Experimentelle und klinische Untersuchungen bei Bluthochdruck- und Nierenerkrankungen mit Fokus auf glomeruläre Hyperfiltration und Verträglichkeit der Therapie

Hypertension is the leading cause of premature death worldwide and results in damage of multiple organs including the kidney. Hypertensive kidney disease involves glomerular hyperfiltration, which is an important mechanism in the development of albuminuria and chronic kidney disease (CKD). During hyperfiltration, podocytes are damaged by increased fluid flow shear stress (FFSS) in Bowman’s space, which was previously shown to upregulate prostaglandin E2 (PGE2) synthesis and cyclooxygenase 2 (COX2). In study 1, the PGE2 autocrine/paracrine pathway was elucidated in human podocytes (hPC) by experimental in vitro studies. Therefore, hPC were treated with PGE2 with or without separate or combined inhibition of prostaglandin E receptors (EP), EP2, and EP4, followed by analysis of the second messenger cyclic adenosine monophosphate (cAMP), mRNA expression of COX2, PTGER2, and PTGER4, and cellular levels of PGE2 and its metabolites 15-keto-PGE2, and 13,14-dihydro-15-keto-PGE2 by lipidomic analysis using liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). To link PGE2-treatment with glomerular hyperfiltration, quantification of the prostaglandin profile in isolated glomeruli and plasma of an in vivo model of hyperfiltration and albuminuria, i.e. the Munich Wistar Frömter rat (MWF) was performed, as well as analysis of COX2, PTGER2, and PTGER4 expression after application of FFSS in hPC. In hPC, stimulation with PGE2 led to an EP2- and EP4-dependent increase of cAMP, COX2, and cellular PGE2. PTGER4 was reduced after PGE2 stimulation in hPC. In the corresponding lipidomic analysis at the tissue level, increased PGE2 and 15-keto-PGE2 levels were detected in isolated glomeruli obtained from MWF, as compared to the albuminuria-resistant spontaneously hypertensive rat, which substantiated an activation of this pathway during hyperfiltration. Moreover, COX2 and PTGER4 were upregulated by FFSS in hPC. Thus, the data of study 1 support an autocrine/paracrine COX2/PGE2 pathway in hPC related to concerted EP2 and EP4 signaling. Irrespective of the pharmacological mechanism, reducing elevated blood pressures is per se renoprotective. Beta-blockers play a fundamental role as combination partners for antihypertensive treatment, especially in patients with cardiac comorbidities, which often accompany CKD. However, previous studies associated depression with beta-blocker use, which may limit their application in clinical practice. Study 2 clarified the question whether beta-blockers cause depression, by means of a systematic review of large-scale data from double-blind, randomized controlled trials and meta-analyses. Depression did not arise more commonly during beta-blockers than during placebo or active agents. Therefore, concerns about the impact of beta-blockers on psychological well-being should not affect their application in clinical practice including their use in patients with or at risk for CKD.Die arterielle Hypertonie ist weltweit der Hauptgrund für frühzeitigen Tod und kann viele Organe, einschließlich der Nieren, schädigen. Als mögliche Folgeerscheinung der Hypertonie spielt die glomeruläre Hyperfiltration bei der Entwicklung der Albuminurie und chronischen Nierenerkrankung (CKD) eine wichtige Rolle. Während der Hyperfiltration werden Podozyten durch erhöhten Scherstress des Flüssigkeitsstromes (FFSS) in der Bowman-Kapsel geschädigt, einhergehend mit einer Hochregulation von Prostaglandin E2 (PGE2) und Cyclooxygenase 2 (COX2). In Studie 1 wurde daher in vitro der autokrine/parakrine PGE2 Signalweg in humanen Podozyten (hPC) untersucht. Dazu wurden hPC mit PGE2 in An- oder Abwesenheit von Einzel- bzw. Doppelinhibition der Prostaglandin E Rezeptoren (EP) EP2 und EP4 behandelt, gefolgt von Untersuchungen des second messengers cAMP, der mRNA Expression von COX2, PTGER2 und PTGER4, sowie Quantifizierung von zellulärem PGE2 und dessen Metabolite 15-keto-PGE2 und 13,14-dihydro-15-keto-PGE2 mittels LC/ESI-MS/MS. Um die PGE2-Stimulation mit der glomerulären Hyperfiltration zu verknüpfen, wurde das Prostaglandinprofil in isolierten Glomeruli und Plasma eines in vivo Hyperfiltrationsmodells mit Albuminurie, der Munich Wistar Frömter Ratte (MWF), sowie die COX2, PTGER2 und PTGER4 Expression nach FFSS in hPC untersucht. Die PGE2-Stimulation bewirkte in hPC einen EP2- und EP4-abhängigen Anstieg von cAMP, COX2 und zellulärem PGE2. PTGER4 wurde durch PGE2-Stimulation vermindert. In der entsprechenden Lipidomanalyse der Gewebe wurden erhöhte PGE2 und 15-keto-PGE2 Level in isolierten Glomeruli von MWF im Vergleich zu Albuminurie-resistenten Kontrolltieren detektiert, was die Aktivierung des Signalweges bei Hyperfiltration untermauert. COX2 und PTGER4 waren durch FFSS in hPC hochreguliert. Diese Ergebnisse unterstützen somit einen autokrinen/parakrinen COX2/PGE2 Signalweg in hPC mit gemeinsamen EP2 und EP4 Signalwegen. Die Senkung eines erhöhten Blutdrucks per se wird unabhängig vom pharmakologischen Wirkmechanismus als nephroprotektiv angesehen. Betablocker spielen eine wesentliche Rolle als Kombinationspartner bei der antihypertensiven Therapie, besonders für Patienten mit kardialen Komorbiditäten, die oft mit CKD einhergehen. Eine Therapie mit Betablockern wurde jedoch mit dem Auftreten einer Depression assoziiert, was ihren Einsatz und die Adhärenz in der klinischen Praxis beeinträchtigen könnte. In Studie 2 wurde daher mithilfe eines systematischen Reviews mit großen Datensätzen von doppelblinden randomisierten kontrollierten Studien und Meta-Analysen untersucht, ob Betablocker Depressionen verursachen. Depressionen kamen unter Betablocker Therapie nicht häufiger vor als unter Placebo oder aktiven Kontrollen. Daher sollten Bedenken hinsichtlich eines erhöhten Risikos für Depression ihre Anwendung in der klinischen Praxis nicht vermindern; dies gilt auch für die Therapie bei Patienten mit CKD oder einem erhöhten CKD-Risiko

The Lives, Lore, and Literature of Cranes: A Catechism for Crane Lovers

This book provides basic information on cranes that should be of interest and importance to crane-loving birders (“craniacs”) as well as to ornithologists and wildlife managers. Primary consideration is given to the sandhill and whooping cranes, but all 13 of the Old World cranes are also discussed. Special consideration is given to the relative abundance and conservation status of all of the world’s species, of which nearly half are declining and a few are in real danger of long-term survival. More than 80 refuges and preserves in the United States and Canada, where the best chances of seeing cranes in the wild exist, are described, as are several zoos and bird parks with notable crane collections. Descriptions of 16 North American annual crane festivals and information on more than 50 birdfinding guides from regions, states, and provinces where cranes are most likely to be seen are included. Lastly, there is a sampling of American, European, and Oriental crane folklore, legends, and myths. The text contains more than 50,000 words and nearly 350 literature references. There are more than 40 drawings and 3 maps by the author and 19 color photographs by Thomas D. Mangelsen.https://digitalcommons.unl.edu/zeabook/1093/thumbnail.jp

Transition Metal Dichalcogenides: Modelling of stacking disorder in the structures of MoS2 and WS2 and magnetotransport properties of HfTe2 and Fe1/3TaS2

In der Dissertation werden Ergebnisse zur Beschreibung der Realstruktur und der physikalischen Eigenschaften ausgewählter Übergangsmetalldichalkogenide vorgestellt. Die Schichtstrukturen der Verbindungen MoS2 und WS2 zeigen häufig ausgeprägte Stapelfehlordnung. Um diese zu beschreiben wurde der Ansatz der Superzelle gewählt, in den Messdaten aus Röntgenbeugung und Totalstreuung eingeflossen sind. Das Halbmetall HfTe2 wurde im Hinblick auf seine Magnetotransporteigenschaften untersucht, wobei ein ausgeprägter positiver magnetoresistiver Effekt nachgewiesen werden konnte. Die magnetischen wie auch die Magnetotransporteigenschaften des ferromagnetischen Metalls Fe1/3TaS2 wurden umfassend untersucht und im Kontext von struktureller Ordnung und Stöchiometrie der Probe diskutiert.This thesis contains results on the description of the real structure as well as physical properties of selected transition metal dichalcogenides. The layered structures of the compounds MoS2 and WS2 are known to be prone to stacking disorder. For modelling thereof the so called supercell approach was chosen and data of both X-ray diffraction and total scattering were included. The semimetal HfTe2 was studied with respect to its magnetotransport properties, revealing a pronounced positive magnetoresistance effect. The magnetic as well as magnetotransport properties of the ferromagnetic metal Fe1/3TaS2 were studied in detail and discussed in the context of its structural order as well as sample stoichiometry

Synthesis and crystal structure of structurally different cadmium selenocyanate and thiocyanate coordination compounds containing 3‐chloropyridine as ligand

Four compounds with the composition Cd(NCSe)2(3-ClPy)4 (1), [Cd(NCSe)2(3-ClPy)2] ⋅ 3-ClPy (2), Cd(NCSe)2(3-ClPy)2 (3) and Cd(NCSe)2(3-ClPy) (4) with 3-ClPy = 3-chloropyridine were synthesized. In the structure of 1 discrete complexes are observed, whereas in 2 the Cd cations are linked by pairs of selenocyanato anions into chains and between the chains 3-chloropyridine solvate molecules are embedded. In compound 3 each two Cd cations are linked by pairs of anionic ligands into dinuclear units, that are further connected into layers by μ-1,3 single bridging selenocyanate anions. In compound 4, both, octahedrally and tetrahe- drally coordinated Cd cations are present, that are linked by μ-1,3- bridging anionic ligands into a three-.dimensional network. Thermoanalytical investigations prove that compound 1 loses the 3-chloropyridine ligands stepwise upon heating and transforms into compound 4 via compound 3 as an intermediate. Further investigations show that the thiocyanate analogue Cd(NCS)2(3-ClPy) 5 that is not reported in the literature can also be prepared. Since no single crystals were available, the structure was solved from PXRD data and refined using the Rietveld method, which revealed that this compound is an isomer of 4. In its crystal structure the Cd cations are linked by μ-1,3(N,S) and μ-1,3,3(N,S,S)-bridging anionic ligands into chains that are further connected via Cd2S2 rings into double chains

The Lives, Lore, and Literature of Cranes: A Catechism for Crane Lovers

This book provides basic information on cranes that should be of interest and importance to crane-loving birders (“craniacs”) as well as to ornithologists and wildlife managers. Primary consideration is given to the sandhill and whooping cranes, but all 13 of the Old World cranes are also discussed. Special consideration is given to the relative abundance and conservation status of all of the world’s species, of which nearly half are declining and a few are in real danger of long-term survival. More than 80 refuges and preserves in the United States and Canada, where the best chances of seeing cranes in the wild exist, are described, as are several zoos and bird parks with notable crane collections. Descriptions of 16 North American annual crane festivals and information on more than 50 birdfinding guides from regions, states, and provinces where cranes are most likely to be seen are included. Lastly, there is a sampling of American, European, and Oriental crane folklore, legends, and myths. The text contains more than 50,000 words and nearly 350 literature references. There are more than 40 drawings and 3 maps by the author and 19 color photographs by Thomas D. Mangelsen.https://digitalcommons.unl.edu/zeabook/1093/thumbnail.jp

Concerted EP2 and EP4 receptor signaling stimulates autocrine prostaglandin E(2) activation in human podocytes

Glomerular hyperfiltration is an important mechanism in the development of albuminuria. During hyperfiltration, podocytes are exposed to increased fluid flow shear stress (FFSS) in Bowman's space. Elevated Prostaglandin E2 (PGE(2)) synthesis and upregulated cyclooxygenase 2 (Cox2) are associated with podocyte injury by FFSS. We aimed to elucidate a PGE2 autocrine/paracrine pathway in human podocytes (hPC). We developed a modified liquid chromatography tandem mass spectrometry (LC/ESI-MS/MS) protocol to quantify cellular PGE(2), 15-keto-PGE(2), and 13,14-dihydro-15-keto-PGE(2) levels. hPC were treated with PGE(2) with or without separate or combined blockade of prostaglandin E receptors (EP), EP2, and EP4. Furthermore, the effect of FFSS on COX2, PTGER2, and PTGER4 expression in hPC was quantified. In hPC, stimulation with PGE(2) led to an EP2- and EP4-dependent increase in cyclic adenosine monophosphate (cAMP) and COX2, and induced cellular PGE(2). PTGER4 was downregulated after PGE(2) stimulation in hPC. In the corresponding LC/ESI-MS/MS in vivo analysis at the tissue level, increased PGE(2) and 15-keto-PGE(2) levels were observed in isolated glomeruli obtained from a well-established rat model with glomerular hyperfiltration, the Munich Wistar Frömter rat. COX2 and PTGER2 were upregulated by FFSS. Our data thus support an autocrine/paracrine COX2/PGE(2) pathway in hPC linked to concerted EP2 and EP4 signaling

Preparation, Structure and Spectroscopic Properties of NH 4 [Ln(S 2 CNH 2 ) 4 ] ⋅ H 2 O (Ln=La, Eu)

The title compounds were prepared under mild ambient conditions by a facile co-precipitation route. NH4[Eu(S2CNH2)4] ⋅ H2O (a) and NH4[La(S2CNH2)4] ⋅ H2O (b) crystallize isotypically in the monoclinic space group P21/c with a=8.4461(3), b=13.6367(3), c=16.2945(5) Å, β=103.759(2)° (for (a)), and a=8.50484(9), b=13.84476(16), c=16.20816(17) Å, β=103.7644(11)° for (b), respectively. The spectroscopic data reveal the presence of a ligand-to-metal charge transfer (LMCT) process of low energy in a and in the solid solutions NH4[La1−xEux(S2CNH2)4] ⋅ H2O (x=0.016 and 0.05). Despite of the consequent efficient luminescent quenching, it was possible to recorded excitation and emission spectra at room temperature. These spectra are characterized by narrow bands due to intraconfigurational-4f transitions of the Eu3+ ion. However, broad bands associated to the LMCT state were also observed, mainly for the solid solutions NH4[La1−xEux(S2CNH2)4] ⋅ H2O (x=0.016 and 0.05). Consequently, an intramolecular energy transfer mechanism is proposed, taking into account the role of the LMCT on the spectroscopic properties of dithiocarbamate complexes

Phylogenetic and comparative gene expression analysis of barley (Hordeum vulgare) WRKY transcription factor family reveals putatively retained functions between monocots and dicots

WRKY proteins belong to the WRKY-GCM1 superfamily of zinc finger transcription factors that have been subject to a large plant-specific diversification. For the cereal crop barley (Hordeum vulgare), three different WRKY proteins have been characterized so far, as regulators in sucrose signaling, in pathogen defense, and in response to cold and drought, respectively. However, their phylogenetic relationship remained unresolved. In this study, we used the available sequence information to identify a minimum number of 45 barley WRKY transcription factor (HvWRKY) genes. According to their structural features the HvWRKY factors were classified into the previously defined polyphyletic WRKY subgroups 1 to 3. Furthermore, we could assign putative orthologs of the HvWRKY proteins in Arabidopsis and rice. While in most cases clades of orthologous proteins were formed within each group or subgroup, other clades were composed of paralogous proteins for the grasses and Arabidopsis only, which is indicative of specific gene radiation events. To gain insight into their putative functions, we examined expression profiles of WRKY genes from publicly available microarray data resources and found group specific expression patterns. While putative orthologs of the HvWRKY transcription factors have been inferred from phylogenetic sequence analysis, we performed a comparative expression analysis of WRKY genes in Arabidopsis and barley. Indeed, highly correlative expression profiles were found between some of the putative orthologs. HvWRKY genes have not only undergone radiation in monocot or dicot species, but exhibit evolutionary traits specific to grasses. HvWRKY proteins exhibited not only sequence similarities between orthologs with Arabidopsis, but also relatedness in their expression patterns. This correlative expression is indicative for a putative conserved function of related WRKY proteins in mono- and dicot species

Magnetic-field-induced FM-AFM metamagnetic transition and strong negative magnetoresistance in Mn1/4_{1/4}NbS2_2 under pressure

Transition metal dichalcogenides (TMDC) stand out with their high chemical stability and the possibility to incorporate a wide range of magnetic species between the layers. The behavior of conduction electrons in such materials intercalated by 3d-elements is closely related to their magnetic properties and can be sensitively controlled by external magnetic fields. Here, we study the magnetotransport properties of NbS$_2$ intercalated with Mn, Mn$_{1/4}$NbS$_2$, demonstrating a complex behavior of the magnetoresistance and of the ordinary and anomalous Hall resistivities. Application of pressure as tuning parameter leads to the drastic changes of the magnetotransport properties of Mn$_{1/4}$NbS$_2$ exhibiting large negative magnetoresistance up to $65 \%$ at 7.1 GPa. First-principles electronic structure calculations indicates pressure-induced transition from ferromagnetic to antiferromagnetic state. Theoretical calculations accounting for the finite temperature magnetic properties of Mn$_{1/4}$NbS$_2$ suggest a field-induced metamagnetic ferromagnetic-antiferromagnetic transition as an origin of the large negative magentoresistance. These results inspire the development of materials for spintronic applications based on intercalated TMDC with a well controllable metamagnetic transition

Cu-Co/ZnAl2O4 Catalysts for CO Conversion to Higher Alcohols Synthesized from Co-Precipitated Hydrotalcite Precursors

The role of Cu:Co composition in bi-metallic Cu-Co/ZnAl2O4 catalysts on higher alcohol synthesis (HAS) was investigated at H2:CO = 4. The addition of Cu strongly facilitated Co reduction upon catalyst activation and suppressed coke deposition during HAS. Formation of predominantly hydrocarbons and higher alcohols was observed on the bi-metallic catalysts. Co/ZnAl2O4 produced mainly CH4 and Cu/ZnAl2O4 mainly CH3OH, while at Cu:Co = 0.6 the best ethanol selectivity of 4.5 % was reached. The microstructure of the spent catalysts confirmed a close interaction of Cu and Co