Allosteric modulation of VLA-4 with the atypical antipsychotic thioridazine

A recent primary drug screen by the University of New Mexico Center for Molecular Discovery uncovered a novel group of allosteric-modulators of VLA-4 integrins known as phenothiazines. Phenothiazine family compounds were initially discovered as organic dyes in the 1800\u27s, the most well-known of which is methylene blue. Relatively soon thereafter phenothiazines were found to be useful clinically, a trend that has continued in the century since peaking as antipsychotics in the 1950\u27s. Today, phenothiazines are still being pursued clinically as seen in a number of recent patents for phenothiazine use in autoimmune disorders. This study sought to further characterize the newly discovered relationship between phenothiazines and VLA-4 integrin in a stepwise progression from in vitro experiments to an in vivo animal model. Here, it is shown that the phenothiazine compound thioridazine causes broad inhibition of adhesion related activity including: the rapid interruption of VLA-4 bound uorescent molecules, the disaggregation of VLA-4 and VCAM-1 attached cells, rapid reduction in intracellular calcium signaling, and loss of cellular motility to G i chemokines. Furthermore, it is shown that thioridazine treatment can cause a 3-fold increase in mobilization of murine hematopoietic stem and progenitor cells. Combined, these data answer forty year old questions about the nature of phenothiazine treatment, provide insight in to the mechanism of action and provide evidence for the potential of VLA-4 allosteric modulators in vivo

Determinants of internet banking adoption by banks in Ghana

Growth in information and communication technology (ICT) is drastically changing the way businesses, especially in the service industries, are conducted. The financial services industry and banking in particular, is not excluded from this technology explosion. Internet banking, even though not new in advanced countries, is a new transaction channel being used by banks in some parts of Africa, especially Ghana, to offer various products and services to their customers. However, this medium has not been fully exploited by these banks as there are many hurdles the banks must triumph over. In deploying this technology and these systems, there are several factors which banks must take into consideration before fully deploying such a system to their customers, hence the motivation for this study. The absence of suitable and sufficient knowledge on this topic also exposes a “rhetoric versus reality” argument of whether the intention to adopt Internet banking is critical to the strategies and ultimate success of banks in Ghana. For banks to stay ahead of competition as well as to attract and maintain their clientele, it is of paramount importance to gather and link the perspectives of both clients and bank managers in order for banks to ensure that they perform according to the needs and expectations of their clients. In order to achieve the intended results, an empirical study was conducted by taking into consideration the viewpoints of both bank clients and bank managers in determining the factors that customers take into consideration before adopting the Internet banking medium. The primary aim of this study was to quantify significant relationships between the selected variables. Therefore the positivism research paradigm was used, while the phenomenological paradigm was employed for the measuring instruments. Because multiple sources of data were used, from the perspectives of banking clients and managers in Ghana, methodological triangulation was adopted for this study. The results of the empirical investigation showed that both groups (clients and managers) considered the variables of market share, technology acceptance, diffusion of innovation, organisational variables, organisational efficiency, and business strategy to have direct influence on the adoption of Internet banking. However, they differed in opinion concerning the degree of influence of these variables. The bank managers’ responses leaned more towards strong agreement with the importance of these variables than did those of the bank clients. Thus, for bank clients to readily adopt the Internet banking medium for their banking transactions, bank managers must take a closer look at these determinant factors described in the study. The study showed that the population group, educational and income levels exerted an influence on the perceptions clients have regarding Internet banking adoption factors. It was found that the higher the education and income levels of the clients, the easier it was for them to adopt Internet banking. Also, the male group dominated the use of the Internet banking. This is supported by the fact that there is a growing middle class in Ghana that falls within this category of banking clients

On asset pricing and the equity premium puzzle

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Presented here are consumption and production related asset pricing models which seek to explain stock market behaviour through the stock premium over risk-free bonds and to do so using parameter values consistent with theory. Our results show that there are models capable of explaining stock market behaviour. For the consumption-based model, we avoid many of the suggestions to artificially boost the predicted stock premium such as modelling consumption as leverage claims; instead we use the notion of surplus consumption. We find that with surplus consumption, there are models including the much-maligned power utility model, capable of yielding theory consistent estimates for the discount rate, risk-free rate as well as the coefficient of relative risk aversion, y. Since real business cycle theory assumes a risk aversion coefficient of 1, we conclude that our model which gives a value close to but not equal to 1, provides an indication of the impact of market imperfections. For production, we present many of the existing models which seek to explain stock market behaviour using production data which we find to be generally incapable of explaining stock market behaviour. We conclude by presenting a profit based formulation which uses deviations of actual from expected profits and dividends via stock price reaction parameters to successfully explain stock market behaviour. We also conclude that the use of a profit based formulation allows for a link to investment, output and pricing decisions and hence link consumption and production.Thames Valley Universit

SOST and DKK: Antagonists of LRP Family Signaling as Targets for Treating Bone Disease

The study of rare human genetic disorders has often led to some of the most significant advances in biomedical research. One such example was the body of work that resulted in the identification of the Low Density Lipoprotein-Related Protein (LRP5) as a key regulator of bone mass. Point mutations were identified that encoded forms of LRP5 associated with very high bone mass (HBM). HBM patients live to a normal age and do not appear to have increased susceptibility to carcinogenesis or other disease. Thus, devising methods to mimic the molecular consequences of this mutation to treat bone diseases associated with low bone mass is a promising avenue to pursue. Two groups of agents related to putative LRP5/6 functions are under development. One group, the focus of this paper, is based on antagonizing the functions of putative inhibitors of Wnt signaling, Dickkopf-1 (DKK1), and Sclerostin (SOST). Another group of reagents under development is based on the observation that LRP5 may function to control bone mass by regulating the secretion of serotonin from the enterrochromaffin cells of the duodenum

Mouse Models of Prostate Cancer

The development and optimization of high-throughput screening methods has identified a multitude of genetic changes associated with human disease. The use of immunodeficient and genetically engineered mouse models that mimic the human disease has been crucial in validating the importance of these genetic pathways in prostate cancer. These models provide a platform for finding novel therapies to treat human patients afflicted with prostate cancer as well as those who have debilitating bone metastases. In this paper, we focus on the historical development and phenotypic descriptions of mouse models used to study prostate cancer. We also comment on how closely each model recapitulates human prostate cancer

Where Wnts Went: The Exploding Field of Lrp5 and Lrp6 Signaling in Bone

Wnt signaling has emerged as a central regulator of skeletal modeling and remodeling. Loss- or gain-of-function mutations in two Wnt co-receptors, Lrp5 and (more recently) Lrp6, have drawn attention to the importance of the Wnt pathway in bone biology. This review summarizes our current understanding of how the Wnt pathway operates on bone and the implications this has for skeletal physiology and drug discovery. Over the past 9 yr, rapid advances have been made in our understanding of the cellular targets for Wnt signaling and of the important regulatory molecules in this metabolic pathway. Both canonical and noncanonical signaling pathways seem to be important for mediating the effects of Wnt in bone. A rapidly expanding catalog of genetically engineered mice has been used to establish the importance of downstream effector molecules (such as β-catenin) in the Wnt pathway, as well as the critical role of endogenous inhibitors of Wnt signaling (such as Dkk1 and sclerostin) in bone metabolism. Indeed, regulation of sclerostin in osteocytes is emerging as an important final pathway for regulating bone anabolism in response to diverse trophic stimuli, from mechnotransduction to the anabolic actions of PTH. From the outset, it had been assumed that the effects of Wnt signaling in bone were caused by direct actions in osteoblast precursors, osteoblasts, and osteocytes. However, startling recent findings have challenged this view and suggest that a key target, at least in mice, is the duodenal enterochromaffin cell. There, Wnt signaling transduced by Lrp5 regulates serotonin synthesis, which acts in an endocrine fashion to regulate bone cell metabolism. It will take time to reconcile this new information with the considerable body of information we already have regarding the actions of Wnt in bone. The Wnt pathway has rapidly emerged as a therapeutic target for drug discovery. Neutralizing antibodies and small-molecule inhibitors of endogenous Wnt inhibitors have shown early promise as bone anabolic agents. However, given the central role of the Wnt pathway in regulating growth and development in extraskeletal tissues, as well as our still rudimentary understanding of how this signaling cascade actually affects bone metabolism, considerable work will be needed to ensure the safety of these new therapies

Analysis of the role of the retinoblastoma susceptibility gene in murine development and tumorigenesis

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 1996.Includes bibliographical references.by Bart O. Williams.Ph.D

Pre-Exposure to Moving Form Enhances Static Form Sensitivity

Background: Motion-defined form can seem to persist briefly after motion ceases, before seeming to gradually disappear into the background. Here we investigate if this subjective persistence reflects a signal capable of improving objective measures of sensitivity to static form. Methodology/Principal Findings: We presented a sinusoidal modulation of luminance, masked by a background noise pattern. The sinusoidal luminance modulation was usually subjectively invisible when static, but visible when moving. We found that drifting then stopping the waveform resulted in a transient subjective persistence of the waveform in the static display. Observers' objective sensitivity to the position of the static waveform was also improved after viewing moving waveforms, compared to viewing static waveforms for a matched duration. This facilitation did not occur simply because movement provided more perspectives of the waveform, since performance following pre-exposure to scrambled animations did not match that following pre-exposure to smooth motion. Observers did not simply remember waveform positions at motion offset, since removing the waveform before testing reduced performance. Conclusions/Significance: Motion processing therefore interacts with subsequent static visual inputs in a way that can improve performance in objective sensitivity measures. We suggest that the brief subjective persistence of motion-defined forms that can occur after motion offsets is a consequence of the decay of a static form signal that has been transiently enhanced by motion processing

Mechanical Loading As Potential Treatment For Wnt inhibitor Induced Bone Loss

The Wnt signaling pathway has been shown to play a role in bone homeostasis and carcinogenesis. On the one hand, a decrease in signaling has been associated with a decrease in bone mass, on the other, an increase in signaling with cancer development. LGK974 is a Wnt signaling inhibitor currently being investigated as a potential cancer therapeutic agent. This molecule inhibits Porcupine, a transmembrane protein necessary for Wnt ligand secretion. In light of the above and based on our preliminary data, treatment with LGK974 leads to bone mass loss. Our investigation aims to address whether such bone loss can be prevented by mechanically inducing stress to the bone during the treatment. We treated twelve 16-week old C57Bl/6J male mice with LGK974 (chemical Porcupine inhibitor) and twelve with a vehicle (0.5% Methyl Cellulose, 0.5% Tween-80 in water) on weekdays for two weeks. During that time, under isoflurane-induced anesthesia, all animals underwent right forearm mechanical loading at 60 cycles per day for 3 consecutive days using a 2-Hz haversine waveform at a peak force of 2.4 N. The non-loaded left forearm served as an internal control. Both loaded and control limbs were harvested 15 days post first loading day and processed for micro-computed tomography (microCT). Also, for dynamic histomorphometry (quantitative study of the microscopic organization and structure of the bone), we injected a small group of animals with two doses of 1% calcein solution on two different days to allow for measurement of bone formation rate and matrix apposition rate (a measure of the amount of bone matrix deposited per osteoblast cluster). All procedures performed in this experiment were in accordance with the Van Andel Research Institute Institutional Animal Care and Use Committee guidelines. So far, we have analyzed half of the collected ulnas, and even though, at this point, our results have not reached statistical significance, we see a trend of increased bone area, as well as cross sectional thickness in the loaded ulnas. We are currently in the process of analyzing the rest of the samples in order to determine if, all combined, our results reach statistical significance. If not, the next step would be processing the samples for histomorphometry. In conclusion, we have successfully established a mechanical ulnar loading model in order to study if mechanical loading can offset drug induced bone loss