Genetic and Environmental Influences on the Relationship between Flow Proneness,Locus of Control and Behavioral Inhibition

Flow is a psychological state of high but subjectively effortless attention that typically occurs during active performance of challenging tasks and is accompanied by a sense of automaticity, high control, low self-awareness, and enjoyment. Flow proneness is associated with traits and behaviors related to low neuroticism such as emotional stability, conscientiousness, active coping, self-esteem and life satisfaction. Little is known about the genetic architecture of flow proneness, behavioral inhibition and locus of control – traits also associated with neuroticism – and their interrelation. Here, we hypothesized that individuals low in behavioral inhibition and with an internal locus of control would be more likely to experience flow and explored the genetic and environmental architecture of the relationship between the three variables. Behavioral inhibition and locus of control was measured in a large population sample of 3,375 full twin pairs and 4,527 single twins, about 26% of whom also scored the flow proneness questionnaire. Findings revealed significant but relatively low correlations between the three traits and moderate heritability estimates of .41, .45, and .30 for flow proneness, behavioral inhibition, and locus of control, respectively, with some indication of non-additive genetic influences. For behavioral inhibition we found significant sex differences in heritability, with females showing a higher estimate including significant non-additive genetic influences, while in males the entire heritability was due to additive genetic variance. We also found a mainly genetically mediated relationship between the three traits, suggesting that individuals who are genetically predisposed to experience flow, show less behavioral inhibition (less anxious) and feel that they are in control of their own destiny (internal locus of control). We discuss that some of the genes underlying this relationship may include those influencing the function of dopaminergic neural systems.     

N-Benzyl-indolo carboxylic acids: Design and synthesis of potent and selective adipocyte fatty-acid binding protein (A-FABP) inhibitors

Small molecule inhibitors of adipocyte fatty-acid binding protein (A-FABP) have gained renewed interest following the recent publication of pharmacologically beneficial effects of such inhibitors. Despite the potential utility of selective A-FABP inhibitors within the fields of metabolic disease, inflammation and atherosclerosis, there are few examples of useful A-FABP inhibitors in the public domain. Herein, we describe the optimization of N-benzyl-tetrahydrocarbazole derivatives through the use of co-crystal structure guided medicinal chemistry efforts. This led to the identification of a potent and selective class of A-FABP inhibitors as illustrated by N-benzyl-hexahydrocyclohepta[b]indole 30.     

The Humanistic Burden of Type 1 Diabetes Mellitus in Europe: Examining Health Outcomes and the Role of Complications

AimsDiagnoses of Type 1 Diabetes Mellitus (T1DM) in Europe appear to be on the rise. Therefore it is imperative that researchers understand the potential impact that increases in prevalence could have on the affected individuals as well as on society as a whole. Accordingly this study examined the humanistic and economic burden of T1DM in patients relative to those without the condition across a number of health outcomes including health status, work productivity loss, activity impairment, and healthcare resource use.MethodsSurvey data from a large, representative sample of EU adults (The EU National Health and Wellness Survey) were examined.ResultsResults suggest that overall burden is higher for those diagnosed with T1DM than respondents without diabetes and that burden increases as complications associated with T1DM increase.ConclusionsTaken together, these results suggest that treatment strategies for T1DM should balance clinical, humanistic, and economic burden and patients should be educated on the role of complications in disease outcomes.     

Early Life-History Consequences of Growth-Hormone Transgenesis in Rainbow Trout Reared in Stream Ecosystem Mesocosms

There is persistent commercial interest in the use of growth modified fishes for shortening production cycles and increasing overall food production, but there is concern over the potential impact that transgenic fishes might have if ever released into nature. To explore the ecological consequences of transgenic fish, we performed two experiments in which the early growth and survival of growth-hormone transgenic rainbow trout (Oncorhynchus mykiss) were assessed in naturalized stream mesocosms that either contained predators or were predator-free. We paid special attention to the survival bottleneck that occurs during the early life-history of salmonids, and conducted experiments at two age classes (first-feeding fry and 60 days post-first-feeding) that lie on either side of the bottleneck. In the late summer, the first-feeding transgenic trout could not match the growth potential of their wild-type siblings when reared in a hydrodynamically complex and oligotrophic environment, irrespective of predation pressure. Furthermore, overall survival of transgenic fry was lower than in wild-type (transgenic = 30% without predators, 8% with predators; wild-type = 81% without predators, 31% with predators). In the experiment with 60-day old fry, we explored the effects of the transgene in different genetic backgrounds (wild versus domesticated). We found no difference in overwinter survival but significantly higher growth by transgenic trout, irrespective of genetic background. We conclude that the high mortality of GH-transgenic trout during first-feeding reflects an inability to sustain the basic metabolic requirements necessary for life in complex, stream environments. However, when older, GH-transgenic fish display a competitive advantage over wild-type fry, and show greater growth and equal survival as wild-type. These results demonstrate how developmental age and time of year can influence the response of genotypes to environmental conditions. We therefore urge caution when extrapolating the results of GH-transgenesis risk assessment studies across multiple life-history or developmental stages.     

Proteolysis in isolated autophagic vacuoles from rat liver : Effect of pH and of proteolytic inhibitors

Autophagic vacuoles (AV) were purified from livers of rats which were pretreated with vinblastine (VBL) to increase the occurrence of AV. To measure proteolysis in the isolated AV rats were labelled with [¹⁴C]leucine 2 or 16 h before sacrifice. The integrity of the AV was studied by measuring the leakage of hydrolytic enzymes during incubation at various pHs. VBL causes an increase in the degradation rate of liver homogenate and isolated AV. This increase was moderate if proteolysis was measured at neutral pH, whereas adjustment to acidic pH enhanced the rate of autodegradation in the AV several-fold. This indicates that the VBL-induced AV have acquired hydrolytic enzymes either by fusion with lysosomes or possibly by the sequestering endoplasmic reticulum (ER) membranes forming the limiting membranes of the AV. The internal pH is not optimal for degradation in vitro of sequestered proteins, indicating insufficient acidification of the isolated AV. Lysosomotropic inhibitors, like chloroquine and propylamine, but not asparagine, impede proteolysis in isolated AV, but not more than 40%.     

Individual variation in bark beetle and moth pheromones - a comparison and an evolutionary background

The presently published data of variation in pheromone content in bark beetles (Coleoptera: Scolytidae) and moths (Lepidoptera) are reviewed. In both taxa high coefficients of variation, often up to around 100% for amount of pheromone, seem to be the rule. The contribution to the variation from errors in the chemical methods was small in most studies compared with the intrinsic biological variation. Examples arc given of variation in both absolute amounts, proportions of geometric isomers and in enantiomeric composition. Ratios of isomers often had lower coefficients of variation (25% or less). A lower average variation among sex pheromone in moths could relate to a mating system involving singly calling females, compared with the aggregation pheromone of bark beetles, which often call in large groups. The origin of a resource-based aggregation pheromone system by evolution working via individual selection is outlined.     

Plasma Membrane Abundance of Human Aquaporin 5 Is Dynamically Regulated by Multiple Pathways

Aquaporin membrane protein channels mediate cellular water flow. Human aquaporin 5 (AQP5) is highly expressed in the respiratory system and secretory glands where it facilitates the osmotically-driven generation of pulmonary secretions, saliva, sweat and tears. Dysfunctional trafficking of AQP5 has been implicated in several human disease states, including Sjögren’s syndrome, bronchitis and cystic fibrosis. In order to investigate how the plasma membrane expression levels of AQP5 are regulated, we studied real-time translocation of GFP-tagged AQP5 in HEK293 cells. We show that AQP5 plasma membrane abundance in transfected HEK293 cells is rapidly and reversibly regulated by at least three independent mechanisms involving phosphorylation at Ser156, protein kinase A activity and extracellular tonicity. The crystal structure of a Ser156 phosphomimetic mutant indicates that its involvement in regulating AQP5 membrane abundance is not mediated by a conformational change of the carboxy-terminus. We suggest that together these pathways regulate cellular water flow.