Using subgoals as a Mechanism for altering perceptions of situational control, mastery, and task-related stress

The empirical literature suggests that subgoals may have an effect upon feelings of task-related stress which is more intense than the effect of distal goals on this variable. First, subgoals my alter an individual\u27s perception of the task in such a way that the task related goal is not seen as being so overwhelming. Second, there is an increased feedback mechanism associated with subgoals that may alter perceptions of situational mastery and control and in turn perceptions of situational stress. The effect of receiving more frequent feedback is dependent upon the valence of the feedback. Specifically, positive feedback leads to an increase in perceptions of situational control and mastery and therefore reduces feelings of situational stress. Negative feedback has the opposite effect. The relationship between subgoals and perceptions of mastery had been investigated; however, the suggested connections between subgoals, control, and stress had not. In order to investigate these possible effects, subjects were divided into six goal type by feedback type conditions. Each group was asked to participate in a timed arithmetic test for which they had been given four, five minute goals, one, 20 minute goal, or no goals. The goals were manipulated so that some groups received consistent negative feedback, some groups received consistent positive feedback, and some groups received no feedback. After the test, subjects were asked to fill out several self-report measures assessing perceptions of situational control, mastery, and feelings of task related stress. It was hypothesized that those subjects in the positive feedback condition would have scores on the mastery and control measures that were significantly higher, and scores on the stress measure that were significantly lower than the no-feedback condition subjects. The same differences were hypothesized between the scores on these measures for the no-feedback group and the negative feedback group. Further, it was hypothesized that those subjects in the positive feedback/subgoal groups would have scores on the mastery and control measures that were significantly higher, and scores on the stress measure that were significantly lower than the subjects in all other goal type/feedback type conditions. The results of this research confirm the hypotheses pertaining to the main effect of feedback on dependent variables. However, no significant differences were discovered due to the variable\u27s interaction

Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials

Background: In patients with genotype 1 chronic hepatitis C infection, telaprevir (TVR) in combination with peginterferon and ribavirin (PR) significantly increased sustained virologic response (SVR) rates compared with PR alone. However, genotypic changes could be observed in TVR-treated patients who did not achieve an SVR. Methods: Population sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment. Results: Resistant variants were observed after treatment with a telaprevir-based regimen in 12% of treatment-naïve patients (ADVANCE; T12PR arm), 6% of prior relapsers, 24% of prior partial responders, and 51% of prior null responder patients (REALIZE, T12PR48 arms). NS3 protease variants V36M, R155K, and V36M+R155K emerged frequently in patients with genotype 1a and V36A, T54A, and A156S/T in patients with genotype 1b. Lower-level resistance to telaprevir was conferred by V36A/M, T54A/S, R155K/T, and A156S variants; and higher-level resistance to telaprevir was conferred by A156T and V36M+R155K variants. Virologic failure during telaprevir treatment was more common in patients with genotype 1a and in prior PR nonresponder patients and was associated with higher-level telaprevir-resistant variants. Relapse was usually associated with wild-type or lower-level resistant variants. After treatment, viral populations were wild-type with a median time of 10 months for genotype 1a and 3 weeks for genotype 1b patients. Conclusions: A consistent, subtype-dependent resistance profile was observed in patients who did not achieve an SVR with telaprevir-based treatment. The primary role of TVR is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The complementary role of PR is to clear any remaining telaprevir-resistant variants, especially higher-level telaprevir-resistant variants. Resistant variants are detectable in most patients who fail to achieve SVR, but their levels decline over time after treatment

Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production

SummaryHyperinsulinemia is associated with obesity and pancreatic islet hyperplasia, but whether insulin causes these phenomena or is a compensatory response has remained unsettled for decades. We examined the role of insulin hypersecretion in diet-induced obesity by varying the pancreas-specific Ins1 gene dosage in mice lacking Ins2 gene expression in the pancreas, thymus, and brain. Age-dependent increases in fasting insulin and β cell mass were absent in Ins1+/−:Ins2−/− mice fed a high-fat diet when compared to Ins1+/+:Ins2−/− littermate controls. Remarkably, Ins1+/−:Ins2−/− mice were completely protected from diet-induced obesity. Genetic prevention of chronic hyperinsulinemia in this model reprogrammed white adipose tissue to express uncoupling protein 1 and increase energy expenditure. Normalization of adipocyte size and activation of energy expenditure genes in white adipose tissue was associated with reduced inflammation, reduced fatty acid spillover, and reduced hepatic steatosis. Thus, we provide genetic evidence that pathological circulating hyperinsulinemia drives diet-induced obesity and its complications

A Multi-Parameter, High-Content, High-Throughput Screening Platform to Identify Natural Compounds that Modulate Insulin and Pdx1 Expression

Diabetes is a devastating disease that is ultimately caused by the malfunction or loss of insulin-producing pancreatic beta-cells. Drugs capable of inducing the development of new beta-cells or improving the function or survival of existing beta-cells could conceivably cure this disease. We report a novel high-throughput screening platform that exploits multi-parameter high-content analysis to determine the effect of compounds on beta-cell survival, as well as the promoter activity of two key beta-cell genes, insulin and pdx1. Dispersed human pancreatic islets and MIN6 beta-cells were infected with a dual reporter lentivirus containing both eGFP driven by the insulin promoter and mRFP driven by the pdx1 promoter. B-score statistical transformation was used to correct systemic row and column biases. Using this approach and 5 replicate screens, we identified 7 extracts that reproducibly changed insulin and/or pdx1 promoter activity from a library of 1319 marine invertebrate extracts. The ability of compounds purified from these extracts to significantly modulate insulin mRNA levels was confirmed with real-time PCR. Insulin secretion was analyzed by RIA. Follow-up studies focused on two lead compounds, one that stimulates insulin gene expression and one that inhibits insulin gene expression. Thus, we demonstrate that multi-parameter, high-content screening can identify novel regulators of beta-cell gene expression, such as bivittoside D. This work represents an important step towards the development of drugs to increase insulin expression in diabetes and during in vitro differentiation of beta-cell replacements

Evasion of IFN-γ Signaling by Francisella novicida Is Dependent upon Francisella Outer Membrane Protein C

Francisella tularensis is a Gram-negative facultative intracellular bacterium and the causative agent of the lethal disease tularemia. An outer membrane protein (FTT0918) of F. tularensis subsp. tularensis has been identified as a virulence factor. We generated a F. novicida (F. tularensis subsp. novicida) FTN_0444 (homolog of FTT0918) fopC mutant to study the virulence-associated mechanism(s) of FTT0918.The ΔfopC strain phenotype was characterized using immunological and biochemical assays. Attenuated virulence via the pulmonary route in wildtype C57BL/6 and BALB/c mice, as well as in knockout (KO) mice, including MHC I, MHC II, and µmT (B cell deficient), but not in IFN-γ or IFN-γR KO mice was observed. Primary bone marrow derived macrophages (BMDM) prepared from C57BL/6 mice treated with rIFN-γ exhibited greater inhibition of intracellular ΔfopC than wildtype U112 strain replication; whereas, IFN-γR KO macrophages showed no IFN-γ-dependent inhibition of ΔfopC replication. Moreover, phosphorylation of STAT1 was downregulated by the wildtype strain, but not the fopC mutant, in rIFN-γ treated macrophages. Addition of NG-monomethyl-L-arginine, an NOS inhibitor, led to an increase of ΔfopC replication to that seen in the BMDM unstimulated with rIFN-γ. Enzymatic screening of ΔfopC revealed aberrant acid phosphatase activity and localization. Furthermore, a greater abundance of different proteins in the culture supernatants of ΔfopC than that in the wildtype U112 strain was observed.F. novicida FopC protein facilitates evasion of IFN-γ-mediated immune defense(s) by down-regulation of STAT1 phosphorylation and nitric oxide production, thereby promoting virulence. Additionally, the FopC protein also may play a role in maintaining outer membrane stability (integrity) facilitating the activity and localization of acid phosphatases and other F. novicida cell components

Morphology and Composition of the Surface of Mars: Mars Odyssey THEMIS Results

The Thermal Emission Imaging System (THEMIS) on Mars Odyssey has produced infrared to visible wavelength images of the martian surface that show lithologically distinct layers with variable thickness, implying temporal changes in the processes or environments during or after their formation. Kilometer-scale exposures of bedrock are observed; elsewhere airfall dust completely mantles the surface over thousands of square kilometers. Mars has compositional variations at 100-meter scales, for example, an exposure of olivine-rich basalt in the walls of Ganges Chasma. Thermally distinct ejecta facies occur around some craters with variations associated with crater age. Polar observations have identified temporal patches of water frost in the north polar cap. No thermal signatures associated with endogenic heat sources have been identified

TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells

TET proteins oxidize 5-methylcytosine in DNA to 5-hydroxymethylcytosine and other oxidation products. We found that simultaneous deletion of Tet2 and Tet3 in mouse CD4+CD8+ double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T cells (iNKT cells). Tet2-Tet3 double-knockout (DKO) iNKT cells displayed pronounced skewing toward the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK. Transfer of purified Tet2-Tet3 DKO iNKT cells into immunocompetent recipient mice resulted in an uncontrolled expansion that was dependent on the nonclassical major histocompatibility complex (MHC) protein CD1d, which presents lipid antigens to iNKT cells. Our data indicate that TET proteins regulate iNKT cell fate by ensuring their proper development and maturation and by suppressing aberrant proliferation mediated by the T cell antigen receptor (TCR)

Formation of gullies on Mars by debris flows triggered by CO_2 sublimation

Martian gully landforms resemble terrestrial debris flows formed by the action of liquid water and have thus been interpreted as evidence for potential habitable environments on Mars within the past few millennia. However, ongoing gully formation has been detected under surface conditions much too cold for liquid water, but at times in the martian year when a thin layer of seasonal CO_2 frost is present and defrosting above the regolith. These observations suggest that the CO_2 condensation–sublimation cycle could play a role in gully formation. Here we use a thermo-physical numerical model of the martian regolith underlying a CO_2 ice layer and atmosphere to show that the pores beneath the ice layer can be filled with CO_2 ice and subjected to extreme pressure variations during the defrosting season. The subsequent gas fluxes can destabilize the regolith material and induce gas-lubricated debris flows with geomorphic characteristics similar to martian gullies. Moreover, we find that subsurface CO_2 ice condensation, sublimation and pressurization occurs at conditions found at latitudes and slope orientations where gullies are observed. We conclude that martian gullies can result from geologic dry ice processes that have no terrestrial analogues and do not require liquid water. Such dry ice processes may have helped shape the evolution of landforms elsewhere on the martian surface