Expression and regulation of VCAM-1 and CD44 by cultured fibroblast-like synoviocytes.

The fibroblast-like synoviocyte (FLS) has been implicated in the destructive process associated with rheumatoid arthritis. In this thesis I demonstrate the expression and regulation of several adhesion molecules expressed on cultured FLSs obtained from inflamed synovium. Unlike fibroblasts from other areas of the body, FLSs constitutively express vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 on RA FLSs is constitutively expressed at high levels during the first 2 weeks of culture. At later time points (4 weeks in culture), VCAM-1 expression declined to low basal levels. A number of strategies were employed to determine the exogenous factors that determine the initially high levels of VCAM-1 in FLSs. Of the extracellular matrix components examined only collagen type I enhanced VCAM-1 expression but this had only limited success. The pro-inflammatory cytokines, IL-1β (10 ng/ml) and TNF-α (10 ng/ml), were also tested and found to induce only transient increases in cell surface VCAM-1 expression. However, the chronic administration of IL-4 or IL-13 in combination with TNF-α resulted in elevated levels of VCAM-1 with prolonged expression Prolonged VCAM-1 expression was found to result in part from the capacity of IL-4 and IL-13 to stabilize VCAM-1 mRNA transcripts. CD44 splice variants, isoforms of the CD44 receptor, that are implicated in the progression of a number of human tumours were also expressed by FLSs isolated from inflamed synovium. Immunohistochemistry, flow cytometry and RT-PCR analysis of CD44 splice variant expression revealed differential expression of a number of variant isoforms. Splice variant expression, at both the mRNA and cell surface protein level, was observed in a large percentage of RA FLSs, it is variable in those from OA synovium, and is absent in cells isolated from non-inflamed joints. However, RA FLSs showed a greater intensity of staining for variants v3, v5 and v7/8. VCAM-1-positive FLSs also demonstrated complex splice variant mRNA transcripts, comprising v3, v6, v7, v8, v9 and v10 in a variety of splicing combinations. These results indicate that the nature of CD44-splice variant expression is closely linked to the inflammatory state of the synovial joint. Moreover, expression of the CD44v7/8 epitope is associated with an increased cellular proliferation rate and could thus be functionally implicated in the hyperplasia observed in RA synovium

Ecological Causes of Life History Variation Tested by Meta-analysis, Comparison, and Experimental Approaches

The ecological causes of life history variation among taxa and the arrangement of such variation along geographic gradients is enigmatic despite the proximity of life history traits to fitness and implications for understanding basic and applied population ecology. One classic explanation for the arrangement of avian life histories along a `slow-fast\u27 gradient, where species at low latitudes have `slow\u27 life history traits (low fecundity and mortality) and species at high latitudes have `fast\u27 life history traits (high fecundity and mortality), is the increase in seasonality of resources with increasing latitude (Ashmole\u27s hypothesis). Despite broad acceptance, this hypothesis has been supported only indirectly. I tested two key predictions of this hypothesis - that most mortality occurs in winter and that most mortality is caused by starvation - using meta-analysis. Surprisingly, in many populations, the season of greatest mortality was summer, and most mortality was caused by predation. These results suggest alternative explanations for life history variation should remain under consideration despite support for Ashmole\u27s hypothesis. The relationship between provisioning behavior and offspring number was long recognized to integrate key life history tradeoffs between number and quality of offspring and between current and future reproductive success. Studies of the response of parental provisioning behavior to brood size variation played a formative role in the development of life history theory. Yet, the inference of such experiments for explaining among-species differences has always been limited by lack of comparative context. I expanded predictions of alternative ecological explanations (food limitation, nest predation, adult mortality) for life history variation to an among-species context and test these predictions using a comparative-experimental design across a broad range of bird species from three continents. I found resource limitation and adult mortality risk interact to explain variation among species in responses to natural and experimental variation in brood size, with the degree of food limitation appearing to vary across a gradient of adult mortality risk. This result helps to explain the potentially conflicting results of previous studies and suggests a pluralistic approach to understanding what factors explain life history variation may be fruitful. Understanding variation among species in mortality rates may thus be pivotal to understanding ecological causes of life history variation. To this end, I compared differences in spatiotemporal variance in survival among three temperate-breeding species with differing migratory strategy. I found that migratory behavior may be associated with reduced spatial variance in annual survival because resident species disperse less, reducing population connectivity. I also found that migratory behavior is associated with increased temporal variance in survival, counter to expectations of general theory. Given the potential importance of mortality risk in life history evolution, expanded geographic comparisons of annual and within-year patterns of variance in survival rates is likely key to understanding variation among species in life history traits

Scenes from Goethe's Faust:: Schumann's Grand Opus

The course of Schumann's career seems to lead m an almost predetermined manner to the composition of the oratorio Scenes from Goethe's Faust as the culmination and summation of all the work that had preceded it, both musically and philosophically, a compositional climax that portrays the characteristics of the theoretical genre of the Grand Opus. This thesis explores a single example from each of the three genres that were most important to Schumann's career – piano composition, song and symphony - and examines how these three works - the C major Fantasie Op. 17, Frauenliebe und-Leben Op.42, and the Second Symphony Op.61 respectively - exemplify the hallmarks of Schumann's creative philosophy through three compositional elements - Schumann's use of genre, the philosophy of the fragment, and a new found historicism and appreciation of tradition - elements that were rooted m the broader context of the Romantic period and its distinct system of values and beliefs. The manifestation, development, and culmination of these three genres and three compositional elements m Scenes from Goethe's Faust provides a perspective from which to view the oratorio, in relation to the composer's previous works, as Schumann's Grand Opus

Embedding constructive alignment of reading lists in course design

Introduction. Reading list practices are long-standing but cause confusion and misunderstanding between module leaders and students. Constructive alignment (Biggs and Tang, 2011), although widely applied in course design across the UK Higher Education sector, has not previously been applied to the practice of reading lists but offers a practical and pedagogically sound method for reinventing reading list practice and bridging the gap of understanding between the intentions of module leaders and the interpretation of students. Objectives. To embed the practice of constructive alignment of reading lists in Oxford Brookes University modules. Method. The module leaders of seven modules were offered the support of a project led by Oxford Brookes Library to redesign their modules so that the reading lists were constructively aligned with the learning outcomes of the modules. After an initial run of the redesigned modules the module leaders were asked whether they would embed the practice of constructively aligned reading lists in their modules. Result. Five of the modules were redesigned and continued with the redesign past the initial instance, one of the modules exited the project before it was redesigned, and one of the modules returned to the pre-project module design and reading list practice. Conclusion. The project was successful in embedding constructively aligned reading list practice in Oxford Brookes University modules past the first run of the module, but several barriers to effective learning and teaching were identified with the most significant being a lack of student engagement with the redesigned reading lists. The implication for practice is that constructively aligned reading lists should include an element of summative assessment to increase the chances of student engagement and the successful embedding of constructively aligned reading lists in the design of modules