Contribution of the PI 3-kinase/Akt survival pathway toward osmotic preconditioning

Osmolytes are rapidly lost from the ischemic heart, an effect thought to benefit the heart by reducing the osmotic load. However, the observation that chronic lowering of one of the prominent osmolytes, taurine, is more beneficial to the ischemic heart than acute taurine loss suggests that osmotic stress may benefit the ischemic heart through multiple mechanisms. The present study examines the possibility that chronic osmotic stress preconditions the heart in part by stimulating a cardioprotective, osmotic-linked signaling pathway. Hyperosmotic stress was produced by treating rat neonatal cardiomyocytes during the pre-hypoxic period with either the taurine depleting agent, #x003B2;-alanine (5 mM), or with medium containing 25 mM mannitol. The cells were then subjected to chemical hypoxia in medium containing 3 mM Amytal and 10 mM deoxyglucose but lacking #x003B2;-alanine and mannitol. Cells that had been pretreated with either 5 mM #x003B2;-alanine or 25 mM mannitol exhibited resistance against hypoxia-induced apoptosis and necrosis. Associated with the osmotically preconditioned state was the activation of Akt and the inactivation of the pro-apoptotic factor, Bad, both events blocked by the inhibition of PI 3-kinase. However, preconditioning the cardiomyocyte with mannitol had no effect on the generation of free radicals during the hypoxic period. Osmotic stress also promoted the upregulation of the anti-apoptotic factor, Bcl-2. Since inhibition of PI 3-kinase with Wortmannin also prevents osmotic-mediated cardioprotection, we conclude that hyperosmotic-mediated activation of the PI 3-kinase/Akt pathway contributes to osmotic preconditioning. (Mol Cell Biochem 269: 59–67, 2005)     

Brown seaweed protein as an inhibitor of marine mollusk endo-(1-->3)-beta-D-glucanases

Aqueous ethanol extracts from brown seaweed were found to contain substances inhibiting endo-(1-->3)-beta-D-glucanases, the digestive enzymes of marine mollusks. The inhibitors were detected in 70% of the brown seaweeds investigated. An irreversible protein inhibitor with high specificity for endo-(1-->3)-beta-D-glucanases of marine mollusks was isolated from the brown seaweed, Laminaria cichorioides. As determined by gel filtration, the molecular weight of the inhibitor was 46 kDa. The value of [I]50 (10(-8) M) for the inhibitor was comparable with the corresponding value for natural alpha-amylase inhibitors from terrestrial plants. Chemical modification results indicated that tryptophan, dicarboxylic acid, histidine and probably tyrosine residues of inhibitor molecule are important for interaction of the inhibitor with the enzyme.     

The Undecided Have the Key: Interaction-Driven Opinion Dynamics in a Three State Model

The effects of interpersonal interactions on individual’s agreements result in a social aggregation process which is reflected in the formation of collective states, as for instance, groups of individuals with a similar opinion about a given issue. This field, which has been a longstanding concern of sociologists and psychologists, has been extended into an area of experimental social psychology, and even has attracted the attention of physicists and mathematicians. In this article, we present a novel model of opinion formation in which agents may either have a strict preference for a choice, or be undecided. The opinion shift emerges, in a threshold process, as a consequence of a cumulative persuasion for either one of the two opinions in repeated interactions. There are two main ingredients which play key roles in determining the steady states: the initial fraction of undecided agents and the change in agents’ persuasion after each interaction. As a function of these two parameters, the model presents a wide range of solutions, among which there are consensus of each opinion and bi-polarization. We found that a minimum fraction of undecided agents is not crucial for reaching consensus only, but also to determine a dominant opinion in a polarized situation. In order to gain a deeper comprehension of the dynamics, we also present the theoretical framework of the model. The master equations are of special interest for their nontrivial properties and difficulties in being solved analytically.     

Cooperation and Defection at the Crossroads

We study a simple traffic model with a non-signalized road intersection. In this model the car arriving from the right has precedence. The vehicle dynamics far from the crossing are governed by the rules introduced by Nagel and Paczuski, which define how drivers behave when braking or accelerating. We measure the average velocity of the ensemble of cars and its flow as a function of the density of cars on the roadway. An additional set of rules is defined to describe the dynamics at the intersection assuming a fraction of drivers that do not obey the rule of precedence. This problem is treated within a game-theory framework, where the drivers that obey the rule are cooperators and those who ignore it are defectors. We study the consequences of these behaviors as a function of the fraction of cooperators and defectors. The results show that cooperation is the best strategy because it maximizes the flow of vehicles and minimizes the number of accidents. A rather paradoxical effect is observed: for any percentage of defectors the number of accidents is larger when the density of cars is low because of the higher average velocity.     

CyPPA, a positive modulator of small-conductance Ca(2+)-activated K(+) channels, inhibits phasic uterine contractions and delays preterm birth in mice

Organized uterine contractions, including those necessary for parturition, are dependent on calcium entry through voltage-gated calcium channels in myometrial smooth muscle cells. Recent evidence suggests that small-conductance Ca(2+)-activated potassium channels (K(Ca)2), specifically isoforms K(Ca)2.2 and 2.3, may control these contractions through negative feedback regulation of Ca(2+) entry. We tested whether selective pharmacologic activation of K(Ca)2.2/2.3 channels might depress uterine contractions, providing a new strategy for preterm labor intervention. Western blot analysis and immunofluorescence microscopy revealed expression of both K(Ca)2.2 and K(Ca)2.3 in the myometrium of nonpregnant (NP) and pregnant (gestation day 10 and 16; D10 and D16, respectively) mice. Spontaneous phasic contractions of isolated NP, D10, and D16 uterine strips were all suppressed by the K(Ca)2.2/2.3-selective activator CyPPA in a concentration-dependent manner. This effect was antagonized by the selective K(Ca)2 inhibitor apamin. Whereas CyPPA sensitivity was reduced in D10 and D16 versus NP strips (pIC(50) 5.33 ± 0.09, 4.64 ± 0.03, 4.72 ± 0.10, respectively), all contractions were abolished between 30 and 60 μM. Blunted contractions were associated with CyPPA depression of spontaneous Ca(2+) events in myometrial smooth muscle bundles. Augmentation of uterine contractions with oxytocin or prostaglandin F(2α) did not reduce CyPPA sensitivity or efficacy. Finally, in an RU486-induced preterm labor model, CyPPA significantly delayed time to delivery by 3.4 h and caused a 2.5-fold increase in pup retention. These data indicate that pharmacologic stimulation of myometrial K(Ca)2.2/2.3 channels effectively suppresses Ca(2+)-mediated uterine contractions and delays preterm birth in mice, supporting the potential utility of this approach in tocolytic therapies.     

Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration

Neurologic disorders often disproportionately affect specific brain regions, and different apoptotic mechanisms may contribute to white matter pathology in leukodystrophies or gray matter pathology in poliodystrophies. We previously showed that neural progenitors that generate cerebellar gray matter depend on the anti-apoptotic protein BCL-xL. Conditional deletion of Bcl-xL in these progenitors produces spontaneous apoptosis and cerebellar hypoplasia, while similar conditional deletion of Mcl-1 produces no phenotype. Here we show that, in contrast, postnatal oligodendrocytes depend on MCL-1. We found that brain-wide Mcl-1 deletion caused apoptosis specifically in mature oligodendrocytes while sparing astrocytes and oligodendrocyte precursors, resulting in impaired myelination and progressive white matter degeneration. Disabling apoptosis through co-deletion of Bax or Bak rescued white matter degeneration, implicating the intrinsic apoptotic pathway in Mcl-1-dependence. Bax and Bak co-deletions rescued different aspects of the Mcl-1-deleted phenotype, demonstrating their discrete roles in white matter stability. MCL-1 protein abundance was reduced in eif2b5-mutant mouse model of the leukodystrophy vanishing white matter disease (VWMD), suggesting the potential for MCL-1 deficiency to contribute to clinical neurologic disease. Our data show that oligodendrocytes require MCL-1 to suppress apoptosis, implicate MCL-1 deficiency in white matter pathology, and suggest apoptosis inhibition as a leukodystrophy therapy.Subject terms: Cell death in the nervous system, Neurodegeneration, Oligodendrocyte     

Testosterone stimulates the expression of a social color signal in Yarrow's Spiny Lizard, Sceloporus jarrovii

The sex steroid testosterone has been shown to regulate the development of male-specific coloration in many organisms that exhibit sexual dichromatism, but the role of testosterone is less certain for species in which both sexes express bright coloration. Lizards in the genus Sceloporus possess bright blue patches on their throats and abdomens. These patches, which are used in social signaling, are often regulated by testosterone and are consequently expressed only in males of most species. However, Yarrow's Spiny Lizard (Sceloporus jarrovii, Cope 1875) exhibits a derived condition in which both sexes express bright blue ventral patches despite dramatic sexual differences in circulating testosterone levels throughout postnatal ontogeny. In this study, we used surgical castration and hormone replacement in juvenile males to test the hypothesis that testosterone stimulates the expression of blue ventral coloration in S. jarrovii. In two separate experiments conducted in captivity and the natural field environment, we found that surgical castration decreased the hue and saturation while increasing the brightness of blue throat and abdominal patches. Castration also decreased the amount of black pigment bordering the blue throat patch. Treatment of castrated males with exogenous testosterone restored all aspects of ventral coloration to values similar to those of intact control males. Early organizational effects of testosterone during prenatal development may lead to the expression of blue coloration in both sexes, but the results of our present experiments indicate that subsequent effects of testosterone during sexual maturation further enhance the coloration of males.     

Chromium(VI) reduction in a membrane bioreactor with immobilized Pseudomonas cells

Chromate reduction was studied in a membrane bioreactor under action of Pseudomonas bacteria immobilized in agar–agar films on the surface of synthetic membrane. Immobilized cells are protected from the excessive toxic action at high chromate concentration that improves cell activity compared with free cells. Almost complete chromate reduction was observed at stepwise introducing of chromate in feed solution allowing maintenance of optimal chromate concentration. Reduction is suppressed by high metabolite concentrations, which reached on the sixth step of chromate adding in studied system. Cell ability to reduce chromate is restored after changing of feed and receiving solutions allowing remediation of Cr(VI)-contaminated water in semi-batch operation of membrane bioreactor.