Creatine and pyruvate prevent behavioral and oxidative stress alterations caused by hypertryptophanemia in rats

It is known that the accumulation of tryptophan and its metabolites is related to brain damage associated with both hypertryptophanemia and neurodegenerative diseases. In this study, we investigated the effect of tryptophan administration on various parameters of behavior in the open-field task and oxidative stress, and the effects of creatine and pyruvate, on the effect of tryptophan. Forty, 60-day-old male Wistar rats, were randomly divided into four groups: saline, tryptophan, pyruvate + creatine, tryptophan + pyruvate + creatine. Animals received three subcutaneous injections of tryptophan (2 μmol/g body weight each one at 3 h of intervals) and/or pyruvate (200 μg/g body weight 1 h before tryptophan), and/or creatine (400 μg/g body weight twice a day for 5 days before tryptophan twice a day for 5 days before training); controls received saline solution (NaCl 0.85%) at the same volumes (30 μl/g body weight) than the other substances. Results showed that tryptophan increased the activity of the animals, suggesting a reduction in the ability of habituation to the environment. Tryptophan induced increase of TBA-RS and total sulfhydryls. The effects of tryptophan in the open field, and in oxidative stress were fully prevented by the combination of creatine plus pyruvate. In case these findings also occur in humans affected by hypertryptophanemia or other neurodegenerative disease in which tryptophan accumulates, it is feasible that oxidative stress may be involved in the mechanisms leading to the brain injury, suggesting that creatine and pyruvate supplementation could benefit patients affected by these disorders.     

Development of isoform selective PI3-kinase inhibitors as pharmacological tools for elucidating the PI3K pathway

Using a parallel synthesis approach to target a non-conserved region of the PI3K catalytic domain a pan-PI3K inhibitor 1 was elaborated to provide alpha, delta and gamma isoform selective Class I PI3K inhibitors 21, 24, 26 and 27. The compounds had good cellular activity and were selective against protein kinases and other members of the PI3K superfamily including mTOR and DNA-PK.     

Dormancy of<Emphasis Type="Italic"> Arabidopsis</Emphasis> seeds and barley grains can be broken by nitric oxide

Seeds of Arabidopsis thaliana (L.) Heynh. and grains of barley (Hordeum vulgare L.) were used to characterize the affects of nitric oxide (NO) on seed dormancy. Seeds of the C24 and Col-1 ecotypes of Arabidopsis are almost completely dormant when freshly harvested, but dormancy was broken by stratification for 3 days at 4°C or by imbibition of seeds with the NO donor sodium nitroprusside (SNP). This effect of SNP on dormancy of Arabidopsis seeds was concentration dependent. SNP concentrations as low as 25 M reduced dormancy and stimulated germination, but SNP at 250 M or more impaired seedling development, including root growth, and inhibited germination. Dormancy was also reduced when Arabidopsis seeds were exposed to gasses that are generated by solutions of SNP. Nitrate and nitrite, two other oxides of nitrogen, reduced the dormancy of Arabidopsis seeds, but much higher concentrations of these were required compared to SNP. Furthermore, the kinetics of germination were slower for seeds imbibed with either nitrate or nitrite than for seeds imbibed with SNP. Although seeds imbibed with SNP had reduced dormancy, seeds imbibed with SNP and abscisic acid (ABA) remained strongly dormant. This may indicate that the effects of ABA action on germination are downstream of NO action. The NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3 oxide (cPTIO) strengthened dormancy of unstratified and briefly stratified Arabidopsis seeds. Dormancy of three cultivars of barley was also reduced by SNP. Furthermore, dormancy in barley grain was strengthened by imbibition of grain with cPTIO. The data presented here support the conclusion that NO is a potent dormancy breaking agent for seeds and grains. Experiments with the NO scavenger suggest that NO is an endogenous regulator of seed dormancy.Abbreviations ABA Abscisic acid - cPTIO 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3 oxide - GA Gibberellin - SNP Sodium nitroprusside - NO_x Gaseous oxides of nitrogen     

Constitutive and transport-related endocytotic pathways in turtle bladder epithelium

Summary Proton secretion in the urinary bladder of the fresh-water turtle is mediated by a proton pump located in the apical membrane of a population of cells characteristically rich in carbonic anhydrase. Earlier studies have demonstrated that these cells exhibit apical-membrane endocytotic and exocytotic processes which are thought to be involved in the regulation of the rate of proton transport via alterations in the number of pumps within the apical membrane. In this study, we sought to characterize these processes using two different methods. Analysis of transepithelial impedance yielded estimates of membrane capacitance which could be related to membrane area, thereby allowing one to monitor net changes in apical-membrane area resulting from changes in the net rates of endo-and exocytosis. Uptake of the fluid-phase marker FITC-dextran provided a measure of net extracellular volume uptake which was related to net rates of endocytosis. Our major conclusions are summarized as follows. The bladder cells exhibit a high baseline rate of endocytosis which appears to be a constitutive process similar to pinocytosis. This process is completely inhibited when ambient temperature is reduced to 15°C. In addition, serosal application of 0.5mm acetazolamide causes a transient increase in the rate of endocytosis, concomitant with a decrease in the rate of transport. Reduction of ambient temperature to 15°C reduces the rate of acetazolamide-induced endocytosis, but does not abolish it. Addition of 1mm serosal azide not only prevents the acetazolamide-induced increase in endocytosis, but also prevents the decrease in transport caused by acetazolamide. Azide has no effect on the baseline rate of endocytosis, nor does it prevent inhibition of carbonic anhydrase by acetazolamide. The specificity of azide, coupled with the different temperature sensitivities, demonstrate that the constitutive and transport-dependent endocytotic pathways are distinct processes. The observation that azide prevents both the acetazolamide-induced increase in endocytosis and the decrease in transport strongly supports the notion that endocytosis of proton-pump-containing membrane is requisite for the inhibition of transport by acetazolamide. Finally, the results also demonstrate that acetazolamide does not inhibit proton secretion simply by inhibiting carbonic anhydrase.     

The Biphasic Effects of Moderate Alcohol Consumption with a Meal on Ambiance-Induced Mood and Autonomic Nervous System Balance: A Randomized Crossover Trial

Background

The pre-drinking mood state has been indicated to be an important factor in the mood effects of alcohol. However, for moderate alcohol consumption there are no controlled studies showing this association. Also, the mood effects of consuming alcohol combined with food are largely unknown. The aim of this study was to investigate the effects of moderate alcohol combined with a meal on ambiance-induced mood states. Furthermore effects on autonomic nervous system activity were measured to explore physiological mechanisms that may be involved in changes of mood state.

Methods

In a crossover design 28 women (age 18–45 y, BMI 18.5–27 kg/m²) were randomly allocated to 4 conditions in which they received 3 glasses of sparkling white wine (30 g alcohol) or alcohol-free sparkling white wine while having dinner in a room with either a pleasant or unpleasant created ambiance. Subjects filled out questionnaires (B-BAES, POMS and postprandial wellness questionnaire) at different times. Skin conductance and heart rate variability were measured continuously.

Results

Moderate alcohol consumption increased happiness scores in the unpleasant, but not in the pleasant ambiance. Alcohol consumption increased happiness and stimulation feelings within 1 hour and increased sedative feelings and sleepiness for 2.5 hour. Skin conductance was increased after alcohol within 1 hour and was related to happiness and stimulation scores. Heart rate variability was decreased after alcohol for 2 hours and was related to mental alertness.

Conclusion

Mood inductions and autonomic nervous system parameters may be useful to evaluate mood changes by nutritional interventions. Moderate alcohol consumption elevates happiness scores in an unpleasant ambiance. However, drinking alcohol during a pleasant mood results in an equally positive mood state.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01426022","term_id":"NCT01426022"}}NCT01426022.     

Associations between Exposure to Intimate Partner Violence,Armed Conflict,and Probable PTSD among Women in Rural C?te d’Ivoire

Background

Objectives were to assess associations between intimate partner violence (IPV), violence during armed conflict (i.e. crisis violence), and probable post-traumatic stress disorder (PTSD).

Methods

Using a sample of 950 women in rural Côte d’Ivoire, logistic generalized estimating equations assessed associations between IPV and crisis violence exposures with past-week probable PTSD.

Results

Over one in 5 (23.4%) women reported past-year IPV, and over one in 4 women (26.5%) reported experiencing IPV prior to the past year (i.e. remote IPV). Crisis violence was experienced by 72.6% of women. In adjusted models including demographics, crisis violence (overall and specific forms), and IPV (remote and past-year), women who reported past-year IPV had 3.1 times the odds of reporting probable past-week PTSD (95%CI: 1.8–5.3) and those who reported remote IPV had 1.6 times the odds (95%CI: 0.9–2.7). Violent exposures during the crisis were not significantly associated with probable PTSD (any crisis violence: aOR: 1.04 (0.7–1.5); displacement: aOR: 0.9 (95%CI: 0.5–1.7); family victimization during crisis: aOR: 1.1 (95%CI: 0.8–1.7); personal victimization during crisis: aOR: 1.7 (95%CI: 0.7–3.7)).

Conclusion

Past-year IPV was more strongly associated with past-week probable PTSD than remote IPV and violence directly related to the crisis. IPV must be considered within humanitarian mental health and psychosocial programming.     

Relationship of the Perceived Social and Physical Environment with Mental Health-Related Quality of Life in Middle-Aged and Older Adults: Mediating Effects of Physical Activity

Background

Mental health conditions are among the leading non-fatal diseases in middle-aged and older adults in Australia. Proximal and distal social environmental factors and physical environmental factors have been associated with mental health, but the underlying mechanisms explaining these associations remain unclear. The study objective was to examine the contribution of different types of physical activity in mediating the relationship of social and physical environmental factors with mental health-related quality of life in middle-aged and older adults.

Methods

Baseline data from the Wellbeing, Eating and Exercise for a Long Life (WELL) study were used. WELL is a prospective cohort study, conducted in Victoria, Australia. Baseline data collection took place in 2010. In total, 3,965 middle-aged and older adults (55–65 years, 47.4% males) completed the SF-36 Health Survey, the International Physical Activity Questionnaire, and a questionnaire on socio-demographic, social and physical environmental attributes. Mediation analyses were conducted using the MacKinnon product-of-coefficients test.

Results

Personal safety, the neighbourhood physical activity environment, social support for physical activity from family or friends, and neighbourhood social cohesion were positively associated with mental health-related quality of life. Active transportation and leisure-time physical activity mediated 32.9% of the association between social support for physical activity from family or friends and mental health-related quality of life. These physical activity behaviours also mediated 11.0%, 3.4% and 2.3% respectively, of the relationship between the neighbourhood physical activity environment, personal safety and neighbourhood social cohesion and mental health-related quality of life.

Conclusions

If these results are replicated in future longitudinal studies, tailored interventions to improve mental health-related quality of life in middle-aged and older adults should use a combined strategy, focusing on increasing physical activity as well as social and physical environmental attributes.     

Solution structure of mu-conotoxin PIIIA,a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels

Mu-conotoxins are peptide inhibitors of voltage-sensitive sodium channels (VSSCs). Synthetic forms of mu-conotoxins PIIIA and PIIIA-(2-22) were found to inhibit tetrodotoxin (TTX)-sensitive VSSC current but had little effect on TTX-resistant VSSC current in sensory ganglion neurons. In rat brain neurons, these peptides preferentially inhibited the persistent over the transient VSSC current. Radioligand binding assays revealed that PIIIA, PIIIA-(2-22), and mu-conotoxins GIIIB discriminated among TTX-sensitive VSSCs in rat brain, that these and GIIIC discriminated among the corresponding VSSCs in human brain, and GIIIA had low affinity for neuronal VSSCs. (1)H NMR studies found that PIIIA adopts two conformations in solution due to cis/trans isomerization at hydroxyproline 8. The major trans conformation results in a three-dimensional structure that is significantly different from the previously identified conformation of mu-conotoxins GIIIA and GIIIB that selectively target TTX-sensitive muscle VSSCs. Comparison of the structures and activity of PIIIA to muscle-selective mu-conotoxins provides an insight into the structural requirements for inhibition of different TTX-sensitive sodium channels by mu-conotoxins.     

Interaction ofH-2 and nonH-2 linked genes in the regulation of antibody response to a threshold dose of sheep erythrocytes

The antibody response to a threshold dose (¹⁰) of SE was studied in the High responder line (H) and the Low responder line (L) of mice obtained by bidirectional selective breeding for the character quantitative agglutinin response to an optimal dose of SE, and in interline hybrids: F₁, F₁ and both backcrosses. Whereas the interline difference in agglutinin responses at the optimal dose is due to the additive effect of about ten independently segregating loci, one of which isH-2 linked, the responsiveness to the threshold dose is determined by the effect of two loci. The direction of the dominance effect also varies with the antigen dose: high responsiveness is partially dominant at the optimal dose while at the threshold dose nonresponder character is partially dominant. The role of theH-2 linked locus was investigated. It has been demonstrated that on an identical background (equivalent to that of F₁ hybrids) this locus is responsible for 12% of the interline difference at the optimal antigen dose, and for 61% at the threshold antigen dose. For the two antigen doses, the quantitative effect of theH-2 locus is in agreement with the estimate of the number of loci obtained by variance analysis. The intervention of a second gene, non-H-2 linked, in the regulation of responsiveness to 10⁶ SE is demonstrated by appropriate assortative matings. The interaction between the two genes is discussed.     

Segregation analysis and RFLP mapping of the R1 and R3 alleles conferring race-specific resistance to Phytophthora infestans in progeny of dihaploid potato parents

Phytophthora infestans (Mont.) de Bary is the most important fungal pathogen of the potato (Solanum tuberosum). The introduction of major genes for resistance from the wild species S. demissum into potato cultivars is the earliest example of breeding for resistance using wild germplasm in this crop. Eleven resistance alleles (R genes) are known, differing in the recognition of corresponding avirulence alleles of the fungus. The number of R loci, their positions on the genetic map and the allelic relationships between different R variants are not known, except that the R1 locus has been mapped to potato chromosome V The objective of this work was the further genetic analysis of different R alleles in potato. Tetraploid potato cultivars carrying R alleles were reduced to the diploid level by inducing haploid parthenogenetic development of 2n female gametes. Of the 157 isolated primary dihaploids, 7 set seeds and carried the resistance alleles R1, R3 and R10 either individually or in combinations. Independent segregation of the dominant R1 and R3 alleles was demonstrated in two F₁ populations of crosses among a dihaploid clone carrying R1 plus R3 and susceptible pollinators. Distorted segregation in favour of susceptibility was found for the R3 allele in 15 of 18 F₁ populations analysed, whereas the RI allele segregated with a 1:1 ratio as expected in five F₁ populations. The mode of inheritance of the R10 allele could not be deduced as only very few F₁ hybrids bearing R10 were obtained. Linkage analysis in two F₁ populations between R1, R3 and RFLP markers of known position on the potato RFLP maps confirmed the position of the R1 locus on chromosome V and localized the second locus, R3, to a distal position on chromdsome XI.