A new class of isothiocyanate-based irreversible inhibitors of macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is a homotrimeric multifunctional proinflammatory cytokine that has been implicated in the pathogenesis of several inflammatory and autoimmune diseases. Current therapeutic strategies for targeting MIF focus on developing inhibitors of its tautomerase activity or modulating its biological activities using anti-MIF neutralizing antibodies. Herein we report a new class of isothiocyanate (ITC)-based irreversible inhibitors of MIF. Modification by benzyl isothiocyanate (BITC) and related analogues occurred at the N-terminal catalytic proline residue without any effect on the oligomerization state of MIF. Different alkyl and arylalkyl ITCs modified MIF with nearly the same efficiency as BITC. To elucidate the mechanism of action, we performed detailed biochemical, biophysical, and structural studies to determine the effect of BITC and its analogues on the conformational state, quaternary structure, catalytic activity, receptor binding, and biological activity of MIF. Light scattering, analytical ultracentrifugation, and NMR studies on unmodified and ITC-modified MIF demonstrated that modification of Pro1 alters the tertiary, but not the secondary or quaternary, structure of the trimer without affecting its thermodynamic stability. BITC induced drastic effects on the tertiary structure of MIF, in particular residues that cluster around Pro1 and constitute the tautomerase active site. These changes in tertiary structure and the loss of catalytic activity translated into a reduction in MIF receptor binding activity, MIF-mediated glucocorticoid overriding, and MIF-induced Akt phosphorylation. Together, these findings highlight the role of tertiary structure in modulating the biochemical and biological activities of MIF and present new opportunities for modulating MIF biological activities in vivo.

Melan-A/MART-1-specific CD4 T cells in melanoma patients: identification of new epitopes and ex vivo visualization of specific T cells by MHC class II tetramers.

Over the past decade, many efforts have been made to identify MHC class II-restricted epitopes from different tumor-associated Ags. Melan-A/MART-1(26-35) parental or Melan-A/MART-1(26-35(A27L)) analog epitopes have been widely used in melanoma immunotherapy to induce and boost CTL responses, but only one Th epitope is currently known (Melan-A51-73, DRB1*0401 restricted). In this study, we describe two novel Melan-A/MART-1-derived sequences recognized by CD4 T cells from melanoma patients. These epitopes can be mimicked by peptides Melan-A27-40 presented by HLA-DRB1*0101 and HLA-DRB1*0102 and Melan-A25-36 presented by HLA-DQB1*0602 and HLA-DRB1*0301. CD4 T cell clones specific for these epitopes recognize Melan-A/MART-1+ tumor cells and Melan-A/MART-1-transduced EBV-B cells and recognition is reduced by inhibitors of the MHC class II presentation pathway. This suggests that the epitopes are naturally processed and presented by EBV-B cells and melanoma cells. Moreover, Melan-A-specific Abs could be detected in the serum of patients with measurable CD4 T cell responses specific for Melan-A/MART-1. Interestingly, even the short Melan-A/MART-1(26-35(A27L)) peptide was recognized by CD4 T cells from HLA-DQ6+ and HLA-DR3+ melanoma patients. Using Melan-A/MART-1(25-36)/DQ6 tetramers, we could detect Ag-specific CD4 T cells directly ex vivo in circulating lymphocytes of a melanoma patient. Together, these results provide the basis for monitoring of naturally occurring and vaccine-induced Melan-A/MART-1-specific CD4 T cell responses, allowing precise and ex vivo characterization of responding T cells.

Understanding academics' popular science publishing : institution culture and management style effects

Most universities and higher education systems have formally taken up a third mission, which involves various public outreach and engagement activities. Little is known regarding how higher education institutions' organisations interact with academic's level of public outreach. This article examines to which extent the perceptions academics have of their institutions' culture and management style, as well as some of their own individual and statutory characteristics interact with their level of public outreach. Using the Academic Profession in Europe comparative and quantitative research database, this article focuses on two countries on the extremities of the spectrum - Switzerland and the United Kingdom.

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases.

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article.

T Cell Priming by Activated Nlrc5-Deficient Dendritic Cells Is Unaffected despite Partially Reduced MHC Class I Levels.

NLRC5, a member of the NOD-like receptor (NLR) protein family, has recently been characterized as the master transcriptional regulator of MHCI molecules in lymphocytes, in which it is highly expressed. However, its role in activated dendritic cells (DCs), which are instrumental to initiate T cell responses, remained elusive. We show in this study that, following stimulation of DCs with inflammatory stimuli, not only did NLRC5 level increase, but also its importance in directing MHCI transcription. Despite markedly reduced mRNA and intracellular H2-K levels, we unexpectedly observed nearly normal H2-K surface display in Nlrc5(-/-) DCs. Importantly, this discrepancy between a strong intracellular and a mild surface defect in H2-K levels was observed also in DCs with H2-K transcription defects independent of Nlrc5. Hence, alongside with demonstrating the importance of NLRC5 in MHCI transcription in activated DCs, we uncover a general mechanism counteracting low MHCI surface expression. In agreement with the decreased amount of neosynthesized MHCI, Nlrc5(-/-) DCs exhibited a defective capacity to display endogenous Ags. However, neither T cell priming by endogenous Ags nor cross-priming ability was substantially affected in activated Nlrc5(-/-) DCs. Altogether, these data show that Nlrc5 deficiency, despite significantly affecting MHCI transcription and Ag display, is not sufficient to hinder T cell activation, underlining the robustness of the T cell priming process by activated DCs.

The improvement of enclosure protection class of power electronics device

Tässä diplomityössä tutkittiin vaihtoehtoja tehoelektroniikkalaitteiden kotelointiluokan kehittämiseksi. Haasteena paremman suojauksen suunnittelussa on laitteiden tuottama suuri määrä lämpöä, joka vaatii tehokkaan jäähdytyksen. Työn tuloksena saatu prototyyppi IP33 luokkaa varten täyttää standardissa SFS-EN 60529+A1 asetetut vaatimukset kyseiselle kotelointiluokalle. Rakenteessa ja valmistettavuudessa havaittiin muutama ongelma, jotka ovat korjattavissa pienillä muutoksilla. Korkeampia suojausluokkia varten testattiin IP54-luokiteltujen filtterituulettimien vaikutusta laitteen jäähdytykseen. Testien perusteella jäähdytysteho on riittävä ja filtterituulettimet todettiin toimivaksi ratkaisuksi korkeammille suojausluokille. Työn perusteella voidaan todeta, että nykyiset laitteet voidaan muokata vastaamaan IP33 luokan vaatimuksia kohtuullisen pienillä muutoksilla. Tätä korkeammat suojausluokat vaatisivat niin suuria muutoksia designiin, että todennäköisesti täysin uuden laitteen suunnittelu olis kannattavin vaihtoehto.

Production under glass : working conditions and class-consciousness of the Niagara greenhouse workers

This study applies a Marxist theoretical paradigm to examine the working conditions of greenhouse workers in the Niagara Region, and the range of factors that bear upon the formation of their class-consciousness. The Niagara greenhouse industry represents one of the most developed horticultural regions in Canada and plays a prominent role in the local economy. The industry generates substantial revenues and employs a significant number of people, yet the greenhouse workers are paid one of the lowest rates in the region. Being classified as agricultural workers, the greenhouse employees are exempted from many provisions of federal and provincial labour regulations. Under the current provincial statutes, agricultural workers in Ontario are denied the right to organize and bargain collectively. Except for a few technical and managerial positions, the greenhouse industry employs mostly low-skilled workers who are subjected to poor working conditions that stem from the employer's attempts to adapt to larger structural imperatives of the capitalist economy. While subjected to these poor working conditions, the greenhouse workers are also affected by objectively alienated social relations and by ruling class ideological domination and hegemony. These two sets of factors arise from the inherent conflict of interests between wage-labour and capital but also militate against the development of class-consciousness. Semi-structured interviews were conducted with 12 greenhouse workers to examine the role played by their material circumstances in the formulation of their social and political views as well as the extent to which they are aware of their class location and class interests. The hegemonic notions of 'common sense' acted as impediments to formation of classconsciousness. The greenhouse workers have virtually no opportunities to access alternative perspectives that would address the issues associated with exploitation in production and offer solutions leading to 'social justice'. Fonnidable challenges confront any organized political body seeking to improve the conditions of the working people.

The new woman, femininity and modernity in Margery Allingham's detective novels of the 1930s /

This thesis examines Death of a Ghost (1934), Flowers for the Judge (1935), Dancers in Mourning (1937), and The Fashion in Shrouds (1938), a group of detective novels by Margery Allingham that are differentiated from her other work by their generic hybridity. The thesis argues that the hybrid nature of this group of Campion novels enabled a highly skilled and insightful writer such as Allingham to negotiate the contradictory notions about the place of women that characterized the 1930s, and that in dOing so, she revealed the potential of one of the most popular and accessible genres, the detective novel of manners, to engage its readers in a serious cultural dialogue. The thesis also suggests that there is a connection between Allingham's exploration of modernity and femininity within these four novels and her personal circumstances. This argument is predicated upon the assumption that during the interwar period in England several social and cultural attitudes converged to challenge long-held beliefs about gender roles and class structure; that the real impact of this convergence was felt during the 1930s by the generation that had come of age in the previous decade-Margery Allingham's generation; and that that generation's ambivalence and confusion were reflected in the popular fiction of the decade. These attitudes were those of twentieth-century modernity--contradiction, discontinuity, fragmentation, contingency-and in the context of this study they are incorporated in a literary hybrid. Allingham uses this combination of the classical detective story and the novel of manners to examine the notion of femininity by juxtaposing the narrative of a longstanding patriarchal and hierarchical culture, embodied in the image of the Angel in the House, with that of the relatively recent rights and freedoms represented by the New Woman of the late nineteenth-century. Pierre Bourdieu's theory of social difference forms the theoretical foundation of the thesis's argument that through these conflicting narratives, as well as through the lives of her female characters, Allingham questioned the Hsocial myth" of the time, a prevailing view that, since the First World War, attitudes toward the appropriate role and sphere of women had changed.

Marginal/minority popular music : the concept of the "third space" and the case for "hybridities" of cultures/identities /

The topic of this thesis is marginaVminority popular music and the question of identity; the term "marginaVminority" specifically refers to members of racial and cultural minorities who are socially and politically marginalized. The thesis argument is that popular music produced by members of cultural and racial minorities establishes cultural identity and resists racist discourse. Three marginaVminority popular music artists and their songs have been chosen for analysis in support of the argument: Gil Scott-Heron's "Gun," Tracy Chapman's "Fast Car" and Robbie Robertson's "Sacrifice." The thesis will draw from two fields of study; popular music and postcolonialism. Within the area of popular music, Theodor Adorno's "Standardization" theory is the focus. Within the area of postcolonialism, this thesis concentrates on two specific topics; 1) Stuart Hall's and Homi Bhabha's overlapping perspectives that identity is a process of cultural signification, and 2) Homi Bhabha's concept of the "Third Space." For Bhabha (1995a), the Third Space defines cultures in the moment of their use, at the moment of their exchange. The idea of identities arising out of cultural struggle suggests that identity is a process as opposed to a fixed center, an enclosed totality. Cultures arise from historical memory and memory has no center. Historical memory is de-centered and thus cultures are also de-centered, they are not enclosed totalities. This is what Bhabha means by "hybridity" of culture - that cultures are not unitary totalities, they are ways of knowing and speaking about a reality that is in constant flux. In this regard, the language of "Otherness" depends on suppressing or marginalizing the productive capacity of culture in the act of enunciation. The Third Space represents a strategy of enunciation that disrupts, interrupts and dislocates the dominant discursive construction of US and THEM, (a construction explained by Hall's concept of binary oppositions, detailed in Chapter 2). Bhabha uses the term "enunciation" as a linguistic metaphor for how cultural differences are articulated through discourse and thus how differences are discursively produced. Like Hall, Bhabha views culture as a process of understanding and of signification because Bhabha sees traditional cultures' struggle against colonizing cultures as transforming them. Adorno's theory of Standardization will be understood as a theoretical position of Western authority. The thesis will argue that Adorno's theory rests on the assumption that there is an "essence" to music, an essence that Adorno rationalizes as structure/form. The thesis will demonstrate that constructing music as possessing an essence is connected to ideology and power and in this regard, Adorno's Standardization theory is a discourse of White Western power. It will be argued that "essentialism" is at the root of Western "rationalization" of music, and that the definition of what constitutes music is an extension of Western racist "discourses" of the Other. The methodological framework of the thesis entails a) applying semiotics to each of the three songs examined and b) also applying Bhabha's model of the Third Space to each of the songs. In this thesis, semiotics specifically refers to Stuart Hall's retheorized semiotics, which recognizes the dual function of semiotics in the analysis of marginal racial/cultural identities, i.e., simultaneously represent embedded racial/cultural stereotypes, and the marginal raciaVcultural first person voice that disavows and thus reinscribes stereotyped identities. (Here, and throughout this thesis, "first person voice" is used not to denote the voice of the songwriter, but rather the collective voice of a marginal racial/cultural group). This dual function fits with Hall's and Bhabha's idea that cultural identity emerges out of cultural antagonism, cultural struggle. Bhabha's Third Space is also applied to each of the songs to show that cultural "struggle" between colonizers and colonized produces cultural hybridities, musically expressed as fusions of styles/sounds. The purpose of combining semiotics and postcolonialism in the three songs to be analyzed is to show that marginal popular music, produced by members of cultural and racial minorities, establishes cultural identity and resists racist discourse by overwriting identities of racial/cultural stereotypes with identities shaped by the first person voice enunciated in the Third Space, to produce identities of cultural hybridities. Semiotic codes of embedded "Black" and "Indian" stereotypes in each song's musical and lyrical text will be read and shown to be overwritten by the semiotic codes of the first person voice, which are decoded with the aid of postcolonial concepts such as "ambivalence," "hybridity" and "enunciation."

Revisiting girlhood : defining a postmodern/popular feminist culture /

It has bee1l said that feminism is dead, but in fact feminism is alive in popular cultural fonlls that offer pleasure, style, fUll and advice, as well as political messages that are internalized alld continuously enacted in the lives of North American female youth. This thesis discusses popular feminism with respect to mainstream girls' cultural discourses in music alld magazine reading. Specifically this thesis examines the importance of Madonna, Gwen Stefani, and the Spice Girls, in addition to the numerous girl magazines available on the market today, such as Seventeen and YM. Focusing on the issue of the feminine versus feminist polarity and its importance to girls' culture, this thesis attempts to demonstrate how popular feminism can be used as a mode of empowerment and illustrates the mode of consumption of popular feminist texts that frames female selfimage, attitude, behaviour and speech. Through the employment of popular feminist theories and a discourse alld semiotic analysis of musical lyrics, performance and style, in addition to magazine reading and advertisements, this thesis highlights the use of active media reading and being by girls to gaill an understanding with regards to social positioning and postmodern political identity. More fundamentally, this thesis questions how popular feminism disables, questions and critiques popular ideologies ill a patriarchal society.

Fade to black : picturing mortality in contemporary popular film /

This thesis attempts to understand representations of death in contemporary popular film within a framework that posits mortality as a category of particular social and political importance for the way we understand both individual subjectivity and social responsibility in the postmodern cultural moment. It addresses concerns over the social organizing categories of time and space, and performs a sustained consideration of predominant themes related to the popular representation of death, such as contingency, existential.meaning, and temporal finitude. Death consciousness and social consciousness are shown to be not just intertwined, but also vitally dependent on one another, and the analyses undertaken are ultimately aimed at making these intersections explicit in order • l to think through their potential implications for challenging consumer capitalist hegemony and envisioning the possibility of progressive social change through the lens of our mortality.

An exploration of transformation theory and the western tradition: a critical evaluation of a graduate studies class

This qualitative study is an exploration of transformation theory, the Western tradition, and a critical evaluation of a graduate studies class at a university. It is an exploration of assumptions that are embedded in experience, that influence the experience and provide meaning about the experience. An attempt has been made to identify assumptions that are embedded in Western experience and connect them with assumptions that shape the graduate class experience. The focus is on assumptions that facilitate and impede large group discussions. Jungian psychology of personality type and archetype and developmental psychology is used to analyze the group experience. The pragmatic problem solving model, developed by Knoop, is used to guide thinking about the Western tradition. It is used to guide the analysis, synthesis and writing of the experience of the graduate studies class members. A search through Western history, philosophy. and science revealed assumptions about the nature of truth, reality, and the self. Assumptions embedded in Western thinking about the subject-object relationship, unity and diversity are made explicit. An attempt is made to identify Western tradition assumptions underlying transformation theory. The critical evaluation of the graduate studies class experience focuses upon issues associated with group process, self-directed learning, the educator-learner transaction and the definition of adult education. The advantages of making implicit assumptions explicit is explored.

Is there a difference in artistic ability between learning -disabled students and "regular-class" students?

Research and practice regarding LO students usually has focussed upon defining and supplementing deficiencies rather than seeking unique talents and capability patterns for learning and expression. This study examined nine dimensions that may constitute artistic or creative talent and compared LDs with "regular-class" students, pair-wise and as groups, for levels and distributions of the dimensions. For 14 LO and 9 "regular-class" elementary-school subjects, both genders, data were taken by direct observation, from a standardized test and assessments by two practicing artists. Assessments by artists were in concord. LOs improved more in "Composition". No other significant class, age or gender-related differences were found.

The evaluation of a predialysis class on client knowledge and attitude toward compliant behaviours

In this quasi-experimental study, the theory of reasoned action was used as a conceptual framework to assess the outcome effect of a predialysis class. A pretest, posttest design was used to determine changes in client knowledge about their condition and its treatment, and their intention, attitudes and social norm towards compliant behaviours. The related compliant behaviours were following a low-salt diet and taking medications as proscribed. Thirty-eight End Stage Renal Diseases (ESRD) clients were self-selected into the treatment or control groups. Both groups received the standard predialysis education from members of the multidisciplinary renal team. In addition, the treatment group also attended the predialysis class. Subjects' health locus of control, anxiety and demographic variables were measured as possible extraneous variables. Study subjects from both groups demonstrated a high internal and powerful others health locus of control and a normal range of anxiety. Although not statistically significant ill = .64), the experimental group demonstrated higher knowledge level and greater intention to follow a low salt diet UL= .73). They developed more significantly positive attitudes towards following a low salt diet and increased subjective norm influence after attending the predialysis class. Attending the predialysis class did not have an effect on subjects' intentions, attitudes or subjective norm towards taking medications as prescribed. Conclusion: The predialysis class was only marginally effective in increasing client knowledge, but influenced clients' attitudes towards following a low-salt diet. Based on the results, recommendations for improvements to the class have been suggested.