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RICOEUR (1988) nos diz que a conceituação do mal é um problema que atravessa séculos, devido a sua necessidade de coerência lógica. Já se discutiu sua origem, suas causas e seus efeitos, porém nunca se chegou a um termo que eliminasse a contradição em seu cerne. Neste espaço, as obras literárias de Heinrich von Kleist (1777-1811) apresentam uma temática que abarca uma quebra de limites entre os conceitos de maldade e bondade desenvolvidos durante a Aufklärung, evidenciando essa problemática. Essa quebra nos parece estar fortemente associada à relação existente entre o "eu" e o mundo caótico em que este está inserido, implicando em uma complexidade das fontes do mal moral que diluem as barreiras entre bem e mal e nos levam à contestação destes limites estanques. Procuraremos, portanto, neste texto, demonstrar em que consiste essa quebra de limites e como a composição de uma realidade pautada no engano integra o universo literário kleistiano, principalmente na obra Michael Kohlhaas.
No âmbito da literatura infantil e juvenil em língua alemã contemporânea, destaca-se a produção de Cornelia Funke. Nascida em Dorsten em 1958, a autora - ou mais especificamente a contadora (Erzählerin), como gosta de se denominar -, acrescenta a seus textos a habilidade de ilustradora. Desde o sucesso mundial da triologia Tintenherz (Coração de tinta), Funke tornou-se uma personalidade de sucesso no universo infantil e juvenil. Em grande parte de suas obras, há a presença latente do imaginário ocidental acerca do medievo. Todavia, trata-se de uma recepção desse medievo, seja através da (re)criação de imagens ou da (re)estruturação de temáticas referentes ao universo cortês. O artigo aqui proposto analisa três obras de Funke, a saber: Die geraubten Prinzen (1994), Igraine ohne Furcht (1998) e Der geheimnisvolle Ritter Namenlos (2001), tendo como ponto de partida entrevistas da própria autora acerca do tema; ou seja, pensar-se-á a relação estabelecida entre o factual e o ficcional. Ao focar na questão da releitura do medievo, o artigo prentende compreender a ressignificação do medievo através tanto de imagens recriadas quanto da inserção de um novo tipo de herói, protagonistas femininas.
The present study aims to investigate how foreign language learners at the German for Academic Purposes (GAP) program at a Brazilian federal university interact in their mother tongue about their motivations to learn a foreign language as well as their motivations to participate in study abroad programs. Data were collected using focus group methodology with three focus groups of six students each (A1, A2 and B1 levels). We chose to analyze the A1 group. We conducted metaphor-led discourse analysis of the data in order to examine metaphors and metonymies, which emerged in the focus group interactions. We were able to identify the presence of systematic metaphors such as learning is hard work and learning is jumping hurdles, intertwined with conceptual metaphors such as education is a journey and difficulties are weights, which point at the motivation for learning verbalized by Brazilian foreign language learners who took part in the study.
O presente artigo advoga a necessidade de um trabalho voltado para o desenvolvimento de estratégias de autonomia que possam contribuir para a conscientização de estudantes de Alemão como Língua Estrangeira (ALE), em contexto universitário, sobre sua importância no processo de aprendizagem. Para tal, foi desenvolvida uma pesquisa junto a estudantes de graduação em Letras, Português-Alemão, de uma Universidade no Rio de Janeiro, com vistas a se verificar a influência do uso de recursos metodológicos como consultoria individual e diário de aprendizagem sobre sua percepção acerca de aspectos relacionados a aprendizado autônomo e centralidade do aprendiz no processo de aprendizagem/aquisição de ALE. Assim, nesse trabalho, serão discutidos não somente os resultados dessa pesquisa, mas também serão apresentados os principais pressupostos teóricos que balizaram a análise dos dados.
Através da ideia de quimera, esse ensaio tentará compreender a constituição aberta do personagem Odradek, da narrativa curta "A preocupação do pai de família" de Franz Kafka. O interestante nessa construção literária seria o deslocamento (inclusive das possibilidades de expressão de gênero nas línguas) que Odradek impõe ao esforço constante do narrador (representante de grupos sociais específicos) em categorizá-lo e, por consequência, do leitor, que tentaria encerrá-lo num tipo fechado de interpretação. Odradek parece um tipo de ser incapturável pelas principais categorias, sejam elas literárias, biológicas ou sociais, que ajudaram a fundar a ideia de Modernidade.
O presente texto objetiva expor e divulgar ao mais amplo público leitor um panorama cronológico comentado dos estudos críticos publicados sobre a literatura produzida por imigrantes de língua alemã e seus descendentes no Brasil, mostrando que e por que se tratam de uma crítica parcial, o que evidencia a necessidade de atrair a atenção para este campo de pesquisa, partindo dos novos horizontes abertos pelos estudos culturais, pela imagologia, pelos estudos da memória, além da crítica poética. Parte-se das palavras encorajadoras de Boris Fausto em Fazer a América (1999) e de Wander de Melo Miranda em Nações literárias (2010), pois a literatura de língua alemã gerada no país pertence à cultura brasileira, é uma das nações literárias encastoadas no Brasil.
Die Österreichische Dichterin Paula Ludwig ist eine tragische Figur der Exilgeschichte deutschsprachiger Autoren in Brasilien. Der vorliegende Artikel behandelt den Weg der Autorin, die am Verlust ihrer Liebe, Iwan Goll, und vor allem ihrer Sprache nahezu zerbricht. Anhand verschiedener Stationen, Publikationen und anderen Lebensereignissen wird ihr Werdegang nachvollzogen. Hier soll es primär um die von der Exilerfahrung geprägte persönliche Geschichte einer Dichterin gehen, die ein nahezu vergessenes lyrisches Erbe hinterlassen hat, das womöglich weitaus bedeutender hätte ausfallen können.
Edições publicadas entre 2011 e 2014 no Brasil e em Portugal dos romances Os sonâmbulos e A morte de Virgílio, de Hermann Broch, mais que indícios de um interesse crescente ou uma acolhida tardia, incentivam pensar que episódios vêm compondo a história de sua presença em língua portuguesa. O artigo apresenta um levantamento inédito da recepção lusófona das obras ficcional e teórica de Hermann Broch desde o fim da década de 1950 até o presente e fornece um quadro se não conclusivo ao menos organizador dos principais momentos - inclusões na historiografia literária, traduções, aproveitamentos teóricos e artísticos - que dão forma a essa história apenas começada. O objetivo é expandir o mapa de suas leituras e dispor referências a discussões futuras que resolvam avançar com a pesquisa do autor e sua obra.
Viscum album L. extracts (VE) are applied as complementary cancer therapeutics for more than one century. Extracts contain several compounds like mistletoe lectins (ML) 1-3 and viscotoxins, but also several minor ingredients. Since ML-1 has been described as one of the main active components harboring antitumor activity, purified native or recombinant ML-1 has been also used in clinical trials in the last years. The present study examined and compared the immunoboosting effects of three ML-1 containing drugs (the extract ISCADOR Qu, the recombinant ML-1 Aviscumine, and purified native ML-1) in the context of the T-cell mediated killing of glioma cells. Additionally we examined the possible underlying T-cell stimulating mechanisms. Using cocultures of immune and glioma cells, a PCR-based microarray, quantitative RT-PCR, and an antibody-based array to measure cytokines in blood serum, immunosupporting effects were determined. A highly aggressive, orthotopic, immunocompetent syngeneic mouse glioma model was used to determine the survival of mice treated with ISCADOR Qu alone or in combination with tumor irradiation and temozolomide (TMZ). Treatment of glioblastoma (GBM) cells with ISCADOR Qu that contains a high ML concentration, but also viscotoxins and other compounds, as well as with Aviscumine or native ML-1, enhanced the expansion of cancer cell-specific T-cells as well as T-cell-mediated tumor cell lysis, but to a different degree. In GBM cells all three ML-1-containing preparations modulated the expression of immune response associated genes. In vivo, subcutaneous ISCADOR Qu injections at increasing concentration induced cytokine release in immunocompetent VM/Dk-mice. Finally, ISCADOR Qu, if applied in combination with tumor irradiation and TMZ, further prolonged the survival of glioma mice. Our findings indicate that ML-1 containing drugs enhance anti-GBM immune responses and work in synergy with radiochemotherapy. Therefore, adjuvant mistletoe therapy should be considered as an auspicious treatment option for glioma patients.
Dating of extensive alluvial fan surfaces and fluvial features in the hyperarid core of the Atacama Desert, Chile, using cosmogenic nuclides provides unrivalled insights about the onset and variability of aridity. The predominantly hyperarid conditions help to preserve the traces of episodic climatic and/or slow tectonic change. Utilizing single clast exposure dating with cosmogenic 10Be and 21Ne, we determine the termination of episodes of enhanced fluvial erosion and deposition occurring at ~19, ~14, ~9.5 Ma; large scale fluvial modification of the landscape had ceased by ~2–3 Ma. The presence of clasts that record pre-Miocene exposure ages (~28 Ma and ~34 Ma) require stagnant landscape development during the Oligocene. Our data implies an early onset of (hyper-) aridity in the core region of the Atacama Desert, interrupted by wetter but probably still arid periods. The apparent conflict with interpretation that favour a later onset of (hyper-) aridity can be reconciled when the climatic gradients within the Atacama Desert are considered.
Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B‐cell malignancies. Notwithstanding, CAR T‐cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19‐CAR T cells can be generated directly in vivo using the lentiviral vector CD8‐LV specifically targeting human CD8+ cells. Administration into mice xenografted with Raji lymphoma cells and human peripheral blood mononuclear cells led to CAR expression solely in CD8+ T cells and efficacious elimination of CD19+ B cells. Further, upon injection of CD8‐LV into mice transplanted with human CD34+ cells, induction of CAR T cells and CD19+ B‐cell depletion was observed in 7 out of 10 treated animals. Notably, three mice showed elevated levels of human cytokines in plasma. Tissue‐invading CAR T cells and complete elimination of the B‐lymphocyte‐rich zones in spleen were indicative of a cytokine release syndrome. Our data demonstrate the feasibility of in vivo reprogramming of human CD8+ CAR T cells active against CD19+ cells, yet with similar adverse effects currently notorious in the clinical practice.
Aberrant activation of hedgehog (Hh) signaling has been observed in a wide variety of tumors and accounts for more than 25% of human cancer deaths. Inhibitors targeting the Hh signal transducer Smoothened (SMO) are widely used and display a good initial efficacy in patients suffering from basal cell carcinoma (BCC); however, a large number of patients relapse. Though SMO mutations may explain acquired therapy resistance, a growing body of evidence suggests that the non-canonical, SMO-independent activation of the Hh pathway in BCC patients can also account for this adverse effect. In this review, we highlight the importance of glioma-associated oncogene (GLI) transcription factors (the main downstream effectors of the canonical and the non-canonical Hh cascade) and their putative role in the regulation of multiple oncogenic signaling pathways. Moreover, we discuss the contribution of the Hh signaling to malignant transformation and propose GLIs as central hubs in tumor signaling networks and thus attractive molecular targets in anti-cancer therapies.
One of the notable features of penguin evolution is the occurrence of very large species in the early Cenozoic, whose body size greatly exceeded that of the largest extant penguins. Here we describe a new giant species from the late Paleocene of New Zealand that documents the very early evolution of large body size in penguins. Kumimanu biceae, n. gen. et sp. is larger than all other fossil penguins that have substantial skeletal portions preserved. Several plesiomorphic features place the new species outside a clade including all post-Paleocene giant penguins. It is phylogenetically separated from giant Eocene and Oligocene penguin species by various smaller taxa, which indicates multiple origins of giant size in penguin evolution. That a penguin rivaling the largest previously known species existed in the Paleocene suggests that gigantism in penguins arose shortly after these birds became flightless divers. Our study therefore strengthens previous suggestions that the absence of very large penguins today is likely due to the Oligo-Miocene radiation of marine mammals.
Embora a linguagem oral seja fundamental em nossas vidas, pois é por intermédio dela que expressamos nossos sentimentos, pensamentos, desejos, experiências e construímos conhecimento, pouco se fala sobre ela na educação infantil. Nesse sentido, amparados na teoria dos gêneros textuais, na perspectiva do interacionismo sociodiscursivo (ISD) (BRONCKART 2012; SCHNEUWLY/ DOLZ 2013), elaboramos uma sequência didática (SD) com base em dois contos de animais. Por meio dessa proposta intervencionista buscamos aprimorar a ordem do ensino e aprendizagem em um contexto escolar composto por crianças de faixa etária entre 03 e 04 anos de idade, os quais estão inseridos na rede particular de ensino. Para este artigo intentamos descrever e avaliar as configurações da SD elaborada, bem como analisar a presença de capacidades de linguagem. Além disso, apresentaremos resultados parciais das produções orais dos alunos. Ao analisarmos a SD, verificamos a predominância das capacidades de significação (15%) e das capacidades linguístico-discursivas (12,5%). Além disso, constatamos que a SD provê atividades para as produções orais das crianças, tendo em vista que os dois contos escolhidos e as atividades os envolvem emocionalmente, psicologicamente, bem como cognitivamente. Além de recontar a história, os alunos passaram a utilizar o vocabulário e até determinadas expressões em seu cotidiano
Este trabalho reúne e compara relatos de pesquisas, publicados no Brasil e na Alemanha, que tratam de constelações plurilíngues em que o alemão é uma das três ou mais línguas faladas ou aprendidas no contexto analisado. Trata-se de uma pesquisa bibliográfica, tanto de viés quantitativo, por observar quantos artigos a respeito foram publicados no Brasil e na Europa nos últimos dez anos, como também qualitativo, na medida em que busca pontos de convergência e de divergência entre eles e recomendações teóricas recentes, e também entre as próprias temáticas trabalhadas nesses artigos. Primeiramente, é estabelecido um elo entre três pontos-chave da didática do plurilinguismo. Então, são apresentadas questões específicas da pós-modernidade e as linhas gerais dos artigos aqui analisados, seguidas de três seções justapondo cada um dos pontos-chave com os respectivos artigos em que são abordados. A seguir, são comentadas perspectivas do ensino de alemão em contexto plurilíngue de outras partes do mundo. As considerações finais retomam alguns pontos teóricos apontados ao longo do texto e apresentam sugestões para a melhoria do ensino de alemão no Brasil.
Este trabalho tem como objetivo refletir acerca do ensino da língua alemã em escolas públicas com foco na promoção do letramento crítico. Para tanto, partimos da definição de Letramento e de Letramento Crítico, articulando o último com as atividades desenvolvidas por graduandos em Letras-alemão no âmbito do Programa Institucional de Iniciação à Docência (PIBID) - subprojeto Letras-alemão - em duas escolas estaduais do interior paulista. As reflexões apresentadas basearam-se nos planejamentos e nos diários reflexivos dos licenciandos e nas percepções da coordenadora do subprojeto. Os resultados apontam para o potencial do ensino de alemão em escolas públicas brasileiras, não apenas para a aprendizagem de um novo idioma, mas também para uma formação crítica e cidadã dos alunos.
Zichronos de Glückl von Hameln, uma obra de caráter memorialista escrita por uma matriarca judia de Hamburgo na passagem do século XVII para o século XVIII, sob o impacto do advento da heresia sabataísta e da Guerra dos Trinta Anos, antecipa, por meio das perplexidades e das dúvidas que enuncia, um novo topos literário judaico-alemão, fundado não mais nas certezas da doutrina religiosa e dos ensinamentos tradicionais, mas na percepção da distância crescente que separa da vida tal doutrina, na percepção do abismo que se abre entre o mundo tal qual ele deveria ser e o mundo tal qual ele é, e que, portanto, parte em busca por maneiras ou respostas para se franquear tal distância, ou se volta, simplesmente, sobre o crescente estranhamento e sobre a crescente alienação. É sobre este imenso vazio e sobre estas interrogações que se construirão, como pontes dirigidas ao infinito e fadadas a nunca alcançarem seus destinos, as obras-chave da literatura judaica moderna dos séculos XIX e XX. Se o romance judaico-alemão moderno surge como representação ou como tentativa de superação deste abismo, a narrativa autobiográfica de Glückl von Hameln pode ser compreendida como um prelúdio a este gênero fundado na incompreensão, na perplexidade e na nostalgia pelo mundo impregnado de sentido.
Este artigo explora a produção e transmissão de ilustrações que Candido Portinari fez para uma edição norte-americana do livro de Hans Staden sobre o Brasil no século XVI. Realizados em 1941, os desenhos caíram em esquecimento por quase sessenta anos até a sua publicação póstuma em 1998 no Brasil. Este artigo argumenta que o destino dos desenhos é sintomático da articulação da memória cultural social do passado colonial brasileiro. Com base na análise da recepção crítica e do repertório visual dos desenhos, sugere que as ilustrações de Portinari divergem de representações tradicionais da morte dos povos indígenas por desafiarem a temporalidade subjacente às molduras nacionais da memória colonial.
Este artigo é baseado em duas publicações anteriores (BAßLER 2013a; 2013b) e analisa o realismo como procedimento narrativo do nosso presente; para esse fim, são tratadas obras da literatura de expressão alemã e da televisão. O autor constata, tanto na chamada alta literatura quanto em gêneros como fantasia e séries televisivas um realismo que invoca e confirma, mediante frames convencionalizados, a imagem corrente da realidade e os códigos de significado vigentes do presente, indiferente da apresentação do conteúdo como realista ou fantástico. Este tipo de literatura é bem-sucedida porque possibilita uma leitura fácil e, ao mesmo tempo, reclama legitimidade através de uma autenticidade de alta literatura. Como alternativa a este estilo internacional de realismo trivial se oferecem, por um lado, obras pós-modernas e da cultura pop que expõem abertamente ser construídas por citações e, por outro, procedimentos como short cuts que dissecam a narrativa linear metonímica e a reconfiguram numa nova totalidade complexa e significativa.
This paper focuses on the Heimat (home) metaphor of the Pit Bull bitch in Yilmaz Arslan's Brudermord/Fratricide (2005), a film about Turkish migrants in Germany. Updating the genre for a world of fluid boundaries, this is a Heimatfilm of the German margin. Arslan's film self-reflexively posits transnational Heimat film as a possible bridge between "Others", as a means to facilitate conversations which might decrease the violence of the present dog eat dog world of the margin the film portrays.
Dea Loher (1964-), dramaturga contemporânea alemã, propõe ao seu leitor/espectador
histórias que retratam a sociedade, conduzindo seu público a uma reflexão acerca de temas
inerentes à realidade na qual eles se encontram inseridos. Através de um estilo próprio e
peculiar, de uma estética que combina elementos vários, Loher retoma o teatro político
enfocando os menos favorecidos, com o objetivo de criar espaços para que seu interlocutor
encontre possibilidades de mudança. A escritora dá vida a personagens que, livres de uma
utopia salvadora, têm a opção da rebeldia ou da resignação até o aniquilamento total, garantindo
uma vertente trágica à escrita da dramaturga. Dea Loher compila histórias diversas que, embora
retratem figuras descaracterizadas e tristes, não as coloca em posição de vítimas, mas enfatizam
as múltiplas perspectivas que as levaram à ação ou ao ostracismo. Uma abordagem que
privilegia as micronarrativas e as relações de poder que as circundam, além de um
questionamento acerca do tênue limite que há entre realidade e ficção.
Neste texto, iremos proceder a uma exposição crítica sobre a peça de teatro de Elfriede Jelinek, Die Kontrakte des Kaufmanns, que visa apresentar os princípios de composição literária utilizados pela escritora na sua proposta de um "drama parasitário". Ao mesmo tempo, vamos procurar resgatar o conjunto de referências contextuais que precedem essa teatralização. Para tanto, começaremos por mostrar o contexto de incubação da peça, passando, em seguida, a introduzir a aproximação irônica e paródica que a escritora conduz sobre o mecanismo de legitimação e naturalização do mercado e suas operações financeiras, em particular pela metafísica econométrica e pelo senso comum mediático. Num terceiro ponto, vamos apresentar os procedimentos especificamente literários com que a escritora vai revelar a lógica da economia capitalista como regime de aniquilação de corpos. Por fim, resumimos a intenção da escritora em usar o teatro como dispositivo de ativação dos espectadores pelo "horror".
Behavioural traits of individual homing pigeons, Columba livia f. domestica, in their homing flights
(2018)
Homing tracks of two groups of pigeons, Columba livia f. domestica, were analyzed in view of difference between individual birds and correlations between characteristic variables, looking at the initial phase while the pigeons were still at the release site, and the homing phase separately. Individual birds differed significantly in their flying speed during the initial phase, and one pigeon tended to stay longer at the release site than the others. There were no significant differences in steadiness and efficiency, indicating that all pigeons homed equally well. Differences in correlation dimension, a variable reflecting the complexity of the navigational process, reflect differences in the use of navigational information, with one bird apparently using less complex information than others. The flying speed during the initial phase was positively correlated with the flying speed during the homing phase. During the homing phase, the steadiness of flight and the efficiency of homing were closely correlated, and both tended to be positively correlated with the correlation dimension, suggesting that birds that use more complex navigational information home more efficiently.
The regulation of temporo-spatial compartmentalization of protein synthesis is of crucial importance for a variety of physiologic cellular functions. Here, we demonstrate that the cell membrane-anchored disintegrin metalloproteinase ADAM15, upregulated in a variety of aggressively growing tumor cells, in the hyperproliferative synovial membrane of inflamed joints as well as in osteoarthritic chondrocytes, transiently binds to poly(A) binding protein 1 (PABP) in cells undergoing adhesion. The cytoplasmic domain of ADAM15 was shown to selectively interact with the proline-rich linker of PABP. Immunostainings of adhesion-triggered cells demonstrate an ADAM15-dependent recruitment of PABP to cell membrane foci coinciding with ongoing mRNA translation as visualized by the detection of puromycin-terminated polypeptides. Moreover, the increase in cell membrane-associated neosynthesis of puromycylated proteins upon induction of cell adhesion was proven linked to ADAM15 expression in HeLa and ADAM15-transfected chondrocytic cells. Thus, down regulation of ADAM15 by siRNA and/or the use of a cell line transfected with a mutant ADAM15-construct lacking the cytoplasmic tail resulted in a considerable reduction in the amount of cell membrane-associated puromycylated proteins formed during induced cell adhesion.
These results provide first direct evidence for a regulatory role of ADAM15 on mRNA translation at the cell membrane that transiently emerges in response to triggering cell adhesion and might have potential implications under pathologic conditions of matrix remodeling associated with ADAM15 upregulation.
Der Kurator der Ausstellung Wir brauchen einen ganz anderen Mut! Stefan Zweig - Abschied von Europa, Klemens Renoldner, spricht im Interview über Text-Kontext-Beziehungen in Hinblick auf das Werk des österreichischen Schriftstellers Stefan Zweig (1881-1942). Dabei kommen u.a. unterschiedliche Rezeptionskontexte und Interpretationsansätze ans Licht, die dazu beitragen, traditionelle Klischees rund um das Leben und das Werk des Autors zu relativieren. Außerdem wird auf die Zusammenarbeit des Stefan Zweig Centres in Salzburg und der Casa Stefan Zweig in Petrópolis (Rio de Janeiro) hingewiesen und abgeschlossene, sowie zukünftige Projekte vorgestellt.
Cada vez mais, o ensino baseado em textos ganha espaço nas salas de aula de línguas e nos livros didáticos. A teoria dos gêneros do discurso, advinda do Círculo de Bakhtin, tem fundamentado diversas análises e é o ponto de partida das teorias de gêneros discursivos e/ou textuais. Essa teoria é centrada no estudo das materialidades discursivas em seus aspectos sócio-históricos e ideológicos, considerando também as condições de produção e as situações de comunicação dos discursos. Diante de tais considerações, os objetivos deste trabalho são: verificar a concepção de gêneros em um livro didático de alemão como língua estrangeira para iniciantes Planet A1 e investigar o modo como as atividades com os gêneros são abordadas nesse material. A análise apresentada neste artigo é qualitativa e não há qualquer quantificação dos gêneros abordados no livro didático. Para tanto, foram escolhidas três propostas de atividades baseadas em três gêneros, entre os mais recorrentes do livro didático: uma conversa telefônica, e-mails e um gráfico. Os resultados das análises demonstram que o livro didático
O presente trabalho discute diferentes estratégias de retextualização no processo de tradução de um texto acadêmico, especialmente no caso de transposição de um gênero mais próximo à oralidade a outro, mais próximo da escrituralidade. A edição crítica em português que incorpora estas estratégias de retextualização é desenvolvida tomando como base não só a primeira edição do manual didático-científico Textlinguistik de Eugenio Coseriu, fixada em alemão por Albrecht a partir de gravações em áudio de aulas ministradas por Coseriu em 1977/78, como também as edições em italiano e espanhol. Neste trabalho, diferentes estratégias de verbalização que permitem o deslocamento do texto em direção à escrituralidade são ilustradas e fundamentadas teoricamente, segundo os pressupostos teóricos do modelo de Tradições Discursivas, de base coseriana, que entende a língua como um diassistema de textos e variedades linguísticas localizadas no contínuo de oralidade e escrituralidade.
Este trabalho se propõe a utilizar os princípios inerentes à Linguística de Corpus – listas de palavras, palavras-chave e linhas de concordância – com o intuito de fazer uma análise comparativa do texto Trauer und Melancholie, escrito por Freud em 1917, e suas cinco retraduções publicadas em português no Brasil. Devido à insatisfação em relação às traduções indiretas dos escritos freudianos, desde a década de 1990 têm surgido propostas de retraduções que visam recuperar nos textos em português a terminologia e o estilo que o pai da Psicanálise utilizou em alemão. A fim de verificar até que ponto as escolhas tradutórias estão diretamente ligadas ao texto-fonte, partimos de dados empíricos levantados por ferramentas computacionais. As análises quantitativas e qualitativas revelaram que as retraduções diretas foram influenciadas pelas anteriores – indiretas –, mostrando que outros fatores, além do texto de partida, afetam o texto traduzido, ainda que os tradutores não se deem conta disso.
O conceito de Witz, como aparece nos fragmentos de Friedrich Schlegel, publicados entre 1798 e 1800, está ligado ao entendimento estético e foi recuperado por Walter Benjamin em O conceito de crítica de arte no romantismo alemão. O Witz faz parte da "terminologia filosófica" romântica, é um instante na reflexão crítica sobre uma obra de arte onde se dá o conhecimento súbito. O Witz opera na obra uma iluminação de diferentes níveis: semanticamente, aparece na obra como as figuras de estilo da subitaneidade, ou como parabase, a ruptura que autoexplica a obra. Witz, etimologicamente, seria uma corruptela de wissen (saber), e representado pela metáfora da luz. O termo original Witz mantém uma relação sonora com Blitz (relâmpago), é o saber que emerge à consciência subitamente, como um relâmpago, uma iluminação súbita da cena. Witz/Bliz constituem-se em um par conceitual, ou seja, a sonoridade dos termos permite um permuta visual e fonética que vem ao encontro das possibilidades semânticas, compondo um par de opostos.
The aim of this paper is to analyze the concept of body developed by Luhmann's systems theory. Privileged places where one can look for the body will be the interpenetration between human beings and the concept of socialization. Another fundamental problem is the relationship between semantics and body, although the most explicit presence of the body in this theory comes with the concept of symbiotic mechanisms or symbols. The last place where this enquiry will look for a bodily reference are emotions, which were highly ignored by Luhmann. Alternative approaches explored in the paper are treating the body as a structure, as a medium or as an internal environment.
O artigo aborda as experiências fotografias e narrativas do fotojornalista austríaco Mario Baldi, que trabalhou entre os índios brasileiros na primeira metade do século XX. Baldi escreveu um livro sobre sua convivência com os Carajá e publicou tanto no Brasil quanto na Alemanha. O objetivo dessa análise é comparar as duas versões e abordar as inovações e limites das representações que Baldi faz da alteridade cultural brasileira, influenciadas por um romantismo etnológico compartilhado por alguns estudiosos brasileiros e alemães, denominado nos anos 1940 e 1950 de indiologia brasileira.
Este trabalho tem como objetivo analisar a construção das Stimmungen (atmosferas) na livre-adaptação do Fausto de Goethe realizada, em 2011, pelo diretor russo Aleksandr Sokurov. Dentro dessa perspectiva, buscaremos demonstrar, particularmente, como o diálogo entre Sokurov e Goethe não se dá somente no domínio do enredo, mas também no modo peculiar como ambos se utilizam da técnica como forma de modulação dos afetos dos espectadores.
El presente artículo se propone analizar la interpretación benjaminiana de Kafka tomando como eje central el problema de la tradición y su resignificación política en el contexto de producción tardío. Son relevantes en este sentido, los conceptos de hagadá y halajá con los que Benjamin estructura sus análisis. El objetivo es entonces rastrear los elementos que en la elaboración de una teoría política permiten recuperar al narrador checo para la revisión de un concepto de lo humano.
Klemens Renoldner, curador da exposição Precisamos de uma coragem bem diferente! -Stefan Zweig - despedida da Europa, aborda, em entrevista, as relações entre entre textos e contextos no âmbito da obra do escritor austríaco Stefan Zweig (1881-1942). Com isso, traz à tona diferentes contextos de recepção e vertentes interpretativas da obra zweigiana, contribuindo assim à relativização de tradicionais clichês em torno da vida e da obra do autor. Além disso, a conversa trata da cooperação entre o Stefan Zweig Centre, em Salzburgo, e a Casa Stefan Zweig, em Petrópolis (Rio de Janeiro), e apresenta projetos realizados e futuros.
Background: Atakora mountains in Benin are a unique but fragile ecosystem, harboring many endemic plant species. The ecosystem is undergoing degradation, and the woody vegetation is dramatically declining due to high anthropogenic actions and recurrent drought. This study aimed to (i) assess the diversity of threatened woody species and (ii) identify their potential substitutes in the three regions of the Atakora mountains namely East Atakora, Central Atakora, and West Atakora.
Methods: The data were collected during expeditions on surveyed localities through semi-structured individual interviews. Free-listing was used to record threatened woody species and which were important and why. Alpha-diversity indices were used to assess diversity of threatened and important threatened woody species. A correspondence analysis was used to determine the reason supporting their importance. Differences in species composition were assessed using analysis of similarities. A number of potential substitutes were compared among species using generalized linear models.
Results: A total of 117 woody species (37 families and 92 genera) were identified. The most prominent families were Fabaceae (19.66%), Combretaceae (12.82%), and Moraceae (10.26%), and the richest genera were Ficus (10 species), Combretum (6), and Terminalia (5). Most threatened species differed across regions (East Atakora, Central Atakora, and West Atakora) and included Afzelia africana, Anogeissus leiocarpa, Borassus aethiopum, Diospyros mespiliformis, Khaya senegalensis, Milicia excelsa, and Pterocarpus erinaceus. Most socio-economically important species (K. senegalensis, Parkia biglobosa, Vitellaria paradoxa, and V. doniana) were used mainly for food, timber, and fuelwood purposes. Old and adult people, and Dendi and Fulfulde sociolinguistic groups had greater knowledge of threatened woody plant species. High intercultural differentiations in species composition were detected between Bariba-Berba and Bariba-Natimba. Knowledge of substitutes also differed across regions with P. erinaceus, Isoberlinia spp., and A. africana being the most cited substitutes.
Conclusion: Basic data was provided here to inform decision and guide efficient management of woody resources. There was evidence that immediate conservation measures are required for some high economic value woody taxa which were critically threatened. Ex-situ conservation of these species while promoting their integration into agroforestry-based systems were recommended. Besides, community-based management programs and community-led initiatives involving knowledgeable people from different horizons will lead to a long-lasting conservation of these threatened resources.
Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differentiated phenotype and proliferate. Here we demonstrate that microRNA-92a (miR-92a) is enriched in podocytes of patients and mice with RPGN. The CDK inhibitor p57Kip2 is a major target of miR-92a that constitutively safeguards podocyte cell cycle quiescence. Podocyte-specific deletion of miR-92a in mice de-repressed the expression of p57Kip2 and prevented glomerular injury in RPGN. Administration of an anti-miR-92a after disease initiation prevented albuminuria and kidney failure, indicating miR-92a inhibition as a potential therapeutic strategy for RPGN. We demonstrate that miRNA induction in epithelial cells can break glomerular tolerance to immune injury.
The mitophagy receptor Nix interacts with LC3/GABARAP proteins, targeting mitochondria into autophagosomes for degradation. Here we present evidence for phosphorylation-driven regulation of the Nix:LC3B interaction. Isothermal titration calorimetry and NMR indicate a ~100 fold enhanced affinity of the serine 34/35-phosphorylated Nix LC3-interacting region (LIR) to LC3B and formation of a very rigid complex compared to the non-phosphorylated sequence. Moreover, the crystal structure of LC3B in complex with the Nix LIR peptide containing glutamic acids as phosphomimetic residues and NMR experiments revealed that LIR phosphorylation stabilizes the Nix:LC3B complex via formation of two additional hydrogen bonds between phosphorylated serines of Nix LIR and Arg11, Lys49 and Lys51 in LC3B. Substitution of Lys51 to Ala in LC3B abrogates binding of a phosphomimetic Nix mutant. Functionally, serine 34/35 phosphorylation enhances autophagosome recruitment to mitochondria in HeLa cells. Together, this study provides cellular, biochemical and biophysical evidence that phosphorylation of the LIR domain of Nix enhances mitophagy receptor engagement.
Background: Recently, public and political interest has focused on people living with rare diseases and their health concerns. Due to the large number of different types of rare diseases and the sizable number of patients, taking action to improve the life of those affected is gaining importance. In 2013, the federal government of Germany adopted a national action plan for rare diseases, including the call to establish a central information portal on rare diseases (Zentrales Informationsportal über seltene Erkrankungen, ZIPSE).
Objective: The objective of this study, therefore, was to conduct scientific research on how such a portal must be designed to meet the needs of patients, their families, and medical professionals, and to provide high-quality information for information seekers.
Methods: We chose a 3-step procedure to develop a needs-based prototype of a central information portal. In the first step, we determined the information needs of patients with rare diseases, their relatives, and health care professionals by means of qualitative interviews and their content-analytical evaluation. On the basis of this, we developed the basic structure of the portal. In the second step, we identified quality criteria for websites on rare diseases to ensure that the information linked with ZIPSE meets the quality demands. Therefore, we gathered existing criteria catalogs and discussed them in an expert workshop. In the third step, we implemented and tested the developed prototypical information portal.
Results: A portal page was configured and made accessible on the Web. The structure of ZIPSE was based on the findings from 108 qualitative interviews with patients, their relatives, and health care professionals, through which numerous information needs were identified. We placed particularly important areas of information, such as symptoms, therapy, research, and advisory services, on the start page. Moreover, we defined 13 quality criteria, referring to factors such as author information, creation date, and privacy, enabling links with high-quality information. Moreover, 19 users tested all the developed routines based on usability and comprehensibility. Subsequently, we improved the visual presentation of search results and other important search functions.
Conclusions: The implemented information portal, ZIPSE, provides high-quality information on rare diseases from a central point of access. By integrating the targeted groups as well as different experts on medical information during the construction, the website can assure an improved search for information for users. ZIPSE can also serve as a model for other Web-based information systems in the field of rare diseases.
Registered Report Identifier: RR1-10.2196/7425.
Objective: To conduct subset analyses of SPIRIT-P2 (Standard Protocol Items: Recommendations for Interventional Trials, NCT02349295) to investigate the efficacy and safety of ixekizumab versus placebo in three subgroups of patients with active psoriatic arthritis (PsA) according to the concomitant conventional synthetic disease-modifying antirheumatic drug (cDMARD) received: any background cDMARDs (including methotrexate), background methotrexate only
Methods: Patients were randomised to receive placebo, ixekizumab 80 mg every 4 weeks (IXEQ4W) or every 2 weeks (IXEQ2W). Efficacy and safety were assessed when patients were subdivided according to cDMARD use at baseline. Efficacy was evaluated versus placebo at week 24 by the American College of Rheumatology criteria (ACR20/50), achievement of minimal disease activity (MDA) state, DiseaseActivityIndex for PsA (DAPSA), 28-joint DiseaseActivityScore using C reactive protein (DAS28-CRP), HealthAssessmentQuestionnaire-Disability Index and the 36-item Short-Form health survey physical functioning domain.
Results: Regardless of background cDMARD status, ACR20, ACR50 and MDA response rates were significantly higher than placebo with IXEQ4W or IXEQ2W treatment. Similarly, significant improvements were observed relative to placebo for DAS28-CRP and DAPSA across subgroups. Physical function also significantly improved relative to placebo with IXEQ4W treatment regardless of background cDMARD status and with IXEQ2W alone. Percentages of reported treatment emergent adverse events (AEs), serious AEs (including serious infections) and discontinuations due to AEs in each subgroup were comparable to the overall SPIRIT-P2 population.
Conclusion: Ixekizumab was efficacious in patients with active PsA and previous tumour necrosis factor inhibitor (TNFi)inadequate response or TNFi intolerance treated with ixekizumab alone or when added to cDMARDswith subgroup safety profiles that were consistent with that observed in the overall SPIRIT-P2 population.
80'li ve 90'lı yıllarda çeviribilim çalışmaları yaşanan kültürel dönemeç (Cultural turn) ile yeni ve bütüncül yaklaşımlarla ele alınmaya başlanmıştır. O tarihe kadar geliştirilmiş yaklaşımlardaki yapısalcı tutum, çeviriyi anlamak ve tanımlamak açısından yetersiz kaldığı nedeniyle çeviride işlev odaklı yaklaşımlara ağırlıklı olarak yer verilmeye başlanmıştır. Reiβ / Vermeer’in (1984) "Skopos Kuramı" yaklaşımı, dil ve kültürbilimin bir parçası olarak kabul etmektedirler. Bu kuram çerçevesinde çeviri örnekleri irdelenecek ve işlev odaklı çeviri yaklaşımının kültürel öğelerin çevirisi için ne gibi açılımlar sağladığı incelenecektir. Bu bağlamda işlev odaklı çeviri sürecinin birbirinden farklı dilsel ve kültürel edince sahip olan çevirmen adaylarının çeviri yaklaşımlarına nasıl yansıdığı gözlemlenecektir. Bu amaçla farklı dilsel ve kültürel edince sahip çevirmen adayların çeviri sürecinde hangi çeviri yaklaşımını benimsedikleri ve bu çevimen adaylarının işlev odaklı çeviriye ne ölçüde yaklaşabildikleri üzerinde durulacaktır. Ayrıca bu süreç içerisinde bu iki farklı grubun uyguladığı çeviri stratejilerinde fark ve benzerliklerin niteliği incelenecektir. Bu bağlamda çevirmen adaylarının çeviri örnekleri incelenmiş, işlev odaklı çeviriye ne ölçüde yaklaşıldığı ortaya konmaya çalışılmıştır. Elde edilen sonuçlar birbirinden farklı dilsel ve kültürel edince sahip iki grubun farklı çevirmen tutumlarını beraberinde getirdiğini ve işlev odaklı çeviride de farklı sonuçlara götürdüğünü ortaya koymuştur. Bu inceleme işlev odaklı çevirinin süreçleri hakkında yeni açılımlara varmayı amaçlamaktadır.
Cardiovascular disease remains a leading cause of morbidity and mortality globally. Changing natural history of the disease due to improved care of acute conditions and ageing population necessitates new strategies to tackle conditions which have more chronic and indolent course. These include an increased deployment of safe screening methods, life-long surveillance, and monitoring of both disease activity and tailored-treatment, by way of increasingly personalized medical care. Cardiovascular magnetic resonance (CMR) is a non-invasive, ionising radiation-free method, which can support a significant number of clinically relevant measurements and offers new opportunities to advance the state of art of diagnosis, prognosis and treatment. The objective of the SCMR Clinical Trial Taskforce was to summarizes the evidence to emphasize where currently CMR-guided clinical care can indeed translate into meaningful use and efficient deployment of resources results in meaningful and efficient use. The objective of the present initiative was to provide an appraisal of evidence on analytical validation, including the accuracy and precision, and clinical qualification of parameters in disease context, clarifying the strengths and weaknesses of the state of art, as well as the gaps in the current evidence This paper is complementary to the existing position papers on standardized acquisition and post-processing ensuring robustness and transferability for widespread use. Themed imaging-endpoint guidance on trial design to support drug-discovery or change in clinical practice (part II), will be presented in a follow-up paper in due course. As CMR continues to undergo rapid development, regular updates of the present recommendations are foreseen.
Introduction Current: evidence suggests that the loss of mechanoreceptors after anterior cruciate ligament (ACL) tears might be compensated by increased cortical motor planning. This occupation of cerebral resources may limit the potential to quickly adapt movements to unforeseen external stimuli in the athletic environment. To date, studies investigating such neural alterations during movement focused on simple, anticipated tasks with low ecological validity. This trial, therefore, aims to investigate the cortical and biomechanical processes associated with more sport-related and injury-related movements in ACL-reconstructed individuals.
Methods and analysis: ACL-reconstructed participants and uninjured controls will perform repetitive countermovement jumps with single leg landings. Two different conditions are to be completed: anticipated (n=35) versus unanticipated (n=35) successful landings. Under the anticipated condition, participants receive the visual information depicting the requested landing leg prior to the jump. In the unanticipated condition, this information will be provided only about 400 msec prior to landing. Neural correlates of motor planning will be measured using electroencephalography. In detail, movement-related cortical potentials, frequency spectral power and functional connectivity will be assessed. Biomechanical landing quality will be captured via a capacitive force plate. Calculated parameters encompass time to stabilisation, vertical peak ground reaction force, and centre of pressure path length. Potential systematic differences between ACL-reconstructed individuals and controls will be identified in dependence of jumping condition (anticipated/ unanticipated, injured/uninjured leg and controls) by using interference statistics. Potential associations between the cortical and biomechanical measures will be calculated by means of correlation analysis. In case of statistical significance (α<0.05.) further confounders (cofactors) will be considered.
Ethics and dissemination: The independent Ethics Committee of the University of Frankfurt (Faculty of Psychology and Sports Sciences) approved the study. Publications in peer-reviewed journals are planned. The findings will be presented at scientific conferences.
Trial status: At the time of submission of this manuscript, recruitment is ongoing.
Trial registration number: NCT03336060; Pre-results.
Background: Conversion from calcineurin inhibitor (CNI) therapy to a mammalian target of rapamycin (mTOR) inhibitor following kidney transplantation may help to preserve graft function. Data are sparse, however, concerning the impact of conversion on posttransplant diabetes mellitus (PTDM) or the progression of pre-existing diabetes.
Methods: PTDM and other diabetes-related parameters were assessed post hoc in two large open-label multicenter trials. Kidney transplant recipients were randomized (i) at month 4.5 to switch to everolimus or remain on a standard cyclosporine (CsA)-based regimen (ZEUS, n = 300), or (ii) at month 3 to switch to everolimus, remain on standard CNI therapy or convert to everolimus with reduced-exposure CsA (HERAKLES, n = 497).
Results: There were no significant differences in the incidence of PTDM between treatment groups (log rank p = 0.97 [ZEUS], p = 0.90 [HERAKLES]). The mean change in random blood glucose from randomization to month 12 was also similar between treatment groups in both trials for patients with or without PTDM, and with or without pre-existing diabetes. The change in eGFR from randomization to month 12 showed a benefit for everolimus versus comparator groups in all subpopulations, but only reached significance in larger subgroups (no PTDM or no pre-existing diabetes).
Conclusions: Within the restrictions of this post hoc analysis, including non-standardized diagnostic criteria and limited glycemia laboratory parameters, these data do not indicate any difference in the incidence or severity of PTDM with early conversion from a CsA-based regimen to everolimus, or in the progression of pre-existing diabetes.
Trial registration: clinicaltrials.gov, NCT00154310 (registered September 2005) and NCT00514514 (registered August 2007); EudraCT (2006-007021-32 and 2004-004346-40).
Gout is the most common arthritic disease in human but was long neglected and therapeutic options are not satisfying. However, with the recent approval of the urate transporter inhibitor lesinurad, gout treatment has experienced a major innovation. Here we show that lesinurad possesses considerable modulatory potency on peroxisome proliferator-activated receptor γ (PPARγ). Since gout has a strong association with metabolic diseases such as type 2 diabetes, this side-activity appears as very valuable contributing factor to the clinical efficacy profile of lesinurad. Importantly, despite robustly activating PPARγ in vitro, lesinurad lacked adipogenic activity, which seems due to differential coactivator recruitment and is characterized as selective PPARγ modulator (sPPARγM).
Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis.
This study was designed to investigate whether epigenetic modulation by histone deacetylase (HDAC) inhibition might circumvent resistance towards the mechanistic target of rapamycin (mTOR) inhibitor temsirolimus in a prostate cancer cell model. Parental (par) and temsirolimus-resistant (res) PC3 prostate cancer cells were exposed to the HDAC inhibitor valproic acid (VPA), and tumor cell adhesion, chemotaxis, migration, and invasion were evaluated. Temsirolimus resistance was characterized by reduced binding of PC3res cells to endothelium, immobilized collagen, and fibronectin, but increased adhesion to laminin, as compared to the parental cells. Chemotaxis, migration, and invasion of PC3res cells were enhanced following temsirolimus re-treatment. Integrin α and β receptors were significantly altered in PC3res compared to PC3par cells. VPA significantly counteracted temsirolimus resistance by down-regulating tumor cell–matrix interaction, chemotaxis, and migration. Evaluation of integrin expression in the presence of VPA revealed a significant down-regulation of integrin α5 in PC3res cells. Blocking studies demonstrated a close association between α5 expression on PC3res and chemotaxis. In this in vitro model, temsirolimus resistance drove prostate cancer cells to become highly motile, while HDAC inhibition reversed the metastatic activity. The VPA-induced inhibition of metastatic activity was accompanied by a lowered integrin α5 surface level on the tumor cells.
Der vorliegende Beitrag setzt sich Zweifaches zum Ziel: erstens, Karl Dedecius' Weg zum renommierten Übersetzer der polnischen Lyrik in Deutschland sowie sein Konzept der Übersetzungskunst zu skizzieren, und daran anschließend – an zwei Gedichten von Wisława Szymborska in der Übersetzung von Dedecius ('Das erste Foto' und 'Katze in der leeren Wohnung') – aufzuzeigen, wie selbst eine große Meisterschaft an bestimmte Grenzen stößt, die dem Übertragen der Lyrik in eine andere Sprache innewohnen.
Wie keine andere kulturelle Handlung spiegelt das Tätowieren eine intentionale Ästhetisierung des menschlichen Körpers, zwischen individueller (und damit hoch-persönlicher) Schönheitsvorstellung auf der einen und öffentlicher (Selbst-)Inszenierung auf der anderen Seite schwankend. Die Haut wird dabei – quasi lebenslang beschrieben – zum Medium der Erinnerung. Zwar wurde bereits in der Antike 'tätowiert', der heutige Begriff sowie die 'Wiederentdeckung' dieser Praxis geht allerdings auf die Forschungs- und Entdeckungsreisen des 18. Jahrhunderts zurück, in denen Europäer mit fremden Kulturen in Kontakt kamen, die solche Verfahren mit einem ästhetischen oder rituellen Hintergrund praktizierten. So übernahm James Cook in seinen Aufzeichnungen den samoanischen Begriff "tatau", etymologisch die Grundlage für "to tattoo" und das deutsche "tätowieren". Inzwischen gilt die Modifikation des eigenen Körpers durch eine Tätowierung längst nicht mehr als 'verrucht' und stellt ebenso auch keine Ausnahmeerscheinung mehr dar, was sich vor allem an der explosionsartig gestiegenen Zahl von Tattoo-Studios in der Bundesrepublik ablesen lässt – und so trägt in Deutschland heute (konservativ geschätzt) etwa zehn Prozent der Gesamtbevölkerung und 23 Prozent der 16- bis 29-Jährigen mindestens ein Tattoo auf der Haut. Aber längst nicht jede Tätowierung ist auch der Ausdruck des eigenen Schönheitsempfindens oder eine vom Träger intentional auf dem Körper eingeschriebene Botschaft. Denn bereits in der griechischen Antike wurde das Verfahren auch dazu benutzt, Sklaven zu markieren, Besitzverhältnisse und damit ihre Unfreiheit auf der Haut einzuritzen; diese entpersonalisierende Markierung setzt sich mit der Häftlingstätowierung in Gefängnissen und schließlich den nationalsozialistischen Konzentrationslagern fort, die vor allem in literarischen Texten des Shoah-Diskures aufgegriffen und verhandelt wird.
Die Hauptquelle für die romantische Wiederentdeckung der Renaissance ist zweifellos Vasaris 'Vite', welche im Cinquecento, in der gottesgesegneten 'aetas aurea' (durch die Werke des Trifoliums Raffael-Leonardo-Michelangelo verkörpert) die vollbrachte "Rinascita delle arti" erreicht sah. Das Wort "Rinascimento" wird von Vasari nie verwendet, dafür aber synonymische Wörter wie "Rinascita", "Resurrezione" und "Risorgimento". 1795 hatte aber der von den Romantikern so hoch geschätzte Revolutionsmann Condorcet in seiner "Esquisse d’un tableau historique des progrès de l’esprit humain" (von Friedrich Schlegel prompt enthusiastisch rezensiert) die Renaissance reartikuliert – als vorletzte 'huitième époque' in jener langen Progression, die in die Französische Revolution münden sollte. Der in den frühromantischen Werken latente Bezug zwischen Renaissance und Revolution war den Romantikern wohl präsent, sodass F. Schlegels berühmtes Athenäums-Fragment, nach welchem die Französische Revolution, Fichtes Wissenschaftslehre und Goethes 'Meister' die drei großen Tendenzen des Zeitalters darstellen, durch eine vierte integriert werden könnte, die auf die Wiederentdeckung der Renaissance als wiedergewonnene "aetas aurea" hinweist.
Die deutschsprachige ästhetische und kulturtheoretisch-anthropologische Debatte des ausgehenden 18. Jahrhunderts thematisiert in unterschiedlichsten Kontexten immer wieder den Umgang mit Fremdheitserfahrung. Sie umfasst in diesem Zusammenhang unterschiedlichste theoretische Modelle der prekären Vermittlung zwischen gegensätzlichen Polen wie besonderer Einzelerfahrung und allgemeinem Erfahrungsganzem, zwischen Einzelphänomen und Kontext, zwischen Fragment und Totalität oder zwischen Singularität und Universalität. Entsprechende Fragestellungen rücken in der Zeit der Spätaufklärung vor allem mit Blick auf die Vermittlung (inter)kultureller Fremdheit in den Fokus des theoretischen und literarischen Interesses: Dies gilt vor allem für die Kulturpraxis inner- und außereuropäischer Reisen, die im Rahmen der zeitgenössischen 'Reisemode' zu Debatten über die Möglichkeit kosmopolitischen Weltbürgertums, über Modi interkultureller Begegnung oder die Legitimität kolonialer Expansion ebenso wie zur Entwicklung einer konkreten ethnopoetischen Reise- und Reisedarstellungspoetik Anlass gibt. Dieser philosophisch-theoretischen und literarischen Konjunktur von Reisediskursen korrespondieren gleichzeitig unterschiedliche Entwürfe einer transnationalen vergleichenden Kulturgeschichte, die immer wieder in kulturelle Hierarchisierungsmodelle münden, in denen europäischen Kulturen erwartungsgemäß eine wenn nicht qualitative oder normative, so doch immerhin strategische Überlegenheit zuerkannt wird. Hiermit verbinden sich drittens frühe Ansätze zur Theorie und Praxis 'weltliterarischer' Bildung sowie Appelle für eine grenzüberschreitende Beschäftigung mit literarischen und kulturellen Artefakten als Vorläufermodelle komparatistischer Literatur- und Kulturwissenschaft.
Im Jahr 1926 erschien in der 'Revista de Occidente', einer von José Ortega y Gasset in Madrid herausgegebenen Zeitschrift mit kulturpolitischer und philosophischer Ausrichtung, eine merkwürdige Publikation unter dem rätselhaften Titel "Cancionero apócrifo de Abel Martín. Recopilación y estudio de Juan de Mairena." Auf den ersten Blick scheint es so, als fungiere Antonio Machado hier lediglich als Herausgeber einer von Juan de Mairena kompilierten Sammlung, welche wiederum der Autorschaft eines Abel Martín zugeschrieben wird. Trotz der rätselhaften doppelten Herausgeberfiktion hatte das damalige Lesepublikum offenbar keine Probleme damit, Antonio Machado als den eigentlichen Autor der genannten "apokryphen" Prosa- und Gedichttexte zu identifizieren. Denn die Namen Juan de Mairena und Abel Martín bezeichnen nicht etwa reale Dichterpersönlichkeiten der damaligen Epoche oder der spanischen Literatur- geschichte, sondern sie sind – wie die damaligen Leser durch Ausschlussverfahren selbst erraten konnten – Konstrukte von Machados Phantasie, fiktive Autorprojektionen, deren Erfindung und Gestaltung er mit erstaunlichem gedanklichen Aufwand und Akribie betrieben hatte. Abel Martín und sein 'Schüler' Mairena gehören zu einem ganzen Spektrum von imaginierten Dichtern und Philosophen, deren fingierte Werke ihr Erfinder Machado als "apokryph" bezeichnete. Die bemerkenswerte Praktik, eigene Hervorbringungen, Lyrik und Prosa, nicht unter dem eigenen Namen zu publizieren, sondern einem Kreis fingierter Autorpersönlichkeiten zuzuordnen, hebt sich von dem gewöhnlichen Gebrauch von Pseudonymen, von künstlerischen Decknamen, deutlich ab. Zumal der Autor in jenem Zeitraum in den 1910er und 1920er Jahren keineswegs mehr ein Unbekannter war.
Der Begriff 'apokryph' taucht bei Johann Georg Hamann (1730-1788), dem 'Magus in Norden', seltener auf als man es vielleicht erwarten würde, jedenfalls so man Hamann noch immer nach dem gängigen Klischee für 'dunkel', einen 'Mystiker' oder einen 'Obskurantisten' oder gar für den Ursprung des modernen und spezifisch deutschen Irrationalismus und extremsten Feind der Aufklärung hält, gegenüber dessen "gewollter und künstlicher Dunkelheit", die er wie eine "Nebelwand um sich zog", sogar Hegels Phänomenologie des Geistes "eine wahre Ferienlektüre" sei. Ein schöpferischer Kopf also, "der manche tiefsinnigen Einfälle hatte, aber in welch geheimnisvolle Gewänder pflegte er sie zu verkleiden!" Entsprechend ist Hamanns Ruf: "Dunkelheit ist das traditionelle Prädicat, das jedem deutschen Primaner über ihn geläufig ist." Mit seiner Dunkelheit, so die unausgesprochene Annahme, möchte Hamann willentlich und wissentlich etwas verbergen, vielleicht nicht nur bei sich, sondern letztlich sogar das Licht der Aufklärung überhaupt; ein Umstand, der auf das Schönste zum griechischen apokryptein: 'verbergen, verdunkeln' (so die Übersetzung in Josef Nadlers Schlüssel zu Hamanns Werken) zu passen scheint. Entsprechend ist es, um eine weitere Bedeutung des Begriffes "apokryph" als des 'Gegen-Kanonischen' heranzuziehen, kaum verwunderlich, dass Texte Hamanns es nicht in den akademisch etablierten Kanon philosophischer Werke geschafft haben, ja sogar gegen entsprechende kanonische Texte (etwa die Metakritik über den Purismum der Vernunft gegen die Kritik der reinen Vernunft oder Golgatha und Scheblimini gegen Mendelssohns Jerusalem) gerichtet zu sein scheinen.
Diskursive Praktiken, insbesondere Texte, bewegen sich in einem kulturellen Feld, das in raumtheoretischer Metaphorisierung als von der Trias Zentrum- Peripherie-Außenraum konstituiertes chronotopisches Feld bezeichnet werden kann, mindestens bi-, wahrscheinlich multidirektional und in unterschiedlichen Geschwindigkeiten zwischen seinen beiden Polen verlaufend. Der in den Theologien etablierte Begriff des 'Apokryphen' ist demgegenüber kaum zufällig schon in seiner Semantik statisch und vermag nur die Situierung einer Schrift oder einer Wissenstradition 'im Verborgenen', nicht hingegen ihre Bewegung in Richtung dieses Bereichs, zu thematisieren. Dahinter steht bekanntlich das Anliegen einer Strukturierung epistemischer Bestände mit dem Ziel der Kanonisierung und Gewinnung von Autorität in der (im weitesten Sinne) gesellschaftlichen Kommunikation. Tatsächlich bildet das Konzept von kanonischer und apokrypher Literatur, nimmt man die Kategorie verbotener, indizierter Bücher im Sinne eines diskursiven Außenraums hinzu, auch die oben genannte Trias ab. Denn als 'Apokryphen' lassen sich dann Texte bezeichnen, die nicht kanonisch geworden sind, obwohl ihre inhaltlichen Potentiale das nicht a priori ausgeschlossen hätten. Apokryphe Texte stehen demnach in der diskursiven Peripherie. Grundsätzlich haben sie die Chance, zu einem ferneren Zeitpunkt kanonisch zu werden, sie könnten aber auch zu einer Existenz im Verbotenen verdammt werden.
Unter dem Terminus "Apokryphen" versteht man in der alttestamentlichen protestantischen Wissenschaft jene biblischen Bücher, die in der griechischen Übersetzung der Hebräischen Bibel, der sog. Septuaginta, bzw. der lateinischen Übersetzung, der Vulgata, zu finden sind, jedoch nicht im Kanon der Hebräischen Bibel. In der Septuaginta sind dies die vier Makkabäerbücher, das 3. Esrabuch, Jesus Sirach, die Weisheit Salomos, die Psalmen Salomos, Tobit, Judit, Baruch, der Brief Jeremias und Baruch sowie die Zusätze zu Daniel und zu Ester. Wie alt dieser Kanon ist und ob er bereits auf einen jüdischen Kanon zurückgeht, ist eine offene Frage der Forschung; in jedem Fall gehören diese Schriften der Septuaginta bis heute zum Kanon der Ostkirche. Im Westen dagegen setzte sich der etwas weniger umfangreiche Kanon der Vulgata durch, in dem das 3. und 4. Makkabäerbuch und das 3. Esrabuch fehlen. Da diese Texte nicht auf Hebräisch überliefert wurden und auch nicht Bestandteil der jüdischen Bibel sind, haben die Reformatoren, die unter dem Einfluss des Humanismus mit seinem Leitgedanken "ad Fontes", der Hinwendung zu den Quellen, standen, diese aus ihrem Kanon ausgeschieden.
Dem Apokryphen einen Themenschwerpunkt im Rahmen einer komparatistischen Zeitschrift zu widmen ist eine Entscheidung, die auf den ersten Blick erstaunen mag. Ist doch das Wort "apokryph" ein in der heutigen Alltagssprache wenig geläufiger Begriff, der, auf das Register der Theologie verweisend, speziellen Fragen und fachwissenschaftlichen Debatten der Religionsgeschichte vorbehalten zu sein scheint. Wenn wir gleichwohl Begriff und Phänomen des Apokryphen als Schwerpunktthema des Jahrbuchs 'Komparatistik' zur Diskussion stellen wollen, so deshalb, weil der damit angesprochene Sachverhalt von Prozessen der Auswahl, Marginalisierung und Ausgrenzung im Rahmen kultureller und textueller Überlieferung ein Problemfeld markiert, das im Bereich der Literaturgeschichte vielfältige Resonanzen und Parallelen findet und in systematischer Hinsicht über Verfahren und Mechanismen literarischer Traditionsbildung Aufschluss zu geben verspricht. Weit davon entfernt, nur ein spezialdiskursives Sonderphänomen zu sein, erweist sich das Apokryphe bei näherem Hinsehen als eine Figur, an der sich grundsätzliche Fragen der Formation von Text- und Wissensbeständen, der literarischen Autorität und Kanonbildung beobachten lassen. Apokryphe Texte, so ließe sich in einer vorläufigen, im Folgenden noch zu präzisierenden Beschreibung formulieren, sind Texte, die sich am Rande der großen Traditionen religiöser und kultureller Bewegungen situieren. Es sind Texte oder Textensembles, die es, wie sich im Rückblick bemerken lässt, nicht geschafft haben, in das Inventar jener Schriften aufgenommen zu werden, die als anerkannt, bewahrenswert oder wahr gelten. Als Einstieg bietet es sich an, zunächst von den Bedeutungsdimensionen des Ausdrucks apokryph auszugehen, die dieser im Kontext der religionsgeschichtlichen Tradition angenommen hat und der für das heute übliche Verständnis des Begriffs bestimmend ist. Der religiöse bzw. theologische Begriffsgebrauch greift auf das altgriechische Wort ἀπόκρυφος (apókryphos) zurück, um dieses vor allem in einer seiner beiden Bedeutungsschichten zum Einsatz zu bringen, nämlich als Bezeichnung eines Gegenstands bzw. Textes, der als 'unecht', 'zweifelhaft', 'nicht-authentisch' zu gelten habe. Der Begriff apokryph führt hier also eine Unterscheidung ein zwischen dem, was als gesichert, gültig und autorisiert anzusehen ist und dem, was solche Geltung zu besitzen nicht oder nur unter dem Vorbehalt des Zweifelhaften beanspruchen kann. Bei dem Begriffspaar gültig vs. apokryph haben wir es also mit einer Figur der Verknappung zu tun, die ein gegebenes Textensemble oder eine kulturelle Überlieferung einem mitunter radikalen Verfahren der Auswahl und Reduktion unterzieht.
Kaum eine geistes- und kulturwissenschaftliche Disziplin hat in Italien in solchem Ausmaß unter Selbstdarstellungs- und Rechtfertigungszwang gestanden und sich über so heftige Widerstände hinwegsetzen müssen wie die Komparatistik. Ein Leserbrief des Literaturwissenschaftlers Armando Gnisci, der in den 1980er- und 1990er-Jahren die Szene der italienischen Komparatistik wesentlich geprägt, aber nur marginal bis ins neue Jahrtausend mitbestimmen konnte, gibt einen konzis-kritischen – wenn auch leicht polemischen – Einblick in das, was seit dem letzten state of the art aus dem Jahre 1991 auf dem Gebiet der Allgemeinen und Vergleichenden Literaturwissenschaft in Italien passiert ist. Entlang dieser Linie verlief nämlich die wichtigste Front im Streit zwischen den Nationalphilologen und den Komparatisten. Gniscis Schreiben mit dem programmatischen wie suggestiven Titel "Comparatisti e italianisti, le due tribù" [Komparatisten und Italianisten, die beiden Stämme] – erschienen am 21. März 2004 in der Kulturbeilage Domenica – ist ein Rundumschlag gegen die seinerzeit in Italien weitverbreitete Ansicht, die Allgemeine und Vergleichende Literaturwissenschaft als "sub-category of Italian literature departments" zu betrachten.
Nachruf auf John Neubauer
(2017)
Am 5. Oktober 2015 ist in Amsterdam der Germanist und Komparatist John Neubauer verstorben, an einer erst kurz zuvor diagnostizierten und tapfer ertragenen schweren Krankheit, im Kreise seiner Angehörigen und im Alter von nicht ganz zweiundachtzig Jahren. Unser Fach verliert in ihm einen hervorragenden Vertreter, und alle, die ihn kannten, verlieren einen hochsympathischen und inspirierenden Mitmenschen.
In order to elucidate the causes for the increased mortality of aged patients with bacterial central nervous system (CNS) infections, we compared the course of Streptococcus pneumoniae (S. pneumoniae) meningitis in aged and young mice. Aged (21.2 ± 3.1 months, n = 40) and young (3.2 ± 0.9 months, n = 42) C57BL/6N and B6/SJL mice were infected by intracerebral injection of 50–70 CFU S. pneumoniae serotype 3 and monitored for 15 days. Aged and young mice did not differ concerning mortality (35% versus 38%), weight loss, development of clinical symptoms, bacterial concentrations in cerebellum and spleen as well as the number of leukocytes infiltrating the CNS. In contrast to results from our geriatric mouse model of Escherichia coli (E. coli) meningitis, where aged mice showed a higher mortality and an impaired elimination of bacteria, we did not find any differences between aged and young mice after intracerebral infection with S. pneumoniae serotype 3. This indicates that the increased susceptibility of aged mice to bacterial CNS infections is pathogen-specific: It appears less prominent in infections caused by hardly phagocytable pathogens with thick capsules like S. pneumoniae serotype 3, where the age-related decline of the phagocytic capacity of microglia and macrophages has a minor influence on the disease course.
Cyclin-dependent kinase (CDK) 4/6 inhibitors have shown great results in numerous clinical trials and have improved the clinical outcome for patients with hormone-receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer significantly. To date, three CDK4/6 inhibitors are approved by the US Food and Drug Administration (FDA): palbociclib, ribociclib and abemaciclib; the first two compounds are aproved by the European Medicines Agency (EMA) as well. In combination with endocrine therapy, all of them led to significantly improved progression-free survival compared with endocrine therapy alone. The aim of this article is to give an overview of the efficacy data and to describe the CDK4/6 inhibitor-based treatment-associated adverse events, including hematological and nonhematological adverse events. In addition, it describes the corrrect approach to patient monitoring and adverse event mangement and summarizes the current recommendations for dose reductions and dose interruptions regarding the key adverse events, such as neutropenia, diarrhea, QTc prolongation and hepatobiliary toxicity. Accurate patient monitoring and management of the side effects is crucial, as several clinical trials in early breast cancer are in progress and may lead to an additional approval in the neo-/adjuvant setting.
Aim: To evaluate protective immunosuppressive dose and time-dependent effects of ethanol in an in vitro model of acute inflammation in human Chang liver cells.
Method: The study was performed in 2016 and 2017 in the research laboratory of the Department of Trauma, Hand and Reconstructive Surgery, the University Hospital of the Goethe-University Frankfurt. Chang liver cells were stimu - lated with either interleukin (IL)-1β or IL-6 and subsequent - ly treated with low-dose ethanol (85 mmol/L) or high-dose ethanol (170 mmol/L) for one hour (acute exposure) or 72 hours (subacute exposure). IL-6 and IL-1β release were de - termined by enzyme-linked immunosorbent assay. Neu - trophil adhesion to Chang liver monolayers, production of reactive oxygen species, and apoptosis or necrosis were analyzed.
Results: Contrary to high-dose ethanol, acute low-dose ethanol exposure significantly reduced IL-1β-induced IL-6 and IL-6-induced IL-1β release ( P <0.05). Subacute etha - nol exposure did not change proinflammatory cytokine release. Acute low-dose ethanol exposure significantly decreased inflammation-induced formation of reactive oxygen species ( P <0.05) and significantly improved cell survival ( P <0.05). Neither acute nor subacute high-dose ethanol exposure significantly changed inflammationinduced changes in reactive oxygen species or survival. Acute and subacute ethanol exposure, independently of the dose, significantly decreased neutrophil adhesion to inflamed Chang liver cells ( P <0.05).
Conclusion: Acute treatment of inflamed Chang liver cells with ethanol showed its immunosuppressive potential. However, the observed effects were limited to low-dose setting, indicating the relevance of ethanol dose in the modulation of inflammatory cell response.
The field of dynamic nuclear polarization has undergone tremendous developments and diversification since its inception more than 6 decades ago. In this review we provide an in-depth overview of the relevant topics involved in DNP-enhanced MAS NMR spectroscopy. This includes the theoretical description of DNP mechanisms as well as of the polarization transfer pathways that can lead to a uniform or selective spreading of polarization between nuclear spins. Furthermore, we cover historical and state-of-the art aspects of dedicated instrumentation, polarizing agents, and optimization techniques for efficient MAS DNP. Finally, we present an extensive overview on applications in the fields of structural biology and materials science, which underlines that MAS DNP has moved far beyond the proof-of-concept stage and has become an important tool for research in these fields.
The electron transferring flavoprotein/butyryl-CoA dehydrogenase (EtfAB/Bcd) catalyzes the reduction of one crotonyl-CoA and two ferredoxins by two NADH within a flavin-based electron-bifurcating process. Here we report on the X-ray structure of the Clostridium difficile (EtfAB/Bcd)4 complex in the dehydrogenase-conducting D-state, α-FAD (bound to domain II of EtfA) and δ-FAD (bound to Bcd) being 8 Å apart. Superimposing Acidaminococcus fermentans EtfAB onto C. difficile EtfAB/Bcd reveals a rotation of domain II of nearly 80°. Further rotation by 10° brings EtfAB into the bifurcating B-state, α-FAD and β-FAD (bound to EtfB) being 14 Å apart. This dual binding mode of domain II, substantiated by mutational studies, resembles findings in non-bifurcating EtfAB/acyl-CoA dehydrogenase complexes. In our proposed mechanism, NADH reduces β-FAD, which bifurcates. One electron goes to ferredoxin and one to α-FAD, which swings over to reduce δ-FAD to the semiquinone. Repetition affords a second reduced ferredoxin and δ-FADH−, which reduces crotonyl-CoA.
Ribosome recycling orchestrated by ABCE1 is a fundamental process in protein translation and mRNA surveillance, connecting termination with initiation. Beyond the plenitude of well-studied translational GTPases, ABCE1 is the only essential factor energized by ATP, delivering the energy for ribosome splitting via two nucleotide-binding sites by a yet unknown mechanism. Here, we define how allosterically coupled ATP binding and hydrolysis events in ABCE1 empower ribosome recycling. ATP occlusion in the low-turnover control site II promotes formation of the pre-splitting complex and facilitates ATP engagement in the high-turnover site I, which in turn drives the structural reorganization required for ribosome splitting. ATP hydrolysis and ensuing release of ABCE1 from the small subunit terminate the post-splitting complex. Thus, ABCE1 runs through an allosterically coupled cycle of closure and opening at both sites, consistent with a processive clamp model. This study delineates the inner mechanics of ABCE1 and reveals why various ABCE1 mutants lead to defects in cell homeostasis, growth, and differentiation.
Background: No observational studies have evaluated the "real-world" effectiveness of dual bronchodilation comprising a long-acting β2-agonist plus a long-acting muscarinic antagonist vs that of triple therapy (long-acting β2-agonist plus long-acting muscarinic antagonist plus inhaled corticosteroid) in COPD.
Materials and methods: DACCORD is a non-interventional, observational clinical study that recruited patients following COPD maintenance therapy initiation or change in maintenance therapy between or within therapeutic class. Given the non-interventional nature of the study, the decision to initiate or change medication had to be made by the patients’ physicians prior to inclusion in DACCORD. We used a matched-pairs analysis to compare disease progression in two patient groups: those receiving dual bronchodilation vs those receiving triple therapy (each group n=1,046).
Results: In two subgroups of patients matched according to a broad range of demographic and disease characteristics, over 1 year, fewer patients receiving dual bronchodilation exacerbated than those receiving triple therapy (15.5% vs 26.6%; P<0.001), with a greater improvement from baseline in COPD Assessment Test total score at 1 year (mean±SD -2.9±5.8 vs -1.4±5.5; P<0.001). When analyzed according to prior therapy, the highest rate of exacerbations was in patients on triple therapy prior to the study who remained on triple therapy. Those changing from mono-bronchodilator to dual bronchodilation had the greatest COPD Assessment Test total score improvement.
Conclusion: In this "real-life" cohort of patients with COPD, most of whom had not exacerbated in the 6 months prior to entry, triple therapy did not seem to improve outcomes compared with dual bronchodilation in terms of either exacerbations or health status. Our analyses clearly demonstrate the potential impact of prior medication on study results, something that should be taken into account when interpreting the results even of controlled clinical trials.
Arachidonate 15-lipoxygenase (ALOX15) and arachidonate 15-lipoxygenase, type B (ALOX15B) catalyze the dioxygenation of polyunsaturated fatty acids and are upregulated in human alternatively activated macrophages (AAMs) induced by Th2 cytokine interleukin-4 (IL-4) and/or interleukin-13. Known primarily for roles in bioactive lipid mediator synthesis, 15-lipoxygenases (15-LOXs) have been implicated in various macrophage functions including efferocytosis and ferroptosis. Using a combination of inhibitors and siRNAs to suppress 15-LOX isoforms, we studied the role of 15-LOXs in cellular cholesterol homeostasis and immune function in naïve and AAMs. Silencing or inhibiting the 15-LOX isoforms impaired sterol regulatory element binding protein (SREBP)-2 signaling by inhibiting SREBP-2 processing into mature transcription factor and reduced SREBP-2 binding to sterol regulatory elements and subsequent target gene expression. Silencing ALOX15B reduced cellular cholesterol and the cholesterol intermediates desmosterol, lanosterol, 24,25-dihydrolanosterol, and lathosterol as well as oxysterols in IL-4-stimulated macrophages. In addition, attenuating both 15-LOX isoforms did not generally affect IL-4 gene expression but rather uniquely impacted IL-4-induced CCL17 production in an SREBP-2-dependent manner resulting in reduced T cell migration to macrophage conditioned media. In conclusion, we identified a novel role for ALOX15B, and to a lesser extent ALOX15, in cholesterol homeostasis and CCL17 production in human macrophages.
In contrast to several smaller studies, which demonstrate that remote ischemic preconditioning (RIPC) reduces myocardial injury in patients that undergo cardiovascular surgery, the RIPHeart study failed to demonstrate beneficial effects of troponin release and clinical outcome in propofol-anesthetized cardiac surgery patients. Therefore, we addressed the potential biochemical mechanisms triggered by RIPC. This is a predefined prospective sub-analysis of the randomized and controlled RIPHeart study in cardiac surgery patients (n = 40) that was recently published. Blood samples were drawn from patients prior to surgery, after RIPC of four cycles of 5 min arm ischemia/5 min reperfusion (n = 19) and the sham (n = 21) procedure, after connection to cardiopulmonary bypass (CPB), at the end of surgery, 24 h postoperatively, and 48 h postoperatively for the measurement of troponin T, macrophage migration inhibitory factor (MIF), stromal cell-derived factor 1 (CXCL12), IL-6, CXCL8, and IL-10. After RIPC, right atrial tissue samples were taken for the measurement of extracellular-signal regulated kinase (ERK1/2), protein kinase B (AKT), Glycogen synthase kinase 3 (GSK-3β), protein kinase C (PKCε), and MIF content. RIPC did not significantly reduce the troponin release when compared with the sham procedure. MIF serum levels intraoperatively increased, peaking at intensive care unit (ICU) admission (with an increase of 48.04%, p = 0.164 in RIPC; and 69.64%, p = 0.023 over the baseline in the sham procedure), and decreased back to the baseline 24 h after surgery, with no differences between the groups. In the right atrial tissue, MIF content decreased after RIPC (1.040 ± 1.032 Arbitrary units [au] in RIPC vs. 2.028 ± 1.631 [au] in the sham procedure, p < 0.05). CXCL12 serum levels increased significantly over the baseline at the end of surgery, with no differences between the groups. ERK1/2, AKT, GSK-3β, and PKCɛ phosphorylation in the right atrial samples were no different between the groups. No difference was found in IL-6, CXCL8, and IL10 serum levels between the groups. In this cohort of cardiac surgery patients that received propofol anesthesia, we could not show a release of potential mediators of signaling, nor an effect on the inflammatory response, nor an activation of well-established protein kinases after RIPC. Based on these data, we cannot exclude that confounding factors, such as propofol, may have interfered with RIPC.
Purpose: There is some controversy whether or not saccades change with age. This cross-sectional study aims to clarify the characteristics of reflexive saccades at various ages to establish a normative cohort in a standardized set-up. Second objective is to investigate the feasibility of saccadometry in daily ophthalmological practice.
Methods: One hundred healthy participants aged between 6 and 76 years underwent an ophthalmologic examination and saccadometry, using an infrared video-oculography device, sampling at 220 Hz. The reflexive saccades were evoked in four directions and three target displacements each (5°/15°/30° horizontally and of 5°/10°/20° vertically). Saccadic peak velocity, gain (amplitude/target displacement) and latency were measured.
Results: Mean peak velocity of saccades was 213°/s (± 29°/s), 352°/s (± 50°/s) and 455°/s (± 67°/s) to a target position 5°, 15°and 30° horizontally, respectively, and 208°/s (± 36°/s), 303°/s (± 50°/s) and 391°/s (± 71°/s) to a target position 5°, 10° and 20° vertically. The association between peak velocity and eccentricity proved to be present at any age in all four directions. We found no relevant effect of age on peak velocity, gain and latency in a fitted linear mixed model. However, latency becomes shorter during childhood and adolescence, while in adulthood it is relatively stable with a slight trend to increase in the elderly. Saccades are more precise when the target displacement is small. Isometric saccades are most common, followed by hypometric ones. All children and elderly were able to perform good quality saccadometry in a recording time of approximately 10 minutes.
Conclusion: The presented data may serve as normative control for further studies using such a video-oculography device for saccadometry. The means of peak velocity and the gain can be used independently from age respecting the target displacement. Latency is susceptible to age.
Background: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.
Methods: In a systematic review of OVID MEDLINE—with additional hand-searching of relevant studies' bibliographies— from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5–24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.
Findings: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56–76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36–0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46–11·60; p<0·0001), antiplatelet use (1·68, 1·06–2·66; p=0·026), and anticoagulant use (3·48, 1·96–6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75–0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95–6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03–0·07).
Interpretation: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials.
Funding: UK Medical Research Council and British Heart Foundation.
Asia and its Hindu Kush Himalayan (HKH) region is particularly vulnerable to environmental change, especially climate and land use changes further influenced by rapid population growth, high level of poverty and unsustainable development. Asia has been a hotspot of dengue fever and chikungunya mainly due to its dense human population, unplanned urbanization and poverty. In an urban cycle, dengue virus (DENV) and chikungunya virus (CHIKV) are transmitted by Aedes aegypti and Ae. albopictus mosquitoes which are also competent vectors of Zika virus (ZIKV). Over the last decade, DENV and CHIKV transmissions by Ae. aegypti have extended to the Himalayan countries of Bhutan and Nepal and ZIKV could follow in the footsteps of these viruses in the HKH region. The already established distribution of human-biting Aedes mosquito vectors and a naïve population with lack of immunity against ZIKV places the HKH region at a higher risk of ZIKV. Some of the countries in the HKH region have already reported ZIKV cases. We have documented an increasing threat of ZIKV in Asia and its HKH region because of the high abundance and wide distribution of human-biting mosquito vectors, climate change, poverty, report of indigenous cases in the region, increasing numbers of imported cases and a naïve population with lack of immunity against ZIKV. An outbreak anywhere is potentially a threat everywhere. Therefore, in order to ensure international health security, all efforts to prevent, detect, and respond to ZIKV ought to be intensified now in Asia and its HKH region. To prepare for possible ZIKV outbreaks, Asia and the HKH region can also learn from the success stories and strategies adopted by other regions and countries in preventing ZIKV and associated complications. The future control strategies for DENV, CHIKV and ZIKV should be considered in tandem with the threat to human well-being that is posed by other emerging and re-emerging vector-borne and zoonotic diseases, and by the continuing urgent need to strengthen public primary healthcare systems in the region.
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Pediatric patients with disease refractory to last chemotherapy, relapse after allogeneic hematopoietic stem-cell transplantation (alloHSCT), or second or further relapse have a particularly poor prognosis. Intensive chemotherapy followed by alloHSCT after achieving remission can result in cure for some patients. However, survival is still low with this approach. Thus, additional treatment modalities with acceptable toxicity are needed to improve long-term survival. ...
Background: To study the expression pattern, localisation and potential clinical significance of aquaporin water channels (AQP) both in prostate cancer (PC) cell lines and in benign and malignant human prostate tissue.
Methods: The AQP transcript and protein expression of HPrEC, LNCaP, DU-145 and PC3 cell lines was investigated using reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence (IF) microscopy labelling. Immunohistochemistry (IHC) was performed to assess AQP protein expression in surgical specimens of benign prostatic hyperplasia as well as in PC. Tissue mRNA expression of AQPs was quantified by single-step reverse transcriptase quantitative polymerase chain reaction (qPCR). Relative gene expression was determined using the 40-ΔCT method and correlated to clinicopathological parameters.
Results: Transcripts of AQP 1, 3, 4, 7, 8, 10 and 11 were expressed in all four cell lines, while AQP 9 transcripts were not detected in malignant cell lines. IF microscopy confirmed AQP 3, 4, 5, 7 and 9 protein expression. IHC revealed highly heterogeneous AQP 3 protein expression in PC specimens, with a marked decrease in expression in tumours of increasing malignancy. Loss of AQP 9 was shown in PC specimens. mRNA expression of AQP3 was found to be negatively correlated to PSA levels (ρ = − 0.354; p = 0.013), D’Amico risk stratification (ρ = − 0.336; p = 0.012), ISUP grade (ρ = − 0.321; p = 0.017) and Gleason score (ρ = − 0.342; p = 0.011).
Conclusions: This is the first study to systematically characterize human prostate cell lines, benign prostatic hyperplasia and PC in relation to all 13 members of the AQP family. Our results indicate the differential expression of several AQPs in benign and malignant prostate tissue. A significant correlation was observed between AQP 3 expression and tumour grade, with progressive loss in more malignant tumours. Taken together, AQPs may play a role in the progression of PC and AQP expression patterns may serve as a prognostic marker.
Background: With the aging population and a rising incidence of squamous cell carcinoma of the head and neck (SCCHN), there is an emerging need for developing strategies to treat elderly patients.
Patients and Methods: We retrospectively analyzed 158 patients treated with definitive, concurrent chemoradiotherapy (CRT) for SCCHN. Clinicopathological characteristics, acute toxicities, and oncological outcomes were compared between patients younger and older than (or of age equal to) 65, 70, and 75 years.
Results: RT dose, chemotherapy regimen, and total chemotherapy dose were balanced between the groups. After a median follow-up of 29 months, overall survival (OS), progression-free survival (PFS), local control rate, and distant metastasis-free survival stratified by age of ≥65, ≥70, or ≥75 years revealed no differences. The rate of acute toxicities was also not higher for older patients. Worse ECOG performance score (ECOG 2-3) was associated with impaired OS () and PFS ().
Conclusion: Definitive treatment with CRT for SCCHN is feasible and effective; even in advanced age treatment decisions should be made according to general condition and comorbidity, rather than calendar age alone.
This review provides an overview on components of the sphingolipid superfamily, on their localization and metabolism. Information about the sphingolipid biological activity in cell physiopathology is given. Recent studies highlight the role of sphingolipids in inflammatory process. We summarize the emerging data that support the different roles of the sphingolipid members in specific phases of inflammation: (1) migration of immune cells, (2) recognition of exogenous agents, and (3) activation/differentiation of immune cells.
Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity of symptoms a reliable diagnosis is often difficult to make. Here, we report a genome-wide association study on food allergy diagnosed by oral food challenge in 497 cases and 2387 controls. We identify five loci at genome-wide significance, the clade B serpin (SERPINB) gene cluster at 18q21.3, the cytokine gene cluster at 5q31.1, the filaggrin gene, the C11orf30/LRRC32 locus, and the human leukocyte antigen (HLA) region. Stratifying the results for the causative food demonstrates that association of the HLA locus is peanut allergy-specific whereas the other four loci increase the risk for any food allergy. Variants in the SERPINB gene cluster are associated with SERPINB10 expression in leukocytes. Moreover, SERPINB genes are highly expressed in the esophagus. All identified loci are involved in immunological regulation or epithelial barrier function, emphasizing the role of both mechanisms in food allergy.
The vacuolar-type H+-ATPase (v-ATPase) is the major proton pump that acidifies intracellular compartments of eukaryotic cells. Since the inhibition of v-ATPase resulted in anti-tumor and anti-metastatic effects in different tumor models, this enzyme has emerged as promising strategy against cancer. Here, we used the well-established v-ATPase inhibitor archazolid, a natural product first isolated from the myxobacterium Archangium gephyra, to study the consequences of v-ATPase inhibition in endothelial cells (ECs), in particular on the interaction between ECs and cancer cells, which has been neglected so far. Human endothelial cells treated with archazolid showed an increased adhesion of tumor cells, whereas the transendothelial migration of tumor cells was reduced. The adhesion process was independent from the EC adhesion molecules ICAM-1, VCAM-1, E-selectin and N-cadherin. Instead, the adhesion was mediated by β1-integrins expressed on tumor cells, as blocking of the integrin β1 subunit reversed this process. Tumor cells preferentially adhered to the β1-integrin ligand collagen and archazolid led to an increase in the amount of collagen on the surface of ECs. The accumulation of collagen was accompanied by a strong decrease of the expression and activity of the protease cathepsin B. Overexpression of cathepsin B in ECs prevented the capability of archazolid to increase the adhesion of tumor cells onto ECs. Our study demonstrates that the inhibition of v-ATPase by archazolid induces a pro-adhesive phenotype in endothelial cells that promotes their interaction with cancer cells, whereas the transmigration of tumor cells was reduced. These findings further support archazolid as a promising anti-metastatic compound.
Purpose: The aim of the study was to compare three different elastography methods, namely Strain Elastography (SE), Point Shear-Wave Elastography (pSWE) using Acoustic Radiation Force Impulse (ARFI)-Imaging and 2D-Shear Wave Elastography (2D-SWE), in the same study population for the differentiation of thyroid nodules.
Materials and methods: All patients received a conventional ultrasound scan, SE and 2D-SWE, and all patients except for two received ARFI-Imaging. Cytology/histology of thyroid nodules was used as a reference method. SE measures the relative stiffness within the region of interest (ROI) using the surrounding tissue as reference tissue. ARFI mechanically excites the tissue at the ROI using acoustic pulses to generate localized tissue displacements. 2D-SWE measures tissue elasticity using the velocity of many shear waves as they propagate through the tissue.
Results: 84 nodules (73 benign and 11 malignant) in 62 patients were analyzed. Sensitivity, specificity and NPV of SE were 73%, 70% and 94%, respectively. Sensitivity, specificity and NPV of ARFI and 2D-SWE were 90%, 79%, 98% and 73%, 67%, 94% respectively, using a cut-off value of 1.98m/s for ARFI and 2.65m/s (21.07kPa) for 2D-SWE. The AUROC (Area under the Receiver Operating Characteristic) of SE, ARFI and 2D-SWE for the diagnosis of malignant thyroid nodules were 52%, 86% and 71%, respectively. A significant difference in AUROC was found between SE and ARFI (p = 0.008), while no significant difference was found between ARFI and SWE (86% vs. 71%, p = 0.31), or SWE and SE (71% vs. 52%, p = 0.26).
Conclusion: pSWE using ARFI and 2D-SWE showed comparable results for the differentiation of thyroid nodules. ARFI was superior to elastography using SE.
Background: Caloric restriction is associated with broad therapeutic potential in various diseases and an increase in health and life span. In this study, we assessed the impact of caloric restriction on acute and inflammatory nociception in mice, which were either fed ad libitum or subjected to caloric restriction with 80% of the daily average for two weeks.
Results: The behavioral tests revealed that inflammatory nociception in the formalin test and in zymosan-induced mechanical hypersensitivity were significantly decreased when mice underwent caloric restriction. As potential mediators of the diet-induced antinociception, we assessed genes typically induced by inflammatory stimuli, AMP-activated kinase, and the endocannabinoid system which have all already been associated with nociceptive responses. Zymosan-induced inflammatory markers such as COX-2, TNFα, IL-1β, and c-fos in the spinal cord were not altered by caloric restriction. In contrast, AMPKα2 knock-out mice showed significant differences in comparison to C57BL/6 mice and their respective wild type littermates by missing the antinociceptive effects after caloric restriction. Endocannabinoid levels of anandamide and 2-arachidonyl glyceroldetermined in serum by LC-MS/MS were not affected by either caloric restriction alone or in combination with zymosan treatment. However, cannabinoid receptor type 1 expression in the spinal cord, which was not altered by caloric restriction in control mice, was significantly increased after caloric restriction in zymosan-induced paw inflammation. Since increased cannabinoid receptor type 1 signaling might influence AMP-activated kinase activity, we analyzed effects of anandamide on AMP-activated kinase in cell culture and observed a significant activation of AMP-activated kinase. Thus, endocannabionoid-induced AMP-activated kinase activation might be involved in antinociceptive effects after caloric restriction.
Conclusion: Our data suggest that caloric restriction has an impact on inflammatory nociception which might involve AMP-activated kinase activation and an increased activity of the endogenous endocannabinoid system by caloric restriction-induced cannabinoid receptor type 1 upregulation.
Zielsetzung: Beteiligung von Medizinstudierenden im Rahmen der konzeptionellen Entwicklung eines zielgruppenspezifischen und attraktiven allgemeinmedizinischen Lehrangebots im ländlichen Raum.
Methodik: Es wurde ein Fragebogen entwickelt, der die Bewertung der Studierenden hinsichtlich des aktuellen Ablaufs ihres Studiums, den späteren Berufswunsch sowie die Anforderungen an ein zu entwickelndes allgemeinmedizinisches Schwerpunktprogramm im ländlichen Raum erfasst. Mittels einer Online-Befragung wurden im Sommer 2015 alle Medizinstudierende ab dem vierten vorklinischen Semester (n=2.150) der Goethe-Universität Frankfurt einmalig befragt. Die statistische Auswertung erfolgte primär deskriptiv. Die persönliche Einstellung hinsichtlich der Bereitschaft, als Hausarzt tätig zu werden, wurde auf statistische Signifikanz überprüft. Zudem wurde erhoben, ob ein messbarer Zusammenhang zwischen der eigenen Herkunft und dem späteren Wunscharbeitsort besteht.
Ergebnisse: Von insgesamt 2.150 kontaktierten Studierenden nahmen 617 an der Befragung teil (Rücklaufquote=28,7%). Die Ergebnisse repräsentieren eine große Bandbreite an Ideen und Anregungen, die sowohl die Meinung von Befürwortern als auch eher kritisch gegenüber der Lehre in der Allgemeinmedizin eingestellten Medizinstudierenden widerspiegeln. Von dem geplanten Schwerpunktprogramm erwarten die Studierenden einen starken Praxisbezug ebenso wie das Kennenlernen administrativer sowie wirtschaftlicher Hintergründe zum Führen einer Praxis.
Schlussfolgerungen: Durch die Einbeziehung der Zielgruppe am Entwicklungsprozess bestand die Möglichkeit, das zu entwickelnde Schwerpunktprogramm auf die späteren Teilnehmer passgenauer zuzuschneiden. Zudem ist zu erwarten, dass die Beteiligung der Studierenden zu einer höheren Akzeptanz des Programms führt. Die gewonnenen Ergebnisse zur Gestaltung eines Lehrangebots können als Orientierung für die mögliche Entwicklung ähnlicher Schwerpunktprogramme an anderen medizinischen Fakultäten dienen.
Aim: Participation of medical students in the conceptual development of targeted and attractive teaching content for rural areas.
Method: A questionnaire was developed to gather information on students' views of their current medical studies, career interests, and what requirements should be met by an optional rural health program in general practice. By means of an online survey in summer 2015, all medical students from the fourth preclinical semester onwards (n=2,150) at Goethe University Frankfurt were surveyed on one occasion. Statistical analysis was mainly descriptive. Personal attitudes towards a career as a family practitioner were examined for statistical significance. Further information was gathered on whether a measurable correlation exists between personal background and desired work location.
Results: Of the 2,150 students that were contacted, 617 participated in the survey (response rate=28.7%). The results covered a wide range of ideas and recommendations and were representative both of medical students with a positive attitude toward general practice, as well as those that were rather critical of teaching in general practice. The students expected the planned health program to be of strong practical relevance and to acquaint them with the administrative and economic aspects of running a practice.
Conclusions: By including the target group in the development process, it was possible to tailor the health program to meet the needs of future participants more precisely. Student participation can also be expected to result in greater acceptance of the program. The results on teaching content may also provide other medical faculties with orientation when developing comparable programs.
Ribosome biogenesis is essential for cellular function and involves rRNA synthesis, rRNA processing and modification, and ribosomal protein assembly. Ribosome biogenesis factors and small nucleolar RNA assist these events. Ribosomal maturation takes place in the nucleolus, the nucleoplasm, and the cytosol in a coordinated and controlled manner. For example, some ribosomal proteins are thought to be assembled in the cytoplasm based on the observations in Saccharomyces cerevisiae. Here, we used cellular fractionation to demonstrate that cleavage of the 20S intermediate, the precursor to mature 18S rRNA, does not occur in the nucleoplasm of Arabidopsis thaliana. It most likely occurs in the cytoplasm. Further, we verified the proposed localization of RPS10e, RPS26e, and RPL24a/b in the nucleus and RPP1 in the nucleolus of A. thaliana by ribosome profiling, immunofluorescence, and analysis of the localization of GFP fusion proteins. Our results suggest that the order of events during ribosomal protein assembly in the ribosome biogenesis pathway differs between plants and yeast.
Hydrogenation of CO₂ at ambient pressure catalyzed by a highly active thermostable biocatalyst
(2018)
Background: Replacing fossil fuels as energy carrier requires alternatives that combine sustainable production, high volumetric energy density, easy and fast refueling for mobile applications, and preferably low risk of hazard. Molecular hydrogen (H2) has been considered as promising alternative; however, practical application is struggling because of the low volumetric energy density and the explosion hazard when stored in large amounts. One way to overcome these limitations is the transient conversion of H2 into other chemicals with increased volumetric energy density and lower risk hazard, for example so-called liquid organic hydrogen carriers such as formic acid/formate that is obtained by hydrogenation of CO2. Many homogenous and heterogenous chemical catalysts have been described in the past years, however, often requiring high pressures and temperatures. Recently, the first biocatalyst for this reaction has been described opening the route to a biotechnological alternative for this conversion.
Results: The hydrogen-dependent CO2 reductase (HDCR) is a highly active biocatalyst for storing H2 in the form of formic acid/formate by reversibly catalyzing the hydrogenation of CO2. We report the identification, isolation, and characterization of the first thermostable HDCR operating at temperatures up to 70 °C. The enzyme was isolated from the thermophilic acetogenic bacterium Thermoanaerobacter kivui and displays exceptionally high activities in both reaction directions, substantially exceeding known chemical catalysts. CO2 hydrogenation is catalyzed at mild conditions with a turnover frequency of 9,556,000 h−1 (specific activity of 900 µmol formate min−1 mg−1) and the reverse reaction, H2 + CO2 release from formate, is catalyzed with a turnover frequency of 9,892,000 h−1 (930 µmol H2 min−1 mg−1). The HDCR of T. kivui consists of a [FeFe] hydrogenase subunit putatively coupled to a tungsten-dependent CO2 reductase/formate dehydrogenase subunit by an array of iron–sulfur clusters.
Conclusions: The discovery of the first thermostable HDCR provides a promising biological alternative for a chemically challenging reaction and might serve as model for the better understanding of catalysts able to efficiently reduce CO2. The catalytic activity for reversible CO2 hydrogenation of this enzyme is the highest activity known for bio- and chemical catalysts and requiring only ambient temperatures and pressures. The thermostability provides more flexibility regarding the process parameters for a biotechnological application.
Patients after orthopic liver transplantation (OLT) are at risk of developing graft dysfunction. Sphingolipids (SL’s) have been identified to play a pivotal role in the regulation of hepatocellular apoptosis, inflammation and immunity. We aimed to investigate the serum SL profile in a prospective real-world cohort of post-OLT patients. From October 2015 until July 2016, 149 well-characterized post-OLT patients were analyzed. SL’s were assessed in serum probes via Liquid Chromatography/Tandem Mass Spectrometry. Twenty-nine (20%) patients had a biopsy proven graft rejection with decreased C20-ceramide (Cer) (p = 0.042), C18-dihydroceramide (DHC) (p = 0.022) and C24DHC (p = 0.060) levels. Furthermore, C18DHC (p = 0.044) and C24DHC (p = 0.011) were significantly down-regulated in patients with ischemic type biliary lesions (ITBL; n = 15; 10%). One-hundred and thirty-three patients (89%) have so far received tacrolimus as the main immunosuppressive agent with observed elevations of C14Cer (p = 0.052), C18Cer (p = 0.049) and C18:1Cer (p = 0.024). Hepatocellular carcinoma (HCC) pre-OLT was associated with increases in C24:1Cer (p = 0.024) and C24:1DHC (p = 0.024). In this large prospective cross-sectional study of patients, post-OLT serum levels of (very-)long chain (dihydro-)ceramides associate with graft rejection, ITBL, tacrolimus intake and HCC pre-OLT. Hence, serum SL’s may be indicative of graft complications. Further research is necessary to identify their diverse mechanistic role in regulating immunity and inflammation in patients post-OLT.
More than 70 human adenoviruses with type-dependent pathogenicity have been identified but biological information about the majority of these virus types is scarce. Here we employed multiple sequence alignments and structural information to predict receptor usage for the development of an adenoviral vector with novel biological features. We report the generation of a cloned adenovirus based on human adenovirus type 17 (HAdV17) with high sequence homology to the well characterized human adenovirus type 37 (HAdV37) that causes epidemic keratoconjunctivitis (EKC). Our study revealed that human CD46 (CD46) is involved in cell entry of HAdV17. Moreover, we found that HAdV17 infects endothelial cells (EC) in vitro including primary cells at higher efficiencies compared to the commonly used human adenovirus type 5 (HAdV5). Using a human CD46 transgenic mouse model, we observed that HAdV17 displays a broad tropism in vivo after systemic injection and that it transduces ECs in this mouse model. We conclude that the HAdV17-based vector may provide a novel platform for gene therapy.
Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomas with various therapeutics, including anti-angiogenic agents. Here we identify the epi-/genetic and microenvironmental downregulation of ephrinB2 as a crucial step that promotes tumour invasion by abrogation of repulsive signals. We demonstrate that ephrinB2 is downregulated in human gliomas as a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade glioma model increases invasion. Importantly, ephrinB2 gene silencing is complemented by a hypoxia-induced transcriptional repression. Mechanistically, hypoxia-inducible factor (HIF)-1α induces the EMT repressor ZEB2, which directly downregulates ephrinB2 through promoter binding to enhance tumour invasiveness. This mechanism is activated following anti-angiogenic treatment of gliomas and is efficiently blocked by disrupting ZEB2 activity. Taken together, our results identify ZEB2 as an attractive therapeutic target to inhibit tumour invasion and counteract tumour resistance mechanisms induced by anti-angiogenic treatment strategies.
Purpose: Collaborative care is effective in improving symptoms of patients with depression. The aims of this study were to characterize symptom trajectories in patients with major depression during one year of collaborative care and to explore associations between baseline characteristics and symptom trajectories.
Methods: We conducted a cluster-randomized controlled trial in primary care. The collaborative care intervention comprised case management and behavioral activation. We used the Patient Health Questionnaire-9 (PHQ-9) to assess symptom severity as the primary outcome. Statistical analyses comprised latent growth mixture modeling and a hierarchical binary logistic regression model.
Results: We included 74 practices and 626 patients (310 intervention and 316 control recipients) at baseline. Based on a minimum of 12 measurement points for each intervention recipient, we identified two latent trajectories, which we labeled "fast improvers" (60.5%) and "slow improvers" (39.5%). At all measurements after baseline, "fast improvers" presented higher PHQ mean values than "slow improvers". At baseline, "fast improvers" presented fewer physical conditions, higher health-related quality of life, and had made fewer suicide attempts in their history.
Conclusions: A notable proportion of 39.5% of patients improved only "slowly" and probably needed more intense treatment. The third follow-up in month two could well be a sensible time to adjust treatment to support "slow improvers".
The mechanisms of transfer of crustal material from the subducting slab to the overlying mantle wedge are still debated. Mélange rocks, formed by mixing of sediments, oceanic crust, and ultramafics along the slab-mantle interface, are predicted to ascend as diapirs from the slab-top and transfer their compositional signatures to the source region of arc magmas. However, the compositions of melts that result from the interaction of mélanges with a peridotite wedge remain unknown. Here we present experimental evidence that melting of peridotite hybridized by mélanges produces melts that carry the major and trace element abundances observed in natural arc magmas. We propose that differences in nature and relative contributions of mélanges hybridizing the mantle produce a range of primary arc magmas, from tholeiitic to calc-alkaline. Thus, assimilation of mélanges into the wedge may play a key role in transferring subduction signatures from the slab to the source of arc magmas.
Introduction: Migrants are overrepresented in the European HIV epidemic. We aimed to understand the barriers and facilitators to HIV testing and current treatment and healthcare needs of migrants living with HIV in Europe.
Methods: A cross‐sectional study was conducted in 57 HIV clinics in nine countries (Belgium, Germany, Greece, Italy, The Netherlands, Portugal, Spain, Switzerland and United Kingdom), July 2013 to July 2015. HIV‐positive patients were eligible for inclusion if they were as follows: 18 years or older; foreign‐born residents and diagnosed within five years of recruitment. Questionnaires were completed electronically in one of 15 languages and linked to clinical records. Primary outcomes were access to primary care and previous negative HIV test. Data were analysed using random effects logistic regression. Outcomes of interest are presented for women, heterosexual men and gay/bisexual men.
Results: A total of 2093 respondents (658 women, 446 heterosexual men and 989 gay/bisexual men) were included. The prevalence of a previous negative HIV test was 46.7%, 43.4% and 82.0% for women, heterosexual and gay/bisexual men respectively. In multivariable analysis previous testing was positively associated with: receipt of post‐migration antenatal care among women, permanent residency among heterosexual men and identifying as gay rather than bisexual among gay/bisexual men. Access to primary care was found to be high (>83%) in all groups and was strongly associated with country of residence. Late diagnosis was common for women and heterosexual men (60.8% and 67.1%, respectively) despite utilization of health services prior to diagnosis. Across all groups almost three‐quarters of people on antiretrovirals had an HIV viral load <50 copies/mL.
Conclusions: Migrants access healthcare in Europe and while many migrants had previously tested for HIV, that they went on to test positive at a later date suggests that opportunities for HIV prevention are being missed. Expansion of testing beyond sexual health and antenatal settings is still required and testing opportunities should be linked with combination prevention measures such as access to PrEP and treatment as prevention.
Himalopsyche Banks, 1940 (Trichoptera, Rhyacophilidae) is a genus of caddisflies inhabiting mountain and alpine environments in Central and East Asia and the Nearctic. Of 53 known species, only five species have been described previously in the aquatic larval stage. We perform life stage association using three strategies (GMYC, PTP, and reciprocal monophyly) based on fragments of two molecular markers: the nuclear CAD, and the mitochondrial COI gene. A total of 525 individuals from across the range of Himalopsyche (Himalayas, Hengduan Shan, Tian Shan, South East Asia, Japan, and western North America) was analysed and 32 operational taxonomic units (OTUs) in our dataset delimited. Four distinct larval types of Himalopsyche are uncovered, and these are defined as the phryganea type, japonica type, tibetana type, and gigantea type and a comparative morphological characterisation of the larval types is presented. The larval types differ in a number of traits, most prominently in their gill configuration, as well as in other features such as setal configuration of the pronotum and presence/absence of accessory hooks of the anal prolegs.
Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.
The interaction between the T4 bacteriophage gp37 adhesin and the bacterial lipopolysaccharide (LPS) is a well-studied system, however, the affinity and strength of the interaction haven’t been analyzed so far. Here, we use atomic force microscopy to determine the strength of the interaction between the adhesin and its receptor, namely LPS taken from a wild strain of E. coli B. As negative controls we used LPSs of E. coli O111:B and Hafnia alvei. To study the interaction an AFM tip modified with the gp37 adhesin was used to scan surfaces of mica covered with one of the three different LPSs. Using the correlation between the surface topography images and the tip-surface interaction we could verify the binding between the specific LPS and the tip in contrast to the very weak interaction between the tip and the non-binding LPSs. Using force spectroscopy we could then measure the binding strength by pulling on the AFM tip until it lifted off from the surface. The force necessary to break the interaction between gp37 and LPS from E. coli B, LPS from E. coli O111:B and LPS from H. alvei were measured to be 70 ± 29 pN, 46 ± 13 pN and 45 ± 14 pN, respectively. The latter values are likely partially due to non-specific interaction between the gp37 and the solid surface, as LPS from E. coli O111:B and LPS from H. alvei have been shown to not bind to gp37, which is confirmed by the low correlation between binding and topography for these samples.
The dopamine (DA) system plays a major role in cognitive functions through its interactions with several brain regions including the prefrontal cortex (PFC). Conversely, disturbances in the DA system contribute to cognitive deficits in psychiatric diseases, yet exactly how they do so remains poorly understood. Here we show, using mice with disease-relevant alterations in DA signaling (D2R-OE mice), that deficits in working memory (WM) are associated with impairments in the WM-dependent firing patterns of DA neurons in the ventral tegmental area (VTA). The WM-dependent phase-locking of DA neurons to 4 Hz VTA-PFC oscillations is absent in D2R-OE mice and VTA-PFC synchrony deficits scale with their WM impairments. We also find reduced 4 Hz synchrony between VTA DA neurons and selective impairments in their representation of WM demand. These results identify how altered DA neuron activity—at the level of long-range network activity and task-related firing patterns—may underlie cognitive impairments.
Der Schauinsland – die Mobiliar - das Turm : das referentielle Genus bei Eigennamen und seine Genese
(2014)
Das Genus von Eigennamen verhält sich grundlegend anders als das von Appellativen. Im Zuge der Proprialisierung legen Eigennamen ihr appellativisch ererbtes Genus ab und entwickeln nach und nach ein eigenes, referentiell zugewiesenes Genus, das fest mit einer bestimmten Objektklasse verbunden ist (sieh die Kaiser Wilhelm als Schiff, das Kaiser Wilhelm als Hotel). Damit leisten die onymischen Genera einen echten Beitrag zur Klassifikation und bilden einen Fall von Degrammatikalisierung. Dieser Artikel untersucht die Entstehung und Festigung onymischer Genera am Beispiel von Namen für Flüsse, Berge, Restaurants und Hotels, Versicherungen, Banken, Fluggesellschaften, Autos, Motorräder und Konzerne und stellt das Prinzip eines onymischen Ikonismus auf.
Based on the concept of oxidative stress, reactive oxygen species (ROS) have been incriminated as the drivers behind almost every cardiovascular pathology. Redox alterations are, however, omnipresent bystanders to changes in cellular activity state. Even when ROS levels are altered, their contribution to pathology is not necessarily causal. Researchers should hesitate to engage in global ROS measurements and rather aim on identifying individual molecular targets of redox regulation.
Objectives: The SAVI-TF (Symetis ACURATE neo Valve Implantation Using Transfemoral Access) registry was initiated to study the ACURATE neo transcatheter heart valve in a large patient population treated under real-world conditions.
Background: The self-expanding, supra-annular ACURATE neo prosthesis is a transcatheter heart valve that gained the Conformité Européene mark in 2014, but only limited clinical data are available so far.
Methods: This prospective, multicenter registry enrolled 1,000 patients at 25 European centers who were followed for 1 year post-procedure.
Results: Mean patient age was 81.1 ± 5.2 years; mean logistic European System for Cardiac Operative Risk Evaluation I score, European System for Cardiac Operative Risk Evaluation II score, and Society of Thoracic Surgeons score were 18.1 ± 12.5%, 6.6 ± 7.5%, and 6.0 ± 5.6%, respectively. At 1 year, 8.0% (95% confidence interval [CI]: 6.3% to 9.7%) of patients had died, 2.3% (95% CI: 1.3% to 3.2%) had disabling strokes, and 9.9% (95% CI: 8.1% to 11.8%) had permanent pacemaker implantations. Through 1 year, 5 reinterventions (0.5%; 95% CI: 0.1% to 1.0%) were performed: 3 valve-in-valve and 2 surgical aortic valve replacements. Mean effective orifice area was 1.84 ± 0.43 cm2, mean gradient was 7.3 ± 3.7 mm Hg, and greater than mild paravalvular leakage was observed in 3.6% of patients.
Conclusions: Transfemoral implantation of the ACURATE neo prosthesis resulted in favorable 1-year clinical and echocardiographic outcomes with very low mortality and new pacemaker rates.
Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy.
Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation.
Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers.
Conclusions: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.
BRAF V600E mutations occur frequently in malignant melanoma, but are rare in most malignant glioma subtypes. Besides, more benign brain tumors such as ganglioglioma, dysembryoblastic neuroepithelial tumours and supratentorial pilocytic astrocytomas, only pleomorphic xanthoastrocytomas (50-78%) and epitheloid glioblastoma (50%) regularly exhibit BRAF mutations. In the present study, we report on three patients with recurrent malignant gliomas harbouring a BRAF V600E mutation. All patients presented with markedly disseminated leptomeningeal disease at recurrence and had progressed after radiotherapy and alkylating chemotherapy. Therefore, estimated life expectancy at recurrence was a few weeks. All three patients received dabrafenib as a single agent and all showed a complete or nearly complete response. Treatment is ongoing and patients are stable for 27 months, 7 months and 3 months, respectively. One patient showed a dramatic radiologic and clinical response after one week of treatment. We were able to generate an ex vivo tumor cell culture from CSF in one patient. Treatment of this cell culture with dabrafenib resulted in reduced cell density and inhibition of ERK phosphorylation in vitro. To date, this is the first series on adult patients with BRAF-mutated malignant glioma and leptomeningeal dissemination treated with dabrafenib monotherapy. All patients showed a dramatic response with one patient showing an ongoing response for more than two years.
Serum levels of the lipid mediator sphingosine-1-phosphate (S1P) are reduced in septic patients and are inversely associated with disease severity. We show that serum S1P is reduced in human sepsis and in murine models of sepsis. We then investigated whether pharmacological or genetic approaches that alter serum S1P may attenuate cardiac dysfunction and whether S1P signaling might serve as a novel theragnostic tool in sepsis. Mice were challenged with lipopolysaccharide and peptidoglycan (LPS/PepG). LPS/PepG resulted in an impaired systolic contractility and reduced serum S1P. Administration of the immunomodulator FTY720 increased serum S1P, improved impaired systolic contractility and activated the phosphoinositide 3-kinase (PI3K)-pathway in the heart. Cardioprotective effects of FTY720 were abolished following administration of a S1P receptor 2 (S1P2) antagonist or a PI3K inhibitor. Sphingosine kinase-2 deficient mice had higher endogenous S1P levels and the LPS/PepG-induced impaired systolic contractility was attenuated in comparison with wild-type mice. Cardioprotective effects of FTY720 were confirmed in polymicrobial sepsis. We show here for the first time that the impaired left ventricular systolic contractility in experimental sepsis is attenuated by FTY720. Mechanistically, our results indicate that activation of S1P2 by increased serum S1P and the subsequent activation of the PI3K-Akt survival pathway significantly contributes to the observed cardioprotective effect of FTY720.
Atopic dermatitis (AD) is a chronic inflammatory disease affecting children and adolescence. The traditional therapeutic options for AD, including emollients topically and immune modulatory agents systemically focusing on reducing skin inflammation and restoring the function of the epidermal barrier, are proven ineffective in many cases. Several studies have linked vitamin D supplementation with either a decreased risk to develop AD or a clinical improvement of the symptoms of AD patients. In this report, we present a girl with severe AD who under adequate supplementation with cholecalciferol was treated with calcitriol and subsequently with paricalcitol. She had significant improvement—almost healing of her skin lesions within 2 months, a result sustained for more than 3 years now. Because of hypercalciuria as a side effect from calcitriol therapy, treatment was continued with paricalcitol, a vitamin D analogue used in secondary hyperparathyroidism in chronic kidney disease. Calcitriol therapy may be considered as a safe and efficacious treatment option for patients with severe AD, particularly for those with refractory AD, under monitoring for possible side effects. Treatment with paricalcitol resolves hypercalciuria, is safe, and should be further investigated as an alternative treatment of atopic dermatitis and possibly other diseases of autoimmune origin.
Background: A diagnosis of post-traumatic stress disorder (PTSD) requires the identification of one or more traumatic events, designated the index trauma, which serves as the basis for assessment of severity of PTSD. In patients who have experienced more than one traumatic event, severity may depend on the exact definition of the index trauma. Defining the index trauma as the worst single incident may result in PTSD severity scores that differ from what would be seen if the index trauma included multiple events.
Objective: This study aimed to investigate the impact of the definition of the index trauma on PTSD baseline severity scores and treatment outcome.
Method: A planned secondary analysis was performed on data from a subset (N = 58) of patients enrolled in a trial evaluating the efficacy of a 12 week residential dialectical behavioural therapy programme for PTSD related to childhood abuse (DBT-PTSD). Assessments of the severity of PTSD were conducted at admission, at the end of the 12 week treatment period, and at 6 and 12 weeks post-treatment, using the Clinician-Administered PTSD Scale. The index trauma was defined with respect to both the worst single incident and up to three qualitatively distinct traumatic events.
Results: When the index trauma included multiple traumas, PTSD severity scores were significantly higher and improvements from pre- to post-treatment were significantly lower than when the index trauma was defined as the worst single incident.
Conclusions: In patients with PTSD who have experienced multiple traumas, defining the index trauma as the worst single incident may miss some aspects of clinically relevant symptomatology, thereby leading to a possibly biased interpretation of treatment effects. In DBT-PTSD, treatment effects were lower when the index trauma included multiple traumatic events. More research is needed to determine the impact of the various index trauma definitions on the evaluation of other trauma-focused treatments.