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Showing 31 to 38 of 38 (0.036 seconds)Spelling suggestions: "subject:"phosphatase""
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Fingolimod additionally acts as immunomodulator focused on the innate immune system beyond its prominent effects on lymphocyte recirculationThomas, Katja, Sehr, Tony, Proschmann, Undine, Rodriguez-Leal, Francisco Alejandro, Haase, Rocco, Ziemssen, Tjalf 25 July 2017 (has links)
Background
Growing evidence emphasizes the relevance of sphingolipids for metabolism and immunity of antigen-presenting cells (APC). APCs are key players in balancing tolerogenic and encephalitogenic responses in immunology. In contrast to the well-known prominent effects of sphingosine-1-phosphate (S1P) on lymphocyte trafficking, modulatory effects on APCs have not been fully characterized.
Methods
Frequencies and activation profiles of dendritic cell (DC) subtypes, monocytes, and T cell subsets in 35 multiple sclerosis (MS) patients were evaluated prior and after undergoing fingolimod treatment for up to 24 months. Impact of fingolimod and S1P on maturation and activation profile, pro-inflammatory cytokine release, and phagocytotic capacity was assessed in vitro and ex vivo. Modulation of DC-dependent programming of naïve CD4+ T cells, as well as CD4+ and CD8+ T cell proliferation, was also investigated in vitro and ex vivo.
Results
Fingolimod increased peripheral slanDC count—CD1+ DC, and monocyte frequencies remained stable. While CD4+ T cell count decreased, ratio of Treg/Th17 significantly increased in fingolimod-treated patients over time. CD83, CD150, and HLADR were all inhibited, but CD86 was upregulated in DCs after incubation in the presence of fingolimod. Fingolimod but not S1P was associated with reduced release of pro-inflammatory cytokines from DCs and monocytes in vitro and ex vivo. Fingolimod also inhibited phagocytic capacity of slanDCs and monocytes. After fingolimod, slanDCs demonstrated reduced potential to induce interferon–gamma-expressing Th1 or IL-17-expressing Th17 cells and DC-dependent T cell proliferation in vitro and in fingolimod-treated patients.
Conclusions
We present the first evidence that S1P-directed therapies can act additionally as immunomodulators that decrease the pro-inflammatory capabilities of APCs, which is a crucial element in DC-dependent T cell activation and programming.
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Anionic Phospho-Fries Rearrangements for the Synthesis of Planar-Chiral Ferrocenes and their Application in (atropselective) Suzuki-Miyaura ReactionsKorb, Marcus 05 September 2017 (has links)
The present PhD thesis describes the synthesis and characterization of novel planarchiral 1,2-P,O-ferrocenes and their application in the Pd-catalyzed Suzuki-Miyaura reaction. It was especially focused on the development of a new synthetic pathway to this type of substitution pattern by applying the anionic phospho-Fries rearrangement in ferrocene chemistry.
Starting from hydroxy ferrocene, a high diversity of Fc–O–P- type (Fc = (n5-C5H5)(n5-C5H4)) compounds were synthesized, whereby the electronic properties of the phosphorus fragments were varied. The anionic phospho-Fries rearrangement successfully occurred subsequent to an ortho-lithiation with a non-nucleophilic base giving the 1,2-P,O-ferrocenes in up to quantitative yields. The usage of chiral pool-based alcohols for the synthesis of chiral ferrocenyl phosphates allowed a diastereoselective proceeding, giving single isomers in up to 95% de. Temperature-dependent investigations of mixed ferrocenyl-, phenyl- and Nheterocyclicphosphates revealed a limitation of ferrocenyl-based rearrangements per reaction step, contrary to phenyls.
1,2-P,O-ferrocenyl phosphonates could successfully be converted into phosphines by applying Stelzer P,C cross-coupling reactions on ferrocenes for the first time. Their usage as ligands for C,C cross-coupling reactions was confirmed by the synthesis of sterically hindered biaryls in high yields at 70°C with a low catalyst loading of 1 mol-% Pd.
Functionalization of the 1,2-P,O -structural motif could be achieved by applying nucleophilic aromatic substitution reactions (SNAr) as an alternative pathway for the synthesis of ferrocenyl aryl ethers. Subsequent to a Fries rearrangement sterically-demanding 1,3-di-orthosubstituted aryloxy ferrocenes could be obtained. Multi SNAr reactions of hydroxyferrocenes at polyfluorinated arenes gave up to pentaferrocenyl-functionalized aryl ethers, whose electrochemical properties were investigated.
The reaction of CH2-enlarged ferrocenylmethanols gave α-ferrocenylcarbenium ions instead of phosphates, while treating them with chlorophosphates. Enantiopure 2-P(S)Ph2-substituted derivatives of these ions underwent a subsequent intermolecular “S2−“ migration, resulting in thioethers, for example (Sp,Sp)-(2-(P(S)Ph2)FcCH2)2S, in a unique mechanism. Instead, the presence of electronrich arenes gave electrophilic aromatic substituted benzenes bearing chiral ferrocenylmethyl backbones. These type of ligands gave biaryls with up to 26 % ee. / Die vorliegende Arbeit beschäftigt sich mit der Synthese und Charakterisierung von neuartigen planar-chiralen 1,2-P,O-ferrocenen sowie deren Anwendung in der Pd-katalysierten Suzuki-Miyaura Reaktion. Dabei lag der Focus in der Anwendung anionischer phospho-Fries Verschiebungen auf Ferrocene um dieses spezielle Substitutionsmuster erhalten zu können.
Ausgehend von Hydroxyferrocenen wurde so eine Vielzahl neuer Verbindungen des Typs Fc–O–P (Fc = (n5-C5H5)(n5-C5H4)) synthetisiert, wobei die elektronischen Eigenschaften des Phosphor-tragenden Fragmentes variiert wurden. Die anionische phospho-Fries Verschiebung erfolgte im Anschluss einer ortho-Lithiierung mit einer nicht-nucleophilen Base, was 1,2-P,O-Ferrocene nahezu quantitative ergab. Durch die Verwendung von chiral-pool basierten Alkoholen für die Synthese chiraler Ferrocenylphosphate konnte eine diastereoselective 1,3-O->C Umlagerung mit Isomerenreinheiten von bis zu 95 % erreicht werden. Untersuchungen von gemischten Ferrocenyl-, Phenyl- und N-heterocyclischen Phosphaten bei verschiedenen Temperaturen zeigte eine Limitierung Ferrocenyl-basierter Umlagerungen pro Reaktionsschritt im Gegensatz zu denen von Phenylen.
Die erhaltenen 1,2-P,O-Ferrocenylphosphate wurden erstmals mittels Stelzer P,C Kreuz-Kupplungsreaktionen erfolgreich in Phosphane umgesetzt. Deren Verwendung als Ligand in C,C Kreuz-Kupplungsreaktionen wurde am Beispiel der Synthese räumlich anspruchsvoller Biaryle in hohen Ausbeuten bei nur 70°C und niedrigen Katalysatorbeladungen von 1 mol-% Pd demonstriert. Die Funktionalisierung des 1,2-P,O-Strukturmotifes konnte durch die Anwendung von nucleophilen aromatischen Substitutionsreaktionen erreicht werden, die einen alternativen Zugang zu Ferrocenylarylethern bietet. Im Anschluss an eine Fries Umlagerung konnten so sterisch anspruchsvolle 1,3-di-ortho-substituierte Ferrocenylarylether erhalten werden. Durch mehrfache SNAr Reaktionen von Hydroxyferrocenen an polyfluorierten Aromaten wurden bis zu fünf-fach substituierte Ether erhalten, deren elektrochemischen Eigenschaften untersucht wurden.
Die um eine CH2-Einheit verlängerten Ferrocenylmethanole gaben bei Reaktion mit Chlorophosphaten alpha Ferrocenylcarbeniumionen anstelle der gewünschten Phosphate. Enantiomerenreine 2-P(S)Ph2-substituierte Derivate dieser Ionen durchliefen anschließend einen intermolekularen ”S2–“ Transfer in einem einzigartigen Mechanismus, was bspw. in Thioethern des Typs (Sp,Sp)-(2-(P(S)Ph2)FcCH2)2S resultierte. In Anwesenheit elektronenreicher Aromaten wurden elektrophile aromatischen Substitutuionen und die Bildung chiraler ferrocenylmethyl-substitutuierter Benzene beobachtet. Deren Einsatz als Ligand ergab Biaryle mit bis zu 26 % ee.
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Novel regulators of trafficking in the yeast Golgi-endosomal systemGravert, Maike 29 September 2006 (has links)
Over the past few years a large amount of work has provided growing insight into the molecular mechanisms that direct post-Golgi trafficking events in the budding yeast Saccharomyces cerevisae. However, a key event in this process, the formation of secretory vesicles at the Golgi and sorting of cargo into these transport carriers, remains poorly understood. It has been demonstrated that phosphatidylinositol 4-phosphate (PI(4)P) generated by the PI(4)-kinase Pik1p plays an essential role in maintenance of Golgi secretory function and morphology. Up to now relatively few targets of Pik1/PI(4)P signaling at the Golgi have been identified and it thus remains elusive how Pik1p mediates its essential function in Golgi secretion. During my thesis work, I used synthetic genetic array analysis (SGA) of a temperature-sensitive mutant allele of PIK1 (pik1-101) in order to gain better understanding of Pik1p function at the TGN and to isolate new regulators of post-Golgi transport in yeast. I identified a total of 85 genes, whose deletion resulted in a synthetic growth defect when combined with the pik1-101 mutation. 21 isolated deletion mutants were used for further analysis, several of which were found to share common trafficking phenotypes with the pik mutant. A striking result of the screen was the finding that Pik1p interacts genetically with several components of a potential post-translational modification pathway referred to as “urmylation pathway”. In addition, a novel, previously uncharacterized subunit of the Transport protein particle (TRAPP) complex was isolated as genetic interactor of Pik1p, suggesting a function for the TRAPP complex in a Pik1p dependent trafficking pathway. Using tandem affinity purification, I could also demonstrate that TRAPP shows previously unknown interactions with other regulators of post-Golgi transport. The second part of this thesis describes the development of a new visual screening approach. Recent work indicates that secretory cargo in yeast can be transported to the cell surface via at least two different exocytic branches. Upon block of one pathway cargo can be partially redistributed into the other pathway. This partial redundancy of exocytic pathways provides one explanation why genetic screens in the past were largely unsuccessful in identifying the molecular machinery that directs vesicle budding and cargo sorting at the TGN. I collaborated in the development of a novel screening method that was devised to circumvent this problem. The method took advantage of the systematic yeast knockout array and was based on the assumption that a defect in cargo sorting and cell surface transport could be detected as intracellular accumulation of a GFP-tagged model cargo. The suitability of our approach for identifying regulators of secretory transport has been demonstrated in a small-scale pilot study that will be presented in this thesis. The screening method proofed to be applicable on a genome-wide scale and can now be used for the screening of additional markers. This novel approach provides an entry point to the comprehensive study of TGN sorting.
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Transaldolase 1 is required for Neutrophil Extracellular Trap (NET) FormationMorath, Jakob Paul 12 June 2020 (has links)
Transaldolase-Mangel (TALDO) ist ein extrem seltener, angeborener Stoffwechseldefekt, von dem weltweit nur 34 Fälle bekannt sind. Der Defekt geht auf den Verlust des Enzyms Transaldolase 1 aus dem nicht-oxidativen Pentosephosphat-Weg (nicht-oxPPW) zurück und äußert sich in einem weiten Spektrum klinischer Symptome. Die schwerwiegendsten Folgen sind Leber- und Nierenmangelfunktionen, die zum sehr frühen Tod führen können. Desweiteren leiden 15 % der Patienten an wiederkehrenden Infektionen. Neutrophile Granulozyten (Neutrophile) sind die häufigsten weißen Blutkörperchen im Menschen und essentiell für die angeborene Immunantwort gegen Infektionserreger. Ich habe hier funktionale Aspekte von TALDO-Neutrophilen untersucht. Der oxidative Pentosephosphat-Weg (oxPPW) stellt das Reduktionsäquivalent NADPH bereit, welches indirekt für die Entstehung von reactive oxygen species (ROS)-abhängigen Neutrophil Extracellular Traps (NETs) verantwortlich ist. Der Beitrag des nicht-oxPPW zur ROS-abhängigen NET-Bildung ist bislang nicht bekannt.
In dieser Arbeit konnte ich für Neutrophile aus drei TALDO-Patienten eine jeweils komplett abwesende Entstehung ROS-abhängiger NETs und einen deutlich verringerten oxidativen Burst nach PMA-Stimulation zeigen. Um diese Beobachtungen in einem unabhängigen Modelsystem zu bestätigen, habe ich mit Hilfe des CRISPR-Cas9-Systems, ‚knock-out‘ Mutanten von Transaldolase 1 und dessen Partnerenzym Transketolase in der Neutrophil-ähnlichen Zelllinie PLB-985 hergestellt. Die dergestalt genetisch manipulierten Zellen waren nicht mehr zu PMA-induziertem Zelltod in der Lage. Dies ist somit der erste genetische Beweis für die Abhängigkeit des oxidativen Burst und der Bildung von NETs vom nicht-oxPPW. Diese Erkenntnis trägt zum einen zum mechanistischen Verständnis der NET-Entstehung bei und liefert zum anderen eine potentielle Erklärung für einige der bei TALDO beobachteten Symptome.
Desweiteren wurden einige der metabolischen Erfordernisse für die Bildung von NETs mit Hilfe von Inhibitoren untersucht. Die erhaltenen Erkenntnisse zeigen, dass das initiale Maximum des oxidativen Bursts für NET-Bildung unerheblich ist und vielmehr die ROS-Generierung nach ca. 50 Minuten entscheidende Bedeutung für diese hat. / Transdaldolase 1-deficiency (TALDO) is a rare genetic disease with only 34 described cases globally. Transaldolase 1 is part of the non-oxidative pentose phosphate pathway (PPP) and its deficiency results in many clinical symptoms including kidney and liver failure, which can lead to early child-mortality. Some of these patients suffer from recurrent infections, for example in the respiratory tract. Neutrophils are the most abundant white blood cells and essential for the innate immune defence against bacterial and fungal pathogens. The PPP generates reduced NADPH that is crucial for the generation of superoxide by the NADPH oxidase NOX2. In turn, NOX2 is essential for neutrophil extracellular trap (NET) formation. NETs occur through the neutrophil-specific cell death netosis and consist of chromatin decorated with granular proteins.
Here I report that neutrophils of three TALDO patients did not make NETs. Deletion of transaldolase 1, and its partner enzyme transketolase, in the neutrophil-like PLB-985 cell line reduced ROS generation and cell death. This confirms that transaldolase 1 is required for NET formation. We present, to the best of our knowledge, the first genetic evidence that the non-oxidative PPP is required for ROS generation and NET formation. Furthermore, some of the metabolic requirements for NET formation were assessed. The obtained data indicate that the initial peak of the oxidative burst is irrelevant for NET formation but the ROS generation after 50 minutes on the contrary has crucial significance.
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Assessing the role of native plant growth-promoting rhizobacteria (PGPR) isolated from Cameroon soil as bio-inoculant in improving plant growthTchuisseu Tchakounte, Gylaine Vanissa 10 March 2021 (has links)
Der Mangel an Nährstoffen im Boden, hauptsächlich an Phosphor (P) und Stickstoff (N), verbunden mit einem hohen Salzgehalt und der generellen Verarmung landwirtschaftlicher Böden , sind ein ernstes Problem für die landwirtschaftliche Produktion weltweit. Daher besteht ein dringender Bedarf an Forschung und Entwicklung geeigneter landwirtschaftlicher Praktiken, um ungünstige Bodenbedingungen zu verringern und wenn möglich die Fruchtbarkeit von Kulturland wiederherzustellen. Die Verwendung von Rhizobakterien, die das Pflanzenwachstum (PGPR) fördern, kann sich bei der Entwicklung von Strategien zur Erleichterung des Pflanzenwachstums unter normalen Wachstumsbedingungen sowie unter abiotischen Stress als nützlich erweisen. Diese Bakterien bieten ihren pflanzlichen Wirten Vorteile, indem sie die Aufnahme von Bodenmineralien fördern und Pflanzen vor schädlichen Umwelteinflüssen schützen. Die vorliegende Arbeit bewertet die Rolle von in Kamerun natürlich vorkommenden PGPR an Mais und untersucht deren Potenzial als Bioimpfstoffe zur Steigerung des Pflanzenwachstums in Kamerun. Wir prüfen die Hypothese, dass einheimische Bakteriengemeinschaften aus Kamerun einen hohen Anteil an Bakterien aufweisen, deren Eigenschaften Kulturpflanzen helfen, mit ungünstigen Bedingungen umzugehen. In der vorliegenden Arbeit wurden dazu Bakteriengemeinschaften der Rhizosphäre von in Kamerun angebautem Mais isoliert und untersucht. Zum ersten Mal erfolgte eine umfassende phylogenetische Zuordnung aller kultivierbaren Bakterien, auf Grundlage ihrer potenziellen Fähigkeiten zur Förderung des Pflanzenwachstums. / Nutrient deficiencies in soil, mainly in phosphorus (P) and nitrogen (N), coupled to salinity and the impoverishment of agricultural soils, are a severe problem for agricultural production worldwide. Therefore, there is an urgent need for research and development of more suitable agricultural practices in order to reduce unfavorable conditions, and if possible, to restore the fertility of cultivated lands. The use of rhizobacteria, which promote plant growth (PGPR), can prove useful in developing strategies to facilitate plant growth under normal as well as under abiotic stress conditions. These bacteria offer benefits to plant hosts by promoting the uptake of soil minerals and protecting plants from environmental stresses. The thesis evaluates the role of native PGPR associated with maize as potential bio-inoculants for plants growth in Cameroon. We hypothesized that native bacterial communities from Cameroon include a high potential of bacteria helping the plant cope with unfavorable conditions. Here, we provide for the first time a comprehensive phylogenetic affiliation of cultivable bacterial communities associated with maize rhizosphere grown in Cameroon in relationship to their potential plant growth-promoting abilities.
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Differential effects of selective versus unselective sphingosine 1-phosphate receptor modulators on T- and B-cell response to SARS-CoV-2 vaccinationProschmann, Undine, Mueller-Enz, Magdalena, Woopen, Christina, Katoul Al Rahbani, Georges, Haase, Rocco, Dillenseger, Anja, Dunsche, Marie, Atta, Yassin, Ziemssen, Tjalf, Akgün, Katja 05 August 2024 (has links)
Background: Sphingosine 1-phosphat receptor modulators (S1PRMs) have been linked to attenuated immune response to SARS-CoV-2 vaccines.
Objective: To characterize differences in the immune response to SARS-CoV-2 vaccines in patients on selective versus unselective S1PRMs.
Methods: Monocentric, longitudinal study on people with multiple sclerosis (pwMS) on fingolimod (FTY), siponimod (SIP), ozanimod (OZA), or without disease-modifying therapy (DMT) following primary and booster SARS-CoV-2 vaccination. Anti-SARS-CoV-2 antibodies and T-cell response was measured with electro-chemiluminescent immunoassay and interferon-γ release assay. Results: Primary vaccination induced a significant antibody response in pwMS without DMT while S1PRM patients exhibited reduced antibody titers. The lowest antibodies were found in patients on FTY, whereas patients on OZA and SIP presented significantly higher levels. Booster vaccinations induced increased antibody levels in untreated patients and comparable titers in patients on OZA and SIP, but no increase in FTY-treated patients. While untreated pwMS developed a T-cell response, patients on S1PRMs presented a diminished/absent response. Patients undergoing SARS-CoV-2 vaccination before onset of S1PRMs presented a preserved, although attenuated humoral response, while T-cellular response was blunted.
Conclusion: Our data confirm differential effects of selective versus unselective S1PRMs on T- and B-cell response to SARS-CoV-2 vaccination and suggest association with S1PRM selectivity rather than lymphocyte redistribution.
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Analyzing Transactions in Linked Value Chains of Wastewater Treatment and Crop ProductionMaaß, Oliver 12 July 2019 (has links)
In dieser Dissertation wird der Einfluss von Transaktionen zur Wiederverwendung von Nährstoffen und gereinigtem kommunalen Abwasser auf die Wertschöpfungsketten der Abwasserbehandlung und Pflanzenproduktion untersucht. Ziel ist es, Kosten und Nutzen sowie die Wertschöpfung von Transaktionen in verknüpften Wertschöpfungsketten der Abwasserbehandlung und Pflanzenproduktion zu analysieren. Darüber hinaus wird untersucht, wie Transaktionen und Interdependenzen zwischen Akteuren in verknüpften Wertschöpfungsketten die lokalen Governance-Strukturen für die Wiederverwendung von Abwasser beeinflussen. Die Analyse wird hauptsächlich durch das Wertschöpfungskettenkonzept, das Konzept der Kreislaufwirtschaft und die Theorie der Transaktionskostenökonomie geleitet. Mit verschiedenen Methoden, wie der Kosten-Nutzen-Analyse, der Wertschöpfungskettenanalyse und der Transaktionskostenanalyse, werden zwei Fallstudien in Deutschland untersucht: (1) die Fällung von Struvit (Magnesium-Ammonium-Phosphat) und dessen Verwendung als Dünger in Berlin-Brandenburg und (2) das Modell der landwirtschaftlichen Abwasserwiederverwendung in Braunschweig. Die Ergebnisse zeigen, dass die Wiederverwendung von Nährstoffen und Abwasser zu geringeren Kosten für die Abwasserbehandlung, höherer Rentabilität und Wertschöpfung in der Pflanzenproduktion und zu einem hohen Anteil an regionaler Wertschöpfung führen. Die Ergebnisse verdeutlichen aber auch, dass die Wiederverwendung von Abwasser zu Einschränkungen, Verdrängungseffekten und Veränderungen in der Verteilung der Wertschöpfung führen kann. Des Weiteren zeigen die Ergebnisse, dass differenzierte Governance-Strukturen erforderlich sind, um den unterschiedlichen Eigenschaften der Transaktionen zwischen Abwasserbehandlung und der Pflanzenproduktion gerecht zu werden. Interdependenzen zwischen Abwasseranbietern und Landwirten erhöhen den Bedarf an hybriden und hierarchischen Elementen in den Governance-Strukuren für die Wiederverwendung von Abwasser. / This dissertation explores the impact of transactions for reusing nutrients and treated municipal wastewater on the value chains of wastewater treatment and crop production. It aims to analyze what costs and benefits and what added-value can result from transactions in linked value chains of wastewater treatment and crop production. Furthermore, it aims to analyze how transactions and interdependences between actors in linked value chains shape the governance structures for reusing wastewater at the local level. The analysis is mainly guided by the value chain concept, the concept of the circular economy and the theory of transaction costs economics. Different methods including cost-benefit analysis, value chain analysis and transaction cost analysis are used to investigate two case studies located in Germany: (1) the precipitation of struvite (magnesium ammonium phosphate) in the wastewater treatment plant in Waßmannsdorf and its application as fertilizer in Berlin-Brandenburg, and (2) the agricultural wastewater reuse scheme of the Wastewater Association Braunschweig. The results show that transactions for reusing nutrients and wastewater result in the development of linked regional value chains with lower costs of wastewater treatment, higher profitability and added-value in crop production, and a high share of regional added-value. However, the results also highlight that the reuse of wastewater can lead to restrictions (e.g., cultivation bans on certain crops), crowding out effects and changes in the distribution of the added-value. Furthermore, the findings suggest that different governance structures are needed to match the different properties of the transactions between wastewater treatment and crop production. Interdependences resulting from transactions between wastewater providers and farmers increase the need for hybrid and hierarchical elements in the governance structures for reusing wastewater.
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Das Auftreten acidophiler/calcifuger Pflanzenarten in Kalk-Halbtrockenrasen / The occurence of acidophile/calcifuge plant species in semi-arid calcareous grasslandsFühner, Christoph 02 November 2005 (has links)
No description available.
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