Immunregulation durch alternative Antigenpräsentation am Beispiel der HCV- und HIV-Infektion

Das nicht-klassische MHC-I Molekül HLA-E spielt eine bedeutende Rolle bei der Regulation der NK-Zell-vermittelten Zytotoxizität und der zytotoxischen CD8(+) T-Zellantwort. Im Gegensatz zu klassischen MHC-I Molekülen ist HLA-E jedoch nur wenig polymorph. Bislang konnten zwei HLA-E Allele, das HLA-ER (HLA-E*0101) und das HLA-EG (HLA-E*0103) Allel, beschrieben werden. In vorangegangenen Arbeiten konnte unsere Arbeitsgruppe zeigen, dass HLA-E bei der HCV- und der HIV-Infektion verstärkt exprimiert vorliegt und über die Interaktion mit NKG2A-Rezeptoren die zytotoxische Aktivität NKG2A-positiver NK-Zellen gehemmt wird. Als möglichen zugrunde liegenden Mechanismus wiesen wir nach, dass das HC-Virus (HCV p1835-44) und auch das HI-Virus (HIV p2414-22) für ein Peptid kodieren, welches an HLA-E binden und dadurch dessen Expression auf der Zelloberfläche stabilisieren kann. Zunächst sollte im ersten Teil der Doktorarbeit die Rolle des HLA-E Moleküls bei der HCV-Infektion betrachtet werden. Da neben der Interaktion mit NKG2-Rezeptoren in der Literatur auch mehrfach die Interaktion von HLA-E / Peptid-Komplexen mit dem T-Zellrezeptor (TCR) zytotoxischer CD8(+) T-Lymphozyten beschrieben wurde, wurde untersucht, ob das HCV p1835-44 Peptid im Kontext von HLA-E durch zytotoxische CD8(+) T-Zellen von HCV(+) Patienten erkannt werden kann. HCV-spezifische HLA-E restringierte T-Zellen konnten bei 40 % der untersuchten HCV(+) Patienten nachgewiesen werden und eine mögliche funktionelle Relevanz dieser T-Zellen konnte durch die Assoziation mit einer signifikant niedrigeren HCV-Viruslast und erhöhten Serumspiegeln der Enzyme Alanin-Aminotransferase (ALT) und Aspartat-Aminotransferase (AST) belegt werden. Die anschließende immungenetische Analyse der in diese Studie eingeschlossenen Patienten ergab, dass die Träger des HLA-ER / HLA-ER Genotyps eine höhere Frequenz an HCV p1835-44-spezifischen HLA-E restringierten T-Zellantworten aufwiesen als die Träger eines anderen HLA-E Genotyps. Eine Untersuchung der Verteilung der HLA-E Allele in einer größeren Kohorte HCV-infizierter Patienten zeigte zudem, dass Patienten, die das HC-Virus spontan eliminierten, signifikant häufiger den HLA-ER/HLA-ER Genotyp aufwiesen als Patienten mit einer chronischen HCV-Infektion. Im zweiten Teil der Doktorarbeit sollte die Rolle des HLA-E Moleküls bei der HIV-Infektion näher betrachtet werden. Da eine Assoziation des Polymorphismus im HLA-E Gen mit der sexuellen Transmission des HI-Virus beschrieben wurde, jedoch der zugrunde liegende Mechanismus dieser Assoziation bislang nicht aufgeklärt werden konnte, wurde analysiert, ob die HLA-E Allele die Immunantwort unterschiedlich modulieren. Es konnte gezeigt werden, dass das HIV p2414-22 Peptid im Kontext von HLA-E durch zytotoxische CD8(+) T-Zellen von HIV(+) Patienten erkannt werden kann. Jedoch konnte weder die Assoziation mit klinischen Parametern der HIV-Infektion, noch eine differentielle T-Zellantwort nach Präsentation des HIV-Peptids durch die beiden HLA-E Moleküle nachgewiesen werden. Zudem konnte demonstriert werden, dass die HLA-E Allele die zytotoxische Aktivität und auch den Aktivierungszustand von NK-Zellen nicht unterschiedlich beeinflussten. Anschließend wurde untersucht, inwiefern die HIV p2414-22 vermittelte Oberflächenstabilisierung von HLA-E den Crosstalk zwischen NK-Zellen und Dendritischen Zellen (DC) beeinflusst. Interessanterweise konnte gezeigt werden, dass aus Monozyten generierte DC (monocyte derived dendritic cells, MODC), die mit Zellüberständen aus der Kokultur von NK-Zellen mit HIV p2414-22 beladenen HLA-EG-K562 Zellen stimuliert wurden, signifikant weniger MHC-I, HLA-DR und CD40 auf ihrer Zelloberfläche exprimierten als MODC, die mit Überständen stimuliert wurden, die aus der Kokultur von NK-Zellen mit unbeladenen HLA-EG-K562 Zellen stammten. Bei der anschließenden Untersuchung der NK-Zellüberstände mittels ELISA konnte jedoch kein Zusammenhang zwischen der Sekretion von IFN-γ und TNF-α und der Stabilisierung von HLA-E nachgewiesen werden. Schließlich konnte eine kürzlich erschienene Arbeit zeigen, dass durch das Zytokin TNF-α die sexuelle Transmission von HIV-1 wesentlich beeinflusst wird. In der vorliegenden Dissertation gelang es, mit einer immungenetischen Analyse zu zeigen, dass eine signifikante Kopplung zwischen HLA-E Genotyp und TNF-α -308 Polymorphismus vorlag. Individuen, die homozygot das HLA-EG Allel trugen, hatten häufiger einen „TNF-α low producer“ (TNF-α G/G) Genotyp als Patienten mit einer der beiden anderen HLA-E Genotyp Kombinationen. Zudem konnte bei Individuen mit homozygotem HLA-EG Genotyp eine signifikant geringere Frequenz TNF-α positiver Monozyten im peripheren Blut nachgewiesen werden, als dies bei Individuen mit anderen HLA-E Genotypen der Fall war. Da keine Assoziation zwischen HLA-E Genotyp und dem gehäuften Auftreten weiterer bekannter, protektiver Wirtsfaktoren gefunden wurde, lassen die erbrachten Daten darauf schließen, dass die verminderte Produktion von TNF-α bei Individuen mit dem HLA-EG/HLA-EG Genotyp für die geringere Empfänglichkeit gegenüber einer HIV-Infektion verantwortlich ist

Oxygen reduction reaction (orr) on bimetallic AuPt and AuPd(1 0 0)–electrodes: Effects of the heteroatomic junction on the reaction paths

The seek for materials to enhance the oxygen reduction reaction (orr) rate is a highly relevant topic due to its implication in fuel cell devices. Herein, the orr on bimetallic electrocatalysts based on Au-M (M = Pt, Pd) has been studied computationally, by performing density functional theory calculations. Bimetallic (1 0 0) electrode surfaces with two different Au:M ratios were proposed, and two possible pathways, associative and dissociative, were considered for the orr. Changes in the electronic properties of these materials with respect to the pure metals were acknowledged to gain understanding in the overall reactivity trend. The effect of the bimetallic junction on the stability of the intermediates O 2 and OOH was also evaluated by means of geometrical and energetic parameters; being the intermediates preferably adsorbed on Pt/Pd atoms, but presenting in some cases higher adsorption energies compared with bare metals. Finally, the kinetics of the O–O bond breaking in O 2 ∗ and OOH ∗ adsorbed intermediates in the bimetallic materials and the influence of the Au-M junction were studied by means of the nudge elastic-band method. A barrierless process for the scission of O 2 ∗ was found in Au-M for the higher M ratios. Surprisingly, for Au-M with lower M ratios, the barriers were much lower than for pure Au surfaces, suggesting a highly reactive surface towards the orr. The O–O scission of the OOH ∗ was found to be a barrierless process in Au–Pt systems and nearly barrierless in all Au–Pd systems, implying that the reduction ofO 2 in these systems proceeds via the full reduction of O 2 to H 2 O, avoiding H 2 O 2 formation.Fil: Schulte, Erica Daniela. Universidad Nacional del Litoral. Instituto de Química Aplicada del Litoral. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Química Aplicada del Litoral.; ArgentinaFil: Belletti, Gustavo Daniel. Universidad Nacional del Litoral. Instituto de Química Aplicada del Litoral. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Química Aplicada del Litoral.; ArgentinaFil: Arce, Mauricio Damián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; ArgentinaFil: Quaino, Paola Monica. Universidad Nacional del Litoral. Instituto de Química Aplicada del Litoral. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Química Aplicada del Litoral.; Argentin

S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-α pathway

Peer reviewedPublisher PD

RENDENDO-SE AO BILRO: A RESSIGNIFICAÇÃO CONTEMPORÂNEA DO LUXO EM PRODUTOS ARTESANAIS SUSTENTÁVEIS

Given the contemporary emergence of a new luxury market, based on symbolic, cultural and experiential values, without giving up exclusivity, there is a growing demand for sustainable products. Handcrafted products correspond to two of these phenomena: luxury and sustainability, as they have attributes of exclusivity, symbolic and cultural value, as well as employing the slow manufacturing process and local labor. In this sense, Santa Catarina Renda de Bilro was chosen as the object of study of a basic, qualitative research, with a descriptive and exploratory objective of theoretical concepts, in which it was intended to highlight Santa Catarina Renda de Bilro as a "sustainable luxury product", proposing, thus, a resignification of concepts within this category. The results showed that bobbin lace presents parameters that fit both in the production based on slow fashion and in the list of new luxury goods of the 21st century, instigating to think - mainly, in the productive, creative and innovative union between fashion designers and local artisans, in the valorization, by the brands, of the well-paid manual work, with profits well distributed to the artisans; and, in the new choices guided by emotional consumption.Diante da emergência contemporânea de um novo mercado de luxo, pautado em valores simbólicos, culturais e experienciais, sem abrir mão da exclusividade, percebe-se uma crescente procura por produtos sustentáveis. Produtos artesanais feitos à mão se encaixam nos dois fenômenos – luxo e sustentabilidade, pois possuem atributos de exclusividade, valor simbólico e cultural, bem como empregam o processo slow de fabricação e mão-de-obra local. Nesse sentido, a renda de Bilro catarinense foi escolhida como objeto de estudo de uma pesquisa básica, qualitativa, de objetivo descritivo e exploratório de conceitos teóricos, na qual pretendeu-se demonstrar o enquadramento desta renda na categoria de “produto de luxo sustentável”, propondo assim uma ressignificação de conceitos. Os resultados apontaram que a renda de bilro apresenta parâmetros que se enquadram tanto na produção baseada no slow fashion quanto no rol de novas mercadorias de luxo do século XXI, instigando a pensar principalmente na união produtiva, criativa e inovadora entre designers de moda e artesãos locais, na valorização por parte das marcas pelo trabalho manual bem pago com lucros bem distribuídos aos artesãos e nas novas escolhas guiadas pelo consumo emocional

RENDENDO-SE AO BILRO: A RESSIGNIFICAÇÃO CONTEMPORÂNEA DO LUXO EM PRODUTOS ARTESANAIS SUSTENTÁVEIS

Given the contemporary emergence of a new luxury market, based on symbolic, cultural and experiential values, without giving up exclusivity, there is a growing demand for sustainable products. Handcrafted products correspond to two of these phenomena: luxury and sustainability, as they have attributes of exclusivity, symbolic and cultural value, as well as employing the slow manufacturing process and local labor. In this sense, Santa Catarina Renda de Bilro was chosen as the object of study of a basic, qualitative research, with a descriptive and exploratory objective of theoretical concepts, in which it was intended to highlight Santa Catarina Renda de Bilro as a "sustainable luxury product", proposing, thus, a resignification of concepts within this category. The results showed that bobbin lace presents parameters that fit both in the production based on slow fashion and in the list of new luxury goods of the 21st century, instigating to think - mainly, in the productive, creative and innovative union between fashion designers and local artisans, in the valorization, by the brands, of the well-paid manual work, with profits well distributed to the artisans; and, in the new choices guided by emotional consumption.Diante da emergência contemporânea de um novo mercado de luxo, pautado em valores simbólicos, culturais e experienciais, sem abrir mão da exclusividade, percebe-se uma crescente procura por produtos sustentáveis. Produtos artesanais feitos à mão se encaixam nos dois fenômenos – luxo e sustentabilidade, pois possuem atributos de exclusividade, valor simbólico e cultural, bem como empregam o processo slow de fabricação e mão-de-obra local. Nesse sentido, a renda de Bilro catarinense foi escolhida como objeto de estudo de uma pesquisa básica, qualitativa, de objetivo descritivo e exploratório de conceitos teóricos, na qual pretendeu-se demonstrar o enquadramento desta renda na categoria de “produto de luxo sustentável”, propondo assim uma ressignificação de conceitos. Os resultados apontaram que a renda de bilro apresenta parâmetros que se enquadram tanto na produção baseada no slow fashion quanto no rol de novas mercadorias de luxo do século XXI, instigando a pensar principalmente na união produtiva, criativa e inovadora entre designers de moda e artesãos locais, na valorização por parte das marcas pelo trabalho manual bem pago com lucros bem distribuídos aos artesãos e nas novas escolhas guiadas pelo consumo emocional

Design and Insights Gained in a Real-World Laboratory for the Implementation of New Coastal Protection Strategies

Novel strategies in coastal protection are needed to cope with climate change-induced sea level rise. They aim at the sustainable development of coastal areas in light of intensification and land use changes. A promising approach is the design of nature-based solutions (NbS), complementing the safety levels of technical infrastructure. However, NbS lack a widespread and large-scale implementation. To address this deficit, co-design concepts are needed that combine experiences from science and practice. This work presents and discusses the approach of a coast-specific real-world laboratory (RwL) addressing the inclusive design of ecosystem-based coastal protection. Strategies of RwLs are applied for the first time in a coastal context along the North Sea coastline in Germany. We found the concept of RwLs suitable for coastal transdisciplinary research, although adaptions in the spatial reference level or flexibility in location and time of experimentation are necessary. A profound actor analysis is indispensable to specify participatory processes and interaction levels. A criteria-based cooperative selection of RwL sites helps to reveal and solve conflicting interests to achieve trust between science and practice. Addressing site-specific characteristics and practitioners’ needs, our coastal RwL provides a mutual learning space to develop and test NbS to complement technical coastal protection

Eccrine porocarcinoma of the head: An important differential diagnosis in the elderly patient

Background: Eccrine porocarcinoma is a rare malignant tumor of the sweat gland, characterized by a broad spectrum of clinicopathologic presentations. Surprisingly, unlike its benign counterpart eccrine poroma, eccrine porocarcinoma is seldom found in areas with a high density of eccrine sweat glands, like the palms or soles. Instead, eccrine porocarcinoma frequently occurs on the lower extremities, trunk and abdomen, but also on the head, resembling various other skin tumors, as illustrated in the patients described herein. Observations: We report 5 cases of eccrine porocarcinoma of the head. All patients were initially diagnosed as having epidermal or melanocytic skin tumors. Only after histopathologic examination were they classified as eccrine porocarcinoma, showing features of epithelial tumors with abortive ductal differentiation. Characteristic clinical, histopathologic and immunohistochemical findings of eccrine porocarcinomas are illustrated. Conclusion: Eccrine porocarcinomas are potentially fatal adnexal malignancies, in which extensive metastatic dissemination may occur. Porocarcinomas are commonly overlooked, or misinterpreted as squamous or basal cell carcinomas as well as other common malignant and even benign skin tumors. Knowledge of the clinical pattern and histologic findings, therefore, is crucial for an early therapeutic intervention, which can reduce the risk of tumor recurrence and serious complications. Copyright (c) 2008 S. Karger AG, Basel

De novo 454 sequencing of barcoded BAC pools for comprehensive gene survey and genome analysis in the complex genome of barley

<p>Abstract</p> <p>Background</p> <p><it>De novo </it>sequencing the entire genome of a large complex plant genome like the one of barley (<it>Hordeum vulgare </it>L.) is a major challenge both in terms of experimental feasibility and costs. The emergence and breathtaking progress of next generation sequencing technologies has put this goal into focus and a clone based strategy combined with the 454/Roche technology is conceivable.</p> <p>Results</p> <p>To test the feasibility, we sequenced 91 barcoded, pooled, gene containing barley BACs using the GS FLX platform and assembled the sequences under iterative change of parameters. The BAC assemblies were characterized by N50 of ~50 kb (N80 ~31 kb, N90 ~21 kb) and a Q40 of 94%. For ~80% of the clones, the best assemblies consisted of less than 10 contigs at 24-fold mean sequence coverage. Moreover we show that gene containing regions seem to assemble completely and uninterrupted thus making the approach suitable for detecting complete and positionally anchored genes.</p> <p>By comparing the assemblies of four clones to their complete reference sequences generated by the Sanger method, we evaluated the distribution, quality and representativeness of the 454 sequences as well as the consistency and reliability of the assemblies.</p> <p>Conclusion</p> <p>The described multiplex 454 sequencing of barcoded BACs leads to sequence consensi highly representative for the clones. Assemblies are correct for the majority of contigs. Though the resolution of complex repetitive structures requires additional experimental efforts, our approach paves the way for a clone based strategy of sequencing the barley genome.</p

COMPRENDO: Focus and approach

Tens of thousands of man-made chemicals are in regular use and discharged into the environment. Many of them are known to interfere with the hormonal systems in humans and wildlife. Given the complexity of endocrine systems, there are many ways in which endocrine-disrupting chemicals (EDCs) can affect the body’s signaling system, and this makes unraveling the mechanisms of action of these chemicals difficult. A major concern is that some of these EDCs appear to be biologically active at extremely low concentrations. There is growing evidence to indicate that the guiding principle of traditional toxicology that “the dose makes the poison” may not always be the case because some EDCs do not induce the classical dose–response relationships. The European Union project COMPRENDO (Comparative Research on Endocrine Disrupters—Phylogenetic Approach and Common Principles focussing on Androgenic/Antiandrogenic Compounds) therefore aims to develop an understanding of potential health problems posed by androgenic and antiandrogenic compounds (AACs) to wildlife and humans by focusing on the commonalities and differences in responses to AACs across the animal kingdom (from invertebrates to vertebrates)

Gut Microbiome Signatures of Risk and Prodromal Markers of Parkinson Disease

Objective Alterations of the gut microbiome in Parkinson disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they relate to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition. Methods Established risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function, and medication were studied in relation to bacterial alpha-/beta-diversity, enterotypes, and differential abundance in stool samples of 666 elderly TREND (Tubingen Evaluation of Risk Factors for Early Detection of Neurodegeneration) study participants. Results Among risk and prodromal markers, physical activity, occupational solvent exposure, and constipation showed associations with alpha-diversity. Physical activity, sex, constipation, possible rapid eye movement sleep behavior disorder (RBD), and smoking were associated with beta-diversity. Subthreshold parkinsonism and physical activity showed an interaction effect. Among other factors, age and urate-lowering medication were associated with alpha- and beta-diversity. Physical inactivity and constipation were highest in individuals with theFirmicutes-enriched enterotype. Constipation was lowest and subthreshold parkinsonism least frequent in individuals with thePrevotella-enriched enterotype. Differentially abundant taxa were linked to constipation, physical activity, possible RBD, smoking, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history, and the prodromal PD probability showed no significant microbiome associations. Interpretation Several risk and prodromal markers of PD are associated with gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome-dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases. ANN NEUROL 2020Peer reviewe