Synthesis and evaluation of novel quinolines and quinazolinediones as potential anti-cancer agents

This thesis outlines the design and effectuation of novel chemical routes towards a nascent class of functionalised quinoline-5,8-diones and the expansion of a series of contemporary quinazolinediones towards an innovative family of pyridinoquinazolinetetrone derivatives. This fragment based approach is envisaged to lead to advancements in the three scaffolds, expanding the SAR pool of both quinolines and quinazolinediones with subsequent evaluation of chemotherapeutic potential as well as furnishing a new class of tricycle for biological investigation. Development of novel quinoline-5,8-diones is provided for by expanding on existing methodology. Using a variety of nucleophiles on a critical intermediate, a broad range of novel compounds was afforded allowing chemotherapeutic potential to be assessed, while also serving as intermediates for accomplishing novel pyridinoquinazolinetetrone congeners. In order to incorporate functionality into our quinazolinedione template, an efficient synthetic strategy was constructed which provided a robust route to effectuate a highly derivatised pyrimidinedione ring. As derivatisation of this template is unreported our chief priority was to synthesise a range of diverse quinazolinediones. The application of annulation methodology using functionalised precursors provided a library of N-3 derivatised quinazolinedione analogues. These, along with their N-1 functionalised derivatives provide a wide scope from which to construct a series of pyridinoquinazolinetetrone derivatives while also serving as a unique class of molecules whose biological potential is uncharted. Although the actualisation of the pyridinoquinazolinetetrone was ultimately unsuccessful, our work has led to the development of novel quinoline-5,8-diones which were found to possess excellent anti-cancer activity when assessed by the NCI screen. Of the quinazolinediones synthesised eight compounds were accepted for screening by the NCI. Results from the single-dose tests however indicated that these compounds possessed little cytotoxic activity at 10 μM. The development of this novel template in conjunction with the highly active quinolinediones serves as an excellent rostrum for future synthetic endeavours.

The Role of mRNA Translation in the Regulation of Ribosome Trafficking to the Endoplasmic Reticulum

The goal of this research is to identify the trafficking patterns that direct ribosomes to the endoplasmic reticulum (ER). It is widely believed that the SRP pathway is the only mechanism that cells use to localize mRNA and ribosomes to the ER, but this has been found not to be a sufficient explanation for the patterns of RNA localization in cells, namely that non-signal sequence-containing mRNA are translated on the ER and that ribosomes retain their membrane association after translation termination. First, a summary of the history of the field is presented to provide context for the key, unanswered questions in the field. Then, experiments employing [32Pi] pulse-chase labeling of HeLa cells over a time course to follow nascent ribosome trafficking are presented. The purpose of the cell labeling was to track rRNA processing and assembly into nascent ribosomes, followed by their export into the cytoplasm and recruitment into active polysomes. A detergent-based cell fractionation procedure was also utilized to separate the cytosol and ER compartments in order to observe ribosomes on their path as they exit the nucleus and either localize to the ER or cytosolic cellular compartment. Through this method, it was seen that ribosomes appear in both compartments at the same time, suggesting a mechanism may be occurring in addition to SRP-dependent ribosome trafficking. This research provides an understanding toward a mechanism that is not currently known, but will one day more fully explain the patterns of ribosomal localization.

ARFGAP1 promotes the formation of COPI vesicles, suggesting function as a component of the coat.

The role of GTPase-activating protein (GAP) that deactivates ADP-ribosylation factor 1 (ARF1) during the formation of coat protein I (COPI) vesicles has been unclear. GAP is originally thought to antagonize vesicle formation by triggering uncoating, but later studies suggest that GAP promotes cargo sorting, a process that occurs during vesicle formation. Recent models have attempted to reconcile these seemingly contradictory roles by suggesting that cargo proteins suppress GAP activity during vesicle formation, but whether GAP truly antagonizes coat recruitment in this process has not been assessed directly. We have reconstituted the formation of COPI vesicles by incubating Golgi membrane with purified soluble components, and find that ARFGAP1 in the presence of GTP promotes vesicle formation and cargo sorting. Moreover, the presence of GTPgammaS not only blocks vesicle uncoating but also vesicle formation by preventing the proper recruitment of GAP to nascent vesicles. Elucidating how GAP functions in vesicle formation, we find that the level of GAP on the reconstituted vesicles is at least as abundant as COPI and that GAP binds directly to the dilysine motif of cargo proteins. Collectively, these findings suggest that ARFGAP1 promotes vesicle formation by functioning as a component of the COPI coat.

LUCIANO BERIO’S NATURALE: A STORY COMBINING FOLK MUSIC AND ART MUSIC

The study of a score by a serious performer is a fundamental step in the process of arriving at a knowledgeable and deeply informed approach to performing a piece of music. In order to obtain this knowledge numerous aspects of the score must be taken into consideration. It is the intent of this dissertation to gather and analyze the information concerning Naturale, a work written by Luciano Berio in 1985 for viola, percussion and recorded voice, based on Sicilian folk songs. All the aspects surrounding Naturale’s existence are taken into consideration in this study. First, it is important to reflect on Berio’s compositional style and traits, the manner in which he relates his works one to another, what he sees in folk music and his own personal desire to intertwine art music and folk music. For Berio Naturale is not an isolated venture into the realm of mixing folk music and his own avant-garde style; it is instead one of many works resulting from his long-standing relationship with folk music. Another essential aspect in this case is the study of Sicilian folk music itself, and the sources used by Berio to find the songs by which he was inspired. The work is examined section by section with figures showing both excerpts of Naturale as well as the original songs with their translations. An analysis containing harmonic, thematic and formal aspects of the score was developed in order to arrive at a better understanding of the structure and pacing of the piece. For this research the author went to Italy to conduct an interview with Maestro Aldo Bennici, the Sicilian violist for whom Naturale was composed. This interview helped in the discovery of two more songs used by Berio that have not to this point been identified in any other document. Bennici’s outstanding testimony portrayed the expressive character of this music and the evocative imagery behind this score. I hope to bring this knowledge to other performers, that they may fully understand and appreciate the unique beauty and power of Berio’s Naturale.

Resources, experience and perseverance in entrepreneurs' perceived likelihood of success in an emerging economy

This paper introduces new results obtained from a statistical investigation into a 3071-observation data set collected from a Vietnamese nationwide entrepreneurship survey. From established relationships, such factors as preparedness, financial resources and participation in social networks are confirmed to have significant effects on entrepreneurial decisions. Entrepreneurs, both financially constrained and unconstrained, who have a business plan tend to start their entrepreneurial ventures earlier. Also, financial constraints have a profound impact on the entrepreneurial decisions. When perceiving the likelihood of success to be high, an entrepreneur shows the tendency for prompt action on business ideas. But when seeing the risk of prolonging the waiting time to first revenue, a prospective entrepreneur would be more likely to wait for more favorable conditions despite the vagueness of "favorable". Additionally, empirical computations indicate that there is a 41.3% probability that an extant entrepreneur who is generating revenue sees high chance of success. Past work and entrepreneurial experiences also have positive impacts on both the entrepreneurial decisions and perceived chance of success.

Resulting trusts, joint borrowers and beneficial share

Reviews case law illustrating the courts' approach to beneficial ownership of property purchased in joint name by means of a joint mortgage but without any declaration of beneficial interest, the resulting trust and joint beneficial interest presumptions. Contrast the approach adopted in cases where one party made no contribution to the mortgage payments with those where both parties made a contribution. Highlights the courts' treatment of the right to buy discount afforded tenant purchasers and property purchased as a commercial venture rather than a home.

The type I antifreeze protein gene family in Pleuronectidae

Antifreeze proteins (AFPs) protect marine teleosts from freezing in icy seawater by binding to nascent ice crystals and preventing their growth. It has been suggested that the gene dosage for AFPs in fish reflects the degree of exposure to harsh winter climates. The starry flounder, _Platichthys stellatus_, has been chosen to examine this relationship because it inhabits a range of the Pacific coast from California to the Arctic. This flatfish is presumed to produce type I AFP, which is an alanine-rich, amphipathic alpha-helix. Genomic DNA from four starry flounder was Southern blotted and probed with a cDNA of a winter flounder liver AFP. The hybridization signal was consistent with a gene family of approximately 40 copies. Blots of DNA from other starry flounder indicate that California fish have far fewer gene copies whereas Alaska fish have far more. This analysis is complicated by the fact that there are three different type I AFP isoforms. The first is expressed in the liver and secreted into circulation, the second is a larger hyperactive dimer also thought to be expressed in the liver, and the third is expressed in peripheral tissues. To evaluate the contribution of these latter two isoforms to the overall gene signal on Southern blots, hybridization probes for the three isoforms were isolated from starry flounder DNA by genomic cloning. Two clones revealed linkage of genes for different isoforms, and this was confirmed by genomic Southern blotting, where hybridization patterns indicated that the majority of genes were present in tandem repeats. The sequence and diversity of all three isoforms was sampled in the starry flounder genome by PCR. All coding sequences derived for the skin and liver isoforms were consistent with the proposed structure-function relationships for this AFP, where the flat hydrophobic side of the helix is conserved for ice binding. There was greater sequence diversity in the skin and hyperactive isoforms than in the liver isoform, suggesting that the latter evolved recently from one of the other two. The genomic PCR primers are currently being used to sample isoform diversity in related right-eyed flounders to test this hypothesis.

Mouse Uterine Natural Killer Cell Functions During Early Pregnancy

Early pregnancy is characterized by complex interactions between blood vessels, leukocytes, and conceptus-derived trophoblasts within the gestational uterus. Uterine Natural Killer (uNK) cells become the most abundant leukocyte during decidualization and produce a wide array of angiogenic factors, yet little is known regarding their early pregnancy functions. To characterize the role(s) of uNK cells, whole mount in situ immunohistochemistry of live early implant sites was performed. A timecourse examination of murine early pregnancy (virgin, and gd4.5-9.5) implantation sites was performed. Comparison of Gd6.5, 8.5 and 9.5 implant sites from BALB/c+/+ controls (BALB/c) and BALB/c-Rag2-/-Il2rg-/- (alymphoid) identified anomalies that result from the absence of lymphocytes. In alymphoid decidua basalis, mesometrial angiogenesis was widespread but pruning of nascent vessels within alymphoid decidua basalis was deficient. As early gestation progressed, vessels of alymphoid decidua basalis showed no evidence for remodeling. Alymphoid implantation sites showed ~24h delay in uterine lumen closure and embryonic development. To determine if uNK cells would normalize the anomalies observed in alymphoid implantation sites, adoptive cell transfer of NK+ B- T- marrow to alymphoid mice was performed. All of the above anomalies were reversed by adoptive transfer of NK+B-T- marrow. My results suggest that uNK cells support vascular growth and development which ensures the decidua can support the growing conceptus early in pregnancy prior to formation and function of the placenta. Human decidual NK cells may fill similar roles and be important targets for strategies designed to correct intra-uterine growth restriction.

Desperately Seeking Finance? The Demand for Finance by Women Owned and Led Businesses

The study reported here addresses some issues on gender, entrepreneurship and finance that have been identified as problematic in the literature. For example, much of the research to date is based on the assumption of entrepreneurship as male entrepreneurship; few studies have controlled for structural characteristics that may impact on the relationship between owner gender and a venture's ability to raise finance; and women are less likely than men to seek growth and external financing. Through the conduct of in-depth semi-structured interviews, an attempt has been made to give `voice' to women's intrinsically interesting experiences as the enactment of a situated practice, and not just in comparison with the assumed norm of male entrepreneurial activity. The findings suggest that when variables such as individual and firm characteristics are controlled for, generalizations found in the literature may not be supported. Further, the paper highlights that neither women entrepreneurs nor their businesses are homogeneous in nature and that greater heterogeneity in the study of female entrepreneurship in general, and access to finance in particular, is required.

Investment and Capitalization of Firms in the USA

In the USA today, the precipitous rise of new financial mechanisms for capitalisation of firms as well as the merger and acquisition of others, especially risk equity capital through venture capitalist and investment banking, has sparked growth and helped to bring the economy out of the 1990s recession into a robust continuous growth pattern well positioned for the next century. The scenario is not new. For the venture capitalists of ''Silicon Valley'' in California, the experience is not new. They have seen the new industries arise before, like a phoenix from ashes of ruin, despair and even failure. Venture capital poured into high tech start-up companies has been an enormous source of financial support for the entrepreneurs who head new and growing companies. The mid-1990s marked the most dramatic increase yet recorded. Indicators, such as the NASDAQ document, outlined the solid and continuous growth in high tech industries. The paper discusses investment in US corporations within the context of governance and management of the company. Discussion about the various forms of finance are related to the organisation and management of the US corporation. Critical to any firm today are its ability to find innovative, new products or services. A growing literature on resource-base framework for analysis will be discussed as part of the firm's development of research for commercialisation. The results of a recent survey further shed light on the relationship between corporate financial management and allocated resources for research and development as the ''engine'' for new product development and therefore corporate market share and growth. The conclusion is that more financial mechanisms will be created and changed within US corporate systems to adjust, grow, and expand companies in the global economic arena, as the inevitable economic pattern leads to mergers, consolidations, and increasing cooperation and alliances among firms.

Does Gender Matter? Women Business Angels and the Supply of Entrepreneurial Finance

There is a substantial literature on the relationship between gender and access to finance. However, most studies have been concerned with access to debt finance. More recently, the focus of this research has broadened to examine women and venture capital. This article extends the focus further by examining the role of women in the business angel market, which is more important than the formal venture capital market in terms of both the number of ventures supported and total capital flows. Based on a detailed analysis of business angels in the U.K., the study concludes that women investors who are active in the market differ from their male counterparts in only limited respects. Future research into women business angels, and the possible existence of gender differences, needs to be based on more fully elaborated standpoint epistemologies that focus on the experience of the woman angel investor per se, and center on the examination of the role of homophily, social capital, networking, and competition in investment behavior.

Organizational and financial transparency in the website of the foundations: an empirical study for Spain

Transparency in nonprofit sector and foundations, as an element to enhance the confidence of stakeholders in the organization, is a fact shown by several studies in recent decades. Transparency can be considered in various fields and through different channels. In our study we focused on the analysis of the organizational and economic transparency of foundations, shown through the voluntary information on their Website. We review the theoretical previous studies published to put to the foundations within the framework of the social economy. This theoretical framework has focused on accountability that make foundations in relation to its social function and its management, especially since the most recent focus of information transparency across the Website.In this theoretical framework was made an index to quantify the voluntary information which is shown on its website. This index has been developed ad hoc for this study and applied to a group of large corporate foundations.With the application of these data are obtained two kind of results, to a descriptive level and to a inferential level.We analyzed the statistical correlation between economic transparency and organizational transparency offered in the Website through quantified variables by a multiple linear regression. This empirical analysis allows us to draw conclusions about the level of transparency offered by these organizations in relation to their organizational and financial information, as well as explain the relation between them.

De la cooperativa agroalimentaria a la "learning netchain". Hacia un planteamiento teorico interorganizativo e interpersonal

Se propone un planteamiento teórico/conceptual para determinar si las relaciones interorganizativas e interpersonales de la netchain de las cooperativas agroalimentarias evolucionan hacia una learning netchain. Las propuestas del trabajo muestran que el mayor grado de asociacionismo y la mayor cooperación/colaboración vertical a lo largo de la cadena están positivamente relacionados con la posición horizontal de la empresa focal más cercana del consumidor final. Esto requiere una planificación y una resolución de problemas de manera conjunta, lo que está positivamente relacionado con el mayor flujo y diversidad de la información/conocimiento obtenido y diseminado a lo largo de la netchain. Al mismo tiempo se necesita desarrollar un contexto social en el que fluya la información/conocimiento y las nuevas ideas de manera informal y esto se logra con redes personales y, principalmente, profesionales y con redes internas y, principalmente, externas. Todo esto permitirá una mayor satisfacción de los socios de la cooperativa agroalimentaria y de sus distribuidores y una mayor intensidad en I+D, convirtiéndose la netchain de la cooperativa agroalimentaria, así, en una learning netchain.