Two domains of the V protein of virulent canine distemper virus selectively inhibit STAT1 and STAT2 nuclear import

Canine distemper virus (CDV) causes in dogs a severe systemic infection, with a high frequency of demyelinating encephalitis. Among the six genes transcribed by CDV, the P gene encodes the polymerase cofactor protein (P) as well as two additional nonstructural proteins, C and V; of these V was shown to act as a virulence factor. We investigated the molecular mechanisms by which the P gene products of the neurovirulent CDV A75/17 strain disrupt type I interferon (IFN-alpha/beta)-induced signaling that results in the establishment of the antiviral state. Using recombinant knockout A75/17 viruses, the V protein was identified as the main antagonist of IFN-alpha/beta-mediated signaling. Importantly, immunofluorescence analysis illustrated that the inhibition of IFN-alpha/beta-mediated signaling correlated with impaired STAT1/STAT2 nuclear import, whereas the phosphorylation state of these proteins was not affected. Coimmunoprecipitation assays identified the N-terminal region of V (VNT) responsible for STAT1 targeting, which correlated with its ability to inhibit the activity of the IFN-alpha/beta-mediated antiviral state. Conversely, while the C-terminal domain of V (VCT) could not function autonomously, when fused to VNT it optimally interacted with STAT2 and subsequently efficiently suppressed the IFN-alpha/beta-mediated signaling pathway. The latter result was further supported by a single mutation at position 110 within the VNT domain of CDV V protein, resulting in a mutant that lost STAT1 binding while retaining a partial STAT2 association. Taken together, our results identified the CDV VNT and VCT as two essential modules that complement each other to interfere with the antiviral state induced by IFN-alpha/beta-mediated signaling. Hence, our experiments reveal a novel mechanism of IFN-alpha/beta evasion among the morbilliviruses.

Detecting BRAF Mutations in Formalin-Fixed Melanoma: Experiences with Two State-of-the-Art Techniques

Melanoma is characterized by a high frequency of BRAF mutations. It is unknown if the BRAF mutation status has any predictive value for therapeutic approaches such as angiogenesis inhibition.

Contemporary Hollywood And The Attention Economy

This thesis had two goals: to explore the transformation of Hollywood from the 1930s to present, and to investigate how Contemporary Hollywood functions in a growing attention economy. Evident in the types of films that it produces as well as its evolving industrial structure, Contemporary Hollywood significantly differs from the Classical Hollywood of the 1930s. New digital technologies like surround sound and computer-generated imagery (CGI) have allowed studios to create a different type of film like the blockbuster and to have more extensive control over their films. Additionally, growing exhibition and distribution platforms have also fundamentally altered the industrial landscape of Hollywood. In order to combat this more egalitarian distribution system, Contemporary Hollywood has turned to conglomeratization. But, what has caused such a radical shift in the form and function of Contemporary Hollywood and its films? This thesis argues that Hollywood is failing to thrive in this new media landscape¿not because of changing technologies¿but because of a changing consumer. Richard Lanham theorizes that we are living in a growing attention economy, where human attention is the most valuable commodity in such an information-saturated society. For the current consumer, there is near-constant media over-stimulation: he or she is exposed to any number of screens (mobile phones, laptops, tablets, televisions, etc.) at any given time. Because we can access anything from anywhere at anytime, we¿ve become somewhat schizophrenic and impatient in terms of the media that we consume in our lives.

Validation of Two Methods of Data Collection of Self-Reported Medicine Use Among the Elderly

The accuracy of medicine use information was compared for a telephone interview and mail questionnaire, using an in-home medicine check as the standard of assessment The validity of medicine use information varied by data source, level of specificity of data, and respondent characteristics. The mail questionnaire was the more valid source of overall medicine use information. Implications for both service providers and researchers are provided.

Anemia during adjuvant non-taxane chemotherapy for early breast cancer: Incidence and risk factors from two trials of the International Breast Cancer Study Group

GOAL OF THE WORK: Anemia is a common side effect of chemotherapy. Limited information exists about its incidence and risk factors. The objective of this study was to evaluate the incidence of anemia and risk factors for anemia occurrence in patients with early breast cancer who received adjuvant chemotherapy. MATERIALS AND METHODS: We evaluated risk factors for anemia in pre- and post/perimenopausal patients with lymph node-positive early breast cancer treated with adjuvant chemotherapy in two randomized trials. All patients received four cycles of doxorubicin and cyclophosphamide (AC) followed by three cycles of cyclophosphamide, methotrexate, fluorouracil (CMF). Anemia incidence was related to baseline risk factors. Multivariable analysis used logistic and Cox regression. MAIN RESULTS: Among the 2,215 available patients, anemia was recorded in 11% during adjuvant chemotherapy. Grade 2 and 3 anemia occurred in 4 and 1% of patients, respectively. Pretreatment hemoglobin and white blood cells (WBC) were significant predictors of anemia. Adjusted odds ratios (logistic regression) comparing highest versus lowest quartiles were 0.18 (P < 0.0001) for hemoglobin and 0.52 (P = 0.0045) for WBC. Age, surgery type, platelets, body mass index, and length of time from surgery to chemotherapy were not significant predictors. Cox regression results looking at time to anemia were similar. CONCLUSIONS: Moderate or severe anemia is rare among patients treated with AC followed by CMF. Low baseline hemoglobin and WBC are associated with a higher risk of anemia.

Education and Ideologies of the Knowledge Economy: Europe and the Politics of Emulation

The Austrian philosopher Ludwig Wittgenstein famously proposed a style of philosophy that was directed against certain pictures [bild] that tacitly direct our language and forms of life. His aim was to show the fly the way out of the fly bottle and to fight against the bewitchment of our intelligence by means of language: “A picture held us captive. And we could not get outside it, for it lay in our language and language seemed to repeat it to us inexorably” (Wittgenstein 1953, 115). In this context Wittgenstein is talking of philosophical pictures, deep metaphors that have structured our language but he does also use the term picture in other contexts (see Owen 2003, 83). I want to appeal to Wittgenstein in my use of the term ideology to refer to the way in which powerful underlying metaphors in neoclassical economics have a strong rhetorical and constitutive force at the level of public policy. Indeed, I am specifically speaking of the notion of ‘the performative’ in Wittgenstein and Austin. The notion of the knowledge economy has a prehistory in Hayek (1937; 1945) who founded the economics of knowledge in the 1930s, in Machlup (1962; 1970), who mapped the emerging employment shift to the US service economy in the early 1960s, and to sociologists Bell (1973) and Touraine (1974) who began to tease out the consequences of these changes for social structure in the post-industrial society in the early 1970s. The term has been taken up since by economists, sociologists, futurists and policy experts recently to explain the transition to the so-called ‘new economy’. It is not just a matter of noting these discursive strands in the genealogy of the ‘knowledge economy’ and related or cognate terms. We can also make a number of observations on the basis of this brief analysis. First, there has been a succession of terms like ‘postindustrial economy’, ‘information economy’, ‘knowledge economy’, ‘learning economy’, each with a set of related concepts emphasising its social, political, management or educational aspects. Often these literatures are not cross-threading and tend to focus on only one aspect of phenomena leading to classic dichotomies such as that between economy and society, knowledge and information. Second, these terms and their family concepts are discursive, historical and ideological products in the sense that they create their own meanings and often lead to constitutive effects at the level of policy. Third, while there is some empirical evidence to support claims concerning these terms, at the level of public policy these claims are empirically underdetermined and contain an integrating, visionary or futures component, which necessarily remains untested and is, perhaps, in principle untestable.

The Digital Economy Act in the dock: a proportionate ruling

The UK’s Digital Economy Act 2010 contains measures to enforce copyright on the Internet, specifically a two-tiered form of a graduated response.The Act was challenged in the High Court by two of the UK’s biggest Internet Service Providers (ISP), who obtained a Judicial Review of the copyright enforce- ment provisions. This paper is an overview of the case, based on the hearing of March 2011 and the ensuing judgement. It focuses on the two most hotly contested grounds for the challenge, namely an al- leged failure to notify the European Commission under the Technical Standards Directive, and the pro- portionality or otherwise of the contested provisions. It observes how the judgement accepted the defence argumentation of the government and the copyright owners as interested parties, and how the ISPs appeared to be put on the back foot.

Effects of two traits of the ecological state equation on our understanding of species coexistence and ecosystem services

Species coexistence has been a fundamental issue to understand ecosystem functioning since the beginnings of ecology as a science. The search of a reliable and all-encompassing explanation for this issue has become a complex goal with several apparently opposing trends. On the other side, seemingly unconnected with species coexistence, an ecological state equation based on the inverse correlation between an indicator of dispersal that fits gamma distribution and species diversity has been recently developed. This article explores two factors, whose effects are inconspicuous in such an equation at the first sight, that are used to develop an alternative general theoretical background in order to provide a better understanding of species coexistence. Our main outcomes are: (i) the fit of dispersal and diversity values to gamma distribution is an important factor that promotes species coexistence mainly due to the right-skewed character of gamma distribution; (ii) the opposite correlation between species diversity and dispersal implies that any increase of diversity is equivalent to a route of “ecological cooling” whose maximum limit should be constrained by the influence of the third law of thermodynamics; this is in agreement with the well-known asymptotic trend of diversity values in space and time; (iii) there are plausible empirical and theoretical ways to apply physical principles to explain important ecological processes; (iv) the gap between theoretical and empirical ecology in those cases where species diversity is paradoxically high could be narrowed by a wave model of species coexistence based on the concurrency of local equilibrium states. In such a model, competitive exclusion has a limited but indispensable role in harmonious coexistence with functional redundancy. We analyze several literature references as well as ecological and evolutionary examples that support our approach, reinforcing the meaning equivalence between important physical and ecological principles.

The development and characterization of two types of chronic responses in irradiated mouse colon

The hypothesis to be tested is that there are two distinct types of chronic responses in irradiated normal tissues, each resulting from damage to different cell populations in the tissue. The first is a sequala of chronic epithelial depletion in which the tissue's integrity cannot be maintained, i.e. a "consequential" chronic response. The other response is due to cell loss in the connective tissue and/or vascular stroma, i.e. a "primary" chronic response. The purpose of this study was to test the hypothesis in the murine colon by first, establishing a model of each chronic response and then, by determining whether the responses differed in timing of expression, histology, and expression of specific collagen types. The model of late damage used was colonic obstructions/strictures induced by a single dose of 27 Gy ("consequential" response) and two equal doses of 14.75 Gy (t = 10 days) ("primary" response). "Consequential" lesions appeared as early as 5 weeks after 27 Gy and were characterized by a deep mucosal ulceration and a thickened fibrotic serosa containing excessive accumulations of collagen types I and III. Both types were commingled in the scar at the base of the ulcer. Fibroblasts were synthesizing pro-collagen types I and III mRNA 10 weeks prior to measurable increases in collagen. A significant decrease in the ratio of collagen types I:III was associated with the "consequential" response at 4-5 months post-irradiation. The "primary" response, on the other hand, did not appear until 40 weeks after the split dose even though the total dose delivered was approximately the same as that for the "consequential" response. The "primary" response was characterized with an intact mucosa and a thickened fibrotic submucosa which contained excessive amounts of only collagen type I. An increased number of fibroblasts were synthesizing pro-collagen type I mRNA nearly 25 weeks before collagen type I levels were increased. The "primary" response lesion had a significantly elevated collagen type I:III ratio at 10-13 months post-irradiation. These data show a clear difference between the two chronic response and suggest that not all chronic responses share a common pathogenesis, but depend on the cell population in the tissue that is damaged. ^

Two Decades of Measuring Environmental Attitudes: An Analysis of the ISSP Environmental Modules 1993, 2000, and 2010

This paper analyzes the development of environmental concern by using the three waves of the environmental modules of the International Social Survey Programme (ISSP). First, we discuss the measurement of environmental concern and construct a ranking of countries according to the new 2010 ISSP results. Second, we analyze the determinants of environmental concern by employing multilevel models that take individual as well as context effects into account. Third, we explore the impact of attitudes on environmental behavior and support of environmental policies. The results show that environmental concern is closely correlated with the wealth of nations. However, environmental concern decreased in OECD as well as non-OECD nations slightly during the last two decades. The decline was lower in countries with improving economic conditions suggesting that economic growth helps to maintain higher levels of environmental concern. Furthermore, attitudes have a stronger impact on support of environmental policies as compared to everyday environmental behavior.