TAK1 Is Required for Dermal Wound Healing and Homeostasis

Dermal connective tissue is a supportive structure required for skin’s barrier function; dysregulated dermal homeostasis results in chronic wounds and fibrotic diseases. The multifunctional cytokine transforming growth factor (TGF) β promotes connective tissue deposition, repair, and fibrosis. TGF-β acts through well-defined canonical pathways; however, the non-canonical pathways through which TGF-β selectively promotes connective tissue deposition are unclear. In dermal fibroblasts, we show that inhibition of the non-canonical TGF-β-activated kinase 1 (TAK1) selectively reduced the ability of TGF-β to induce expression of a cohort of wound healing genes, such as collagens, CCN2, TGF-β1, and IL-6. Fibroblast-specific TAK1-knockout mice showed impaired cutaneous tissue repair and decreased collagen deposition, α-smooth muscle actin and CCN2 expression, proliferating cell nuclear antigen staining, and c-Jun N-terminal kinase and p38, but not Smad3, phosphorylation. TAK1-deficient fibroblasts showed reduced cell proliferation, migration, cell attachment/spreading, and contraction of a floating collagen gel matrix. TAK1-deficient mice also showed progressively reduced skin thickness and collagen deposition. Thus, TAK1 is essential for connective tissue deposition in the dermis

Strategic groups and competitive groups in the UK pharmaceutical industry 1993-2002

Strategic group research originated in the 1970s and a number of notable studies centered on the US pharmaceutical industry. Results were however, conflicting. This thesis explores the nature of strategic groups and the related concept of competitive groups in the UK pharmaceutical industry during the period 1993 to 2002. The research follows three related themes. The first research theme identifies two stable strategic time periods each of five years duration across the period studied. Within each of these time periods strategic groups were identified using a combination of Ward's method and aK means clustering algorithm and the presence of a relatively stable strategic group structure was confirmed. A statistically significant relationship between these strategic groups and performance is demonstrated using three performance measures. The second research theme then explores the movement of firms between strategic groups and finds some support for the proposition that firms moving between strategic groups move to more advantageousp ositions. The relationship between strategicg roups and mergers is also investigated and this research finds that mergers between firms occur preferentially across strategic groups rather than within strategic groups. This relationship is confirmed as highly statistically significant. Finally in the third research theme the relationship between strategic groups, how firms compete and competitive groups, where firms compete, are investigated. Six different competitive groups are identified, all but one of which is concentrated around a dominant therapeutic area. This finding suggests that direct competition between firms is reduced by market segmentation. A weak relationship was found between competitive groups and performance but when competitive groups (where firms compete) and strategic groups how firms compete) are examined in combination a strong statistically significant relationship with performance was found.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Pericytes display increased CCN2 expression upon culturing

By providing a source of α-smooth muscle actin (α-SMA)-expressing myofibroblasts, microvascular pericytes contribute to the matrix remodeling that occurs during tissue repair. However, the extent to which pericytes may contribute to the fibroblast phenotype post-repair is unknown. In this report, we test whether pericytes isolated from human placenta can in principle become fibroblast-like. Pericytes were cultured in vitro for 11 passages. The Affymetrix mRNA expression profile of passage 2 and passage 11 pericytes was compared. The expression of type I collagen, thrombospondin and fibronectin mRNAs was induced by passaging pericytes in culture. This induction of a fibroblast phenotype was paralleled by induction of connective tissue growth factor (CTGF/CCN2) and type I collagen protein expression and the fibroblast marker ASO2. These results indicate that, in principle, pericytes have the capacity to become fibroblast-like and that pericytes may contribute to the population of fibroblasts in a healed wound

The whole of university experience: retention, attrition, learning and personal support interventions during undergraduate business studies

The Whole of University Experience (WoUE) project examined factors underpinning attrition in the first, second and third year of a business degree at six Australian universities – Griffith University, Monash University, Murdoch University, University of South Australia, University of Southern Queensland, and University of the Sunshine Coast. A questionnaire completed in 2008, 2009, and 2010 by a total of 7,486 students enabled gathering of data relating to demographics; students’ experience of university; their use and perceptions of the usefulness of student support interventions; open-ended comments about the best and worst aspects of the university experience; and aspects in need of improvement. In each year a small number of students were also interviewed for the purpose of fleshing out the survey data and exploring the interactions between various factors associated with attrition. Overall, the data strongly indicates that factors related to attrition are generally university-specific and reflect both student characteristics and their responses to the specific institutional culture and environment. The only attrition triggers which span most universities and most years of study are ‘lack of a clear reason for being at university’ and ‘the feeling of having insufficient ability to succeed at university’. Correlation analysis relating 70 statements probing students’ experience of university to the strength of their intention to leave before completing a degree revealed notable differentiation in attrition triggers on the basis of year of study. Follow-up analysis in one university indicated further differentiation in the triggers for attrition, semester by semester. It seems that many different factors underpin attrition decisions in any one institution and for any one individual, for whom attrition appears to be the result of the aggregation of diverse factors generally followed by ‘the straw that broke the camel’s back’. When responses are grouped by demographic variables some difference in the factors associated with domestic and international student attrition is apparent, but no difference in the factors associated with their sense of satisfaction or belonging is obvious. In the responses of international and domestic students to issues of teaching quality, differences primarily related to expectations regarding teaching staff approachability, availability and helpfulness. For students enrolled part-time or full-time different factors underpin attrition, and attrition triggers also differ on the basis of time spent on campus and average grades. Preliminary analysis suggests that having to take a loan or engage in full-time work to fund studies is a greater attrition risk factor in most universities than is the receipt of Centrelink benefits (which may be seen as a proxy indicator for low socio-economic status). Analysis of responses to questions about the use and usefulness of student support interventions indicates that, in general, when students use personal support interventions these are mostly seen as very useful. However, data also indicate that many, and often the majority of, students have either not used or are not aware of the support services available. Practically, the project has delivered, and will continue to deliver, significant value to the higher education sector. On the basis of evidence from the project, partner universities have begun addressing high-value student retention issues and it is expected that this evidence will continue to influence institutional decision-making for several years beyond the life of the project. Dissemination activities external to partner universities, including publication of five journal articles and numerous workshops or presentations, have assisted staff in other universities to reflect upon issues critical to student retention in both first year and beyond. Further publication outcomes are expected. Critically, as indicated in the independent project evaluation, “the project has directed much needed attention to factors associated with attrition in later years of the student experience (second and third years) … facilitated discussion around frameworks for evidence-based institutional responses that constitute effective interventions … [and] reinforced the need for institutions to collect their own data on the student experience to inform individual institutional responses and interventions”

Use of inert gas jets to measure the forces required for mechanical gene transfection

BACKGROUND: Transferring genes and drugs into cells is central to how we now study, identify and treat diseases. Several non-viral gene therapy methods that rely on the mechanical disruption of the plasma membrane have been proposed, but the success of these methods has been limited due to a lack of understanding of the mechanical parameters that lead to cell membrane permeability. METHODS: We use a simple jet of inert gas to induce local transfection of plasmid DNA both in vitro (HeLa cells) and in vivo (chicken chorioallantoic membrane). Five different capillary tube inner diameters and three different gases were used to treat the cells to understand the dependency of transfection efficiency on the dynamic parameters. RESULTS: The simple setup has the advantage of allowing us to calculate the forces acting on cells during transfection. We found permeabilization efficiency was related to the dynamic pressure of the jet. The range of dynamic pressures that led to transfection in HeLa cells was small (200 ± 20 Pa) above which cell stripping occurred. We determined that the temporary pores allow the passage of dextran up to 40 kDa and reclose in less than 5 seconds after treatment. The optimized parameters were also successfully tested in vivo using the chorioallantoic membrane of the chick embryo. CONCLUSIONS: The results show that the number of cells transfected with the plasmid scales with the dynamic pressure of the jet. Our results show that mechanical methods have a very small window in which cells are permeabilized without injury (200 to 290 Pa). This simple apparatus helps define the forces needed for physical cell transfection methods

Corynebacterium pseudotuberculosis associated with otitis media-interna in goats

Corynebacterium pseudotuberculosis or caseous lymphadenitis is a common condition in sheep and goats. Two cases are described involving otitis media-interna and, in one case, cerebellar abscessation. The first case began with otitis externa and progressed to cerebellar abscessation, presumably as a result of C. pseudotuberculosis infection based on the macroscopic appearance of the abscess. The second case of otitis media-interna involved C. pseudotuberculosis with parasitic encephalitis or secondary meningo-encephalitis. Caseous lymphadenitis is a worldwide problem in livestock and also has zoonotic implications. Antimicrobial therapy of abscesses is often unrewarding due to the thick encapsulation of the abscesses and the extremely contagious nature of the organism. Alternative measures of treating this condition must be sought. In flocks or herds where caseous lymphadenitis has been diagnosed, it should be considered as a differential diagnosis for neurological conditions. The potential for spread must be kept in mind when it is suspected to be the cause of otitis in livestock.http://www.jsava.co.zaam2013ab201

Activation of the Connective Tissue Growth Factor (CTGF)-Transforming Growth Factor β 1 (TGF-β 1) Axis in Hepatitis C Virus-Expressing Hepatocytes

Background: The pro-fibrogenic cytokine connective tissue growth factor (CTGF) plays an important role in the development and progression of fibrosis in many organ systems, including liver. However, its role in the pathogenesis of hepatitis C virus (HCV)-induced liver fibrosis remains unclear. Methods: In the present study, we assessed CTGF expression in HCV-infected hepatocytes using replicon cells containing full-length HCV genotype 1 and the infectious HCV clone JFH1 (HCV genotype 2) by real-time PCR, Western blot analysis and confocal microscopy. We evaluated transforming growth factor β1 (TGF-β1) as a key upstream mediator of CTGF production using neutralizing antibodies and shRNAs. We also determined the signaling molecules involved in CTGF production using various immunological techniques. Results: We demonstrated an enhanced expression of CTGF in two independent models of HCV infection. We also demonstrated that HCV induced CTGF expression in a TGF-β1-dependent manner. Further dissection of the molecular mechanisms revealed that CTGF production was mediated through sequential activation of MAPkinase and Smad-dependent pathways. Finally, to determine whether CTGF regulates fibrosis, we showed that shRNA-mediated knock-down of CTGF resulted in reduced expression of fibrotic markers in HCV replicon cells. Conclusion: Our studies demonstrate a central role for CTGF expression in HCV-induced liver fibrosis and highlight the potential value of developing CTGF-based anti-fibrotic therapies to counter HCV-induced liver damage

"On the Spot": travelling artists and Abolitionism, 1770-1830

Until recently the visual culture of Atlantic slavery has rarely been critically scrutinised. Yet in the first decades of the nineteenth century slavery was frequently represented by European travelling artists, often in the most graphic, sometimes voyeuristic, detail. This paper examines the work of several itinerant artists, in particular Augustus Earle (1793-1838) and Agostino Brunias (1730–1796), whose very mobility along the edges of empire was part of a much larger circulatory system of exchange (people, goods and ideas) and diplomacy that characterised Europe’s Age of Expansion. It focuses on the role of the travelling artist, and visual culture more generally, in the development of British abolitionism between 1770 and 1830. It discusses the broad circulation of slave imagery within European culture and argues for greater recognition of the role of such imagery in the abolitionist debates that divided Britain. Furthermore, it suggests that the epistemological authority conferred on the travelling artist—the quintessential eyewitness—was key to the rhetorical power of his (rarely her) images. Artists such as Earle viewed the New World as a boundless source of fresh material that could potentially propel them to fame and fortune. Johann Moritz Rugendas (1802-1858), on the other hand, was conscious of contributing to a global scientific mission, a Humboldtian imperative that by the 1820s propelled him and others to travel beyond the traditional itinerary of the Grand Tour. Some artists were implicated in the very fabric of slavery itself, particularly those in the British West Indies such as William Clark (working 1820s) and Richard Bridgens (1785-1846); others, particularly those in Brazil, expressed strong abolitionist sentiments. Fuelled by evangelical zeal to record all aspects of the New World, these artists recognised the importance of representing the harsh realities of slave life. Unlike those in the metropole who depicted slavery (most often in caustic satirical drawings), many travelling artists believed strongly in the evidential value of their images, a value attributed to their global mobility. The paper examines the varied and complex means by which visual culture played a significant and often overlooked role in the political struggles that beset the period

The Status of Alaska Natives Report 2004 Volumes I - III

The Alaska Federation of Natives asked ISER to report on social and economic conditions among Alaska Natives. We found that Natives have more jobs, higher incomes, and better living conditions, health care, and education than ever. But they remain several times more likely than other Alaskans to be poor and out of work. Alcohol continues to fuel widespread social problems. Native students continue to do poorly on standard tests, and they’re dropping out in growing numbers. Rates of heart disease and diabetes are rising. In the face of all these challenges, subsistence remains critical for cultural and economic reasons. And there are more challenges to come. In the coming decade, when economic growth is likely to be slower than in the past, thousands more young Alaska Natives will be moving into the job market. Volume II and Volume III of the Status of Alaska Natives Report contain data tables generated from the 2000 U.S. census describing the Alaska Native American population by the 12 Alaska Native Regional Corporation boundaries. Volume II shows data for the population in Alaska reporting Native American as their only race (Alaska Native or American Indian Alone) and Volume III shows data for the population reporting Native American in combination with some other race (Alaska Native or American Indian Alone or in Combination). At the time of the 2000 Census, there were 98,043 single-race Native Americans in Alaska and 119,241 people who identified themselves as Native American in combination with some other race. The tables in these volumes have been generated from a special file prepared by the U.S. Census Bureau that contains detailed information on the Native American population for the entire United States. The AIANSF (American Indian and Alaska Native Summary File) is accessible on the internet at http://factfinder.census.gov/servlet/DatasetMainPageServlet"Alaskan Federation of Native

Congenital reflex myoclonus in two Merino cross lambs in South Africa

No abstract available.The Onderstepoort Veterinary Academic Hospital, the Department of Production Animal Studies and the Veterinary Genetics Laboratory, University of Pretoria.http://veterinaryrecord.bmj.com/ab201