This article studies the signal effects between different distribution channels. In this article, we assume the quality of goods only depends on production cost. The production cost is private information only belongs to manufacturers in direct channel. On the other hand, in indirect channel, production cost is information shared by manufactures and retailers, but the consumers will not know the production cost. Referring to consumer side, the demand of high quality goods is higher than the demand of low quality goods. All information is public to all players except the production cost. Therefore, the manufactures who provide high quality goods must signal their quality to consumers to get high sales volume. This research will verify the signaling effect in direct channel then explore the effect in indirect channel. After proving how the signaling effects work in both channels, we compare the effects among different channels. The comparison could help venders who face the adverse selection problems to make their channel strategies. The research results are as following: 1. No matter direct or indirect channels, the signaling effect get weak with the increase of consumer¡¦s price sensitivity, demand for high end goods and production cost of the goods. 2. The signaling effect in indirect channel is more effective than the effect in direct channel when consumers are with low price sensitivities. 3. The signaling effect in direct channel is more effective than the effect in indirect channel when the cost of goods in the same category is low. Keywords: signaling game; channel strategies; price strategies.

Chromium has been reported to increase glucose clearance in insulin resistant and diabetic populations. Skeletal muscle is the tissue primarily responsible for glucose clearance. We therefore tested the effect of chromium chloride (CrCl3) on skeletal muscle glucose uptake both in the absence and presence of a submaximal level of insulin via the rat hindlimb perfusion technique. 0.096 μM CrCl3 was used with and without 200 μU/ml insulin. Our testing showed that insulin significantly increased [H3]-2 deoxyglucose (2-DG) uptake in both the gastrocnemius and quadriceps muscles. Additionally, the combination of CrCl3 and insulin (Cr-sIns) led to greater amounts of 2-DG uptake than insulin alone (sIns) in both the gastrocnemius (Cr-sIns 6.49±0.75 μmol/g/h, sIns 4.83±0.42 μmol/g/h) and quadriceps (Cr-sIns 6.74±0.62 μmol/g/h, sIns 4.54±0.43 μmol/g/h). However, CrCl3 without insulin (Cr) had no affect on 2-DG uptake above basal (Bas) in both the gastrocnemius (Cr 1.45±0.14 μmol/g/h, Bas 1.61±30 μmol/g/h) and the quadriceps (Cr 1.35±0.15 μmol/g/h, Bas 1.27±0.13 μmol/g/h). It has been speculated that chromium works to increase glucose uptake by increasing insulin signaling. To examine this, we used western blotting analysis to test both Akt and AS160 phosphorylation in the mixed gastrocnemius. We found that insulin increased Akt and AS160 phosphorylation, but chromium had no affect on Akt (Cr-sIns 25%±2%, sIns 22%±4%) or AS160 (Cr-sIns 35%±5%, sIns 36%±4%) phosphorylation in the absence or presence of insulin. Our results suggest that supplementation with CrCl3 can lead to an increase in glucose uptake in skeletal muscle, but only in the presence of insulin. However, this effect of CrCl3 does not appear to be a result of enhanced insulin signaling. / text

This project focused on determining the effect of lithium on glucose uptake, glycogen synthesis, and insulin signaling proteins, protein kinase B (Akt1) and GSK-3, in isolated soleus muscle from female lean Zucker rats. We also investigated the role of the stress-activated p38 MAPK in the action of lithium to activate skeletal muscle glucose transport. In the absence of insulin, lithium (10 mM LiCl) increased basal glucose transport by 62% (p<0.05) and glycogen synthesis by 112%. Lithium did not alter phosphorylation of Akt ser473, but enhanced GSK-3β ser9 phosphorylation by 41%. Lithium further enhanced the effect of insulin on glucose transport (42%), glycogen synthesis (44%), and GSK-3ß phosphorylation (13%). Lithium increased phosphorylated p38 MAPK 31% without and 19% with insulin. Moreover, a selective p38 MAPK inhibitor, A304000, completely prevented the lithium-induced enhancement of glucose transport revealing the critical involvement of p38 MAPK phosphorylation in lithium-induced glucose transport in isolated skeletal muscle.

The larva of the fruit fly Drosophila melanogaster is an excellent model to study the molecular control of innate cellular immune responses. Cellular responses take place, and can be studied, following infestation of the wasp Leptopilina boulardi. This response includes proliferation and activation (differentiation) of the blood cells (hemocytes). In a successful anti-parasitic response, an immune-induced lineage of hemocytes, the lamellocytes, forms a cellular capsule covering and killing the foreign intruder. I will in this thesis present data about the finding and characterization of a novel marker that is expressed specifically in the hemocytes, the Hemese gene. I furthermore describe the construction of a useful tool, the transgenic Hemese-Gal4 fly, which enables blood cell specific expression of any gene of interest. By using the Hemese-Gal4 fly in a directed screen, I have found that a surprisingly large number of genes, that in turn are members of seemingly diverse signaling pathways, are able to induce a cellular response. In many cases their expression is also associated with a blood cell tumor phenotype. Overexpression of certain genes, such as hopscotch (a Drosophila Jak homologue) and hemipterous (a c-jun kinase kinase) lead to the formation of lamellocytes. Other genes may control the cell number, such as Egfr and Ras, as their expression produced a massive in increase the numbers of hemocytes. A third group of genes, including, e.g. Alk, Rac1 and Pvr give a mixed response, promoting both hemocyte proliferation and activation. Surprisingly, the suppression of WNT signaling in hemocytes lead to hemocyte activation. In one case, with a UAS-Pvr dominant negative construct, we observe a reduction of the circulating blood cells in uninfested larva. The expression of DN-Pvr additionally contributes to reduce encapsulation rates in larvae subjected to Leptopilina infestation. In conclusion: the control of blood cells in larval hematopoiesis, and during parasitic wasp attacks, is complex and may involve multiple pathways. In a broader sense, the gene functions found in the directed screen may have implications also for understanding the molecular control of mammalian myeloid lineage blood cells.

Glioblastoma is the commonest form of brain neoplasm and among the most malignant forms of cancer. The identification of a subpopulation of self-renewing and multipotent cancer stem cells within glioblastoma has revealed a novel cellular target for the treatment of this disease. The role of developmental cell signaling pathways in these cell populations remains poorly understood. Herein, we examine the role of the Notch signaling pathway in glioblastoma stem cells. In this thesis we have demonstrated that the canonical Notch pathway is active in glioblastoma stem cells and functions to inhibit neuronal lineage commitment in a subset of patient derived glioblastoma stem cells in vitro. Gamma secretase (γ-secretase) small molecule inhibitors or dominant-negative co-activators inhibit glioblastoma stem cell proliferation and induce neuronal lineage commitment in a fashion that synergizes with Wingless pathway activation via GSK-3β blockade. Our data suggest that subsets of patient samples show a Notch gene expression profile that predicts their abilities to undergo neuronal lineage differentiation in response to γ-secretase small molecule inhibitors. Additionally, the data suggests that Notch may perturb the relative fractions of cells undergoing symmetric division, in favour of asymmetric division, limiting clonal expansion from single cells. These data may have important implications for treating human glioblastoma, and suggest that in addition to inhibition of proliferation, influencing lineage choice of the tumor stem cells may be a mechanism by which these tumors may be pharmacologically inhibited.

Glioblastoma is the commonest form of brain neoplasm and among the most malignant forms of cancer. The identification of a subpopulation of self-renewing and multipotent cancer stem cells within glioblastoma has revealed a novel cellular target for the treatment of this disease. The role of developmental cell signaling pathways in these cell populations remains poorly understood. Herein, we examine the role of the Notch signaling pathway in glioblastoma stem cells. In this thesis we have demonstrated that the canonical Notch pathway is active in glioblastoma stem cells and functions to inhibit neuronal lineage commitment in a subset of patient derived glioblastoma stem cells in vitro. Gamma secretase (γ-secretase) small molecule inhibitors or dominant-negative co-activators inhibit glioblastoma stem cell proliferation and induce neuronal lineage commitment in a fashion that synergizes with Wingless pathway activation via GSK-3β blockade. Our data suggest that subsets of patient samples show a Notch gene expression profile that predicts their abilities to undergo neuronal lineage differentiation in response to γ-secretase small molecule inhibitors. Additionally, the data suggests that Notch may perturb the relative fractions of cells undergoing symmetric division, in favour of asymmetric division, limiting clonal expansion from single cells. These data may have important implications for treating human glioblastoma, and suggest that in addition to inhibition of proliferation, influencing lineage choice of the tumor stem cells may be a mechanism by which these tumors may be pharmacologically inhibited.

Canonical Wnt signaling is involved in many aspects of development including axis specification and anterior-posterior neuroectoderm formation during vertebrate embryogenesis. Axin2, a homologue of Axin1, is thought to have a similar regulatory role within the cell, but differences in their expression and binding partners suggest Axin2 is not completely redundant with Axin1. To better understand Axin2 in canonical Wnt signaling, I utilized several approaches to explore its expression and function. In the zebrafish embryo, I found Axin2 is expressed in known active domains of Wnt signaling, suggesting an inducible regulatory role. Additionally, canonical Wnt signaling was sufficient and necessary to induce Axin2 expression and Axin2 was sufficient and necessary to inhibit Wnt signaling. As Wnt signaling is important in development and its dysregulation has been implicated in diseases such as colorectal cancer, this study helps advance our understanding of how Wnt signaling regulates itself through the use of negative feedback inhibitors, such as Axin2.

Numerous studies have identified that elevated plasma concentrations of lipoprotein(a) [Lp(a)] are an emerging risk factor for a variety of atherothrombotic disorders. Apolipoprotein(a) [apo(a)], the unique glycoprotein component of Lp(a), consists of tandem repeats of a plasminogen kringle (K) IV-like domain, followed by sequences homologous to the plasminogen KV and protease domains. Apo(a)/Lp(a) has been consistently shown to regulate endothelial function and inhibit plasminogen activation. In the present study, we have demonstrated that apo(a), signaling via integrin alphaVbeta3, is the functional unit in Lp(a) to stimulate in vitro endothelial cell (EC) proliferation and migration, and activate focal adhesion kinase (FAK) and mitogen-activated protein kinases (MAPK) in cultured ECs. Both apo(a) and Lp(a) have also been shown to reduce the levels of active and total transforming growth factor (TGF)-beta in cultured EC medium in an integrin alphaVbeta3–dependent manner. Despite the stimulatory effects of apo(a) on EC proliferation and migration, we have further confirmed an inhibitory effect of apo(a) on EC in vitro angiogenesis using a fibrin gel tube formation assay. We have provided evidence proving apo(a) inhibits angiogenesis through inhibition of plasminogen activation, and this inhibitory effect is dependent on the presence of apo(a) KV domain. Lastly, apo(a) is shown to reduce the protein levels of annexin A2 and S100A10 in ECs, which implies another potential mechanism by which apo(a)/Lp(a) could impair plasminogen activation on cell surface. In summary, we have discovered the first complete outside-in signaling pathway elicited by apo(a)/Lp(a) in ECs and have built up a connection between the ability of apo(a) to inhibit plasminogen activation and its inhibition of angiogenesis. / Thesis (Ph.D, Biochemistry) -- Queen's University, 2009-09-25 18:29:47.106

Cells of the cardiovascular system translate incoming extracellular signals from hormones and drugs through binding of cell surface receptors, and activation of intracellular signaling cascades allowing modulation of specific cellular function. cAMP and cGMP are ubiquitous second messengers that activate specific signaling machinery used to promote or inhibit cellular functions such as cell migration, cell adhesion and proliferation. Increases in intracellular cAMP or cGMP levels occurs through activation of adenylyl cyclase (cAMP) or guanylyl cyclase (cGMP) or by inhibition of the cAMP and cGMP hydrolyzing enzymes, cyclic nucleotide phosphodiesterases (PDEs). Cyclic nucleotides achieve signaling specificity through compartmentation, a mechanism allowing effective regulation of cAMP or cGMP signaling in discrete parts of the cell in a spatial and temporal manner. Cells of the cardiovascular system such as platelets, vascular endothelial cells (VECs), vascular smooth muscle cells (VSMCs) maintain cyclic nucleotide compartmentation through coordinating signaling complexes containing a cAMP or cGMP effector protein and PDEs. Studies reported in this thesis demonstrate that human platelets, VECs and VSMCs each contain distinct cyclic nucleotide signaling complexes, and that based on their composition and selective subcellular localization, regulate specific cellular functions. In platelets, subcellular localization of PDE5 results in differential regulation of PDE5 and selective regulation of Ca2+ release from endoplasmic reticulum stores, an initial step in platelet aggregation and provides a potential therapeutic target in preventing thrombosis. VECs utilize multiple signaling systems to regulate cellular function including cAMP signaling pathways and modification of phosphatidylinositols. These studies demonstrate that a PDE3B-based signaling complex allows integration of both cAMP and phosphatidylinositol-3-kinase-γ (PI3Kγ) signals resulting in increased cell adhesion and cell spreading. Finally, studies in VSMCs demonstrate that PDE5 localization in cells allows cAMP/cGMP cross talk through PDE5 and PDE3A. These results are discussed in the context of further understanding the role of PDEs in mediating cAMP and cGMP signaling and modulation of cell function in cells of the cardiovascular system. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2011-06-28 13:31:51.428

Background. Growth-arrest specific 6 (gas6) is a novel vitamin-K dependent protein whose role in venous thromboembolism was recently characterized in murine models. Gas6 is suggested to be a prothrombotic protein capable of mediating thrombus stability. However, the association between gas6 and venous thromboembolism has yet to be elucidated in humans. The present work aims to delineate the existence of such an association in humans and propose a mechanism by which gas6 expression is related to venous thromboembolic disease. / Methods. To analyze the association between gas6 and venous thromboembolism, a highly specific ELISA method was used to measure plasma gas6 levels in 306 patients with a history of deep-vein thrombosis (DVT) and 89 control volunteers. Medication history, comorbid conditions and DVT characteristics were documented for the purposes of statistical analyses. Median gas6 levels were compared between the subgroups, and prevalence rate ratios were calculated. Human umbilical vein endothelial cells were used to measure the effect of gas6 treatment on the expression of various mediators of coagulation. Murine thrombosis models were developed to serve as in vivo models for thrombosis. / Results. The median levels of gas6 were 28.21 ng/ml in patients compared to 26.15 ng/ml in controls (p=0.01). After adjustment for age, sex, comorbidity and medications, DVT patients had a PRR of 2.5 (95% CI 1.36 to 4.61, p=0.003) compared with controls. Within the DVT subgroup, median gas6 levels were significantly higher in those with cancer-associated (vs. unprovoked or secondary) DVT (p&lt;0.001) and in those with more extensive DVT (p=0.037), while levels were significantly lower in those taking warfarin (vs. no warfarin) (p=0.03). Preliminary results with endothelial cell cultures are inconclusive with regards to the effect of gas6 on endothelium derived mediators of coagulation. / Conclusions. Elevated plasma gas6 is associated with venous thromboembolism. The etiology of the clot influences detected levels of gas6, with the highest levels seen in cancer-patients. Furthermore, increasing clot burden correlates with elevated levels of gas6. A mechanistic explanation for how gas6 modulates this association is in its preliminary stages, and is worth pursuing.