Genome-wide examination of the transcriptional response to ecdysteroids 20-hydroxyecdysone and ponasterone A in Drosophila melanogaster

<p>Abstract</p> <p>Background</p> <p>The 20-hydroxyecdysone (20E) hierarchy of gene activation serves as an attractive model system for studying the mode of steroid hormone regulated gene expression and development. Many structural analogs of 20E exist in nature and among them the plant-derived ponasterone A (PoA) is the most potent. PoA has a higher affinity for the 20E nuclear receptor, composed of the ecysone receptor (EcR) and Ultraspiracle proteins, than 20E and a comparison of the genes regulated by these hormones has not been performed. Furthermore, in <it>Drosophila </it>different cell types elicit different morphological responses to 20E yet the cell type specificity of the 20E transcriptional response has not been examined on a genome-wide scale. We aim to characterize the transcriptional response to 20E and PoA in <it>Drosophila </it>Kc cells and to 20E in salivary glands and provide a robust comparison of genes involved in each response.</p> <p>Results</p> <p>Our genome-wide microarray analysis of Kc167 cells treated with 20E or PoA revealed that far more genes are regulated by PoA than by 20E (256 vs 148 respectively) and that there is very little overlap between the transcriptional responses to each hormone. Interestingly, genes induced by 20E relative to PoA are enriched in functions related to development. We also find that many genes regulated by 20E in Kc167 cells are not regulated by 20E in salivary glands of wandering 3^rdinstar larvae and we show that 20E-induced levels of <it>EcR </it>isoforms <it>EcR-RA, ER-RC</it>, and <it>EcR-RD/E </it>differ between Kc cells and salivary glands suggesting a possible cause for the observed differences in 20E-regulated gene transcription between the two cell types.</p> <p>Conclusions</p> <p>We report significant differences in the transcriptional responses of 20E and PoA, two steroid hormones that differ by only a single hydroxyl group. We also provide evidence that suggests that PoA induced death of non-adapted insects may be related to PoA regulating different set of genes when compared to 20E. In addition, we reveal large differences between Kc cells and salivary glands with regard to their genome-wide transcriptional response to 20E and show that the level of induction of certain EcR isoforms differ between Kc cells and salivary glands. We hypothesize that the differences in the transcriptional response may in part be due to differences in the EcR isoforms present in different cell types.</p

Cooperation, Norms, and Revolutions: A Unified Game-Theoretical Approach

Cooperation is of utmost importance to society as a whole, but is often challenged by individual self-interests. While game theory has studied this problem extensively, there is little work on interactions within and across groups with different preferences or beliefs. Yet, people from different social or cultural backgrounds often meet and interact. This can yield conflict, since behavior that is considered cooperative by one population might be perceived as non-cooperative from the viewpoint of another. To understand the dynamics and outcome of the competitive interactions within and between groups, we study game-dynamical replicator equations for multiple populations with incompatible interests and different power (be this due to different population sizes, material resources, social capital, or other factors). These equations allow us to address various important questions: For example, can cooperation in the prisoner's dilemma be promoted, when two interacting groups have different preferences? Under what conditions can costly punishment, or other mechanisms, foster the evolution of norms? When does cooperation fail, leading to antagonistic behavior, conflict, or even revolutions? And what incentives are needed to reach peaceful agreements between groups with conflicting interests? Our detailed quantitative analysis reveals a large variety of interesting results, which are relevant for society, law and economics, and have implications for the evolution of language and culture as well

Organic Geochemical Studies. I. Molecular Criteria for Hydrocarbon Genesis

In recent years the search for life-forms at the earliest periods of geological time has been continued not only at the morphological level but also at the molecular level. This has been possible as a result of the increase in the biochemical knowledge and with the advent of analytical techniques that are capable of describing the intimate molecular architecture of individual molecules in acute detail. The fundamental premises upon which this organic geochemical approach rest are the following: that certain molecules, possessing a characteristic structural skeleton, show a reasonable stability to degradation over long periods of geological time; that their structural specificity can be understood in terms of known biosynthetic sequences; and that their formation by any non-biological means is of negligible probability. In this manuscript it is proposed to critically re-examine these premises and to establish criteria whereby one can differentiate molecules derived from biological systems from those that have their origin in non-biological processes. The importance of establishing such criteria lies in the significance these criteria have in determining whether life exists, or has existed, on other planets. Within the very near future it may be possible to provide an initial answer to this question when the first lunar samples are returned to the earth for analysis

1, 9-Pyrazoloanthrones Downregulate HIF-1α and Sensitize Cancer Cells to Cetuximab-Mediated Anti-EGFR Therapy

Cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR), is currently approved for the treatment of several types of solid tumors. We previously showed that cetuximab can inhibit hypoxia-inducible factor-1 alpha (HIF-1α) protein synthesis by inhibiting the activation of EGFR downstream signaling pathways including Erk, Akt, and mTOR. 1, 9-pyrazoloanthrone (1, 9 PA) is an anthrapyrazolone compound best known as SP600125 that specifically inhibits c-jun N-terminal kinase (JNK). Here, we report 1, 9 PA can downregulate HIF-1α independently of its inhibition of JNK. This downregulatory effect was abolished when the oxygen-dependent domain (ODD) of HIF-1α (HIF-1α-ΔODD, the domain responsible for HIF-1α degradation) was experimentally deleted or when the activity of HIF-1α prolyl hydroxylase (PHD) or the 26S proteasomal complex was inhibited, indicating that the 1, 9 PA downregulates HIF-1α by promoting PHD-dependent HIF-1α degradation. We found that the combination of 1, 9 PA and cetuximab worked synergistically to induce apoptosis in cancer cells in which cetuximab or 1, 9 PA alone had no or only weak apoptotic activity. This synergistic effect was substantially decreased in cancer cells transfected with HIF-1α-ΔODD, indicating that downregulation of HIF-1α was the mechanism of this synergistic effect. More importantly, 1, 9 PA can downregulate HIF-1α in cancer cells that are insensitive to cetuximab-induced inhibition of HIF-1α expression due to overexpression of oncogenic Ras (RasG12V). Our findings suggest that 1, 9 PA is a lead compound of a novel class of drugs that may be used to enhance the response of cancer cells to cetuximab through a complementary effect on the downregulation of HIF-1α

Impaired Growth and Force Production in Skeletal Muscles of Young Partially Pancreatectomized Rats: A Model of Adolescent Type 1 Diabetic Myopathy?

This present study investigated the temporal effects of type 1 diabetes mellitus (T1DM) on adolescent skeletal muscle growth, morphology and contractile properties using a 90% partial pancreatecomy (Px) model of the disease. Four week-old male Sprague-Dawley rats were randomly assigned to Px (n = 25) or Sham (n = 24) surgery groups and euthanized at 4 or 8 weeks following an in situ assessment of muscle force production. Compared to Shams, Px were hyperglycemic (>15 mM) and displayed attenuated body mass gains by days 2 and 4, respectively (both P<0.05). Absolute maximal force production of the gastrocnemius plantaris soleus complex (GPS) was 30% and 50% lower in Px vs. Shams at 4 and 8 weeks, respectively (P<0.01). GP mass was 35% lower in Px vs Shams at 4 weeks (1.24±0.06 g vs. 1.93±0.03 g, P<0.05) and 45% lower at 8 weeks (1.57±0.12 vs. 2.80±0.06, P<0.05). GP fiber area was 15–20% lower in Px vs. Shams at 4 weeks in all fiber types. At 8 weeks, GP type I and II fiber areas were ∼25% and 40% less, respectively, in Px vs. Shams (group by fiber type interactions, P<0.05). Phosphorylation states of 4E-BP1 and S6K1 following leucine gavage increased 2.0- and 3.5-fold, respectively, in Shams but not in Px. Px rats also had impaired rates of muscle protein synthesis in the basal state and in response to gavage. Taken together, these data indicate that exposure of growing skeletal muscle to uncontrolled T1DM significantly impairs muscle growth and function largely as a result of impaired protein synthesis in type II fibers

The effectiveness of financial incentives for smoking cessation during pregnancy: is it from being paid or from the extra aid?

<p>Abstract</p> <p>Background</p> <p>Financial incentives appear to be effective in promoting smoking cessation in pregnancy. The mechanisms by which they might operate however, are poorly understood. The present study examines how financial incentives for smoking cessation during pregnancy may work, by exploring pregnant women's experiences of trying to stop smoking, within and outside of a financial incentives scheme.</p> <p>Methods</p> <p>Thirty-six (n = 36) UK-based pregnant smokers (n = 36), offered standard NHS Stop-Smoking Services, of whom twenty (n = 20) were enrolled in a financial incentives scheme for smoking cessation (n = 20) and sixteen (n = 16) were not, were interviewed about (i) their motivation to stop smoking, and (ii) the factors they perceived as influencing their quitting efforts. Framework Analysis was used to analyse the data.</p> <p>Results</p> <p>Women in the two groups reported similar reasons for wanting to stop smoking during pregnancy. However, they described dissimilar experiences of the Stop-Smoking Services, which they perceived to have differentially influenced their quit attempts. Women who were incentivised reported using the services more than women who were not incentivised. In addition, they described the motivating experience of being monitored and receiving feedback on their progress. Non-incentivised women reported problems receiving the appropriate Nicotine Replacement Therapy, which they described as having a detrimental effect on their quitting efforts.</p> <p>Conclusion</p> <p>Women participating in a financial incentives scheme to stop smoking reported greater engagement with the Stop-Smoking Services, from which they described receiving more help in quitting than women who were not part of the scheme. These results highlight the complexity of financial incentives schemes and the intricacies surrounding the ways in which they operate to affect smoking cessation. These might involve influencing individuals' motivation and self-regulation, changing engagement with and provision of support services, or a combination of these.</p

Design, recruitment, and retention of African-American smokers in a pharmacokinetic study

<p>Abstract</p> <p>Background</p> <p>African-Americans remain underrepresented in clinical research despite experiencing a higher burden of disease compared to all other ethnic groups in the United States. The purpose of this article is to describe the study design and discuss strategies used to recruit and retain African-American smokers in a pharmacokinetic study.</p> <p>Methods</p> <p>The parent study was designed to evaluate the differences in the steady-state concentrations of bupropion and its three principal metabolites between African-American menthol and non-menthol cigarette smokers. Study participation consisted of four visits at a General Clinical Research Center (GCRC) over six weeks. After meeting telephone eligibility requirements, phone-eligible participants underwent additional screening during the first two GCRC visits. The last two visits (pharmacokinetic study phase) required repeated blood draws using an intravenous catheter over the course of 12 hours.</p> <p>Results</p> <p>Five hundred and fifteen African-American smokers completed telephone screening; 187 were phone-eligible and 92 were scheduled for the first GCRC visit. Of the 81 who attended the first visit, 48 individuals were enrolled in the pharmacokinetic study, and a total of 40 individuals completed the study (83% retention rate).</p> <p>Conclusions</p> <p>Although recruitment of African-American smokers into a non-treatment, pharmacokinetic study poses challenges, retention is feasible. The results provide valuable information for investigators embarking on non-treatment laboratory-based studies among minority populations.</p

Temporal Information Processing in Short- and Long-Term Memory of Patients with Schizophrenia

Cognitive deficits of patients with schizophrenia have been largely recognized as core symptoms of the disorder. One neglected factor that contributes to these deficits is the comprehension of time. In the present study, we assessed temporal information processing and manipulation from short- and long-term memory in 34 patients with chronic schizophrenia and 34 matched healthy controls. On the short-term memory temporal-order reconstruction task, an incidental or intentional learning strategy was deployed. Patients showed worse overall performance than healthy controls. The intentional learning strategy led to dissociable performance improvement in both groups. Whereas healthy controls improved on a performance measure (serial organization), patients improved on an error measure (inappropriate semantic clustering) when using the intentional instead of the incidental learning strategy. On the long-term memory script-generation task, routine and non-routine events of everyday activities (e.g., buying groceries) had to be generated in either chronological or inverted temporal order. Patients were slower than controls at generating events in the chronological routine condition only. They also committed more sequencing and boundary errors in the inverted conditions. The number of irrelevant events was higher in patients in the chronological, non-routine condition. These results suggest that patients with schizophrenia imprecisely access temporal information from short- and long-term memory. In short-term memory, processing of temporal information led to a reduction in errors rather than, as was the case in healthy controls, to an improvement in temporal-order recall. When accessing temporal information from long-term memory, patients were slower and committed more sequencing, boundary, and intrusion errors. Together, these results suggest that time information can be accessed and processed only imprecisely by patients who provide evidence for impaired time comprehension. This could contribute to symptomatic cognitive deficits and strategic inefficiency in schizophrenia