Student use of Brühl Boulevard Chemnitz

Diese Bachelor Arbeit, soll durch die genaue Betrachtung des Standortumfeldes (insbesondere des Brühl Boulevards), die Auseinandersetzung mit der Zielgruppe Studenten und der Identifikation möglicher Investoren Anregungen, den Verkauf des Gebäudes August-Bebel Str. 11 -13 betreffend, geben

Graves Hyperthyroidism After Stopping Immunosuppressive Therapy in Type 1 Diabetic Islet Cell Recipients With Pretransplant TPO Autoantibodies

OBJECTIVE — After an initially successful islet cell transplantation, a number of patients return to C-peptide negativity, and therefore immunosuppressive therapy is discontinued. Some are then found to have developed Graves disease. We examined the risk of Graves disease after immunosuppression. RESEARCHDESIGNANDMETHODS — Immunosuppressive therapy was stopped in 13 type 1 diabetic islet cell recipients who had received one course of antithymocyte globulin and maintenance doses of mycophenolate mofetil and a calcineurin inhibitor. None had a history of thyroid disease. RESULTS — In four patients, clinical Graves hyperthyroidism was observed within 21 months after discontinuation and 30–71 months after the start of immunosuppressive therapy. All four patients exhibited a pretransplant positivity for thyroid peroxidase (TPO) autoantibod-ies, while the nine others were TPO negative pre- and posttransplantation. CONCLUSIONS — Type 1 diabetic recipients of islet cell grafts with pretransplant TPO autoantibody positivity exhibit a high risk for developing Graves hyperthyroidism after immu-nosuppressive therapy is discontinued for a failing graft. Diabetes Care 32:1817–1819, 2009 I slet cell transplantation has beenshown to reproducibly achieve meta-bolic correction in nonuremic type 1 diabetic patients (1,2). However, in the years following transplantation, several of them return to C-peptide negativity and thus to a discontinuation of their immu-nosuppressive therapy (2)

Sub-Nucleocapsid Nanoparticles: A Nasal Vaccine against Respiratory Syncytial Virus

Background: Bronchiolitis caused by the respiratory syncytial virus (RSV) in infants less than two years old is a growing public health concern worldwide, and there is currently no safe and effective vaccine. A major component of RSV nucleocapsid, the nucleoprotein (N), has been so far poorly explored as a potential vaccine antigen, even though it is a target of protective anti-viral T cell responses and is remarkably conserved between human RSV A and B serotypes. We recently reported a method to produce recombinant N assembling in homogenous rings composed of 10–11 N subunits enclosing a bacterial RNA. These nanoparticles were named sub-nucleocapsid ring structure (N SRS). Methodology and Principal Findings: The vaccine potential of N SRS was evaluated in a well-characterized and widely acknowledged mouse model of RSV infection. BALB/c adult mice were immunized intranasally with N SRS adjuvanted with the detoxified E. coli enterotoxin LT(R192G). Upon RSV challenge, vaccinated mice were largely protected against virus replication in the lungs, with a mild inflammatory lymphocytic and neutrophilic reaction in their airways. Mucosal immunization with N SRS elicited strong local and systemic immunity characterized by high titers of IgG1, IgG2a and IgA anti-N antibodies, antigen-specific CD8+ T cells and IFN-c-producing CD4+ T cells. Conclusions/Significance: This is the first report of using nanoparticles formed by the recombinant nucleocapsid protein as an efficient and safe intra-nasal vaccine against RSV

Engineering of Three-Finger Fold Toxins Creates Ligands with Original Pharmacological Profiles for Muscarinic and Adrenergic Receptors

Protein engineering approaches are often a combination of rational design and directed evolution using display technologies. Here, we test “loop grafting,” a rational design method, on three-finger fold proteins. These small reticulated proteins have exceptional affinity and specificity for their diverse molecular targets, display protease-resistance, and are highly stable and poorly immunogenic. The wealth of structural knowledge makes them good candidates for protein engineering of new functionality. Our goal is to enhance the efficacy of these mini-proteins by modifying their pharmacological properties in order to extend their use in imaging, diagnostics and therapeutic applications. Using the interaction of three-finger fold toxins with muscarinic and adrenergic receptors as a model, chimeric toxins have been engineered by substituting loops on toxin MT7 by those from toxin MT1. The pharmacological impact of these grafts was examined using binding experiments on muscarinic receptors M1 and M4 and on the α1A-adrenoceptor. Some of the designed chimeric proteins have impressive gain of function on certain receptor subtypes achieving an original selectivity profile with high affinity for muscarinic receptor M1 and α1A-adrenoceptor. Structure-function analysis supported by crystallographic data for MT1 and two chimeras permits a molecular based interpretation of these gains and details the merits of this protein engineering technique. The results obtained shed light on how loop permutation can be used to design new three-finger proteins with original pharmacological profiles

Snake Cytotoxins Bind to Membranes via Interactions with Phosphatidylserine Head Groups of Lipids

The major representatives of Elapidae snake venom, cytotoxins (CTs), share similar three-fingered fold and exert diverse range of biological activities against various cell types. CT-induced cell death starts from the membrane recognition process, whose molecular details remain unclear. It is known, however, that the presence of anionic lipids in cell membranes is one of the important factors determining CT-membrane binding. In this work, we therefore investigated specific interactions between one of the most abundant of such lipids, phosphatidylserine (PS), and CT 4 of Naja kaouthia using a combined, experimental and modeling, approach. It was shown that incorporation of PS into zwitterionic liposomes greatly increased the membrane-damaging activity of CT 4 measured by the release of the liposome-entrapped calcein fluorescent dye. The CT-induced leakage rate depends on the PS concentration with a maximum at approximately 20% PS. Interestingly, the effects observed for PS were much more pronounced than those measured for another anionic lipid, sulfatide. To delineate the potential PS binding sites on CT 4 and estimate their relative affinities, a series of computer simulations was performed for the systems containing the head group of PS and different spatial models of CT 4 in aqueous solution and in an implicit membrane. This was done using an original hybrid computational protocol implementing docking, Monte Carlo and molecular dynamics simulations. As a result, at least three putative PS-binding sites with different affinities to PS molecule were delineated. Being located in different parts of the CT molecule, these anion-binding sites can potentially facilitate and modulate the multi-step process of the toxin insertion into lipid bilayers. This feature together with the diverse binding affinities of the sites to a wide variety of anionic targets on the membrane surface appears to be functionally meaningful and may adjust CT action against different types of cells

Alum Adjuvant Enhances Protection against Respiratory Syncytial Virus but Exacerbates Pulmonary Inflammation by Modulating Multiple Innate and Adaptive Immune Cells

Respiratory syncytial virus (RSV) is well-known for inducing vaccine-enhanced respiratory disease after vaccination of young children with formalin-inactivated RSV (FI-RSV) in alum formulation. Here, we investigated alum adjuvant effects on protection and disease after FIRSV immunization with or without alum in comparison with live RSV reinfections. Despite viral clearance, live RSV reinfections caused weight loss and substantial pulmonary inflammation probably due to high levels of RSV specific IFN-γ+IL4-, IFN-γ-TNF-α+, IFN-γ+ TNF-α- effector CD4 and CD8 T cells. Alum adjuvant significantly improved protection as evidenced by effective viral clearance compared to unadjuvanted FI-RSV. However, in contrast to unadjuvanted FI-RSV, alum-adjuvanted FI-RSV (FI-RSV-A) induced severe vaccine- enhanced RSV disease including weight loss, eosinophilia, and lung histopathology. Alum adjuvant in the FI-RSV-A was found to be mainly responsible for inducing high levels of RSV-specific IFN-γ-IL4+, IFN-γ-TNF-α+ CD4+ T cells, and proinflammatory cytokines IL-6 and IL-4 as well as B220+ plasmacytoid and CD4+ dendritic cells, and inhibiting the induction of IFN-γ+CD8 T cells. This study suggests that alum adjuvant in FI-RSV vaccines increases immunogenicity and viral clearance but also induces atypical T helper CD4+ T cells and multiple inflammatory dendritic cell subsets responsible for vaccine-enhanced severe RSV disease

O tratamento da polissemia e da homonímia nos learner's dictionaries: subsídios da semântica cognitiva para a disposição das acepções

No âmbito lexicográfico, diversas são as questões impostas pela consideração dos fenômenos da polissemia e da homonímia. Neste trabalho, abordamos dois problemas centrais: (i) a solução adotada para a estruturação dos verbetes (solução polissêmica ou solução homonímica) e (ii) os critérios empregados para a organização das acepções dentro dos verbetes. Para isso, apresentamos análises de itens lexicais presentes nos quatro principais learner’s dictionaries – CALD (2008), COBUILD (2006), LDCE (2009) e OALD (2005)1. Nelas constatamos que não há homogeneidade nas soluções empregadas, tanto entre as obras quanto dentro da mesma obra para o tratamento do mesmo fenômeno, e que o critério empregado pelos dicionários para a organização das acepções, a frequência, é problemático, tanto por questões anteriores a sua aplicação quanto por problemas exclusivos a esse critério. Dessa forma, buscamos na concepção de polissemia da Semântica Cognitiva um modelo de descrição que auxiliasse na disposição das acepções nos verbetes de learner’s dictionaries. Ao final, apresentamos nossa sugestão de verbete para o item lexical band. Concluímos com uma avaliação das questões que nosso modelo consegue tratar de forma mais efetiva e trazemos ainda problemas para os quais continuamos sem solução

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection