain poorly understood. Herein we show that the extracellular purines, adenosine (Ado) and adenosine 5'-[γ-thio]-triphosphate (ATPγS) can strengthen the barrier function of human lung microvascular EC (HLMVEC). This ability involves protein kinase A (PKA) activation and decreases in myosin light chain 20 (MLC20) phosphorylation secondary to the involvement of MLC phosphatase (MLCP). In contrast to Ado, ATPγS-induced PKA activation is accompanied by a modest, but significant decrease in cyclic adenosine monophosphate (cAMP) levels supporting the existence of an unconventional cAMP-independent pathway of PKA activation. Furthermore, ATPγS-induced EC barrier strengthening does not involve the Rap guanine nucleotide exchange factor 3 (EPAC1) which is directly activated by cAMP but is instead dependent upon PKA-anchor protein 2 (AKAP2) expression. We also found that AKAP2 can directly interact with the myosin phosphatase-targeting protein MYPT1 and that depletion of AKAP2 abolished ATPγS-induced increases in transendothelial electrical resistance. Ado-induced strengthening of the HLMVEC barrier required the coordinated activation of PKA and EPAC1 in a cAMP-dependent manner. In summary, ATPγS-induced enhancement of the EC barrier is EPAC1-independent and is instead mediated by activation of PKA which is then guided by AKAP2, in a cAMP-independent mechanism, to activate MLCP which dephosphorylates MLC20 resulting in reduced EC contraction and preservation.

Using PPT to account for randomness in perception.

According to many theories of decision making, of which signal detection theory is the most prominent, randomness is the main factor responsible for imperfect performance. These theories imply that correcting for attenuation due to randomness should result in perfect scores as long as the participants use nonextreme decision criteria. On the basis of a recent advance termed potential performance theory (Trafimow & Rice, Psychological Review 115:447-462, 2008), we performed auditory and visual detection experiments and corrected the scores for attenuation. Most participants in both experiments tended to perform at a less-than-perfect level, even after their scores were corrected. The findings demonstrate that at least one systematic factor influences detection that is not included in signal detection theory.

Using the ideal observer to predict performance in perceptual tasks: an example from the auditory temporal masking domain.

This article provides a demonstration of an analytical technique that can be used to investigate the causes of perceptual phenomena. The technique is based on the concept of the ideal observer, an optimal signal classifier that makes decisions that maximize the probability of a correct response. To demonstrate the technique, an analysis was conducted to investigate the role of the auditory periphery in the production of temporal masking effects. The ideal observer classified output from four models of the periphery. Since the ideal observer is the best of all possible observers, if it demonstrates masking effects, then all other observers must as well. If it does not demonstrate masking effects, then nothing about the periphery requires masking to occur, and therefore masking would occur somewhere else. The ideal observer exhibited several forward masking effects but did not exhibit backward masking, implying that the periphery has a causal role in forward but not backward masking. A general discussion of the strengths of the technique and supplementary equations are also included.

Improving upon the in vitro biological activity of antithrombotic disulfides.

Several sulfur-containing compounds, isolated from garlic, have been implicated as highly active antithrombotic agents. We have prepared 10 new aromatic disulfides and an aromatic thiosulfonate in order to determine the in vitro response of human platelets to dosages of these compounds. The poor biological activity of PhSSCH3 was enhanced by the introduction of, inter alia, a nitro group onto the aromatic ring. The nitro group increased potency by activating the disulfide linkage. Anti-platelet aggregation activity was also enhanced by increasing the lipophilicity of one test compound. The ability of an aromatic disulfide to inhibit platelet aggregation can be enhanced by appending an electron-withdrawing group to the aromatic ring. The results presented establish that the aromatic thiosulfonate is a very effective inhibitor of platelet aggregation.