Comparison of the modes of action of Apremilast and Roflumilast

The phosphodiesterase 4 (PDE4) family are cAMP specific phosphodiesterases that play an important role in the inflammatory response and is the major PDE type found in inflammatory cells. A significant number of PDE4 specific inhibitors have been developed and are currently being investigated for use as therapeutic agents. Apremilast, a small molecule inhibitor of PDE 4 is in development for chronic inflammatory disorders and has shown promise for the treatment of psoriasis, psoriatic arthritis as well as other inflammatory diseases. It has been found to be safe and well tolerated in humans and in March 2014 it was approved by the US food and drug administration for the treatment of adult patients with active psoriatic arthritis. The only other PDE4 inhibitor on the market is Roflumilast and it is used for treatment of respiratory disease. Roflumilast is approved in the EU for the treatment of COPD and was recently approved in the US for treatment to reduce the risk of COPD exacerbations. Roflumilast is also a selective PDE4 inhibitor, administered as an oral tablet once daily, and is thought to act by increasing cAMP within lung cells. As both (Apremilast and Roflumilast) compounds selectively inhibit PDE4 but are targeted at different diseases, there is a need for a clear understanding of their mechanism of action (MOA). Differences and similarity of MOA should be defined for the purposes of labelling, for communication to the scientific community, physicians, and patients, and for an extension of utility to other diseases and therapeutic areas. In order to obtain a complete comparative picture of the MOA of both inhibitors, additional molecular and cellular biology studies are required to more fully elucidate the signalling mediators downstream of PDE4 inhibition which result in alterations in pro- and anti-inflammatory gene expression. My studies were conducted to directly compare Apremilast with Roflumilast, in order to substantiate the differences observed in the molecular and cellular effects of these compounds, and to search for other possible differentiating effects. Therefore the main aim of this thesis was to utilise cutting-edge biochemical techniques to discover whether Apremilast and Roflumilast work with different modes of action. In the first part of my thesis I used novel genetically encoded FRET based cAMP sensors targeted to different intracellular compartments, in order to monitor cAMP levels within specific microdomains of cells as a consequence of challenge with Apremilast and Roflumilast, which revealed that Apremilast and Roflumilast do regulate different pools of cAMP in cells. In the second part of my thesis I focussed on assessing whether Apremilast and Roflumilast cause differential effects on the PKA phosphorylation state of proteins in cells. I used various biochemical techniques (Western blotting, Substrate kinase arrays and Reverse Phase Protein array and found that Apremilast and Roflumilast do lead to differential PKA substrate phosphorylation. For example I found that Apremilast increases the phosphorylation of Ribosomal Protein S6 at Ser240/244 and Fyn Y530 in the S6 Ribosomal pathway of Rheumatoid Arthritis Synovial fibroblast and HEK293 cells, whereas Roflumilast does not. This data suggests that Apremilast has distinct biological effects from that of Roflumilast and could represent a new therapeutic role for Apremilast in other diseases. In the final part of my thesis, Phage display technology was employed in order to identify any novel binding motifs that associate with PDE4 and to identify sequences that were differentially regulated by the inhibitors in an attempt to find binding motifs that may exist in previously characterised signalling proteins. Petide array technology was then used to confirm binding of specific peptide sequences or motifs. Results showed that Apremilast and Roflumilast can either enhance or decrease the binding of PDE4A4 to specific peptide sequences or motifs that are found in a variety of proteins in the human proteome, most interestingly Ubiquitin-related proteins. The data from this chapter is preliminary but may be used in the discovery of novel binding partners for PDE4 or to provide a new role for PDE inhibition in disease. Therefore the work in this thesis provides a unique snapshot of the complexity of the cAMP signalling system and is the first to directly compare action of the two approved PDE4 inhibitors in a detailed way.

Smoke and mirrors in trade disputes will harm public health

The 2014 World Cancer Report, issued by the World Health Organisation (WHO), indicates that the number of new cancer cases has reached an all-time high. On the 19 May 2014, Dr Margaret Chan, the Director-General of the WHO, gave a stirring speech to the 67th Health Assembly on the heavy health burden associated with cancer. Chan was particularly interested in public health measures designed to combat the global tobacco epidemic...

Linnunkiikut ja kallen kaulukset : Kotitekoiset kuukautissiteet 1900-luvun alkupuolen Suomessa

The aim of this thesis was to study what kind of home-made menstrual pads were used in the early 20th century in Finland, how the home-made pads were made and which techniques and materials were used. The use and taking care of menstrual pads were also explored. The history of menstrual pads has been studied in Sweden, Germany and United States but none of those studies has concentrated on home-made pads. Instead, there are many studies about womanhood and menstruation. In many studies home-made menstrual pads are only briefly mentioned. Menstrual pads were not commonly used in Finland at the beginning of the 20th century, but already in the 1940s the use of menstrual pads had become common in every stratum of society. Home-made menstrual pads were used even until the 1960s. In Finland, factory-made disposable menstrual pads became common only in the 1930s and they were only slowly accepted. The study material consisted of nine interviews, three archival inquiries, health care guidebooks from 1893 to 1943 and authentic menstrual pads, menstrual belts and other objects related to them. The interviewed women were born between 1915 and 1939. The narrative approach was used in the study and it also guided the analysis. The interview and archival data were studied according to the basic rules of oral history studies. Literature consisted of publications from several disciplines. The extensive primary material played the most important role in this study. The reconstructions of the menstrual pads were made according to the interviewed women s advice. In Finland there were innumerable variations of home-made menstrual pads. The pads were most commonly crocheted and knitted either by hand or by knitting machine. Pads were also sewn of cloth, old bed linen or old underwear. The menstrual pads were self-made or made by a female relative. Word of mouth was important in spreading information on how to make pads, because there were hardly any instructions available. The biggest pads were 54 cm long and 13 cm wide. The most widely used pad model was a rectangle, which had triangle-shaped ends with a buttonhole or a loop. The pad was attached to the menstrual belt or to the buttons of the suspender belt. Knitted and crocheted pads had one, two or three layers. In sewn pads, there could be even more layers. Cellulose wadding or pieces of cloth could be placed inside the pad to increase the absorption ability. The experiences of the comfort of self-made pads varied. The crocheted and sewn pads were found chafing, knitted ones were found soft and comfortable. The menstrual pads were laborious to wash and boil in lye water. Therefore disposable pads made everyday life easier. The home-made menstrual pads were part of a unique tradition of handicrafts and folk culture. Hand-made pads were one of the most common handicraft products and were a part of every woman s life. Even so, the menstrual pads were unnoticeable. The large number of variations was probably caused by the silence around menstrual topics and by the lack of instructions for making pads. Variations are also explained by the uniqueness of every handicraft product. In Finland the home-made pads were used until relatively recent times. This was caused by the conditions of wartime and the following years and the rarity of commercial pads. Furthermore, until the late 20th century Finland was an agricultural society where all innovations spread slowly. Home-made menstrual pad was a secret handicraft of women and every woman needed to know how to make it by herself.

AHC interview with Gloria Gray Katz.

June 7, 2010

Flow and heat transfer in steady laminar compressible boundary layer swirling flow in a nozzle

The axisymmetric steady laminar compressible boundary layer swirling flow of a gas with variable properties in a nozzle has been investigated. The partial differential equations governing the non-similar flow have been transformed into new co-ordinates having finite ranges by means of a transformation which maps an infinite range into a finite one. The resulting equations have been solved numerically using an implicit finite-difference scheme. The computations have been carried out for compressible swirling flow through a convergent conical nozzle. The results indicate that the swirl exerts a strong influence on the longitudinal skin friction, but its effect on the tangential skin friction and heat transfer is comparatively small. The effect of the variation of the density-viscosity product across the boundary layer is appreciable only at low-wall temperature. The results are in good agreement with those of the local-similarity method for small values of the longitudinal distance.

Fisheries conservation and habitat improvement in marine ecosystems

The following discussion presents information on human-made reefs and their role--as one tool of many--in the management of both fisheries and habitat. Principal subjects covered in this paper include a definition of marine habitat improvement and determination of its attainment, the present applications of reef construction technology to environmental situations both generally and in three case-studies, and suggested desirable attributes for incorporation into future use of this technology. (PDF has 11 pages.)

Historical knowledge of sharks: ancient science, earliest American encounters, and American science, fisheries, and utilization

In western civilization, the knowledge of the elasmobranch or selachian fishes (sharks and rays) begins with Aristotle (384–322 B.C.). Two of his extant works, the “Historia Animalium” and the “Generation of Animals,” both written about 330 B.C., demonstrate knowledge of elasmobranch fishes acquired by observation. Roman writers of works on natural history, such as Aelian and Pliny, who followed Aristotle, were compilers of available information. Their contribution was that they prevented the Greek knowledge from being lost, but they added few original observations. The fall of Rome, around 476 A.D., brought a period of economic regression and political chaos. These in turn brought intellectual thought to a standstill for nearly one thousand years, the period known as the Dark Ages. It would not be until the middle of the sixteenth century, well into the Renaissance, that knowledge of elasmobranchs would advance again. The works of Belon, Salviani, Rondelet, and Steno mark the beginnings of ichthyology, including the study of sharks and rays. The knowledge of sharks and rays increased slowly during and after the Renaissance, and the introduction of the Linnaean System of Nomenclature in 1735 marks the beginning of modern ichthyology. However, the first major work on sharks would not appear until the early nineteenth century. Knowledge acquired about sea animals usually follows their economic importance and exploitation, and this was also true with sharks. The first to learn about sharks in North America were the native fishermen who learned how, when, and where to catch them for food or for their oils. The early naturalists in America studied the land animals and plants; they had little interest in sharks. When faunistic works on fishes started to appear, naturalists just enumerated the species of sharks that they could discern. Throughout the U.S. colonial period, sharks were seldom utilized for food, although their liver oil or skins were often utilized. Throughout the nineteenth century, the Spiny Dogfish, Squalus acanthias, was the only shark species utilized in a large scale on both coasts. It was fished for its liver oil, which was used as a lubricant, and for lighting and tanning, and for its skin which was used as an abrasive. During the early part of the twentieth century, the Ocean Leather Company was started to process sea animals (primarily sharks) into leather, oil, fertilizer, fins, etc. The Ocean Leather Company enjoyed a monopoly on the shark leather industry for several decades. In 1937, the liver of the Soupfin Shark, Galeorhinus galeus, was found to be a rich source of vitamin A, and because the outbreak of World War II in 1938 interrupted the shipping of vitamin A from European sources, an intensive shark fishery soon developed along the U.S. West Coast. By 1939 the American shark leather fishery had transformed into the shark liver oil fishery of the early 1940’s, encompassing both coasts. By the late 1940’s, these fisheries were depleted because of overfishing and fishing in the nursery areas. Synthetic vitamin A appeared on the market in 1950, causing the fishery to be discontinued. During World War II, shark attacks on the survivors of sunken ships and downed aviators engendered the search for a shark repellent. This led to research aimed at understanding shark behavior and the sensory biology of sharks. From the late 1950’s to the 1980’s, funding from the Office of Naval Research was responsible for most of what was learned about the sensory biology of sharks.

Kierowanie pracą ucznia w licealnych podręcznikach do języka polskiego

Wydział Filologii Polskiej i Klasycznej: Pracownia Innowacji Dydaktycznych

Conversion as transformative experience: a sociological study of identity formation and transformation processes

This thesis contributes to the understanding of the processes involved in the formation and transformation of identities. It achieves this goal by establishing the critical importance of ‘background’ and ‘liminality’ in the shaping of identity. Drawing mainly from the work of cultural anthropology and philosophical hermeneutics a theoretical framework is constructed from which transformative experiences can be analysed. The particular experience at the heart of this study is the phenomenon of conversion and the dynamics involved in the construction of that process. Establishing the axial age as the horizon from which the process of conversion emerged will be the main theme of the first part of the study. Identifying the ‘birth’ of conversion allows a deeper understanding of the historical dynamics that make up the process. From these fundamental dynamics a theoretical framework is constructed in order to analyse the conversion process. Applying this theoretical framework to a number of case-studies will be the central focus of this study. The transformative experiences of Saint Augustine, the fourteenth century nun Margaret Ebner, the communist revolutionary Karl Marx and the literary figure of Arthur Koestler will provide the material onto which the theoretical framework can be applied. A synthesis of the Judaic religious and the Greek philosophical traditions will be the main findings for the shaping of Augustine’s conversion experience. The dissolution of political order coupled with the institutionalisation of the conversion process will illuminate the mystical experiences of Margaret Ebner at a time when empathetic conversion reached its fullest expression. The final case-studies examine two modern ‘conversions’ that seem to have an ideological rather than a religious basis to them. On closer examination it will be found that the German tradition of Biblical Criticism played a most influential role in the ‘conversion’ of Marx and mythology the best medium to understand the experiences of Koestler. The main ideas emerging from this study highlight the fluidity of identity and the important role of ‘background’ in its transformation. The theoretical framework, as constructed for this study, is found to be a useful methodological tool that can offer insights into experiences, such as conversion, that otherwise would remain hidden from our enquiries.

La ofensiva cinematográfica de la URSS en la guerra civil española

This article explores Soviet cinema and the Spanish Civil War, 1936-1939. The article focuses on three separate components of Moscow’s cinematic operations vis-à-vis the Spanish imbroglio: 1.) the distribution of Soviet-made feature films in the Loyalist zone, 2.) the production of Soviet propaganda newsreels on Spanish subjects intended for distribution within the Soviet Union, and 3.) the significance of the Spanish war for Soviet cinema throughout the balance of the Bolshevik period. The narrative and conclusions herein are supported by new research from archives in both Spain and the Russian Federation, as well as analyses of films rarely if ever discussed in the scholarly literature, either within film studies or twentieth century European history.

Guggenheim Art Gallery, Moulton Hall, Chapman College, Orange, California

Guggenheim Gallery in Moulton Hall, Chapman College, Orange, California. Completed in 1975 (2 floors, 44,592 sq.ft.), Moulton Hall is named in memory of an artist and patroness of the arts, Nellie Gail Moulton. Within this structure are the departments of Art, Communications, and Theatre/Dance as well as the Guggenheim Gallery and Waltmar Theatre. Waltmar Theatre was a gift from the late Walter and Margaret Schmid. The Guggenheim Gallery is used for the art exhibits presented by the art department and other departments on campus. It gives students and local artists an opportunity to display their work. Student art shows are held each semester to showcase art, photography, and graphic design works.

Rittermere Farm Craft Studio Fonds, 1951-2006

During the 1950’s, the Rittenhouse family of Vineland in the Niagara Peninsula opened a craft store and studio. Within a short period of time, they realized that resources for the craft of rug hooking were in demand and they began to build their business around this niche. Edna Rittenhouse, the mother, was the wool dyer; Margaret Rowan, the daughter, was the pattern designer; Ted Rowan, the son-in-law, changed careers and became the manager of the family business. The 1960’s were a prosperous time, not only in the Niagara Peninsula, but also for the Rittenhouse business. Edna Rittenhouse had been hooking rugs for decades but she and her family worked at developing and sharing newer techniques with newer materials. Shading manuals were authored and published; students became teachers; creativity abounded in the demand for and the creation of new designs. Instead of using woolen yarn, they were using pure woolen fabric; instead of using a standard cutter, they began using a uniquely designed cutter; instead of using frames, they employed a table top method. The new material and technique resulted in a rug with a smooth, uniform texture and a soft nap. Since many crafters belonged to crafters guilds, Margaret and Ted Rowan began promoting the idea of a guild for rug hookers and in time the Ontario Hooking Craft Guild was also a reality. A joint project between Chatelaine magazine and the Rittermere studio for Canada’s centennial year of 1967 was extremely well received within the circle of hooking crafters and the Rittermere Farm Craft Studio became a North American landmark for crafters. From this point onward the studio had a large customer base not only in North America but also overseas. The studio remained popular until 1984 when Margaret and Ted Rowan decided to retire. The Rittermere name has been preserved in the name of Rittermere-Hurst-Field which is a similar business located in Aurora which is just north of Toronto.

Moulton Hall, Chapman College, Orange, California

Moulton Hall, Chapman College, Orange, California, ca. 1975. Designed by Leason Pomeroy III & Associates of Orange, using a tilt-up concrete construction method. Completed in 1975, this 44,592 sq.ft. building is named in memory of an artist and patroness of the arts, Nellie Gail Moulton. Within this structure are the departments of Art, Communications, and Theatre/Dance as well as the Guggenheim Gallery and Waltmar Theatre. Waltmar Theatre was a gift from the late Walter and Margaret Schmid. The Guggenheim Gallery is used for the art exhibits presented by the art department and other departments on campus.

Moulton Hall, Chapman College, Orange, California

Moulton Hall, Chapman College, Orange, California, ca. 1975. Designed by Leason Pomeroy III & Associates of Orange, using a tilt-up concrete construction method. Completed in 1975, this 44,592 sq.ft. building is named in memory of an artist and patroness of the arts, Nellie Gail Moulton. Within this structure are the departments of Art, Communications, and Theatre/Dance as well as the Guggenheim Gallery and Waltmar Theatre. Waltmar Theatre was a gift from the late Walter and Margaret Schmid. The Guggenheim Gallery is used for the art exhibits presented by the art department and other departments on campus.